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Introduction: Firearms are now the leading cause of pediatric mortality in the U.S., but few studies have investigated the economic impact of these deaths. Thus, this study determined whether multiple different gun-related measures, political partisanship and Medicaid expansion were related to the costs of pediatric gun deaths., Methods: Each states' medical costs, years of potential life lost (YPLL), and value of statistical life (VSL) lost due to pediatric gun deaths were extracted from the WISQARS database from 2015 to 2020. Seven firearm laws or restrictiveness measures (assault weapons bans, child access prevention laws, firearm registration and permit to purchase requirements, safe storage laws, Giffords Law Center ranking, and the number of firearm provisions), the Cook Partisan Voting Index (PVI), and Medicaid expansion status were determined across states. Unadjusted analyses compared each measure and (1) medical costs, (2) VSL, and (3) YPLL for each state. These were repeated using adjusted analyses, controlling for poverty, educational attainment, poor mental health, and race., Results: Of the 9 variables assessed, unadjusted analyses revealed that 8 variables were significantly associated with increased medical costs, all 9 were associated with higher VSL and 8 were associated with higher YPLL due to pediatric firearm-related mortality. Multivariable analyses revealed that 7 variables were associated with medical costs, 7 were associated with VSL and 6 were associated with YPLL., Conclusion: States with fewer gun laws and those which have not adopted Medicaid expansion were more likely to experience a higher economic burden due to pediatric gun deaths. Quantifying the costs of these deaths can demonstrate the social toll of gun violence to policymakers and the general public., Level of Evidence: III., Competing Interests: Conflicts of interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Social communication is crucial for the survival of many species. In most vertebrates, a dedicated chemosensory system, the vomeronasal system (VNS), evolved to process ethologically relevant chemosensory cues. The first central processing stage of the VNS is the accessory olfactory bulb (AOB), which sends information to downstream brain regions via AOB mitral cells (AMCs). Recent studies provided important insights about the functional properties of AMCs, but little is known about the principles that govern their coordinated activity. Here, we recorded local field potentials (LFPs) and single-unit activity in the AOB of adult male and female mice during presentation of natural stimuli. Our recordings reveal prominent LFP theta-band oscillatory episodes with a characteristic spatial pattern across the AOB. Throughout an experiment, the AOB network shows varying degrees of similarity to this pattern, in a manner that depends on the sensory stimulus. Analysis of LFP signal polarity and single-unit activity indicates that oscillatory episodes are generated locally within the AOB, likely representing a reciprocal interaction between AMCs and granule cells. Notably, spike times of many AMCs are constrained to the negative LFP oscillation phase in a manner that can drastically affect integration by downstream processing stages. Based on these observations, we propose that LFP oscillations may gate, bind, and organize outgoing signals from individual AOB neurons to downstream processing stages. Our findings suggest that, as in other neuronal systems and brain regions, population-level oscillations play a key role in organizing and enhancing transmission of socially relevant chemosensory information. SIGNIFICANCE STATEMENT The accessory olfactory bulb (AOB) is the first central stage of the vomeronasal system, a chemosensory system dedicated to processing cues from other organisms. Information from the AOB is conveyed to other brain regions via activity of its principal neurons, AOB mitral cells (AMCs). Here, we show that socially relevant sensory stimulation of the mouse vomeronasal system leads not only to changes in AMC activity, but also to distinct theta-band (∼5 Hz) oscillatory episodes in the local field potential. Notably AMCs favor the negative phase of these oscillatory events. Our findings suggest a novel mechanism for the temporal coordination of distributed patterns of neuronal activity, which can serve to efficiently activate downstream processing stages., (Copyright © 2023 the authors.)

Cigarette smoking is a leading cause of mortality in people with HIV (PWH) in the United States (US). A rising proportion of US tobacco users smoke non-daily, a phenomenon that is common among PWH. PWH who smoke non-daily may be attractive targets for cessation efforts, and, thus, a fuller understanding of non-daily smoking in PWH is important. We merged datasets from two randomized controlled tobacco treatment trials for PWH conducted in three cities from 2014-2020. The final dataset included 872 PWH. We analyzed sociodemographic characteristics and behavioral measures, such as nicotine dependence, motivation to quit, anxiety, and other substance use for associations with non-daily smoking, and we assessed non-daily smoking as a predictor of cessation. 13.4% of the sample smoked non-daily. In multivariable analyses, non-White race, higher anxiety, and higher motivation to quit were associated with non-daily smoking. PWH who smoked non-daily had 2.14 times the odds of those who smoked daily of quitting at six-months (95% C.I.:1.30-3.51, P =0.002). PWH who smoke non-daily differ in some demographic and behavioral characteristics from those who smoke daily. PWH reporting non-daily smoking were more likely to quit in our trials and targeting them should be a priority of future cessation efforts.

The circadian rhythm pacemaker, the suprachiasmatic nucleus (SCN), mediates light entrainment via vasoactive intestinal peptide (VIP) neurons (SCN VIP ). Yet, how these neurons uniquely respond and connect to intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing melanopsin (Opn4) has not been determined functionally in freely behaving animals. To address this, we first used monosynaptic tracing from SCN VIP neurons in mice and identified two SCN VIP subpopulations. Second, we recorded calcium changes in response to ambient light, at both bulk and single-cell levels, and found two unique activity patterns in response to high- and low-intensity blue light. The activity patterns of both subpopulations could be manipulated by application of an Opn4 antagonist. These results suggest that the two SCN VIP subpopulations connect to two types of Opn4-expressing ipRGCs, likely M1 and M2, but only one is responsive to red light. These findings have important implications for our basic understanding of non-image-forming circadian light processing., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Optical implants to control and monitor neuronal activity in vivo have become foundational tools of neuroscience. Standard two-dimensional histology of the implant location, however, often suffers from distortion and loss during tissue processing. To address that, we developed a three-dimensional post hoc histology method called "light-guided sectioning" (LiGS), which preserves the tissue with its optical implant in place and allows staining and clearing of a volume up to 500 μm in depth. We demonstrate the use of LiGS to determine the precise location of an optical fiber relative to a deep brain target and to investigate the implant-tissue interface. We show accurate cell registration of ex vivo histology with single-cell, two-photon calcium imaging, obtained through gradient refractive index (GRIN) lenses, and identify subpopulations based on immunohistochemistry. LiGS provides spatial information in experimental paradigms that use optical fibers and GRIN lenses and could help increase reproducibility through identification of fiber-to-target localization and molecular profiling., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The ability to recognize motivationally salient events and adaptively respond to them is critical for survival. Here, we tested whether dopamine (DA) neurons in the dorsal raphe nucleus (DRN) contribute to this process in both male and female mice. Population recordings of DRN DA neurons during associative learning tasks showed that their activity dynamically tracks the motivational salience, developing excitation to both reward-paired and shock-paired cues. The DRN DA response to reward-predicting cues was diminished after satiety, suggesting modulation by internal states. DRN DA activity was also greater for unexpected outcomes than for expected outcomes. Two-photon imaging of DRN DA neurons demonstrated that the majority of individual neurons developed activation to reward-predicting cues and reward but not to shock-predicting cues, which was surprising and qualitatively distinct from the population results. Performing the same fear learning procedures in freely-moving and head-fixed groups revealed that head-fixation itself abolished the neural response to aversive cues, indicating its modulation by behavioral context. Overall, these results suggest that DRN DA neurons encode motivational salience, dependent on internal and external factors. SIGNIFICANCE STATEMENT Dopamine (DA) contributes to motivational control, composed of at least two functional cell types, one signaling for motivational value and another for motivational salience. Here, we demonstrate that DA neurons in the dorsal raphe nucleus (DRN) encode the motivational salience in associative learning tasks. Neural responses were dynamic and modulated by the animal's internal state. The majority of single-cells developed responses to reward or paired cues, but not to shock-predicting cues. Additional experiments with freely-moving and head-fixed mice showed that head-fixation abolished the development of cue responses during fear learning. This work provides further characterization on the functional roles of overlooked DRN DA populations and an example that neural responses can be altered by head-fixation, which is commonly used in neuroscience., (Copyright © 2021 the authors.)

Microglia, the brain's resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival 1 . Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes. ATP triggers the recruitment of microglial protrusions and is converted by the microglial ATP/ADP hydrolysing ectoenzyme CD39 into AMP; AMP is then converted into adenosine by CD73, which is expressed on microglia as well as other brain cells. Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and the adenosine-mediated suppression of neuronal responses via the adenosine receptor A 1 R are essential for the regulation of neuronal activity and animal behaviour. Our findings suggest that this microglia-driven negative feedback mechanism operates similarly to inhibitory neurons and is essential for protecting the brain from excessive activation in health and disease.

Objective: During the COVID-19 pandemic, experience-based guidelines are needed in the pediatric population in order to deliver high quality care in a new way that keeps patients and healthcare workers safe and maximizes hospital resource utilization., Background: The COVID-19 pandemic has created an unprecedented strain on national health care resources, particularly in New York City, the epicenter of the outbreak in the United States. Prudent allocation of surgical resources during the pandemic quickly became essential, and there is an unprecedented need to weigh the risks of operating versus delaying intervention in our pediatric patients., Methods: Here we describe our experience in surgical decision-making in the pediatric surgical population at Morgan Stanley Children's Hospital of New York-Presbyterian (MSCHONY), which has served as a major urban catchment area for COVID-19 positive pediatric patients. We describe how we have adjusted our current treatment of multiple facets of pediatric surgery including oncology, trauma, minimally invasive procedures, and extracorporeal membrane oxygenation (ECMO)., Conclusions: Our pediatric surgery department had to creatively and expeditiously adjust our protocols, guidelines, and workforce to not only serve our pediatric population but merge ourselves with our adult hospital system during the COVID pandemic., Type of Study: Clinical research paper LEVEL OF EVIDENCE: Level V., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Brain circuits comprise vast numbers of interconnected neurons with diverse molecular, anatomical and physiological properties. To allow targeting of individual neurons for structural and functional studies, we created light-inducible site-specific DNA recombinases based on Cre, Dre and Flp (RecVs). RecVs can induce genomic modifications by one-photon or two-photon light induction in vivo. They can produce targeted, sparse and strong labeling of individual neurons by modifying multiple loci within mouse and zebrafish genomes. In combination with other genetic strategies, they allow intersectional targeting of different neuronal classes. In the mouse cortex they enable sparse labeling and whole-brain morphological reconstructions of individual neurons. Furthermore, these enzymes allow single-cell two-photon targeted genetic modifications and can be used in combination with functional optical indicators with minimal interference. In summary, RecVs enable spatiotemporally precise optogenomic modifications that can facilitate detailed single-cell analysis of neural circuits by linking genetic identity, morphology, connectivity and function.

The ependyma of the adult spinal cord is a latent stem cell niche that is reactivated by spinal cord injury contributing new cells to the glial scar. The cellular events taking place in the early stages of the reaction of the ependyma to injury remain little understood. Ependymal cells are functionally heterogeneous with a mitotically active subpopulation lining the lateral domains of the central canal (CC) that are coupled via gap junctions. Gap junctions and connexin hemichannels are key regulators of the biology of neural progenitors during development and in adult neurogenic niches. Thus, we hypothesized that communication via connexins in the CC is developmentally regulated and may play a part in the reactivation of this latent stem cell niche after injury. To test these possibilities, we combined patch-clamp recordings of ependymal cells with immunohistochemistry for various connexins in the neonatal and the adult (P > 90) normal and injured spinal cord of male and female mice. We find that coupling among ependymal cells is downregulated as postnatal development proceeds but increases after injury, resembling the immature CC. The increase in gap junction coupling in the adult CC was paralleled by upregulation of connexin 26, which correlated with the resumption of proliferation and a reduction of connexin hemichannel activity. Connexin blockade reduced the injury-induced proliferation of ependymal cells. Our findings suggest that connexins are involved in the early reaction of ependymal cells to injury, representing a potential target to improve the contribution of the CC stem cell niche to repair. SIGNIFICANCE STATEMENT Ependymal cells in the adult spinal cord are latent progenitors that react to injury to support some degree of endogenous repair. Understanding the mechanisms by which these progenitor-like cells are regulated in the aftermath of spinal cord injury is critical to design future manipulations aimed at improving healing and functional recovery. Gap junctions and connexin hemichannels are key regulators of the biology of neural progenitors during development and in adult neurogenic niches. We find here that connexin signaling in the ependyma changes after injury of the adult spinal cord, functionally resembling the immature active-stem cell niche of neonatal animals. Our findings suggest that connexins in ependymal cells are potential targets to improve self-repair of the spinal cord., (Copyright © 2020 the authors.)

When agencies such as the US Environmental Protection Agency (EPA) establish future greenhouse gas emissions standards for new vehicles, forecasting future vehicle purchases due to changes in fuel economy and prices provides insight into regulatory impacts. We compare predictions from a nested logit model independently developed for US EPA to a simple model where past market share predicts future market share using data from model years 2008, 2010, and 2016. The simple model outperforms the nested logit model for all goodness-of-prediction measures for both prediction years. Including changes in vehicle price and fuel economy increases bias in forecasted market shares. This bias suggests price increases are correlated with unobserved increases in vehicle quality, changes in preferences, or brand-specific changes in market size but not cost pass-through. For 2010, past shares predict better than a nested logit model despite a major shock, the economic disruption caused by the Great Recession. Observed share changes during this turbulent period may offer upper bounds for policy changes in other contexts: the largest observed change in market share across the two horizons is 6.6% for manufacturers in 2016 and 3.4% for an individual vehicle in 2010.

Objective: Rituximab (RTX) is an anti-CD20 monoclonal antibody that selectively depletes B-cell population. Thus, it presents a potential risk for the development of hypogammaglobulinemia and related infectious events. Our aim was to identify predictors of hypogammaglobulinemia in RA patients long-term treated with RTX., Methods: Multicenter observational usual care study of patients with RA on RTX maintenance therapy (minimal exposition of 30 months). Serum protein electrophoresis was performed before each RTX infusion. Hypogammaglobulinemia and severe hypogammaglobulinemia were defined as total gammaglobulin <6g/L and <4g/L, respectively. The primary outcome was the occurrence within the follow-up period of hypogammaglobulinemia., Results: 134 patients met inclusion criteria and were followed-up for 79.5 ± 24.6 months. Hypogammaglobulinemia occurred during the follow-up period in 23 patients (2.7 events per 100 pt-yrs). The mean time to development of hypogammaglobulinemia was 64 ± 23 months. Patients who developed hypogammaglobulinemia were more likely to experience severe infections (26.1% vs. 6.3%, P = 0.033). Multivariate Cox analysis identified gammaglobulin levels <8g/L at baseline as an independent predictor of hypogammaglobulinemia (HR 7.34 [95% CI: 2.00-26.90], P = 0.003). Concomitant methotrexate (MTX) intake was also predictive of a reduced risk of hypogammaglobulinemia occurrence (HR 0.26 [95% CI: 0.08-0.87], P = 0.03)., Conclusion: Our results show that gammaglobulin levels of less than 8g/L at baseline is a strong independent risk factor for developing subsequent hypogammaglobulinemia, whereas concomitant MTX therapy seems to be a protective factor in RA patients treated long-term with RTX., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The vomeronasal system (VNS) is a major vertebrate chemosensory system that functions in parallel to the main olfactory system (MOS). Despite many similarities, the two systems dramatically differ in the temporal domain. While MOS responses are governed by breathing and follow a subsecond temporal scale, VNS responses are uncoupled from breathing and evolve over seconds. This suggests that the contribution of response dynamics to stimulus information will differ between these systems. While temporal dynamics in the MOS are widely investigated, similar analyses in the accessory olfactory bulb (AOB) are lacking. Here, we have addressed this issue using controlled stimulus delivery to the vomeronasal organ of male and female mice. We first analyzed the temporal properties of AOB projection neurons and demonstrated that neurons display prolonged, variable, and neuron-specific characteristics. We then analyzed various decoding schemes using AOB population responses. We showed that compared with the simplest scheme (i.e., integration of spike counts over the entire response period), the division of this period into smaller temporal bins actually yields poorer decoding accuracy. However, optimal classification accuracy can be achieved well before the end of the response period by integrating spike counts within temporally defined windows. Since VNS stimulus uptake is variable, we analyzed decoding using limited information about stimulus uptake time, and showed that with enough neurons, such time-invariant decoding is feasible. Finally, we conducted simulations that demonstrated that, unlike the main olfactory bulb, the temporal features of AOB neurons disfavor decoding with high temporal accuracy, and, rather, support decoding without precise knowledge of stimulus uptake time. SIGNIFICANCE STATEMENT A key goal in sensory system research is to identify which metrics of neuronal activity are relevant for decoding stimulus features. Here, we describe the first systematic analysis of temporal coding in the vomeronasal system (VNS), a chemosensory system devoted to socially relevant cues. Compared with the main olfactory system, timescales of VNS function are inherently slower and variable. Using various analyses of real and simulated data, we show that the consideration of response times relative to stimulus uptake can aid the decoding of stimulus information from neuronal activity. However, response properties of accessory olfactory bulb neurons favor decoding schemes that do not rely on the precise timing of stimulus uptake. Such schemes are consistent with the variable nature of VNS stimulus uptake., (Copyright © 2018 the authors 0270-6474/18/384957-20$15.00/0.)

Objective: To investigate effectiveness of systematic switching treatment from innovator infliximab to biosimilar infliximab, and its associated factors., Methods: In this prospective observational study, all adult patients receiving maintenance therapy with innovator infliximab in Cochin University Hospital were systematically switched to biosimilar infliximab. Effectiveness was assessed by the retention rate of biosimilar infliximab at the time of the third infusion. Sensitivity analyses for effectiveness included changes of disease activity parameters and infliximab trough levels between baseline and the last visit as well as the occurrence of adverse events leading to drug discontinuation. Factors associated with biosimilar infliximab discontinuation at the last visit were explored., Results: A total of 260 patients fulfilled the inclusion criteria, including 31 rheumatoid arthritis (RA), 131 axial spondyloarthritis (axSpA) and 64 inflammatory bowel diseases. The retention rate was 85% (221/260 patients) at the time of the third biosimilar infusion. Between baseline and the last visit (mean follow-up of 34 weeks), 59 patients (23%) discontinued biosimilar infliximab, mainly due to experienced inefficacy (n = 47, 80%). No clinical or biological factors were associated with biosimilar discontinuation. No serious adverse events occurred. No change in objective disease activity parameters or infliximab trough levels was detected. However, a significant increase of BASDAI (2.94 ± 2.20 vs. 3.18 ± 2.21, P = 0.046, before vs. after switch, respectively) was observed in patients with axSpA. Innovator infliximab was re-established in 47/59 patients (80%)., Conclusion: No changes in drug trough levels or objective parameters were observed after the systematic switch to biosimilar infliximab in a real clinical practice setting. Only changes in patient-reported outcomes were observed, suggesting attribution effects rather than pharmacological differences., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To elucidate the role of gene candidates involved in pulmonary hypertension (PH) associated with systemic sclerosis (SSc)., Methods: Gene candidates were identified through microarray experiments performed on Affymetrix GeneChip Human Exon 1.0 ST arrays in endothelial progenitor cell (EPC)-derived endothelial cells (ECs) obtained from patients with SSc-associated PH, patients with SSc without PH, and healthy control subjects. Expression of identified gene candidates was assessed by quantitative sandwich enzyme-linked immunosorbent assay in the serum, and by immunohistochemistry in lesional lung tissue. The functional importance of the identified gene candidates was then evaluated in fos-related antigen 2-transgenic (Fra-2-Tg) mice that spontaneously develop SSc-like features associated with an intense pulmonary vascular remodeling., Results: Microarray experiments revealed that the matrix metalloproteinase 10 (MMP-10) gene was the top up-regulated gene in SSc-associated PH EPC-derived ECs. Circulating serum proMMP10 concentrations were markedly increased in patients with SSc-associated PH compared to SSc patients without PH and healthy controls. Consistent with these observations, a strong MMP10 staining of the thickened wall of distal pulmonary arteries was found both in the lungs of patients with SSc-associated PH and in the lungs of Fra-2-Tg mice. Daily treatment of Fra-2-Tg mice with neutralizing anti-MMP10 antibodies did not significantly affect the development and severity of pulmonary fibrosis, but did reverse established PH and markedly reduced pulmonary vascular remodeling by reducing cell proliferation, cell survival, and the platelet-derived growth factor signaling axis., Conclusion: Gene expression profiling of EPC-derived ECs identified MMP10 as a novel candidate gene in SSc-associated PH. MMP10 is overexpressed in the serum and pulmonary arteries of patients with SSc-associated PH, and its blockade alleviates PH in the Fra-2-Tg mouse model. MMP10 appears to be a prospective treatment target for this devastating disorder., (© 2017, American College of Rheumatology.)

Objective: To determine the merit of nailfold videocapillaroscopy (NVC) to detect meaningful microvascular changes over time in patients with systemic sclerosis (SSc) and whether these changes are associated with overall disease progression and organ involvements., Methods: A prospective cohort of 140 SSc patients was recruited over a 12-month period and was followed up on an annual basis for 3 years. Detailed NVC analysis was performed at inclusion and repeated annually. Disease progression and organ damage were defined according to validated definitions., Results: Significant NVC changes were detected in 72 SSc patients (51%) during the follow-up period. Patients with incident or increased number of giant capillaries were less at risk to develop new digital ulcers (DU) [hazard ratio (HR) = 0.53, 95% confidence interval (CI): 0.07-0.93]. Loss of capillaries over time was confirmed as a robust and independent marker of organ progression. The reduction of the number of capillaries was associated with overall disease progression (HR = 4.35, 95% CI: 1.87-10.12), occurrence of new DU (HR = 5.33, 95% CI: 1.69-16.71), lung vascular progression (HR = 18.53, 95% CI: 1.28-78.33), progression of skin fibrosis (HR = 4.22, 95% CI: 1.24-14.36), and worsening of the Medsger severity score (HR = 5.26, 95% CI: 1.78-15.52)., Conclusion: Significant NVC changes are observed in almost half of the patients with SSc during a follow-up of 3 years. Sequential NVC examinations have responsiveness to detect disease progression. Sequential NVC is confirmed of value to monitor SSc, as well as progressive loss of capillaries over time as a potential surrogate marker for disease progression., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Specific cardiac involvement in granulomatosis with polyangiitis (GPA) is probably underestimated since many of these conditions are subclinical. The objective of this study was to assess the prevalence and patterns of cardiac abnormalities detected by cardiac MRI (CMRI) in patients with GPA., Methods: Thirty-one consecutive patients with newly diagnosed or relapsing GPA underwent CMRI to assess morphological, functional, perfusion at rest and delayed enhancement abnormalities., Results: At least one abnormality was observed on CMRI for 19 of 31 patients (61%). Four patients (13%) had an impaired left ventricle ejection fraction (LVEF). LV regional wall motion abnormalities were found in 11 patients (35%). Late gadolinium enhancement (LGE) was detected in 10 of 31 patients (32%). LGE was mostly nodular ( n = 9). Myocardial early contrast enhancement was detected in 5 of the 31 patients (16%), which was systematically associated with LGE in the same territory. CMRI detected pericarditis in eight patients (26%). GPA with <18 months duration was associated with a higher LVEF ( P = 0.03), fewer CMRI abnormalities ( P = 0.04) and less LV hypokinesia ( P = 0.04) than GPA with a longer duration. Patients with recent-onset GPA had a higher LVEF ( P = 0.01) and less LV hypokinesia ( P = 0.006) than patients experiencing a relapse ( P = 0.02)., Conclusion: CMR is an accurate technique for detecting heart involvement in GPA. This unique non-invasive technique may provide information with important clinical implications for the accurate early assessment of cardiac lesions in GPA patients and for detecting cumulative, irreversible damage. It may also have prognostic implications., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Objective: To study the mortality profile of patients with rheumatoid arthritis (RA) in France., Methods: Data were collected between 2000 and 2011 from the French Epidemiological Center for the Medical Causes of Death database; all death certificates from adults that either mentioned RA as an underlying cause of death (UCD) or as an associated cause of death (ACD) were evaluated using multiple-cause-of-death analysis. The different causes of death and their frequency were reported, together with the ratio of observed/expected number of death (O/E ratio) to measure the strength of association between RA listed as an ACD and the corresponding UCD., Results: During the study period, 13,208 deaths related to RA were identified. The mean ± SD age at death was 79 ± 9 years (51% with ≥80 years) and the female/male ratio was 3.2. When RA was the UCD (n = 4597), the main causes of death were cardiovascular (29%) and infectious diseases (22%). When RA was an ACD (n = 8611), the most common UCDs were cardiovascular diseases (35%), neoplasms (14%), respiratory disease (9%), and infectious diseases (7%). The overall O/E ratio was >1 for infectious (3.58), respiratory (1.38), and cardiovascular diseases (1.25), but was <1 for neoplasms., Conclusion: We provide the most recent national multiple-cause-of-death analysis assessing the mortality profile of RA patients. Our results show that mortality related to cardiovascular, respiratory, and infectious diseases is highly associated with RA. These data support the need to expand new strategies to prevent infectious and cardiovascular diseases in order to improve survival of RA patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Slider turtles are the only known amniotes with self-repair mechanisms of the spinal cord that lead to substantial functional recovery. Their strategic phylogenetic position makes them a relevant model to investigate the peculiar genetic programs that allow anatomical reconnection in some vertebrate groups but are absent in others. Here, we analyze the gene expression profile of the response to spinal cord injury (SCI) in the turtle Trachemys scripta elegans . We found that this response comprises more than 1000 genes affecting diverse functions: reaction to ischemic insult, extracellular matrix re-organization, cell proliferation and death, immune response, and inflammation. Genes related to synapses and cholesterol biosynthesis are down-regulated. The analysis of the evolutionary distribution of these genes shows that almost all are present in most vertebrates. Additionally, we failed to find genes that were exclusive of regenerating taxa. The comparison of expression patterns among species shows that the response to SCI in the turtle is more similar to that of mice and non-regenerative Xenopus than to Xenopus during its regenerative stage. This observation, along with the lack of conserved "regeneration genes" and the current accepted phylogenetic placement of turtles (sister group of crocodilians and birds), indicates that the ability of spinal cord self-repair of turtles does not represent the retention of an ancestral vertebrate character. Instead, our results suggest that turtles developed this capability from a non-regenerative ancestor (i.e., a lineage specific innovation) that was achieved by re-organizing gene expression patterns on an essentially non-regenerative genetic background. Among the genes activated by SCI exclusively in turtles, those related to anoxia tolerance, extracellular matrix remodeling, and axonal regrowth are good candidates to underlie functional recovery.

Objectives: Cardiovascular involvement is a major contributor to mortality in systemic sclerosis (SSc). We examined whether N-terminal pro-brain natriuretic peptide (NT-proBNP) is a reliable predictor of mortality in SSc., Methods and Results: This multicentre prospective cohort study included 523 patients presenting with SSc, whose mean age was 54±13years, mean disease duration 8±9years, and diffuse cutaneous form in 168. Plasma NT-proBNP was measured at baseline and the patients were followed yearly. Overall mortality was measured at 3years. At baseline, cardiovascular involvement was present in 37 patients, including 17 with pulmonary artery hypertension (PAH) and 20 with a left ventricular ejection fraction (LVEF) <55%. At 3years, 32 (7%) patients had died. The median [25th-75th percentile] NT-proBNP concentration was 203ng/l [129-514] in patients who died within 3years, versus 88ng/l [47-167] in survivors (P<0.001). NT-proBNP was an independent predictor of 3-years mortality in multivariate analysis (P=0.046). The optimal cut-off derived from the ROC curve was 129ng/l; sensitivity and specificity to predict 3y mortality were 78.1 and 66.7%. Using the previously recommended 125-ng/l concentration as threshold value, NT-proBNP reliably and independently predicted 3year mortality, with a sensitivity of 78.1 and a negative predictive value of 97.6%, respectively (P=0.006). The consideration of SSc patients without PAH or LVEF<55% at baseline yielded similar results., Conclusion: NT-proBNP appears as a reliable and independent predictor of mortality in patients with SSc., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Treatment for fibrosis represents a critical unmet need, because fibrosis is the leading cause of death in industrialized countries, and there is no effective therapy to counteract the fibrotic process. The development of fibrosis relates to the interplay between vessel injury, immune cell activation, and fibroblast stimulation, which can occur in various tissues. Immunotherapies have provided a breakthrough in the treatment of immune diseases. The glycoprotein OX40-OX40 ligand (OX40L) axis offers the advantage of a targeted approach to costimulatory signals with limited impact on the whole immune response. Using systemic sclerosis (SSc) as a prototypic disease, we report compelling evidence that blockade of OX40L is a promising strategy for the treatment of inflammation-driven fibrosis. OX40L is overexpressed in the fibrotic skin and serum of patients with SSc, particularly in patients with diffuse cutaneous forms. Soluble OX40L was identified as a promising serum biomarker to predict the worsening of lung and skin fibrosis, highlighting the role of this pathway in fibrosis. In vivo, OX40L blockade prevents inflammation-driven skin, lung, and vessel fibrosis and induces the regression of established dermal fibrosis in different complementary mouse models. OX40L exerts potent profibrotic effects by promoting the infiltration of inflammatory cells into lesional tissues and therefore the release of proinflammatory mediators, thereafter leading to fibroblast activation.

Objective: Digital ulcers (DU) are a burden in systemic sclerosis (SSc). Microangiopathy is a cardinal feature of SSc that plays a critical role in the development of DU. However, whether injury of medium or large vessels also contributes to DU in SSc remains controversial., Methods: To measure concomitantly in SSc patients with and without active DU: (i) the Augmentation Index of the reflected wave (Aix&#95;75) by radial applanation tonometry, an index of small and medium arterial function; (II) the aortic pulse wave velocity (PWV), a marker of large vessel injury (aortic stiffness)., Results: Sixty-three consecutive SSc patients were included (49 females, aged 60 [49-65] years, disease duration of 8.5 [5-13] years), including 10 (15.9%) with active DU. Patients with active DU versus those without had increased Aix&#95;75 (35% [28-38] versus 28% [20-34], P=0.041) whereas no difference existed in PWV (7.0m/s [6.7-10.1] versus 7.6m/s [6.8-8.7], P=0.887), in systolic, diastolic, as well as aortic pulse pressure (P=0.126, 0.592, and 0.161, respectively). When compared to patients in the low tertile, patients having Aix&#95;75 in the highest tertile had 10-fold more DU (OR=10.23; 95% CI 1.12 to 93.34, P=0.039)., Conclusion: The presence of DU is associated with increased Aix&#95;75 whereas there is no relation with PWV. These data suggest that small and medium arteries are involved in the occurrence of DU whether large vessel stiffness does not contribute. Whether Aix&#95;75 is predictive of further DU remained to be studied., (Copyright © 2015 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Objective: Cutaneous telangiectasia (CT) are common in systemic sclerosis (SSc) patients, but their ability to stratify patients by risk is poorly known. We aimed to determine whether the number and size of CT were associated with the pattern of microvascular lesions assessed by nailfold videocapillaroscopy (NVC) and markers reflecting the severity of SSc-related vasculopathy., Methods: We performed a cross-sectional study, including consecutive SSc patients over a 6-month period. We also considered 3 predefined subsets of patients according to the number of hand or face CT: absence, ≤10, or >10 hand or face CT (profuse CT). Pseudotumoral CT were defined as CT with >5 mm diameter., Results: A total of 87 patients were included, of whom 75 (86%) had CT (27 with profuse and 19 with pseudotumoral CT). Profuse and pseudotumoral CT were both associated with capillary loss (P < 0.001 and P = 0.002, respectively) and severe neoangiogenesis (P = 0.015 and P = 0.041, respectively), 2 hallmarks of the late NVC pattern. In multivariate analysis, profuse CT were independently associated with past or current digital ulcers (odds ratio [OR] 2.95 [95% confidence interval (95% CI) 1.09-19.63]), and pseudotumoral CT were independently associated with the late NVC pattern (OR 4.84 [95% CI 1.32-26.19]) and with precapillary pulmonary hypertension (OR 12.60 [95% CI 1.68-94.53])., Conclusion: We demonstrate that the number and size of CT are associated with the most severe NVC pattern. In addition, profuse and pseudotumoral CT identify a subset of patients with a more severe vascular phenotype. Further prospective studies should determine whether CT number and size could serve as an early clinical biomarker for the development of severe vascular disease., (© 2016, American College of Rheumatology.)

The accessory olfactory system controls social and sexual behavior. However, key aspects of sensory signaling along the accessory olfactory pathway remain largely unknown. Here, we investigate patterns of spontaneous neuronal activity in mouse accessory olfactory bulb mitral cells, the direct neural link between vomeronasal sensory input and limbic output. Both in vitro and in vivo, we identify a subpopulation of mitral cells that exhibit slow stereotypical rhythmic discharge. In intrinsically rhythmogenic neurons, these periodic activity patterns are maintained in absence of fast synaptic drive. The physiological mechanism underlying mitral cell autorhythmicity involves cyclic activation of three interdependent ionic conductances: subthreshold persistent Na(+) current, R-type Ca(2+) current, and Ca(2+)-activated big conductance K(+) current. Together, the interplay of these distinct conductances triggers infraslow intrinsic oscillations with remarkable periodicity, a default output state likely to affect sensory processing in limbic circuits., Significance Statement: We show for the first time that some rodent accessory olfactory bulb mitral cells-the direct link between vomeronasal sensory input and limbic output-are intrinsically rhythmogenic. Driven by ≥ 3 distinct interdependent ionic conductances, infraslow intrinsic oscillations show remarkable periodicity both in vitro and in vivo. As a novel default state, infraslow autorhythmicity is likely to affect limbic processing of pheromonal information., (Copyright © 2016 the authors 0270-6474/16/363127-18$15.00/0.)

For many animals, chemosensation is essential for guiding social behavior. However, because multiple factors can modulate levels of individual chemical cues, deriving information about other individuals via natural chemical stimuli involves considerable challenges. How social information is extracted despite these sources of variability is poorly understood. The vomeronasal system provides an excellent opportunity to study this topic due to its role in detecting socially relevant traits. Here, we focus on two such traits: a female mouse's strain and reproductive state. In particular, we measure stimulus-induced neuronal activity in the accessory olfactory bulb (AOB) in response to various dilutions of urine, vaginal secretions, and saliva, from estrus and non-estrus female mice from two different strains. We first show that all tested secretions provide information about a female's receptivity and genotype. Next, we investigate how these traits can be decoded from neuronal activity despite multiple sources of variability. We show that individual neurons are limited in their capacity to allow trait classification across multiple sources of variability. However, simple linear classifiers sampling neuronal activity from small neuronal ensembles can provide a substantial improvement over that attained with individual units. Furthermore, we show that some traits are more efficiently detected than others, and that particular secretions may be optimized for conveying information about specific traits. Across all tested stimulus sources, discrimination between strains is more accurate than discrimination of receptivity, and detection of receptivity is more accurate with vaginal secretions than with urine. Our findings highlight the challenges of chemosensory processing of natural stimuli, and suggest that downstream readout stages decode multiple behaviorally relevant traits by sampling information from distinct but overlapping populations of AOB neurons.

Objective: To determine whether calcinosis and acro-osteolysis are related to specific nailfold videocapillaroscopy (NVC) features in patients with systemic sclerosis (SSc; scleroderma)., Methods: NVC and bilateral hand radiographs were systematically performed in 155 consecutively recruited patients with SSc during a 24-month period. Radiologic assessment of calcinosis and acro-osteolysis was performed blinded for the results on NVC features., Results: Patients with calcinosis (n = 29) or acro-osteolysis (n = 25) on radiographs were more likely to have the late pattern on NVC, defined by severe loss of capillaries and neoangiogenesis (P = 0.003 and P < 0.001, respectively). A reduced number of capillaries was significantly found in patients with calcinosis (mean ± SD 3.55 ± 1.76 versus 5.53 ± 2.32 capillaries per finger; P < 0.001) and acro-osteolysis (mean ± SD 2.88 ± 1.30 versus 5.60 ± 2.26 capillaries per finger; P < 0.001). In addition, neoangiogenesis was more frequently observed in patients with severe acro-osteolysis (P = 0.021). Multivariate logistic regression analysis confirmed the independent association between the late NVC pattern and calcinosis (odds ratio [OR] 3.04, 95% confidence interval [95% CI] 1.20-7.68) or acro-osteolysis (OR 4.57, 95% CI 1.66-12.55), together with history of and/or active digital ulcers., Conclusion: Acro-osteolysis and calcinosis are independently associated with the late NVC pattern and particularly with severe capillary loss. These results strengthen the link between these radiographic lesions and digital destructive vasculopathy. Moreover, severe acro-osteolysis was more likely to occur with neoangiogenesis, which may suggest an attempt to compensate bone resorption. Further studies are now needed to better understand the physiopathology of calcinosis and acro-osteolysis and determine whether any agent may modify the course of these lesions by influencing vessel damages., (© 2016, American College of Rheumatology.)

Objective: Heart involvement in systemic sclerosis (SSc) is a strong prognostic factor. Our aim was to examine left ventricle (LV) and right ventricle (RV) involvement., Methods: We examined LV and RV, systolic and diastolic functions, using echocardiography and Tissue-Doppler echocardiography (TDE) indexes, in a cohort of 212 consecutive SSc patients seen during a 9-month period at 2 institutions (Paris, France and Los Angeles, USA). They were compared to 50 healthy controls., Results: When compared to controls, SSc patients had consistently impaired RV indices that include reduced RV contractility (p < 0.001), larger right atrial area (p = 0.027) and overall RV diastolic dysfunction (25% of SSc patients versus 0% of controls; p < 0.001). Patients also exhibited alterations in LV contractility and diastolic function (p < 0.001 each). In multivariate analysis, RV contractility as expressed by the TDE S(T) parameter was associated with TDE LV contractility S(M) (p = 0.030), DLCO (p = 0.013) whereas RV diastolic impairment was associated with systolic pulmonary artery pressure (p = 0.015). A subgroup of 27 patients had proven pulmonary arterial hypertension (PAH); comparison between SSc-PAH versus SSc free of PAH patients revealed reduced LV diastolic function (transmitral E/A ratio, p = 0.045 and E(A) < 10 cm/s, p = 0.029), reduced overall RV contractility (21.5% versus 4.5%; p = 0.03) and reduced RV diastolic function (transtricuspid E/A ratio; p = 0.014 and 68% versus 29% with impaired function; p = 0.001)., Conclusions: Our data show that RV is commonly affected in SSc with predominant impaired diastolic function. Several factors, including primary heart, lung vascular disease and pulmonary hypertension, contribute to such impairment., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: In agreement with other autoimmune diseases, systemic sclerosis (SSc) is associated with a strong sex bias. However, unlike lupus, the effects of sex on disease phenotype and prognosis are poorly known. Therefore, we aimed to determine sex effects on outcomes., Method: We performed a prospective observational study using the latest 2013 data extract from the EULAR scleroderma trials and research (EUSTAR) cohort. We looked at (i) sex influence on disease characteristics at baseline and (ii) then focused on patients with at least 2 years of follow-up to estimate the effects of sex on disease progression and survival., Results: 9182 patients with SSc were available (1321 men) for the baseline analyses. In multivariate analysis, male sex was independently associated with a higher risk of diffuse cutaneous subtype (OR: 1.68, (1.45 to 1.94); p<0.001), a higher frequency of digital ulcers (OR: 1.28 (1.11 to 1.47); p<0.001) and pulmonary hypertension (OR: 3.01 (1.47 to 6.20); p<0.003). In the longitudinal analysis (n=4499), after a mean follow-up of 4.9 (±2.7) years, male sex was predictive of new onset of pulmonary hypertension (HR: 2.66 (1.32 to 5.36); p=0.006) and heart failure (HR: 2.22 (1.06 to 4.63); p=0.035). 908 deaths were recorded, male sex predicted deaths of all origins (HR: 1.48 (1.19 to 1.84); p<0.001), but did not significantly account for SSc-related deaths., Conclusions: Although more common in women, SSc appears as strikingly more severe in men. Our results obtained through the largest worldwide database demonstrate a higher risk of severe cardiovascular involvement in men. These results raise the point of including sex in the management and the decision-making process., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: Few studies have assessed Health-Related Quality of Life (HR-QoL) in adults following juvenile idiopathic arthritis, and none since the advent of biotherapies. The aim of our study is to assess the impact of juvenile idiopathic arthritis on quality of life in a large transitional cohort, evaluate which factors influence quality of life in juvenile idiopathic arthritis, and determine which questionnaire should be used in practice., Methods: All consecutive juvenile idiopathic arthritis patients followed during adulthood in a transitional care program were included. Demographical, clinical and biological data were collected. The following quality of life questionnaires were administered: SF36 and EuroQoL. Age- and sex-matched controls (without rheumatic disease) were included., Results: One hundred and sixty-one juvenile idiopathic arthritis (120 women and 41 men) and 76 (51/25) controls were included. Out of 161, sixty-five (40%) were considered to be in remission. Juvenile idiopathic arthritis had a large impact on the physical scales of quality of life. Pain seemed to be the most important factor affecting quality of life in cases of juvenile idiopathic arthritis. No significant difference was found between sub-types of juvenile idiopathic arthritis., Conclusion: In this large transitional cohort of patients at the era of biotherapies, juvenile idiopathic arthritis has a larger effect on physical than mental scale of quality of life measures. Pain was the main factor influencing quality of life. Sub-types of juvenile idiopathic arthritis do not seem to influence quality of life., (Copyright © 2015 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Persistent activity has been reported in many brain areas and is hypothesized to mediate working memory and emotional brain states and to rely upon network or biophysical feedback. Here, we demonstrate a novel mechanism by which persistent neuronal activity can be generated without feedback, relying instead on the slow removal of Na+ from neurons following bursts of activity. We show that mitral cells in the accessory olfactory bulb (AOB), which plays a major role in mammalian social behavior, may respond to a brief sensory stimulation with persistent firing. By combining electrical recordings, Ca2+ and Na+ imaging, and realistic computational modeling, we explored the mechanisms underlying the persistent activity in AOB mitral cells. We found that the exceptionally slow inward current that underlies this activity is governed by prolonged dynamics of intracellular Na+ ([Na+]i), which affects neuronal electrical activity via several pathways. Specifically, elevated dendritic [Na+]i reverses the Na+-Ca2+ exchanger activity, thus modifying the [Ca2+]i set-point. This process, which relies on ubiquitous membrane mechanisms, is likely to play a role in other neuronal types in various brain regions.

Acro-osteolysis is not uncommon and occurs in several conditions. Additional clinical and paraclinical findings and sometimes the performance of molecular tests can help to clarify the diagnosis. Here, we report the case of a 36-year-old woman who was referred to our department because of acute pain in the extremity of the left index finger. However, subsequent clinical examination also revealed short digits with pseudo-clubbing related to acro-osteolysis. Furthermore, severe osteoporosis, a moderate dysmorphic face, joint hypermobility, biological variables within normal ranges and her clinical history led us to consider the diagnosis of Hajdu-Cheney syndrome. Molecular analysis confirmed the diagnosis with the identification of a mutation in the NOTCH2 gene. The patient received bisphosphonate therapy, which resulted in some clinical and biological improvement 12 months later., (Copyright © 2015 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Objective: To compare mortality data obtained from randomized controlled trials for the 5 tumor necrosis factor-α (TNF-α) inhibitors used in the treatment of rheumatoid arthritis., Methods: A systematic review of articles published up to November 2014 was performed using electronic databases. We included randomized, controlled trials, with a follow-up period of at least 24 weeks, comparing TNF-α inhibitors to placebo or disease-modifying antirheumatic drugs. The primary outcome was the occurrence of all-cause mortality., Results: Twenty-three studies were selected. These articles included 6525 patients in the anti-TNF-α group and 3523 in the control group. The duration of patient follow-up ranged from 24 to 104 weeks. The risk of all-cause mortality in patients receiving TNF-α inhibitors was not significantly different from those receiving the comparator (odds ratio 1.32; 95% confidence interval, 0.76-2.29). Subgroup analyses with respect to the molecule used, the dose received, the use of TNF-α inhibitors as monotherapy or combination therapy, or the quality of the trial did not modify the findings., Conclusion: This meta-analysis performed on a large number of patients and including the 5 TNF-α inhibitors currently available shows no increased risk of medium-term all-cause mortality in patients with rheumatoid arthritis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To determine the predictive value of functional autoantibodies against vascular receptors for the development of ischemic digital ulcers (DU) in patients with systemic sclerosis (SSc)., Methods: Angiotensin II Type 1 receptor (AT1R) and endothelin 1 Type A receptor (ETAR) autoantibodies were measured at baseline in a prospective cohort of 90 patients with SSc together with 5 validated angiogenic markers. The primary outcome was the occurrence of at least 1 new ischemic DU during the 5-year followup., Results: Twenty-four patients developed at least 1 new DU during the followup period. Univariate Cox analysis revealed that concentrations above the median value of anti-AT1R and anti-ETAR antibodies were predictive of the occurrence of ischemic DU (HR 2.85, 95% CI 1.19-6.84 and HR 3.39, 95% CI 1.35-8.50, respectively). A first multivariate Cox analysis including functional autoantibodies and clinical predictors of new DU confirmed anti-ETAR autoantibodies as independent predictors of the occurrence of new ischemic DU (HR 3.15, 95% CI 1.22-8.13) together with a history of DU at baseline. In a second model implemented with angiogenic markers, anti-ETAR autoantibodies remained an independent predictor of the occurrence of new ischemic DU (HR 9.59, 95% CI 1.75-52.64) together with the presence at baseline of active DU or history of DU., Conclusion: Anti-ETAR autoantibodies can be used together with the presence of current or past DU to identify patients with SSc who are at risk for the development of subsequent DU. These autoantibodies may allow for earlier management and therapeutic intervention.

Objective: To measure plasma concentrations of high-sensitivity cardiac troponin T (HS-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with systemic sclerosis (SSc; scleroderma) and age- and sex-matched healthy control subjects, and to examine the contribution of traditional cardiovascular risk factors and SSc features to the concentrations of these 2 cardiac biomarkers., Methods: Plasma HS-cTnT and NT-proBNP concentrations were measured using the electrochemiluminescence method and sandwich immunoassay, respectively., Results: The study group comprised 161 unrelated patients with SSc and 213 matched control subjects. HS-cTnT and NT-proBNP plasma levels were significantly increased in SSc patients compared with controls (both P < 0.001). Similar results were observed in the subgroup of patients with SSc who had no cardiovascular risk factors (n = 72). Multivariate logistic regression analysis confirmed diabetes mellitus (P = 0.006), high blood pressure (P = 0.021), precapillary pulmonary hypertension (P = 0.039), and the diffuse cutaneous SSc (P = 0.004) as factors independently associated with an HS-cTnT level of >14 ng/liter. Increased NT-proBNP concentrations were associated only with the presence of precapillary pulmonary hypertension (P < 0.001). Normal concentrations of both HS-cTnT and NT-proBNP had a high negative predictive value for precapillary pulmonary hypertension (92%), and the combination of increased values of these 2 markers had the highest strength of association with precapillary pulmonary hypertension in logistic regression analysis., Conclusion: HS-cTnT and NT-proBNP concentrations are increased in patients with SSc, even in those who are free of cardiovascular risk factors. These easily obtained biomarkers may be useful for systematic evaluation and stratification of SSc patients, especially to identify those at risk of pulmonary hypertension., (© 2015 American College of Rheumatology.)

Systemic sclerosis is an orphan connective tissue disease characterized by alterations of the microvasculature, disturbances of the immune system and massive deposition of collagen and other matrix substances in the skin and internal organs. A major achievement of the recent years has been the validation of new classification criteria, allowing earlier diagnosis and earlier treatment of systemic sclerosis, before irreversible fibrosis and organ damage appeared ("window of opportunity"). Raynaud's phenomenon is usually the first sign of the disease and is considered as the main sentinel sign for the identification of very early systemic sclerosis. Systemic sclerosis is clinically heterogeneous and disease course remains unpredictable. Its prognosis depends on cardiopulmonary involvement and recent studies aim to identify serum or genetic biomarkers predictive of severe organ involvement. Moreover, the prospective follow-up of large cohorts has provided and will offer critical material to identify strong prognostic factors. Whereas the outcomes of vascular manifestations of the disease has been recently improved due to targeted therapy, recent data have highlighted that mortality has not changed over the past 40 years. This reflects the absence of efficacy of current available drugs to counteract the fibrotic process. Nevertheless, several targeted immunity therapies, commonly with proven efficacy in other immune diseases, are about to be investigated in systemic sclerosis. Indeed, promising results in small and open studies have been reported. This article deals with recent insights into classification criteria, pathogenesis, organ involvements, outcome and current and possible future therapeutic options in systemic sclerosis., (Copyright © 2014 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

The mouse vomeronasal organ (VNO) plays a critical role in semiochemical detection and social communication. Vomeronasal stimuli are typically secreted in various body fluids. Following direct contact with urine deposits or other secretions, a peristaltic vascular pump mediates fluid entry into the recipient's VNO. Therefore, while vomeronasal sensory neurons (VSNs) sample various stimulatory semiochemicals dissolved in the intraluminal mucus, they might also be affected by the general physicochemical properties of the "solvent." Here, we report cycle stage-correlated variations in urinary pH among female mice. Estrus-specific pH decline is observed exclusively in urine samples from sexually experienced females. Moreover, patch-clamp recordings in acute VNO slices reveal that mouse VSNs reliably detect extracellular acidosis. Acid-evoked responses share the biophysical and pharmacological hallmarks of the hyperpolarization-activated current Ih. Mechanistically, VSN acid sensitivity depends on a pH-induced shift in the voltage-dependence of Ih activation that causes the opening of HCN channels at rest, thereby increasing VSN excitability. Together, our results identify extracellular acidification as a potent activator of vomeronasal Ih and suggest HCN channel-dependent vomeronasal gain control of social chemosignaling. Our data thus reveal a potential mechanistic basis for stimulus pH detection in rodent chemosensory communication., (Copyright © 2015 the authors 0270-6474/15/354025-15$15.00/0.)

Objective: Systemic sclerosis (SSc) is associated with an increased risk of osteoporosis and fractures. To date, the etiology of bone loss in SSc is unclear. Trabecular bone score (TBS) provides an indirect measurement of bone microarchitecture, independent of areal bone mineral density (aBMD). The aims were to assess bone involvement in SSc using TBS in comparison with a "high-risk" population with rheumatoid arthritis (RA) and controls, and to investigate the determinants of a low TBS., Methods: This was a cross-sectional study of 65 women with SSc, 138 age-matched female patients with RA, and 227 age-matched female controls. Spine and hip aBMD were assessed using dual-energy X-ray absorptiometry. TBS was calculated from the anteroposterior image of the spine aBMD., Results: TBS was significantly lower in SSc compared to controls (p < 0.0001) and did not differ from RA (p = 0.128), despite lower cumulative and daily glucocorticoid (GC) dose (p < 0.0001). Further, patients with SSc receiving GC ≥ 5 mg/day had a significantly lower TBS than those receiving GC < 5 mg/day (p = 0.001). Multivariate analysis revealed that a low TBS was independently associated with daily GC dose (OR 5.6, 95% CI 1.7-19.2) and a T score ≤ -2.5 SD (OR 5.0, 95% CI 1.5-7.0) in SSc. No association between GC and TBS was found in RA., Conclusion: Our results support the development of a combined approach using both TBS and aBMD for the assessment of bone microarchitecture in inflammatory rheumatic diseases. Our study showed that SSc-related bone involvement is characterized by an impairment in bone quality in addition to reduced bone quantity, and highlights that TBS can identify the negative effect of GC on bone microarchitecture.

Objective: Anticyclic citrullinated peptide antibodies (anti-CCP) are considered specific markers of rheumatoid arthritis (RA) and have been included in the revised classification criteria for RA diagnosis. However, these antibodies have also been detected in patients with other types of chronic inflammatory rheumatism. Our objectives were to identify the prevalence of positive anti-CCP patients in non-RA diseases, to determine the diagnostic value of anti-CCP for the diagnosis of RA, to specify the clinical characteristics of non-RA patients positive for anti-CCP, and to determine the discriminatory value of the levels of anti-CCP in patients among the various diseases., Methods: We carried out an observational and descriptive study. All the determinations of anti-CCP requested by the 2 rheumatology departments at Cochin Hospital over a period of 18 months were analyzed. Such determinations were requested for 1162 patients in total. Anti-CCP levels were determined with the Euro Diagnostica ELISA kit, with values ≥ 25 U for this test being considered positive. The diagnosis of rheumatic conditions was the responsibility of the treating physician., Results: Anti-CCP antibodies were detected in 357 (30.7%) of the 1162 patients. The prevalence of anti-CCP was 292/417 (70.0%) in RA, 13/122 (10.6%) in patients with psoriatic arthritis, 13/62 (20.9%) in patients with unclassified rheumatism, 11/33 (33.3%) in patients with primary Sjögren syndrome, 5/30 (16.6%) in patients with systemic lupus erythematosus, 3/28 (10.7%) in patients with mixed connective tissue disorder, 3/36 (8.3%) in patients with systemic sclerosis, 7/44 (15.9%) in patients with juvenile arthritis, and 6/220 (2.7%) in patients with noninflammatory diseases. In the population of patients positive for anti-CCP, mean anti-CCP levels were 869.4 (± 978.4) U/ml, with no significant difference between RA [854.8 (± 959.8) U/ml] and any of the non-RA conditions [922.7 (± 1070.0) U/ml]., Conclusion: Anti-CCP are a hallmark of RA, but may be observed in other inflammatory, systemic, or mechanical diseases. In this large cohort of patients, the presence of second-generation anti-CCP (anti-CCP2) antibodies is useful in diagnosing RA (70% sensitivity, 91.3% specificity), but examining the levels of these antibodies does not appear to offer further discriminatory power among patients who are anti-CCP2-positive.

Objectives: There is a paucity of data available on small intestinal bacterial overgrowth (SIBO) in systemic sclerosis (SSc). The objectives of the study were to estimate the prevalence of SIBO in SSc patients exhibiting intestinal symptoms and identify patients at risk of SIBO regarding clinical and biological presentations and gastrointestinal symptoms captured by standardized questionnaires., Methods: Between 2011 and 2012, patients exhibiting intestinal complaints underwent glucose H2/CH4 breath tests (BT) and blood assays. They were interviewed using the University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument 2.0 (UCLA SCTC GTI) and the Short Form-36 (SF-36). For patients diagnosed with SIBO, BT was repeated 1 to 4 months after the end of antibiotics., Results: Among 120 consecutive patients, 37 patients (29 women) exhibiting intestinal complaints were included (median age: 60 years). Fourteen patients (38%) were diagnosed with SIBO; patients from this subset had a longer disease duration (p=0.02), a significant weight loss within the past 6 months (p=0.03) and a higher total UCLA SCTC GTI score (p=0.03). The SF-36 assessment was not discriminant. Among the 14 patients treated for SIBO, 6 had a negative control BT, 4 remained positive, 2 failed to repeat the test and 2 patients died due to severe chronic malabsorption., Conclusions: SIBO is a not uncommon, late onset, severe and not easy to treat complication of SSc. Higher UCLA SCTC GTI score and weight loss appeared to be strongly associated with SIBO.

Unlabelled: In this study, we show that successful parathyroidectomy is followed at 1 year by a significant individual bone mineral density (BMD) gain in nearly half of normocalcemic PHPT patients with reduced bone mass. Alkaline phosphatase levels above median were identified as an independent predictor of individual BMD gain in normocalcemic PHPT patients., Introduction: The aims of this study were to assess bone mineral density (BMD) gains after parathyroidectomy (PTX) in normocalcemic primary hyperparathyroidism (PHPT) at the individual level and to identify predictors of BMD gain after PTX in this context., Methods: Longitudinal cohort study of 55 PHPT patients referred for low bone mass and mild abnormalities of calcium/phosphorus metabolism, and successfully treated by PTX. BMD gain at 1 year was considered significant if ≥0.030 g/cm(2) at one site or more, without any equivalent BMD loss at another site. A logistic regression analysis was performed to identify predictive factors of individual BMD gain., Results: Among the 55 PHPT patients included, 29 patients with hypercalcemia, 36 patients with normocalcemic PHPT, defined by normal pre-PTX serum total (albumin-corrected) calcium (tCa), including 15 patients with normal ionized calcium (iCa), were identified. At 1 year of PTX, an individual BMD gain was observed in 73.7 % of hypercalcemic, 44.4 % of normocalcemic, and 46 % of PHPT patients with both normal tCa and iCa. Site-specific BMD gains were most important at the spine and hip in all subgroups including patients with normal iCa. Alkaline phosphatase activity above median, which reflects high bone turnover, was predictive of individual BMD gain, both in the overall cohort (OR = 4.9, 95 % CI 1.3-18.9), and in the normocalcemic group: OR = 8.4, 95 % CI 1.4-56.6., Conclusions: Successful PTX is followed at 1 year by a significant individual BMD gain in nearly half of normocalcemic PHPT patients with osteoporosis. ALP levels above median could contribute to the therapeutic decision in this context.

Opsonization and apoptotic cell elements are critical in systemic lupus erythematosus (SLE) and could act through the activation of the innate immunity. C-reactive protein (CRP) belongs to opsonins, and polymorphisms of CRP gene have been shown to be associated with SLE susceptibility. Accumulating evidences show that SLE and systemic sclerosis (SSc) share some genetic susceptibility factors. To determine whether polymorphisms of CRP confer susceptibility to SSc, four SNPs (rs1130864, rs1205, rs1800947 and rs1341665), chosen using Hapmap linkage disequilibrium data and published data, were genotyped in a cohort of 651 SSc patients (569 with antinuclear antibodies, 258 with anti-centromere and 153 with anti-topoisomerase I) and 442 controls. All individuals were of French Caucasian origin. The four polymorphisms were in Hardy-Weinberg equilibrium in the control population. Allelic and genotypic frequencies for these four polymorphisms were found to be similar in SSc patients and controls. Moreover, subphenotype analyses in particular for subgroups having antinuclear antibodies did not detect any difference between SSc patients and controls. These results obtained through a large cohort of European Caucasian SSc patients do not support the implication of CRP gene in the pathogenesis of SSc.

Objective: To measure concentrations of high-sensitivity cardiac troponin (HS-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with rheumatoid arthritis (RA) and to examine correlates., Methods: The plasma concentrations of HS-cTnT and NT-proBNP were measured in consecutive patients with RA and compared to values obtained from age-matched and sex-matched healthy controls., Results: We included 236 unrelated patients with RA (192 females, 57 ± 13 yrs) and 213 controls (170 females, 55 ± 15 yrs). Seventy-one patients with RA were free of cardiovascular (CV) risk factors. HS-cTnT and NT-proBNP concentrations were significantly higher in the total cohort of patients with RA (p = 0.03 and p < 0.0001, respectively) and in the subgroup free of CV risk factors (p = 0.02 and p < 0.0001, respectively) compared to controls. In addition, both the total cohort of patients with RA and the subgroup free of CV risk factors were more likely to have levels above the cutoff concentrations of HS-cTnT (p = 0.003 and p = 0.007, respectively) and NT-proBNP (p = 0.0001 and p < 0.0001, respectively) than controls. Patients with RA and increased C-reactive protein (CRP) levels had higher HS-cTnT (p = 0.03) and NT-proBNP (p = 0.02) concentrations. HS-cTnT levels positively correlated with the 28-joint Disease Activity Score (DAS28-CRP; r = 0.2, p = 0.020). Multivariate logistic regression analysis indicated that increased HS-cTnT levels were independently associated with a DAS28-CRP > 5.1 (OR 11.8; 95% CI 1.6-35.5) and a body mass index > 30 kg/m(2) (OR 2.7; 95% CI 1.3-5.5)., Conclusion: HS-cTnT and NTproBNP are increased in patients with RA, independent of CV risk factors. The association between HS-cTnT, NT-proBNP, and CRP, together with the correlation between HS-cTnT and disease activity, support the link between myocardial injury/dysfunction and inflammation.

Objective: Whipple disease is a rare infection caused by Tropheryma whipplei. Although patients commonly complain of osteoarticular involvement, musculoskeletal manifestations have been poorly described. We report cases of Whipple disease with rheumatic symptoms and describe their clinical presentation, modes of diagnosis, and outcomes., Methods: This retrospective multicenter study included patients with Whipple disease diagnosed and referenced between 1977 and 2011 in 10 rheumatology centers in France and Italy., Results: Twenty-nine patients were included. The median age was 55 years. The median time to diagnosis from first symptoms was 5 years. Polyarthritis was the most frequent presentation (20/29), and was most often chronic, intermittent (19/29), seronegative (22/23), and nonerosive (22/29). In all cases, the symptoms had led to incorrect diagnosis of inflammatory rheumatic disease and immunosuppressants, including biotherapy, were prescribed in most cases (24/29) without success. The diagnosis of Whipple disease was made by histological analysis, molecular biology tests, or both in 21%, 36%, and 43% of the cases, respectively. Duodenal biopsies were performed in most cases (86%). Synovial biopsies were performed in 18% of cases, but all contributed to diagnosis. The clinical outcomes after antibiotic therapy were good for all patients., Conclusion: Polyarthritis is the main feature observed in cases of Whipple disease; it is seronegative and associated with general and gastrointestinal symptoms. The molecular analysis of duodenal tissue and/or other tissues remains the method of choice to confirm the diagnosis. Reducing the time to diagnosis is important because severe late systemic and fatal forms of the disease may occur.

Objectives: Several epidemiological studies have revealed the co-occurrence of other autoimmune diseases (AIDs) within patients with systemic sclerosis (SSc). However, some of these studies were based on small cohorts and wide ranges of prevalence have been reported. Therefore to overcome these limitations of individual studies, we sought to perform a meta-analysis to determine the accurate prevalence of polyautoimmunity in SSc., Methods: We performed a systematic review and a meta-analysis of literature in MEDLINE and Embase databases from January 1960 to March 2013. All cohort studies reporting on prevalence of other AIDs known to be associated with SSc were analyzed. Prevalence of polyautoimmunity and of each AID were then calculated., Results: Ten studies reporting polyautoimmunity were identified corresponding to a total of 6102 SSc patients. Overall 1432 patients with at least one AID were identified corresponding to a weighted prevalence of polyautoimmunity equal to 25.7% CI 95% [20.1%-31.6%]. Overall 208/5139 SSc-patients had at least two additional AIDs resulting in a weighted prevalence of 3.9% [3.3%-4.4%]. The most prevalent associated AIDs were autoimmune thyroid disease (10.4%) followed by Sjögren's syndrome (7.7%) and dermatopolymyositis/polymyositis (5.6%)., Conclusion: Our results confirm that SSc polyautoimmunity is a frequent condition in SSc affecting a quarter of SSc-patients. The impact on the phenotype and also on the management and therapy will need to be addressed now in further works., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Context: It is unclear whether bone mineral density (BMD) improves in patients with normocalcemic primary hyperparathyroidism (PHPT) after parathyroidectomy (PTX)., Objective: The objective of the study was to evaluate and compare the impact of PTX on BMD change at 1 year in normocalcemic vs hypercalcemic PHPT., Design: This was a longitudinal cohort study., Setting: The study took place at a referral center., Patients: We included 60 PHPT patients (mean age 64.0 ± 10.1 years), successfully treated by PTX by the same surgeon. Two groups were individualized according to baseline serum total (albumin corrected) calcium: 39 patients with normal baseline serum total calcium (normocalcemic group) and 21 patients with hypercalcemia at baseline (hypercalcemic group)., Main Outcome Measure: BMD changes 1 year after PTX were measured., Results: In the normocalcemic group, BMD increased significantly by +2.3 ± 5.0% at the spine (P = .016) and +1.9 ± 5.7% at the hip (P = .048). In the hypercalcemic group, BMD increased significantly by +4.0 ± 3.8% at the spine (P = .0003) and +3.2 ± 4.2% at the hip (P = .003). There was no difference in these BMD gains between both groups (P > .1). The presence of multiple adenomas or hyperplasia was more frequent in the normocalcemic group than in the hypercalcemic group (P = .04)., Conclusion: Our results indicate for the first time that successful PTX in normocalcemic PHPT patients with osteoporosis is followed with mild but significant BMD improvement at the spine and hip at 1 year, comparable with that observed in hypercalcemic PHPT, suggesting that PTX may be beneficial in normocalcemic PHPT.

Objective: To investigate the contribution of the adhesion receptor DNAX accessory molecule-1 (DNAM-1) in the development of dermal fibrosis on gene inactivation and targeted molecular strategies., Methods: Human skin expression of DNAM-1 was determined by immunohistochemistry. Mice deficient for DNAM-1 (dnam1-/-) and wild-type controls (dnam1+/+) were injected with bleomycin or NaCl. Infiltrating leucocytes, T cells, B cells and monocytes were quantified and inflammatory cytokines were measured in lesional skin of dnam1-/- and dnam1+/+ mice. The anti-fibrotic potential of a DNAM-1 neutralising monoclonal antibody (mAb) was evaluated in the mouse model of bleomycin-induced dermal fibrosis., Results: Overexpression of DNAM-1 was detected in the skin of patients with SSc (systemic sclerosis). Dnam1-/- mice were protected from bleomycin-induced dermal fibrosis with reduction of dermal thickening (75±5%, p=0.03), hydroxyproline content (46±8%, p=0.04) and myofibroblast counts (39±5%, p=0.01). Moreover, the number of T cells was significantly decreased in lesional skin of dnam1-/- mice (69±15%, p=0.0007). Dnam1-/- mice also displayed decreased levels of TNF-α and IL-6 in lesional skin. Consistent with the gene inactivation strategy, treatment of mice with DNAM-1 neutralising mAb prevented dermal fibrosis induced by bleomycin with reduction of dermal thickness (64±6%, p=0.002), hydroxyproline content (61±8%, p=0.004) and myofibroblast counts (83±12%, p=0.002)., Conclusions: An inactivation gene strategy showed that DNAM-1 exerts profibrotic effects by controlling T cell activation and cytokine release. A molecular targeted strategy confirmed that DNAM-1 neutralising mAb has potent antifibrotic properties, supporting the hypothesis that inhibition of DNAM-1 might be a promising new approach for the treatment of SSc and potentially other related fibrotic diseases.