Ly6Chigh Monocytes Protect against Kidney Damage during Sepsis via a CX3CR1-Dependent Adhesion Mechanism

Monocytes have a crucial role in both proinflammatory and anti-inflammatory phenomena occurring during sepsis. Monocyte recruitment and activation are orchestrated by the chemokine receptors CX3CR1 and CCR2 and their cognate ligands. However, little is known about the roles of these cells and chemokines during the acute phase of inflammation in sepsis. Using intravital microscopy in a murine model of polymicrobial sepsis, we showed that inflammatory Ly6C^high monocytes infiltrated kidneys, exhibited altered motility, and adhered strongly to the renal vascular wall in a chemokine receptor CX3CR1-dependent manner. Adoptive transfer of Cx3cr1-proficient monocyte-enriched bone marrow cells into septic Cx3cr1-depleted mice prevented kidney damage and promoted mouse survival. Modulation of CX3CR1 activation in septic mice controlled monocyte adhesion, regulated proinflammatory and anti-inflammatory cytokine expression, and was associated with the extent of kidney lesions such that the number of lesions decreased when CX3CR1 activity increased. Consistent with these results, the pro-adhesive I249 CX3CR1 allele in humans was associated with a lower incidence of AKI in patients with sepsis. These data show that inflammatory monocytes have a protective effect during sepsis via a CX3CR1-dependent adhesion mechanism. This receptor might be a new therapeutic target for kidney injury during sepsis.     

Use of short-acting beta2-agonists during pregnancy and the risk of pregnancy-induced hypertension

BACKGROUND: The effect of inhaled short-acting beta(2)-agonists (SABAs) on pregnancy outcome, especially hypertensive complications, is not well documented. After the finding of a possible protective association of inhaled SABAs with pregnancy-induced hypertension (PIH) in a previous study, we decided to further investigate their effect on this condition. OBJECTIVE: We sought to determine the effect of inhaled SABA use during pregnancy on the risk of PIH (gestational hypertension, preeclampsia, or eclampsia) in asthmatic women. METHODS: Three of Quebec's administrative databases were linked to constitute a cohort of asthmatic women who had at least 1 delivery between 1990 and 2000. A nested case-control study was performed using up to 10 control subjects matched to each case patient for the year of conception and gestational age. Statistical analyses considered 22 confounders. RESULTS: The cohort was composed of 3505 asthmatic women who had a total of 4593 pregnancies. Three hundred two patients with PIH and 3013 control subjects were identified. Compared with nonuse, inhaled SABA use during pregnancy was significantly associated with a reduced risk of PIH (adjusted rate ratios: >0-3 doses/week, 0.62 (95% CI, 0.44-0.87); > 3-10 doses/week, 0.51 (95% CI, 0.34-0.79); and >10 doses/week, 0.48 (95% CI, 0.30-0.75)). CONCLUSIONS: To our knowledge, this is the first study reporting that inhaled SABA use during pregnancy is associated with a reduced risk of PIH. Potential explanations include pharmacologic and physiological effects or residual confounding. CLINICAL IMPLICATIONS: These results increase the evidence about the safety of inhaled SABAs in this population, although they should not undervalue the importance of maintaining good control of asthma symptoms.     

Control of sensorimotor variability by consequences

Studies of reaction-time distributions provide a useful quantitative approach to understand decision processes at the neural level and at the behavioral level. A strong relationship between the spread of latencies and the median is generally accepted even though there has been no attempt to disentangle experimentally these two parameters. Here we test the ability to independently control the median and the variability in reaction times. Reaction times were measured in human subjects instructed to make a discrimination between a target and a distractor in a 2AFC task. In a first experiment, saccadic latencies were measured. In a second experiment, we used manual response reaction times. Subjects were trained to produce four different reaction-time distributions. A reinforcing feedback was given depending on both the variability and the median of the latency distributions. When low variability was reinforced, the standard deviation (SD) of reaction-time distributions were reduced by a factor of two and when high variability was reinforced, the SD returned to baseline level. Our procedure independently affected the spread and the median of the distribution patterns. By fitting the latency distributions using the Reddi and Carpenter LATER model, we found that these effects could be simulated by changing the distribution of the noise affecting the decision process. Our results demonstrate that learned contingencies can affect reaction time variability and support the view that the so-called noise level in decision processes can undergo long-term changes.     

Fc alpha receptor I activation induces leukocyte recruitment and promotes aggravation of glomerulonephritis through the FcR gamma adaptor

Myeloid cells bear Fc receptors (FcR) that mediate inflammatory signaling through the ITAM-containing FcRgamma adaptor. They express FcRgamma-associated FcalphaRI, which modulate either activating or inhibitory signaling depending on the type of ligand interaction. The role of FcalphaRIgamma in disease progression remains unknown, notably in IgA nephropathy (IgAN), one of major causes of end-stage renal disease, in which large amounts of circulating IgA-immune complexes (IC) may mediate receptor activation. To analyze the involvement of FcalphaRI activation in glomerulonephritis (GN), we generated Tg mice expressing a mutated, signaling-incompetent, human FcalphaRI(R209L) that cannot associate with FcRgamma. Like FcalphaRI(wt)-Tg mice, they developed mesangial IgA deposits but not macrophage infiltration. FcalphaRI activation in FcalphaRI(wt), but not in FcalphaRI(R209L), Tg mice resulted in marked inflammation with severe proteinuria and leukocyte infiltration in spontaneous IgAN or anti-glomerular basement membrane Ab-induced GN models. Receptor triggering of syngenically transferred FcalphaRI(wt) Tg macrophages into non-Tg animals induced their recruitment into injured kidneys during GN development. FcalphaRI(wt) cross-linking on macrophages activated MAP kinases and production of TNF-alpha and MCP-1. Moreover, IgA-IC from IgAN patients activated FcalphaRI and induced TNF-alpha production. Thus, FcalphaRI activation mediates GN progression by initiating a cytokine/chemokine cascade that promotes leukocyte recruitment and kidney damage.     

Rapid antidepressant effect of S-ketamine in schizophrenia

Rapid anti-suicidal and antidepressant effects of ketamine have repeatedly been confirmed in unipolar and bipolar depression. Although meaningful antidepressant efficacy of ketamine has also been shown in depressed patients with a history of psychotic symptoms, its administration in psychotic disorders has largely been neglected due to its potential to exacerbate dissociative or psychotic symptoms. Presenting a case of a young female inpatient suffering from schizophrenia with a severe post-psychotic depression, we demonstrate a robust anti-suicidal and antidepressant effect of S-ketamine infusions administered thrice weekly for 3 weeks in total. Importantly, no relevant psychotic or dissociative symptoms occurred during the whole augmentation treatment period leading to a sustained remission of depressive symptoms and suicidality. Our safe and effective experience with intravenous S-ketamine might encourage researchers and clinicians to widen its administration range beyond the diagnosis of depression to enrich the current knowledge of ketamine effects in psychotic disorders.     

What Affects Attendance and Engagement in a Parenting Program in South Africa?

Parenting programs are a promising approach to improving family well-being. For families to benefit, programs need to be able to engage families actively in the interventions. Studies in high-income countries show varying results regarding whether more disadvantaged families are equally engaged in parenting interventions. In low- and middle-income countries (LMICs), almost nothing is known about the patterns of participation in parent training. This paper examines group session attendance and engagement data from 270 high-risk families enrolled in the intervention arm of a cluster-randomized controlled trial in South Africa. The trial evaluated a 14-week parenting intervention aiming to improve parenting and reduce maltreatment by caregivers. The intervention was delivered in 20 groups, one per study cluster, with 8 to 16 families each. Overall, caregivers attended 50% of group sessions and children, 64%. Using linear multilevel models with Kenward-Roger correction, we examined child and caregiver baseline characteristics as predictors of their attendance and engagement in the group sessions. Variables examined as predictors included measures of economic, educational, and social and health barriers and resources, as well as family problems and sociodemographic characteristics. Overall, the study yielded no evidence that the level of stressors, such as poverty, was related to attendance and engagement. Notably, children from overcrowded households attended on average 1.2 more sessions than their peers. Our findings suggest it is possible to engage highly disadvantaged families that face multiple challenges in parenting interventions in LMICs. However, some barriers such as scheduling, and alcohol and substance use, remain relevant.     

The role of CT-scan assessment of muscle mass in predicting postoperative surgical complications after renal transplantation

International Urology and Nephrology - Despite a high rate of undernutrition in renal transplantation recipients, prognostic value of sarcopenia remains unclear. We evaluated the relation between...