Infant's triangular communication in "two for one" versus "two against one" family triangles: Case illustrations

Infants use their social competence very early to communicate not only in dyads but also in triads, in particular in the triangle they form with their mother and father. The development of this triangular communication is largely shaped by the ways the parents support or undermine each other in relation to their child. Whereas triangular communication is facilitated in "two for one" alliances, it is recruited in the service of regulating the parents' conflicts in "two against one" coalitions. These processes are manifest in toddlerhood and may be traced back to the coparenting alliance in formation during pregnancy.

The NLRP3 inflammasome in health and disease: the good, the bad and the ugly.

While interleukin (IL)-1β plays an important role in combating the invading pathogen as part of the innate immune response, its dysregulation is responsible for a number of autoinflammatory disorders. Large IL-1β activating platforms, known as inflammasomes, can assemble in response to the detection of endogenous host and pathogen-associated danger molecules. Formation of these protein complexes results in the autocatalysis and activation of caspase-1, which processes precursor IL-1β into its secreted biologically active form. Inflammasome and IL-1β activity is required to efficiently control viral, bacterial and fungal pathogen infections. Conversely, excess IL-1β activity contributes to human disease, and its inhibition has proved therapeutically beneficial in the treatment of a spectrum of serious, yet relatively rare, heritable inflammasomopathies. Recently, inflammasome function has been implicated in more common human conditions, such as gout, type II diabetes and cancer. This raises the possibility that anti-IL-1 therapeutics may have broader applications than anticipated previously, and may be utilized across diverse disease states that are linked insidiously through unwanted or heightened inflammasome activity.

Variations régionales du recours aux soins: quelques problèmes méthodologiques. [Regional variations in health services: various methodological problems].

Many studies show strong variation of health consumption between regions, suggesting that theses variations are related to the uncertainty of medical practice or to other factors related to health services or patients attitude. However the statistical interpretation of these variations is far from easy: apart from usual and specific information bias, there are statistical problems when observing incidence of events like health care consumption: it is in fact a rare event, which is observed within small population, and among regions with unequal number of person. Therefore, most of the variation reported might be well explained by a purely statistical phenomenon. This paper presents some aspects of this variability for three common indicators of variation, and suggest the use of ad hoc simulation to get statistical criteria.

Cell-cell communication in the biocontrol strain Pseudomonas fluorescens CHA0

Summary Pseudomonas fluorescens CHAO is a soil bacterium which was isolated near Morens (Switzerland) and which protects plants from root-pathogenic fungi. This protection is due to extracellular secondary metabolites whose synthesis is regulated by the two-component system GacS/GacA in strain CHAO. Extracellular signals of bacterial origin activate this regulatory system. These signals are different from N-acyl-homoserine lactones, are extracted by dichloromethane and appear to have a low molecular weight. Preliminary evidence was obtained from a small molecule m/z 278 produced by strain CHAO. Similar signals capable of activating GacS/GacA-dependent regulation in strain CHAO were found in a large number of different Gram-negative bacteria. Once activated by signal(s), the sensor GacS is assumed to phosphorylate the response regulator GacA, which positively influences a regulatory cascade, resulting in the synthesis of secondary metabolites. This cascade includes three GacA-controlled small regulatory RNAs and two translational repressor proteins. The regulatory RNAs titrate the repressor proteins; this allows translation of target genes and the synthesis of exoenzymes and secondary metabolites such as antibiotics and hydrogen cyanide. A GFP-based sensor for signal detection was constructed in strain CHAO by fusing the gfp reporter gene to the rsmZ small RNA gene. CHAO mutants defective for signal production were isolated following transposon insertion mutagenesis. In one class of mutants obtained, the gacS gene was inactivated, indicating that GacS/GacA positively controls signal production. In a second class, the thiC gene required for thiamine (vitamin B1) biosynthesis was disrupted. Addition of excess (> 10E-6 M) thiamine to the medium restored signal production. By contrast, when the thiamine concentration was just sufficient to allow normal growth, no production of signal(s) was observed. The mechanism by which thiamine activates signal production remains to be elucidated. Résumé Pseudomonas fluorescens CHAO est une bactérie du sol, isolée près de Morens (Suisse), qui a la capacité de protéger les plantes contre des champignons pathogènes de la racine. Cette protection provient de métabolites secondaires excrétés par la bactérie, dont la synthèse est régulée par le système à deux composants GacS/GacA. Des signaux extracellulaires d'origine bactérienne activent ce système de régulation. Ces signaux, différents des N-acyl¬homosérines lactones, sont extraits par le dichlorométhane et semblent avoir une petite masse moléculaire. Une molécule (masse m/z 278) a été mise en évidence par des expériences préliminaires chez la souche CHAO. Des signaux similaires, capables d'activer la régulation dépendante de GacS/GacA chez la souche CHAO, ont été trouvés chez un grand nombre de bactéries à Gram négative. Une fois activé par le(s) signal(aux), le senseur GacS est supposé phosphoryler le régulateur de réponse GacA, qui influence positivement la cascade de régulation menant à la synthèse des métabolites secondaires. Cette cascade inclut trois petits ARNs régulateurs contrôlés par GacA et deux protéines répresseurs de la traduction. Les ARNs régulateurs titrent les protéines répresseurs, ce qui permet la traduction des gènes cibles et la synthèse d'exoenzymes et de métabolites secondaires tel les antibiotiques et le cyanure d'hydrogène. Un senseur basé sur la GFP pour la détection de signaux a été construit dans la souche CHAO en fusionnant le gène rapporteur gfp au gène de petit ARN rsmZ. Des mutants de CHAO déficients pour la production de signaux ont été isolés au moyen d'une mutagenèse par insertion de transposon. Chez une classe de mutants obtenus, le gène gacS a été inactivé, indiquant que GacS/GacA contrôle positivement la production de signaux. Dans une seconde classe, le gène thiC nécessaire à la biosynthèse de thiamine (vitamine B1) a été interrompu. L'addition en excès (> 10E-6 M) de thiamine au milieu restaure la production de signaux. A l'opposé, quand la concentration de thiamine est juste suffisante pour permettre une croissance normale, aucune production de signaux n'a été observée. Le mécanisme par lequel la thiamine active la production de signaux reste à élucider.

Rapid Improvement in Health-Related Quality of Life in Gouty Arthritis Patients Treated with Canakinumab (ACZ885) Compared to Triamcinolone Acetonide

Background: Gout patients initiating urate lowering therapy have an increased risk of flares. Inflammation in gouty arthritis is induced by interleukin (IL)-1b. Canakinumab inhibits IL-1b effectively in clinical studies. This study compared different doses of canakinumab vs colchicine in preventing flares in gout patients initiating allopurinol therapy.Methods: In this 24 wk double blind study, gout patients (20-79 years) initiating allopurinol were randomized (1:1:1:1:1:1:2) to canakinumab s.c. single doses of 25, 50, 100, 200, 300 mg, or 150mg divided in doses every 4 wks (50þ50þ25þ25mg [q4wk]) or colchicine 0.5mg p.o. daily for 16 wks. Primary outcome was to determine the canakinumab dose giving comparable efficacy to colchicine with respect to number of flares occurring during first 16 wks. Secondary outcomes included number of patients with flares and C-reactive protein (CRP) levels during the first 16 wks.Results: 432 patients were randomized and 391 (91%) completed the study. All canakinumab doses were better than colchicine in preventing flares and therefore, a canakinumab dose comparable to colchicine couldn't be determined. Based on a negative binomialmodel, all canakinumab groups, except 25 mg, reduced the flare rate ratio per patient significantly compared to colchicine group (rate ratio estimates 25mg 0.60, 50mg 0.34, 100mg 0.28, 200mg 0.37, 300mg 0.29, q4wk 0.38; p_0.05). Percentage of patients with flares was lower for all canakinumab groups (25mg 27.3%, 50mg 16.7%, 100mg 14.8%, 200mg 18.5%, 300mg 15.1%, q4wk 16.7%) compared to colchicine group (44.4%). All patients taking canakinumab were significantly less likely to experience at least one gout flare than patients taking colchicine (odds ratio range [0.22 - 0.47]; p_0.05 for all). Median baseline CRP levels were 2.86 mg/L for 25 mg, 3.42 mg/L for 50 mg, 1.76 mg/L for 100 mg, 3.66 mg/L for 200 mg, 3.21 mg/L for 300 mg, 3.23 mg/L for q4wk canakinumab groups and 2.69 mg/L for colchicine group. In all canakinumab groups with median CRP levels above the normal range at baseline, median levels declined within 15 days of treatment and were maintained at normal levels (ULN¼3 mg/L) throughout the 16 wk period. Adverse events (AEs) occurred in 52.7% (25 mg), 55.6% (50 mg), 51.9% (100 mg), 51.9% (200 mg), 54.7% (300 mg), 58.5% (q4wk) of patients on canakinumab vs 53.7% of patients on colchicine. Serious AEs (SAE) were reported in 2 (3.6%; 25 mg), 2 (3.7%, 50 mg), 3 (5.6%, 100 mg), 3 (5.6%, 200 mg), 3 (5.7%, 300 mg), 1 (1.9%, q4wk) patients on canakinumab and in 5 (4.6%) patients on colchicine. 1 fatal SAE (myocardial infarction, not related to study drug) occurred in colchicine group.Conclusions: In this randomized, double-blind active controlled study of flare prevention in gout patients initiating allopurinol therapy, treatment with canakinumab led to a statistically significant reduction in flares compared with colchicine and was well tolerated.Disclosure statement: U.A., A.B., G.K., D.R. and P.S. are employees of and have stock options or bold holdings with Novartis Pharma AG. E.M. is a principal investigator for Novartis Pharmaceuticals Corporation. E.N. has received consulting fees from Roche. N.S. has received research grants from Novartis Pharmaceuticals Corporation. A.S. has received consultancy fees from Novartis Pharma AG, Abbott, Bristol-Myers Squibb, Essex, Pfizer, MSD, Roche, UCB and Wyeth. All other authors have declared no conflicts of interest.