TLR and RLR Signaling Are Reprogrammed in Opposite Directions after Detection of Viral Infection.

Innate immune recognition of RNA is key for the initiation of immunity in response to viral infection. Although the factors controlling the detection of viral RNA by innate immune receptors in host cells are increasingly well understood, little is known about the dynamic changes in signaling after the initial triggering of these receptors. In this study, we report that preconditioning with the synthetic dsRNA polyinosinic-polycytidylic acid [poly(I:C)], a mimetic of viral RNA, rapidly reprograms murine APCs by simultaneously augmenting sensitivity of endosomal TLRs and inhibiting activation of RIG-I-like receptors (RLRs) in an IFN-ß-dependent manner. These changes in receptor sensitivity were also seen in vivo after treatment of mice with poly(I:C). Mechanistically, the increased sensitivity of the TLR pathway was associated with elevated MAPK and NF-κB activity. The RLR response was inhibited downstream of TANK-binding kinase-1, resulting in decreased IFN regulatory factor 3 phosphorylation. Reprogramming of pattern-recognition receptor signaling also occurred after viral infection, because infection of host cells with Sendai virus or their exposure to supernatant from virus-infected cells induced the same changes in TLR and RLR sensitivity as poly(I:C). Thus, innate recognition of viral infection critically modifies responses to pattern-recognition receptor stimulation. These dynamic adaptations to infection may reinforce antiviral immunity and at the same time serve to limit pathological inflammation.

Genome-wide analyses of borderline personality features.

The heritability of borderline personality (BP) features has been established in multiple twin and family studies. Using data from the borderline subscale of the Personality Assessment Inventory Borderline Features Scale (PAI-BOR) collected in two Dutch cohorts (N=7125), the Netherlands Twin Register and The Netherlands Study of Depression and Anxiety, we show that heritability of the PAI-BOR total score using genome-wide single-nucleotide polymorphism (SNPs) is estimated at 23%, and that the genetic variance is substantially higher in affect instability items compared with the other three subscales of the PAI-BOR (42.7% vs non-significant estimates for self-harm, negative relations and identity problems). We present results from a first genome-wide association study of BP features, which shows a promising signal on chromosome 5 corresponding to SERINC5, a protein involved in myelination. Reduced myelination has been suggested as possibly having a role in the development of psychiatric disorders characterized by lack of social interaction. The signal was confirmed in a third independent Dutch cohort drawn from the Erasmus Rucphen Family study (N=1301). Our analyses were complemented by investigating the heterogeneity that was implied by the differences in genetic variance components in the four subscales of the PAI-BOR. These analyses show that the association of SNPs tagging SERINC5 differs substantially across the 24 items of the PAI-BOR. Further, using reverse regression we showed that the effects were present only in subjects with higher scores on the PAI-BOR. Taken together, these results suggest that future genome-wide analyses can benefit substantially by taking into account the phenotypic and genetic heterogeneity of BP features.

Influence of smoking and obesity on treatment response in patients with axial spondyloarthritis: a systematic literature review.

To assess whether smoking and obesity are predictors of poor treatment response in patients with axial spondyloarthritis (axSpA). A systematic literature review was performed by searching in MEDLINE and EMBASE up to June 2019 with a strategy based on the PICO approach: Population: patients with axSpA; Intervention or exposure: smoking or obesity; Comparison: non-smokers (for smoking) and normal-weight individuals (for obesity); and Outcome: any response criteria currently validated for axSpA. The 2009 Oxford Centre for Evidence-based Medicine levels were used for assessing the studies quality. Out of 1873 references retrieved, 46 studies were selected for full-text review and 12 for data extraction: six stratified patients by smoking and six by obesity. All were longitudinal observational studies, except one, which was cross-sectional. Overall, these studies included 5291 patients (3917 for smoking and 1333 for obesity), and all these patients were on anti-tumor necrosis factor (anti-TNF) therapy. The quality of evidence was graded as level 2b except that from the cross-sectional study which was graded level 4. For smoking, the evidence found is inconsistent: two studies finding negative effects in response to anti-TNF while the other four found no differences in clinical response to this therapy. Regarding obesity, the evidence is more consistent: five of the six studies describing a negative influence in response to anti-TNF. According to the scientific evidence in patients with axSpA, obesity is associated with a more unsatisfactory response to anti-TNF therapy. A poorer response in smokers has yet to be demonstrated. Key Points • Identifying predictors of treatment response in axSpA, especially those that are modifiable, is relevant. • Obesity increases the risk of poorer response to anti-TNF agents in patients with axSpA. • Scientific evidence for smoking habit as a predictor of treatment response in axSpA is inconclusive.

Reprogramming of TLR7 signaling enhances antitumor NK and cytotoxic T cell responses.

Toll-like receptor (TLR) 7 agonists are effective in topical application for the immunotherapy of skin cancers, but their performance for the systemic treatment of solid tumors is limited by the development of TLR tolerance. In this study, we describe a novel strategy to overcome TLR tolerance and enhance TLR7-dependent antitumor immune responses through reprogramming of TLR signaling pathways. The sensitivity of TLR7 signaling in dendritic cells (DC) was increased by prior stimulation with the dsRNA poly(I:C) that mimics virally induced immune activation. Timing of the stimulations was important, as sequential stimulation with poly(I:C) and the TLR7 agonist R848 interspaced by 24 h induced higher MAPK and NFkB signaling in DC than the simultaneous application of the same ligands. DC activated by sequential poly(I:C)/R848 stimulation efficiently induced Th1 differentiation and primed NK-cell and cytotoxic T-cell responses. We have developed a treatment regimen taking advantage of TLR7 reprogram-ming that cured over 80% of large immunogenic tumors in mice by the action of NK cells and cytotoxic T cells. These results have direct implications for the use of these clinically established ligands in the immunotherapy of cancer.

Gaucher disease: accurate identification of asymptomatic French-Canadian carrier using nonlabeled authentic sphingolipid substrate N-palmitoyl dihydroglucocerebroside.

Gaucher disease is an autosomal recessive sphingolipidosis associated with deficient glucocerebroside beta-glucosidase activity. It is a panethnic metabolic disorder, but the carrier frequency is particularly high among Ashkenazi Jews (estimated between 1:12-1:25). In order to establish a reliable and convenient biochemical assay method for differentiating asymptomatic Gaucher carriers from normal individuals, glucocerebroside beta-glucosidase activity was determined in peripheral blood lymphocytes and cultured skin fibroblasts of 11 Gaucher obligate heterozygotes using the authentic nonlabeled sphingolipid substrate N-palmitoyl dihydroglucocerebroside and the artificial fluorogenic substrate 4-methylumbelliferyl-beta-D-glucopyranoside (4MUGP). The level of lymphocyte beta-glucosidase activity on the glucocerebroside substrate was observed to range from 42-65% of that of the control mean, and there was no overlap of enzyme activity between the Gaucher heterozygotes and controls. However, when the artificial fluorogenic substrate 4MUGP was used, the level of beta-glucosidase activity in 2 of the Gaucher obligate heterozygotes was noted to overlap with that of the control individuals. Contrary to findings in the lymphocytes, cultured skin fibroblasts appear to be a reliable enzyme source for Gaucher carrier detection even when the artificial fluorogenic 4MUGP substrate was used, as the level of beta-glucosidase activity in all of the Gaucher obligate heterozygotes tested was intermediate and distinctly separated from that of the control persons. Using the lymphocyte glucocerebroside beta-glucosidase assay and fibroblast 4MUGP beta-glucosidase assay methods, we identified the carrier status in 3 other relatives and ruled it out in 4 others. These data suggest that nonlabeled glucocerebroside is a reliable and highly specific substrate for either lymphocyte or fibroblast beta-glucosidase activity assay in identifying asymptomatic Gaucher carriers. Use of the 4MUGP substrate for differentiating Gaucher heterozygotes from control persons, on the other hand, should be restricted to the fibroblast enzyme assay method, as considerable overlap of enzyme activity was noted in lymphocytes.

Rate of mortality for elderly patients after fracture of the hip in the 1980's.

At an average follow-up of 2.1 years, we reviewed the records of 241 patients who had had a fracture of the hip. The average age of the patients was 75.4 years. The rate of mortality one year after the fracture was 21.6 per cent for the total group, 8.0 per cent for the low-risk group, and 49.4 per cent for the high-risk group. The standard mortality ratio was six times higher for the high-risk group than for the general population (individuals who did not have a fracture), matched for age. It was highest for patients who were less than seventy years old and lowest for those who were older than eighty. However, in the second year after the fracture, the standard mortality ratio approached unity--that is, the rate of mortality approached that of the general population. The results suggest that there is an inverse relationship between mortality and advanced age and that the impact of a fracture of the hip on mortality is seen primarily in the first year after injury.

The abnormal lateral patellofemoral angle: a diagnostic roentgenographic sign of recurrent patellar subluxation.

On roentgenograms made with the patient supine, the knees flexed 20 to 30 degrees, the x-ray tube between the ankles, and the cassette held proximal to the knees and perpendicular to the x-ray beam, it was found that a line between the femoral condyles and a line between the margins of the lateral facet of the patella formed the lateral patellofemoral angle, an angle that was of diagnostic value in patients with subluxation of the patella. In 100 clinically normal patients, these lines were parallel in three and formed an angle open laterally in ninety-seven. In thirty patients with subluxation of the patella, the lines were parallel in twenty-four and formed an angle open medially in six. In 100 patients with chondromalacia of the patella, however, the roentgenographic study was of no diagnostic value since the lines were parallel in ten and formed an angle open laterally in ninety.

Locked facets with fracture of the neural arch of the axis.

This report describes a rare variant represented by the association of locked facets at C2-3 with a fracture of the neural arch of the axis. Fracture of the neural arch of the axis is a broad term including the Hangman fracture, traumatic spondylolisthesis of the axis, fractures of the arch of the axis, or the more recently described fractures of the ring of the axis.

Fractures of the ring of the axis. A classification based on the analysis of 131 cases.

The retrospective analysis of 131 patients suffering from a fracture of the ring of the axis is reported. The injury was classified into three types according to radiological displacement and stability. Associated injuries and neurological deficit are discussed and a theory of pathogenesis presented. Guidelines for the management of each type of fracture are proposed.

[Idiopathic segmental infarct of the omentum. Differential diagnosis in an obese patient]. / Infarctus segmentaire idiopathique du grand épiploon. Savoir y penser chez un patient obèse.

OBJECTIVE: Infarction of the greater omentum is a rare etiology of acute abdominal pain. The differential diagnosis, especially with appendicitis, is difficult to establish. CASE REPORT: A 29 years-old male presented with acute abdominal pain. He underwent a laparoscopic resection on the 5th hospital day because of persistant pain despite conservative management. Histopathological examination confirmed the diagnosis of omental infarction. DISCUSSION: Primary segmental necrosis of the omentum is a rare entity. Obesity and cardiovascular diseases are considered predisposing conditions. The infarctions tend to occur in the right side of the omentum. Abdominal pain is predominant in opposition to the patient's good general condition. Laboratory results are usually nonspecific. Abdominal ultrasound may show a solid, ovoid, hyperechoic lesion. CT-scan may depict a fatty oval-shaped mass below the right anterolateral parietal wall associated with a thickening of the anterior parietal peritoneum. CONCLUSION: The correct diagnosis of omental infarction is important to establish preoperatively in acute abdominal pain, as in uneventful courses surgery can be avoided.

[A study of the tensile strength of cruciate ligaments with regard to the possibilities of prosthetic replacement (author's transl)]. / Etude des propriétés mécaniques des ligaments croisés en vue de leur remplacement prothétique.

Recent clinical and experimental results in the prosthetic replacement of the anterior cruciate ligament are minimal and this fact has incited us to search for additional fundamental characteristics of natural and synthetic ligaments. The dissection of over 30 human knees (5 fresh and 27 embalmed specimens), of 50 dog knees and of 20 cat knees showed that the posterior cruciate ligament was longer and of bigger size than the anterior cruciate ligament. In dogs, the anatomo-radiological study showed a lenghtening of 14,4 p. 100 for the anterior cruciate and of 10,5 p. 1u0 for the posterior cruciate ligament in the various goniometric positions. Traction with the Instron apparatus using whole knee with preserved bony attachments revealed an elastic resistance (yield point) of the ligament of about 50 kg, 60 kg and 30 kg (for human, dog and cat respectively) with elastic elongation (at the yield stress) of 25 p. 100, 35 p. 100 and 45 p. 100 (respectively). Trials on the polyethylene prosthetic ligament used at the present time for replacement of cruciate ligaments in humans showed an elastic resistance of only 16 kg with an elasticity of only 1,4 p. 100. The major differences between the physical properties of the artificial and natural ligaments that we have studied in experimental conditions incite our serious doubt as to the value for the practical use of such a prosthesis and provoque strongly the necessity of search for alternative synthetic or other material more suitable for the task in question.

[Mental illness : a challenge for our collective consciousness.]. / La maladie mentale : un défi à notre conscience collective.

In this article, the author, an actor and a privileged observer of psychiatry in Quebec over the past twenty-five years, outlines the development of that area. He describes the events before 1962, the after effects of the Bedard Commission and the influence of the Castonguay-Nepveu Commission on psychiatric services. Then, he analyses the growth of those services from the angle of institutionaksation, desinstitutionalisation, research and community approach. He queries the ideological theories, the bio-psychosocial approach and speaks of the patients' role in the defense of their rights, and of their families. He ends by proposing ways to improve the actual services.

Gradient Boosting as a SNP Filter: an Evaluation Using Simulated and Hair Morphology Data.

Typically, genome-wide association studies consist of regressing the phenotype on each SNP separately using an additive genetic model. Although statistical models for recessive, dominant, SNP-SNP, or SNP-environment interactions exist, the testing burden makes an evaluation of all possible effects impractical for genome-wide data. We advocate a two-step approach where the first step consists of a filter that is sensitive to different types of SNP main and interactions effects. The aim is to substantially reduce the number of SNPs such that more specific modeling becomes feasible in a second step. We provide an evaluation of a statistical learning method called "gradient boosting machine" (GBM) that can be used as a filter. GBM does not require an a priori specification of a genetic model, and permits inclusion of large numbers of covariates. GBM can therefore be used to explore multiple GxE interactions, which would not be feasible within the parametric framework used in GWAS. We show in a simulation that GBM performs well even under conditions favorable to the standard additive regression model commonly used in GWAS, and is sensitive to the detection of interaction effects even if one of the interacting variables has a zero main effect. The latter would not be detected in GWAS. Our evaluation is accompanied by an analysis of empirical data concerning hair morphology. We estimate the phenotypic variance explained by increasing numbers of highest ranked SNPs, and show that it is sufficient to select 10K-20K SNPs in the first step of a two-step approach.

Systemic cancer therapy with a small molecule agonist of toll-like receptor 7 can be improved by circumventing TLR tolerance.

Topical application of small molecule Toll-like receptor 7 (TLR7) agonists is highly effective for the treatment of skin tumors, whereas their systemic application has been largely unsuccessful for cancer therapy. One reason may be that repeated systemic application of TLR ligands can induce a state of immune unresponsiveness, termed TLR tolerance. We show here that a single injection of the TLR7 agonist R848 in mice induces a short period of increased response to TLR stimulation followed by a state of hyporesponsiveness lasting several days. This state is characterized by inhibited secretion of the key cytokines interleukin (IL)-12p70 and IL-6 as well as by a block in IFN-α production. We show for the first time that at the cellular level, TLR7 tolerance occurs in both plasmacytoid and myeloid dendritic cells, two cell populations that play a critical role in the initiation and amplification of antitumor immune responses. We further show that TLR7 tolerance in plasmacytoid dendritic cells is accompanied by downregulation of the adaptor protein IL-1 receptor-associated kinase 1. On the basis of these findings, we have designed a novel strategy for the treatment of tumors by using cycles of repeated R848 injections separated by treatment-free intervals. We show in CT26 tumor-bearing mice that this protocol circumvents TLR7 tolerance and improves the efficacy of cancer immunotherapy.