Targeting the chemokine receptor CXCR4 with histamine analog to reduce inflammation in juvenile arthritis.

Introduction: Among immune cells, activated monocytes play a detrimental role in chronic and viral-induced inflammatory pathologies, particularly in Juvenile Idiopathic Arthritis (JIA), a childhood rheumatoid arthritis (RA) disease. The uncontrolled activation of monocytes and excessive production of inflammatory factors contribute to the damage of bone-cartilage joints. Despite the moderate beneficial effect of current therapies and clinical trials, there is still a need for alternative strategies targeting monocytes to treat RA. Methods: To explore such an alternative strategy, we investigated the effects of targeting the CXCR4 receptor using the histamine analog clobenpropit (CB). Monocytes were isolated from the blood and synovial fluids of JIA patients to assess CB's impact on their production of key inflammatory cytokines. Additionally, we administered daily intraperitoneal CB treatment to arthritic mice to evaluate its effects on circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption, as indicators of disease progression. Results: Our findings demonstrated that CXCR4 targeting with CB significantly inhibited the spontaneous and induced-production of key inflammatory cytokines by monocytes isolated from JIA patients. Furthermore, CB treatment in a mouse model of collagen-induce arthritis resulted in a significant decrease in circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption, leading to a reduction in disease progression. Discussion: In conclusion, targeting CXCR4 with the small amino compound CB shows promise as a therapeutic option for chronic and viral-induced inflammatory diseases, including RA. CB effectively regulated inflammatory cytokine production of monocytes, presenting a potential targeted approach with potential advantages over current therapies. These results warrant further research and clinical trials to explore the full therapeutic potential of targeting CXCR4 with CB-like molecules in the management of various inflammatory diseases.

Early Magnetic Resonance Imaging to Diagnose Residual Cholesteatoma in Children and Benefit of Radiological Rereview.

OBJECTIVE: Non-echo-planar diffusion-weighted (DW) magnetic resonance imaging (non-EPI MRI) is the appropriate sequence to detect residual cholesteatoma. In the child, MRI may be clinically useful to determine the timing of the second-look procedure. The aim of this paper was to retrospectively evaluate the performance of early MRI (before the 18th postoperative month) in detecting residual cholesteatoma in children after review by experienced specialized neuroradiologists. STUDY DESIGN: Retrospective study. SETTING: One university center comparative cohort. METHODS: All patients who had a 2-staged procedure for cholesteatoma with an MRI before the second stage from 2010 to 2020 were included and analyzed. Three pediatric neuroradiologists reviewed all the images blinded to the surgical result. RESULTS: N = 141 cholesteatoma events (140 children) were included with a mean age at MRI of 10 (±4) years old. Non-EPI MRIs were performed 10.7 (±3.8) months after the first-stage surgery and 2.2 (±2.6) months before the second-stage procedure. Non-EPI MRI had a 0.57 sensitivity (SE) and 0.83 specificity (SP). MRI was reviewed in 112 cases. The diagnosis was corrected in 17 cases (15.1%) (3 true positives, 7 false negatives, and 7 false positives). SE = 0.63 (p = 0.1) and SP = 0.92 (p = 0.08) after rereading. CONCLUSION: Early MRI's SE is poor but SP is excellent after rereading. Evidence does not support the use of early non-EPI MRI to modify the surgical strategy or to postpone the second look. If performed, early non-EPI MRI should be read by specialized experienced radiologists with all 3 sequences (T1, T2, and non-EPI DW) and apparent diffusion coefficient calculation, especially in cases of otitis media with effusion.

Dry synovitis, a rare entity distinct from juvenile idiopathic arthritis.

BACKGROUND: Dry synovitis (DS) is a rare entity as only a few cases have been reported to date. We describe the clinical features, radiological manifestations and course of DS in comparison with rheumatoid factor negative polyarticular juvenile idiopathic arthritis (RFneg-polyJIA). METHODS: We performed a multicenter retrospective collection of data of DS patients who presented with progressive joint limitations without palpable synovitis, absence of elevated acute phase reactants, negative ANA and RF, and imaging showing joint and/or osteochondral involvement. For comparative purposes, we included a cohort of RF neg-polyJIA patients. RESULTS: Twelve DS patients, 8F/4 M, with mean age at onset of 6.1 years, were included. Presenting signs comprised delayed motor development, functional limitations and/or progressive stiffness. Clinical examination showed symmetric polyarticular involvement with variable muscular atrophy. MRI showed mild, diffuse synovial involvement, without effusion. With time, signs of progressive osteochondral damage became evident, despite treatment. All patients were treated with low-dose corticosteroids and methotrexate. Anti-TNF agents were prescribed in five. The response was variable with limited joint mobility in 11/12, and need of joint replacement in 2. In comparison with a cohort of RFneg-polyJIA, DS patients presented higher number of joint involved (p = 0.0001) and contractures (p = 0.0001), less swelling (p = 0.0001) and prolonged diagnostic delay (p = 0.0001). CONCLUSION: DS represents a unique juvenile-onset arthropathy, distinct from polyarticular JIA. Awareness among pediatricians is essential for early recognition and proper treatment. Further studies, including synovial pathology, immunology and genetics may contribute to a better understanding of this rare disorder of childhood.

Criteria Associated with Treatment Decisions in Juvenile Idiopathic Arthritis with a Focus on Ultrasonography: Results from the JIRECHO Cohort.

BACKGROUND: The treatment of children with juvenile idiopathic arthritis (JIA) to prevent disability is a major challenge in paediatric rheumatology. The presence of synovitis, which is difficult to detect in children, is associated with structural damage. Musculoskeletal ultrasonography (MSUS) can be used in patients with JIA to reveal subclinical synovitis. OBJECTIVE: The primary aim was to determine whether the use of MSUS was associated with therapeutic modification in patients with JIA. The secondary aim was to identify other factors associated with therapeutic decisions. METHODS: We conducted an observational study based on the JIRECHO multi-centre cohort, which was developed to provide a systematic MSUS follow-up for patients with JIA. Follow-up occurred every 6 months and included clinical and MSUS examinations. We included children who underwent MSUS of the elbows, wrists, second metacarpophalangeal joints, knees and ankles, which was performed by expert sonographers. Clinical and biological data, disease activity scores and information on therapeutics were collected. RESULTS: A total of 185 visits concerning 112 patients were recorded. Three groups were defined according to the therapeutic decision: escalation (22%, n = 40), de-escalation (14%, n = 26) or stable (64%, n = 119). In the "therapeutic escalation" group: the presence of ultrasonographic synovitis in B-mode and the presence of grade 2 or 3 synovitis in B-mode were not significantly more frequent than in the "stable therapeutic or de-escalation" group (80% versus 65%, p = 0.06; 33% versus 19%, p = 0.06), and the patient's and physician's visual analogue scale (VAS) scores, the clinical JADAS and the C-reactive protein level were significantly higher, but only physician's VAS score remained in the model of logistic regression. In the "therapeutic de-escalation" group: there was no difference in the presence of US synovitis compared with the "stable therapeutic or escalation" group (62% versus 69%, p = 0.48). CONCLUSION: Even though US synovitis tended to be more frequent in patients with therapeutic escalation, the study did not show that the presence of synovitis in MSUS was statistically associated with therapeutic modifications in patients with JIA. Treatment remained stable despite the presence of US synovitis.

Impact of sleep-disordered breathing on the management of children with Chiari malformation type I.

OBJECTIVES: Children with Chiari malformation type I (CM-I) have an increased risk of sleep apnea. The aim of the study was to describe the management of CM-I patients in relation to symptoms, magnetic resonance imaging (MRI) findings and sleep apnea syndrome (SAS). METHODS: We performed a retrospective analysis of clinical charts of all 57 CM-I patients seen between September 2013 and April 2017. RESULTS: A total of 45 patients had isolated CM-I or associated co-morbidity (CM-Iia), 5 had craniosynostosis (CM-Ics), and 7 a polymalformative syndrome (CM-Ipm). The prevalence of SAS, defined as an apnea-hypopnea index >1 event/h, was high in CM-I ranging from 50% to 80% according to the CM-I group. The prevalence of central sleep apnea (CSA) was low, with 5 (9%) patients having CSA and only 3 patients with CM-Iia having isolated CSA. A total of 17 patients (30%) had foramen magnum decompression (FMD). Neither positive symptoms of CM-I nor MRI findings alone, nor both combined were good indicators for FMD. No correlation was observed between the cerebellar tonsil descent and SAS in CM-I. But all 5 patients with CSA had a FMD. The combination of MRI findings and/or symptoms of CM-I together with moderate-to-severe SAS best discriminated patients who needed a FMD. CONCLUSION: Our findings highlight the importance of a combined evaluation of symptoms, MRI and polygraphy results in the management of CM-I patients.

Further delineation of auriculocondylar syndrome based on 14 novel cases and reassessment of 25 published cases.

Auriculocondylar syndrome (ACS) is a rare craniofacial disorder characterized by mandibular hypoplasia and an auricular defect at the junction between the lobe and helix, known as a "Question Mark Ear" (QME). Several additional features, originating from the first and second branchial arches and other tissues, have also been reported. ACS is genetically heterogeneous with autosomal dominant and recessive modes of inheritance. The mutations identified to date are presumed to dysregulate the endothelin 1 signaling pathway. Here we describe 14 novel cases and reassess 25 published cases of ACS through a questionnaire for systematic data collection. All patients harbor mutation(s) in PLCB4, GNAI3, or EDN1. This series of patients contributes to the characterization of additional features occasionally associated with ACS such as respiratory, costal, neurodevelopmental, and genital anomalies, and provides management and monitoring recommendations.

The utility of poly(somno)graphy in evaluating children with Chiari malformation type II before and after surgical intervention: a case series.

BACKGROUND: Children with Chiari Malformation type II (CM-II) have an increased risk of sleep apnoea. The aim of the study was to describe the management of patients with CM-II in relation to sleep apnoea syndrome, clinical symptoms and magnetic resonance imaging (MRI) findings. CASE SERIES PRESENTATION: The paper reports 8 consecutive patients with CM-II followed between September 2013 and April 2017. The prevalence of sleep apnoea syndrome was high with 6 out of 8 patients having mild-to-severe sleep apnoea. Patients with severe sleep apnoea syndrome (3 patients) were treated with upper airway surgery and/or noninvasive ventilation. CONCLUSION: Our findings highlight the importance of respiratory polygraphy in the management of patients with CM-ΙΙ. Poly(somno)graphy is recommended in the follow-up care of children with CM-II.

Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.

We studied a child with severe viral, bacterial, fungal, and parasitic diseases, who was homozygous for a loss-of-function mutation of REL, encoding c-Rel, which is selectively expressed in lymphoid and myeloid cells. The patient had low frequencies of NK, effector memory cells reexpressing CD45RA (Temra) CD8+ T cells, memory CD4+ T cells, including Th1 and Th1*, Tregs, and memory B cells, whereas the counts and proportions of other leukocyte subsets were normal. Functional deficits of myeloid cells included the abolition of IL-12 and IL-23 production by conventional DC1s (cDC1s) and monocytes, but not cDC2s. c-Rel was also required for induction of CD86 expression on, and thus antigen-presenting cell function of, cDCs. Functional deficits of lymphoid cells included reduced IL-2 production by naive T cells, correlating with low proliferation and survival rates and poor production of Th1, Th2, and Th17 cytokines by memory CD4+ T cells. In naive CD4+ T cells, c-Rel is dispensable for early IL2 induction but contributes to later phases of IL2 expression. The patient's naive B cells displayed impaired MYC and BCL2L1 induction, compromising B cell survival and proliferation and preventing their differentiation into Ig-secreting plasmablasts. Inherited c-Rel deficiency disrupts the development and function of multiple myeloid and lymphoid cells, compromising innate and adaptive immunity to multiple infectious agents.

Optimal ilio-sacral screw trajectory in paediatric patients : a computed tomography study.

Pelvic fixation during procedures performed to treat spinal deformities in paediatric patients remains challenging. No computed tomography studies in paediatric have assessed the optimal trajectory of ilio- sacral screws to prevent screw malposition. We used pelvic computed tomography from 80 children divided into four groups : females <10 and ≥10 years and males <10 and ≥10 years. A secure triangular corridor parallel to the upper S1 endplate was delineated based on three fixed landmarks. The optimal screw insertion angle was subtended by the horizontal and the line bisecting the secure corridor. Student's t test was applied to determine whether the optimal screw insertion angle and/or anatomical parameters were associated with age and/or sex. Mean optimal angle was 32.3°±3.6°, 33.8°±4.7°, 30.2°±5.0°, and 30.4°±4.7° in the younger females, younger males, older females, and older males, respectively. The mean optimal angle differed between the two age groups (p=0.004) but not between females and males (p=0.55). Optimal mean screw length was 73.4±9.9 mm. Anatomical spinal canal parameters in the transverse plane varied with age (p=0.02) and with sex in the older children (p=0.008), and those in the sagittal plane varied with sex (p=0.04). Age affected ilio-sacral screw positioning, whereas sex did not. Several anatomical spinal canal parameters varied with age and sex. These results should help to ensure safe and easy ilio-sacral screw placement within a secure corridor.

Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.

BACKGROUND: Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high. CASE REPORT: A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs. CONCLUSION: Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.

Oxia Planum: The Landing Site for the ExoMars "Rosalind Franklin" Rover Mission: Geological Context and Prelanding Interpretation.

The European Space Agency (ESA) and Roscosmos ExoMars mission will launch the "Rosalind Franklin" rover in 2022 for a landing on Mars in 2023.The goals of the mission are to search for signs of past and present life on Mars, investigate the water/geochemical environment as a function of depth in the shallow subsurface, and characterize the surface environment. To meet these scientific objectives while minimizing the risk for landing, a 5-year-long landing site selection process was conducted by ESA, during which eight candidate sites were down selected to one: Oxia Planum. Oxia Planum is a 200 km-wide low-relief terrain characterized by hydrous clay-bearing bedrock units located at the southwest margin of Arabia Terra. This region exhibits Noachian-aged terrains. We show in this study that the selected landing site has recorded at least two distinct aqueous environments, both of which occurred during the Noachian: (1) a first phase that led to the deposition and alteration of ∼100 m of layered clay-rich deposits and (2) a second phase of a fluviodeltaic system that postdates the widespread clay-rich layered unit. Rounded isolated buttes that overlie the clay-bearing unit may also be related to aqueous processes. Our study also details the formation of an unaltered mafic-rich dark resistant unit likely of Amazonian age that caps the other units and possibly originated from volcanism. Oxia Planum shows evidence for intense erosion from morphology (inverted features) and crater statistics. Due to these erosional processes, two types of Noachian sedimentary rocks are currently exposed. We also expect rocks at the surface to have been exposed to cosmic bombardment only recently, minimizing organic matter damage.

Application of the OMERACT synovitis ultrasound scoring system in juvenile idiopathic arthritis: a multicenter reliability exercise.

OBJECTIVES: To evaluate the reliability of the OMERACT paediatric ultrasound (US) synovitis definitions and scoring system in JIA. METHODS: Thirteen sonographers analysed 75 images for the presence/absence of elementary lesions (binary scoring) and for grading synovitis, synovial hypertrophy, effusion and Doppler signals. Static US images of the second metacarpophalangeal joint (MCP-II), wrist, elbow, knee and ankle in JIA patients at different ages and different disease stages were collected with standardized scanning by two experienced sonographers. Intra- and inter-reader reliability were analysed with kappa coefficients. RESULTS: Intra-reader reliability was good for binary scoring (Cohen's kappa 0.62, range 0.47-0.75), synovitis and synovial hypertrophy; excellent for Doppler signals (quadratic weighted kappa 0.77, 0.66-0.86; 0.76, 0.61-0.84; and 0.87, 0.77-0.94, respectively); and moderate for effusion (0.55, 0.24-0.76). Inter-reader reliability was good for synovitis and synovial hypertrophy (Light's kappa 0.68, 95% CI: 0.61, 0.75 and 0.63, 0.54-0.71, respectively), excellent for Doppler signals (0.85, 95% CI: 0.77, 0.90), and moderate for binary scoring and effusion (0.48, 95% CI: 0.36, 0.64 and 0.49, 0.40-0.60, respectively). We obtained the best scores for the knee (0.71, 0.54-0.85) except for Doppler signals, with reliability higher for MCP-II. We found a trend toward better results in older children. CONCLUSIONS: This is the first study establishing the reliability of the OMERACT paediatric US synovitis definitions and scoring system in the five most commonly affected joints in JIA. The reliability was good among a large group of sonographers. These results support the applicability of these definitions and scoring system in clinical practice and multicentre studies.

Overview of STING-Associated Vasculopathy with Onset in Infancy (SAVI) Among 21 Patients.

BACKGROUND: Gain-of-function mutations in STING1 underlie a type I interferonopathy termed SAVI (STING-associated vasculopathy with onset in infancy). This severe disease is variably characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease (ILD). OBJECTIVE: To describe a cohort of patients with SAVI. METHODS: Assessment of clinical, radiological and immunological data from 21 patients (17 families) was carried out. RESULTS: Patients carried heterozygous substitutions in STING1 previously described in SAVI, mainly the p.V155M. Most were symptomatic from infancy, but late onset in adulthood occurred in 1 patient. Systemic inflammation, skin vasculopathy, and ILD were observed in 19, 18, and 21 patients, respectively. Extensive tissue loss occurred in 4 patients. Severity of ILD was highly variable with insidious progression up to end-stage respiratory failure reached at teenage in 6 patients. Lung imaging revealed early fibrotic lesions. Failure to thrive was almost constant, with severe growth failure seen in 4 patients. Seven patients presented polyarthritis, and the phenotype in 1 infant mimicked a combined immunodeficiency. Extended features reminiscent of other interferonopathies were also found, including intracranial calcification, glaucoma and glomerular nephropathy. Increased expression of interferon-stimulated genes and interferon α protein was constant. Autoantibodies were frequently found, in particular rheumatoid factor. Most patients presented with a T-cell defect, with low counts of memory CD8+ cells and impaired T-cell proliferation in response to antigens. Long-term follow-up described in 8 children confirmed the clinical benefit of ruxolitinib in SAVI where the treatment was started early in the disease course, underlying the need for early diagnosis. Tolerance was reasonably good. CONCLUSION: The largest worldwide cohort of SAVI patients yet described, illustrates the core features of the disease and extends the clinical and immunological phenotype to include overlap with other monogenic interferonopathies.

Percutaneous alcohol-based sclerotherapy in aneurysmal bone cyst in children and adolescents.

INTRODUCTION: Aneurysmal bone cyst (ABC) is a benign bone lesion of childhood and adolescence. It can be locally aggressive, with risk of fracture. Management is controversial. The aim of the present study was to assess the efficacy, simplicity and tolerance of percutaneous alcohol-bases sclerotherapy in ABC. HYPOTHESIS: Alcohol-based sclerotherapy for ABC under radiographic control is safe and effective. MATERIAL AND METHODS: A single-center retrospective study for the period 2008-2016 included all of the 55 ABCs, in 54 patients, confirmed on pathology and treated by alcohol-based sclerotherapy under radiographic control. Mean age at diagnosis was 9.6 years. ABC involved the humerus in 30 cases (54%), tibia in 7 (13%) and femur in 5 (9%). Mean follow-up was 50.9 months (range, 16-117 months). Mean number of applications was 1.7 (range, 1-4). Results were assessed clinically (pain, return to sport, limb length and alignment, revision surgery) and radiologically. The main endpoint was lesion volume reduction. The secondary endpoint was failure, defined by open revision surgery or pain preventing return to a sports activity. RESULTS: Clinical progression was favorable in 36 patients (67%), and radiological progression in 45 (85%). Only 1 cyst required secondary resection. One patient experienced spontaneously resolving intraoperative bradycardia. Male gender and young age emerged as factors for poorer response. DISCUSSION: ABC management in children can be made difficult by lesion size, aggressiveness, location, proximity to the growth plate and small bone stock. Alcohol-based sclerotherapy is simple, reliable and effective in childhood ABC, and may be a first-line attitude, avoiding recourse to invasive surgery. LEVEL OF EVIDENCE: IV, retrospective study.

Brucella melitensis Rev.1 vaccination generates a higher shedding risk of the vaccine strain in Alpine ibex (Capra ibex) compared to the domestic goat (Capra hircus).

Epidemiological investigations implemented in wild and domestic ruminants evidenced a reservoir for Brucella in Capra ibex in the French Alps. Vaccination was considered as a possible way to control Brucella infection in this wildlife population. Twelve ibexes and twelve goats were allocated into four groups housed separately, each including six males or six non-pregnant females. Four to five animals were vaccinated and one or two animals were contact animals. Half of the animals were necropsied 45 days post-vaccination (pv), and the remaining ones at 90 days pv. Additional samples were collected 20 and 68 days pv to explore bacterial distribution in organs and humoral immunity. Neither clinical signs nor Brucella-specific lesions were observed and all vaccinated animals seroconverted. Brucella distribution and antibody profiles were highly contrasted between both species. Proportion of infected samples was significantly higher in ibex compared to goats and decreased between 45 and 90 days pv. Two male ibex presented urogenital excretion at 20 or 45 days pv. The bacterial load was higher 45 days in ibexes compared to goats, whereas it remained moderate to low 90 days pv in both species with large variability between animals. In this experiment, differences between species remained the main source of variation, with low impact of other individual factors. To conclude, multiplicative and shedding capacity of Rev.1 was much higher in ibex compared to goats within 90 days. These results provide initial information on the potential use in natura of a commercial vaccine.

Semi-automated crater depth measurements.

Impact cratering is a major process driving planetary landscape evolution. Statistics of craters spatial density is extensively used to date planetary surfaces. Their degradation state and morphometry are also key parameters to understand surface processes. To exploit the increasing coverage of digital terrain models (DEM) on Mars at high spatial resolution, we propose a semi-automated pipeline for crater depth measurement based on coupled optical images and DEM. From a craters map shapefile coupled with a co-registered DEM, we propose to measure crater depth as the difference between the 60th percentile of elevation values on the edge of the crater and the 3rd percentile value of the elevations within the crater. We present here this method and its calibration. •Aside to this paper, we provide a simple python code of this pipeline.•This method can rapidly produce crater depth dataset big enough to be interpreted statistically.•We provide solid tests on the precision of measured crater depth. Especially, we show that minimal elevation value within a crater, sometime used as crater floor elevation, is a far less precise approximation than a low percentile of elevation.

The impact origin and evolution of Chryse Planitia on Mars revealed by buried craters.

Large impacts are one of the most important processes shaping a planet's surface. On Mars, the early formation of the Martian crust and the lack of large impact basins (only four unambiguously identified: Hellas, Argyre, Utopia, and Isidis) indicates that a large part of early records of Mars' impact history is missing. Here we show, in Chryse Planitia, the scarcity of buried impact craters in a near-circular area could be explained by a pre-existing topographic depression with more intense resurfacing. Spatially correlated with positive Bouguer anomaly, this near-circular region with a diameter of ~1090 km likely originated from an impact. This proposed large impact basin must have been quickly relaxed or buried after its formation more than 4.0 billion years ago and heavily modified by subsequent resurfacing events. We anticipate our study to open a new window to unravelling the buried records of early Martian bombardment record.

Pituitary deficiency and precocious puberty after childhood severe traumatic brain injury: a long-term follow-up prospective study.

Objectives Childhood traumatic brain injury (TBI) is a public health issue. Our objectives were to determine the prevalence of permanent pituitary hormone deficiency and to detect the emergence of other pituitary dysfunctions or central precocious puberty several years after severe TBI. Design Follow-up at least 5 years post severe TBI of a prospective longitudinal study. Patients Overall, 66/87 children, who had endocrine evaluation 1 year post severe TBI, were included (24 with pituitary dysfunction 1 year post TBI). Main outcome measures In all children, the pituitary hormones basal levels were assessed at least 5 years post TBI. Growth hormone (GH) stimulation tests were performed 3-4 years post TBI in children with GH deficiency (GHD) 1 year post TBI and in all children with low height velocity (<-1 DS) or low IGF-1 (<-2 DS). Central precocious puberty (CPP) was confirmed by GnRH stimulation test. Results Overall, 61/66 children were followed up 7 (5-10) years post TBI (median; (range)); 17/61 children had GHD 1 year post TBI, and GHD was confirmed in 5/17 patients. For one boy, with normal pituitary function 1 year post TBI, GHD was diagnosed 6.5 years post TBI. 4/61 patients developed CPP, 5.7 (2.4-6.1) years post-TBI. Having a pituitary dysfunction 1 year post TBI was significantly associated with pituitary dysfunction or CPP more than 5 years post TBI. Conclusion Severe TBI in childhood can lead to permanent pituitary dysfunction; GHD and CPP may appear after many years. We recommend systematic hormonal assessment in children 1 year after severe TBI and a prolonged monitoring of growth and pubertal maturation. Recommendations should be elaborated for the families and treating physicians.