The Kinase IKKß Regulates a STING- and NF-κB-Dependent Antiviral Response Pathway in Drosophila.

Antiviral immunity in Drosophila involves RNA interference and poorly characterized inducible responses. Here, we showed that two components of the IMD pathway, the kinase dIKKß and the transcription factor Relish, were required to control infection by two picorna-like viruses. We identified a set of genes induced by viral infection and regulated by dIKKß and Relish, which included an ortholog of STING. We showed that dSTING participated in the control of infection by picorna-like viruses, acting upstream of dIKKß to regulate expression of Nazo, an antiviral factor. Our data reveal an antiviral function for STING in an animal model devoid of interferons and suggest an evolutionarily ancient role for this molecule in antiviral immunity.

RNA SHAPE chemistry with aromatic acylating reagents.

As chemical methods for RNA secondary structure determination, SHAPE chemistry (selective 2'-hydroxyl acylation analyzed by primer extension) has been developed to specifically target flexible nucleotides (often unpaired nucleotides) independently to their purine or pyrimidine nature. In order to improve the specificity of acylating reagents towards unpaired nucleotides, we have explored the reactivity of symmetric anhydrides, acyl fluorides, active esters like succinimidyl ester and cyanomethyl esters for 2'-O-acylation reaction. Among the tested compounds, only the acyl fluoride 4 showed a low reactivity (compared to NMIA). However, this study is the first to show that nucleophilic catalysts like DMAP greatly improved the selective 2'-hydroxyl acylation by symmetric anhydrides, acyl fluorides and succinimidyl ester, with the 2-fluorobenzoic anhydride 5 being the most reactive.

Broad RNA interference-mediated antiviral immunity and virus-specific inducible responses in Drosophila.

The fruit fly Drosophila melanogaster is a good model to unravel the molecular mechanisms of innate immunity and has led to some important discoveries about the sensing and signaling of microbial infections. The response of Drosophila to virus infections remains poorly characterized and appears to involve two facets. On the one hand, RNA interference involves the recognition and processing of dsRNA into small interfering RNAs by the host RNase Dicer-2 (Dcr-2), whereas, on the other hand, an inducible response controlled by the evolutionarily conserved JAK-STAT pathway contributes to the antiviral host defense. To clarify the contribution of the small interfering RNA and JAK-STAT pathways to the control of viral infections, we have compared the resistance of flies wild-type and mutant for Dcr-2 or the JAK kinase Hopscotch to infections by seven RNA or DNA viruses belonging to different families. Our results reveal a unique susceptibility of hop mutant flies to infection by Drosophila C virus and cricket paralysis virus, two members of the Dicistroviridae family, which contrasts with the susceptibility of Dcr-2 mutant flies to many viruses, including the DNA virus invertebrate iridescent virus 6. Genome-wide microarray analysis confirmed that different sets of genes were induced following infection by Drosophila C virus or by two unrelated RNA viruses, Flock House virus and Sindbis virus. Overall, our data reveal that RNA interference is an efficient antiviral mechanism, operating against a large range of viruses, including a DNA virus. By contrast, the antiviral contribution of the JAK-STAT pathway appears to be virus specific.

Interest in daily clinical practice of screening for gouty disease in patients with psoriatic arthritis.

Objectives: PsA and gout are two prevalent rheumatic diseases, that can be associated as part of a rheumatism known as 'Psout'. Both conditions are associated with cardiovascular (CV) risk, thus their co-occurrence could have significant implications for the management of CV risks and patient care. This study aimed to determine the prevalence of gout within a PsA patient cohort and, consequently, to identify factors associated with this pathological association. Methods: This is an observational, descriptive, cross-sectional, single-center study, including patients diagnosed with PsA. Demographic, clinical, biological and imaging data were collected. We identified the proportion of patients simultaneously affected by PsA and gout and compared characteristics between those with and without gout. Results: The prevalence of gout among PSA patients was 9.8% (12/122), with a prevalence of 23% for asymptomatic hyperuricemia and 7.4% presenting with specific US signs of gout. Significant associated factors in the univariate analysis included weight, hypertension, diabetes, certain medications (diuretics, aspirin, lipid-lowering agents), impaired renal function, elevated fasting blood glucose, lipid abnormalities and specific US signs of gout. Conclusion: Our study has described the existence of patients simultaneously affected by PsA and gout ('Psout'). Performing joint US along with uric acid level measurements in PsA patients can enable personalized therapeutic care.

Effects of botulinum toxin injections in the upper limbs of children with cerebral palsy: A systematic review of the literature.

BACKGROUND: Spasticity is a common motor disorder in children with cerebral palsy (CP). Upper limb CP impairment has a significant negative impact on daily activities. Botulinum toxin (BTX-A) injections are widely used to reduce spasticity, but their effectiveness is not well-defined. We performed a systematic review of literature to answer questions about the effectiveness of BTX-A injections in the upper limb in children with CP. METHODS: A systematic review of literature was conducted according to PRISMA guidelines. Eligible studies were randomized controlled trials with a high level of evidence on BTX-A upper limb injections in children. The outcomes analyzed included the study population, spasticity, quality of movement, activity limitations, quality of life, pain, appearance and side effects. RESULTS: A total of 24 studies were included. The number of patients included was 1358 with a mean age between 3 and 11years. Improvement after BTX-A injection compared to the control group was observed for spasticity (n=10/19 studies), bimanual activities (Assisting Hand Assessment) (n=3/7), activity limitations (n=6/11), pain (n=2/2) and appearance (n=2/2). No study found an improvement in quality of life. Side effects were described in 16 studies and were moderate in all cases. CONCLUSION: This review of literature showed that BTX-A injections can improve spasticity and particularly activity limitations when reasonable objectives are established. LEVEL OF EVIDENCE: IV, systematic review.

Surgical Treatment of Juvenile Idiopathic Arthritis in the Era of Novel Drug Therapies.

Juvenile idiopathic arthritis is the most common chronic rheumatic disease encountered in children under the age of sixteen and causes significant impairments in daily life. Over the last two decades, the introduction of new drug treatments (including disease-modifying antirheumatic drugs and biologics) has changed the course of this disease, thus reducing the indication for surgery. However, some patients fail to respond to drug therapy and thus require personalized surgical management, e.g., the local reduction of joint effusion or a synovial pannus (via intra-articular corticosteroid injections, synovectomy, or soft tissue release), and management of the sequelae of arthritis (such as growth disorders and joint degeneration). Here, we provide an overview of the surgical indications and outcomes of the following interventions: intra-articular corticosteroid injections, synovectomy, soft tissue release, surgery for growth disorders, and arthroplasty.

Bone health in children with severe cerebral palsy.

Aim: To describe bone health and associated factors in children with severe cerebral palsy. Method: In a retrospective, single-centre study, we performed a comprehensive bone evaluation (including clinical, densitometric and bone biomarker assessments) of children with severe cerebral palsy. Results: None of the 19 included children had a normal BMCTBLH Z score, and only one had a BMDTBLH Z score greater than -2. Six children had a BMDLS Z score greater than -2. The bone biomarker data were suggestive of excessive bone remodelling. Levels of bone remodelling markers factors and densitometric variables were not significantly related. Age, weight and pubertal stage were significantly related to bone mass. Discussion: Our results highlights the insufficient increase in bone mass with age (probably due to excessive bone remodelling) and confirms the high prevalence of low bone mineral density in children with severe cerebral palsy. Possible preventive measures might include calcium + vitamin D supplementation and the systematic management of underweight and delayed puberty. Bone remodelling markers might be of value for follow-up.

Current characteristics of a population of psoriatic arthritis and gender disparities.

Background and Aim: Psoriatic arthritis (PsA) is a polymorphic disease associated with numerous comorbidities. The objective of this study was to describe the main clinicobiological and imaging characteristics of a population of PsA and to extract any disparities between men and women. Methods: A total of 132 patients in the rheumatology department of Amiens University Hospital with a confirmed diagnosis of PsA according to the CASPAR criteria were included over a period of 4 months. All data were collected retrospectively in this observational and single-center study. Results: The sex ratio was 1 and the average age at inclusion was 54.9 years. Peripheral PsA was the predominant clinical form. Axial PsA represented 12.1% of cases. Enthesitis was noted in 52.3% of cases while dactylitis was identified in 29.5% of cases. Moreover, 12.1% had a joint symptomatology preceding the appearance of cutaneous signs. HLA-B*27 positivity was found in 33.3% of cases. Chronic hyperuricemia accounted for 10% of our population. Sacroiliitis was observed in 41% of cases. The disparities between men and women are multiple and consistent with the literature: Polyarticular form, enthesitis, obesity, more intensive prescription of s-DMARDs, and b-DMARDs are more associated with the female population. Oligoarticular form, psoriatic nail dystrophy, radiological axial involvement, and chronic hyperuricemia are more encountered in the male population. Conclusions: Our study found a very heterogeneous disease, with marked differences between men and women. Peripheral PsA remains predominant but the search for associated axial involvement, which is probably underestimated, seems essential. Relevance for Patients: This work studied the main characteristics of patients with PsA followed in real life, in a regional university reference center. We have highlighted a very heterogeneous disease as well as some gender disparities, not well described in the literature, which should be taken into account in order to optimize therapeutic management.

Dual-task versus single-task gait rehabilitation after stroke: the protocol of the cognitive-motor synergy multicenter, randomized, controlled superiority trial (SYNCOMOT).

BACKGROUND: Gait disorders and cognitive impairments are prime causes of disability and institutionalization after stroke. We hypothesized that relative to single-task gait rehabilitation (ST GR), cognitive-motor dual-task (DT) GR initiated at the subacute stage would be associated with greater improvements in ST and DT gait, balance, and cognitive performance, personal autonomy, disability, and quality of life in the short, medium and long terms after stroke. METHODS: This multicenter (n=12), two-arm, parallel-group, randomized (1:1), controlled clinical study is a superiority trial. With p<0.05, a power of 80%, and an expected loss to follow-up rate of 10%, the inclusion of 300 patients will be required to evidence a 0.1-m.s-1 gain in gait speed. Trial will include adult patients (18-90 years) in the subacute phase (0 to 6 months after a hemispheric stroke) and who are able to walk for 10 m (with or without a technical aid). Registered physiotherapists will deliver a standardized GR program (30 min three times a week, for 4 weeks). The GR program will comprise various DTs (phasic, executive function, praxis, memory, and spatial cognition tasks during gait) in the DT (experimental) group and gait exercises only in the ST (control) group. The primary outcome measure is gait speed 6 months after inclusion. The secondary outcomes are post-stroke impairments (National Institutes of Health Stroke Scale and the motor part of the Fugl-Meyer Assessment of the lower extremity), gait speed (10-m walking test), mobility and dynamic balance (timed up-and-go test), ST and DT cognitive function (the French adaptation of the harmonization standards neuropsychological battery, and eight cognitive-motor DTs), personal autonomy (functional independence measure), restrictions in participation (structured interview and the modified Rankin score), and health-related quality of life (on a visual analog scale). These variables will be assessed immediately after the end of the protocol (probing the short-term effect), 1 month thereafter (the medium-term effect), and 5 months thereafter (the long-term effect). DISCUSSION: The main study limitation is the open design. The trial will focus on a new GR program applicable at various stages after stroke and during neurological disease. TRIAL REGISTRATION: NCT03009773 . Registered on January 4, 2017.

Comparison of Rheumatoid Arthritis Patients' 2-Year Infliximab, Abatacept, and Tocilizumab Persistence Rates.

Background: Drug persistence reflects an agent's efficacy and safety in routine practice. This study was undertaken to compare the 2-year persistence rates of three biologic disease-modifying antirheumatic drugs (bDMARDs) used to treat rheumatoid arthritis (RA) and to describe their efficacy and safety profiles. Methods: This retrospective, observational, single-center study included RA patients who had received at least one intravenous dose of infliximab, abatacept, and/or tocilizumab. Two-year drug persistence was estimated using the Kaplan−Meier method. Efficacy profiles were assessed as changes of Disease-Activity Score-28 (DAS28)-based EULAR-criteria responses. Results: The infliximab, abatacept, and tocilizumab groups included 40, 72, and 93 patients, respectively. Their respective 2-year persistence rates were similar: 55.0%, 45.8%, and 62.4%. Tocilizumab recipients benefited from greater improvement than those given infliximab (p = 0.0005) or abatacept (p < 0.0001). For all groups combined, 93.1% of patients obtained good or moderate EULAR responses. Conclusions: Even if this retrospective work includes different biases (lack of data, recruitment bias, etc.), it highlights that the 2-year persistence rates for infliximab, abatacept, and tocilizumab in daily practice did not differ significantly, thereby confirming the long-term efficacies of these three bDMARDs. However, tocilizumab was associated with more significant DAS28 improvement at 2 years than infliximab and abatacept.

The Masquelet technique: Current concepts, animal models, and perspectives.

Bone reconstruction within a critical-sized defect remains a real challenge in orthopedic surgery. The Masquelet technique is an innovative, two-step therapeutic approach for bone reconstruction in which the placement of a poly (methylmethacrylate) spacer into the bone defect induces the neo-formation of a tissue called "induced membrane." This surgical technique has many advantages and is often preferred to a vascularized bone flap or Ilizarov's technique. Although the Masquelet technique has achieved high clinical success rates since its development by Alain-Charles Masquelet in the early 2000s, very little is known about how the process works, and few animal models of membrane induction have been developed. Our successful use of this technique in the clinic and our interest in the mechanisms of tissue regeneration (notably bone regeneration) prompted us to develop a surgical model of the Masquelet technique in rats. Here, we provide a comprehensive review of the literature on animal models of membrane induction, encompassing the defect site, the surgical procedure, and the histologic and osteogenic properties of the induced membrane. We also discuss the advantages and disadvantages of those models to facilitate efforts in characterizing the complex biological mechanisms that underlie membrane induction.

Complex Coding and Regulatory Polymorphisms in a Restriction Factor Determine the Susceptibility of Drosophila to Viral Infection.

It is common to find that major-effect genes are an important cause of variation in susceptibility to infection. Here we have characterized natural variation in a gene called pastrel that explains over half of the genetic variance in susceptibility to the Drosophila C virus (DCV) in populations of Drosophila melanogaster We found extensive allelic heterogeneity, with a sample of seven alleles of pastrel from around the world conferring four phenotypically distinct levels of resistance. By modifying candidate SNPs in transgenic flies, we show that the largest effect is caused by an amino acid polymorphism that arose when an ancestral threonine was mutated to alanine, greatly increasing resistance to DCV. Overexpression of the ancestral, susceptible allele provides strong protection against DCV; indicating that this mutation acted to improve an existing restriction factor. The pastrel locus also contains complex structural variation and cis-regulatory polymorphisms altering gene expression. We find that higher expression of pastrel is associated with increased survival after DCV infection. To understand why this variation is maintained in populations, we investigated genetic variation surrounding the amino acid variant that is causing flies to be resistant. We found no evidence of natural selection causing either recent changes in allele frequency or geographical variation in frequency, suggesting that this is an old polymorphism that has been maintained at a stable frequency. Overall, our data demonstrate how complex genetic variation at a single locus can control susceptibility to a virulent natural pathogen.

Dengue virus induces mitochondrial elongation through impairment of Drp1-triggered mitochondrial fission.

Mitochondria are highly dynamic organelles that undergo continuous cycles of fission and fusion to maintain essential cellular functions. An imbalance between these two processes can result in many pathophysiological outcomes. Dengue virus (DENV) interacts with cellular organelles, including mitochondria, to successfully replicate in cells. This study used live-cell imaging and found an increase in mitochondrial length and respiration during DENV infection. The level of mitochondrial fission protein, Dynamin-related protein 1 (Drp1), was decreased on mitochondria during DENV infection, as well as Drp1 phosphorylated on serine 616, which is important for mitochondrial fission. DENV proteins NS4b and NS3 were also associated with subcellular fractions of mitochondria. Induction of fission through uncoupling of mitochondria or overexpression of Drp1 wild-type and Drp1 with a phosphomimetic mutation (S616D) significantly reduced viral replication. These results demonstrate that DENV infection causes an imbalance in mitochondrial dynamics by inhibiting Drp1-triggered mitochondrial fission, which promotes viral replication.

18F-Choline Positron Emission Tomography/Computed Tomography and Multiparametric Magnetic Resonance Imaging for the Detection of Early Local Recurrence of Prostate Cancer Initially Treated by Radiation Therapy: Comparison With Systematic 3-Dimensional Transperineal Mapping Biopsy.

PURPOSE: To compare the diagnostic performance of 18F-fluorocholine positron emission tomography/computed tomography (FCH-PET/CT), multiparametric prostate magnetic resonance imaging (mpMRI), and a combination of both techniques for the detection of local recurrence of prostate cancer initially treated by radiation therapy. METHODS AND MATERIALS: This was a retrospective, single-institution study of 32 patients with suspected prostate cancer recurrence who underwent both FCH-PET/CT and 3T mpMRI within 3 months of one another for the detection of recurrence. All included patients had to be cleared for metastatic recurrence. The reference procedure was systematic 3-dimensional (3D)-transperineal prostate biopsy for the final assessment of local recurrence. Both imaging modalities were analyzed by 2 experienced readers blinded to clinical data. The analysis was made per-patient and per-segment using a 4-segment model. RESULTS: The median prostate-specific antigen value at the time of imaging was 2.92 ng/mL. The mean prostate-specific antigen doubling time was 14 months. Of the 32 patients, 31 had a positive 3D-transperineal mapping biopsy for a local relapse. On a patient-based analysis, the detection rate was 71% (22 of 31) for mpMRI and 74% (23 of 31) for FCH-PET/CT. On a segment-based analysis, the sensitivity and specificity were, respectively, 32% and 87% for mpMRI, 34% and 87% for FCH-PET/CT, and 43% and 83% for the combined analysis of both techniques. Accuracy was 64%, 65%, and 66%, respectively. The interobserver agreement was κ = 0.92 for FCH-PET/CT and κ = 0.74 for mpMRI. CONCLUSIONS: Both mpMRI and FCH-PET/CT show limited sensitivity but good specificity for the detection of local cancer recurrence after radiation therapy, when compared with 3D-transperineal mapping biopsy. Prostate biopsy still seems to be mandatory to diagnose local relapse and select patients who could benefit from local salvage therapy.