Nonredundant protective properties of FPR2/ALX in polymicrobial murine sepsis

Sepsis is characterized by overlapping phases of excessive inflammation temporally aligned with an immunosuppressed state, defining a complex clinical scenario that explains the lack of successful therapeutic options. Here we tested whether the formyl-peptide receptor 2/3 (Fpr2/3)—ortholog to human FPR2/ALX (receptor for lipoxin A4)—exerted regulatory and organ-protective functions in experimental sepsis. Coecal ligature and puncture was performed to obtain nonlethal polymicrobial sepsis, with animals receiving antibiotics and analgesics. Clinical symptoms, temperature, and heart function were monitored up to 24 h. Peritoneal lavage and plasma samples were analyzed for proinflammatory and proresolving markers of inflammation and organ dysfunction. Compared with wild-type mice, Fpr2/3^−/− animals exhibited exacerbation of disease severity, including hypothermia and cardiac dysfunction. This scenario was paralleled by higher levels of cytokines [CXCL1 (CXC receptor ligand 1), CCL2 (CC receptor ligand 2), and TNFα] as quantified in cell-free biological fluids. Reduced monocyte recruitment in peritoneal lavages of Fpr2/3^−/− animals was reflected by a higher granulocyte/monocyte ratio. Monitoring Fpr2/3^−/− gene promoter activity with a GFP proxy marker revealed an over threefold increase in granulocyte and monocyte signals at 24 h post-coecal ligature and puncture, a response mediated by TNFα. Treatment with a receptor peptido-agonist conferred protection against myocardial dysfunction in wild-type, but not Fpr2/3^−/−, animals. Therefore, coordinated physio-pharmacological analyses indicate nonredundant modulatory functions for Fpr2/3 in experimental sepsis, opening new opportunities to manipulate the host response for therapeutic development.Sepsis is a clinical syndrome expression of the host reaction to pathogen invasion, as a consequence of either direct dissemination into the bloodstream or postsurgical trauma and gut ischemia/reperfusion-mediated pathogen translocation. The complexity of sepsis is due to multiple local and systemic immune responses that involve release of soluble mediators such as cytokines, bioactive lipid mediators, and cell stress markers, leading to multiple organ failure and ultimately death (1). Originally believed to result exclusively from an overzealous inflammatory response (e.g., cytokine storm), the lack of efficacy of anticytokine therapy in several clinical trials demonstrated that the pathogenesis of sepsis is complex. Notwithstanding the difficulty in clinical cases to establish the beginning of the infection (and the temporal recruitment of failing organs), it is now appreciated that the systemic inflammatory response syndrome (SIRS) can overlap with a compensatory anti-inflammatory response syndrome (CARS) (2). Immunosuppression associated with CARS may explain the failure of classical anti-inflammatory strategies in patients (3, 4).The acute inflammatory reaction against pathogens is in many cases successful, leading to healing and recovery of biological function. To achieve this end point, specific mediators and pathways of endogenous protection must be engaged by the host to promote what is now referred to as “resolution of inflammation” (5). Proresolving mediators share a set of properties that are emerging as paradigmatic (6); these include modulation of immune cell recruitment [inhibition of polymorphonuclear (PMN) migration and promotion of monocyte influx], augmentation of phagocytosis (leading to bacteria containment), promotion of apoptosis and efferocytosis, and eventually tissue/organ repair with restoration of physiological function (6, 7). It is perhaps for these organic and multifactorial biological actions that proresolving mediators like the protein annexin A1 (AnxA1) and the bioactive lipids lipoxin A₄ (LXA₄) and resolvin D₂ exert protection in models of experimental sepsis (8–10). Of relevance, the receptor target for AnxA1 and LXA₄ is a G protein-coupled receptor that belongs to the formyl-peptide receptor (FPR) family, termed FPR2/ALX. To establish the validity of FPR2/ALX for the development of innovative therapeutic approaches, proof-of-concept data within loss-of-function settings should be established.In the mouse, the human FPR2/ALX gene corresponds to two genes, termed Fpr2 and Fpr3, which share the first of the two exons (11). LXA₄ and AnxA1 are largely inactive in a transgenic mouse that lacks both murine genes (12) as shown in models of acute inflammation and ischemia-reperfusion injury (12–15). Herein we establish the patho-pharmacology of Fpr2/3 in experimental polymicrobial sepsis as a way to validate the human ortholog as a genuine receptor target for innovative treatments in sepsis.     

Child maltreatment: variation in trends and policies in six developed countries

We explored trends in six developed countries in three types of indicators of child maltreatment for children younger than 11 years, since the inception of modern child protection systems in the 1970s. Despite several policy initiatives for child protection, we recorded no consistent evidence for a decrease in all types of indicators of child maltreatment. We noted falling rates of violent death in a few age and country groups, but these decreases coincided with reductions in admissions to hospital for maltreatment-related injury only in Sweden and Manitoba (Canada). One or more child protection agency indicators increased in five of six countries, particularly in infants, possibly as a result of early intervention policies. Comparisons of mean rates between countries showed five-fold to ten-fold differences in rates of agency indicators, but less than two-fold variation in violent deaths or maltreatment-related injury, apart from high rates of violent child death in the USA. These analyses draw attention to the need for robust research to establish whether the high and rising rates of agency contacts and out-of-home care in some settings are effectively reducing child maltreatment.     

Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey

Data on the clinical spectrum and therapeutic management of noninfectious mixed cryoglobulinemia vasculitis (CryoVas) in the era of hepatitis C virus screening are lacking. We analyzed data from 242 patients with noninfectious mixed CryoVas included in the French multicenter CryoVas survey. Baseline manifestations were purpura (75%), peripheral neuropathy (52%), arthralgia or arthritis (44%), glomerulonephritis (35%), cutaneous ulcers (16%), and cutaneous necrosis (14%). A connective tissue disease was diagnosed in 30% and B-cell non-Hodgkin lymphoma in 22%, whereas the CryoVas was considered to be essential in 48%. With the use of Cox-marginal structural models, rituximab plus corticosteroids showed the greater therapeutic efficacy compared with corticosteroids alone and alkylating agents plus corticosteroids to achieve complete clinical, renal, and immunologic responses and a prednisone dosage < 10 mg/d at 6 months. However, this regimen was also associated with severe infections, particularly when high doses of corticosteroids were used, whereas death rates did not differ between the therapeutic regimens. The role of each of these strategies remains to be defined in well-designed randomized controlled trials.     

Tumor-specific but not nonspecific cell-free circulating DNA can be used to monitor disease response in lymphoma

Recently, nontumor specific circulating DNA was shown to be elevated in a broad range of lymphomas, implicating a role as a potential biomarker. Epstein-Barr virus' (EBV) presence within a proportion of lymphomas implies EBV-DNA has potential as a lymphoma-specific disease response biomarker. However, application would be restricted to EBV-associated lymphomas. Neither detailed comparison has been performed of lymphoma-specific versus nonspecific DNA as disease response biomarkers nor have the kinetics of circulating DNA during treatment been established, and the optimal methodology remains unknown. We prospectively evaluated DNA levels and clinical response of 63 lymphoma patients. DNA was measured in paired serum, plasma, and cell samples at five predetermined time-points taken prior, during and following treatment. Both cell-free (c-f) circulating EBV-DNA (in EBV-associated lymphoma) and nonspecific c-f DNA levels (in all lymphomas) were elevated and discriminatory at presentation compared to healthy controls. Nonspecific c-f DNA was significantly associated with baseline serum lactate dehydrogenase. Within EBV-associated lymphomas at presentation, there was a strong correlation between specific and nonspecific circulating c-f DNA (r = 0.9, P < 0.0001). However, only c-f EBV-DNA correlated with clinical/radiological response. In addition, c-f EBV-DNA, and not nonspecific c-f DNA, provided an early marker of relapsed and refractory disease. Serum versus plasma, and single versus multiple-copy EBV-gene targets were equivalent. Lymphoma-specific DNA is a disease response biomarker; however, nonspecific DNA reflected neither lymphoma-specific DNA nor therapeutic response. Lymphoma disease response can be monitored by blood tests, but new lymphoma-specific biomarkers need to be identified to broaden applicability.     

Insulin resistance and cognition among HIV-infected and HIV-uninfected adult women: the Women's Interagency HIV Study

Cognitive impairment remains prevalent in the era of combination antiretroviral therapy (cART) and may be partially due to comorbidities. We postulated that insulin resistance (IR) is negatively associated with cognitive performance. We completed a cross-sectional analysis among 1547 (1201 HIV(+)) women enrolled in the Women's Interagency HIV Study (WIHS). We evaluated the association of IR with cognitive measures among all WIHS women with concurrent fasting bloods and cognitive testing [Trails A, Trails B, and Symbol Digit Modalities Test (SDMT)] using multiple linear regression models. A smaller subgroup also completed the Stroop test (n=1036). IR was estimated using the Homeostasis Model Assessment (HOMA). Higher HOMA was associated with poorer performance on the SDMT, Stroop Color-Naming (SCN) trial, and Stroop interference trial, but remained statistically significant only for the SCN in models adjusting for important factors [β=3.78?s (95% CI: 0.48-7.08), p=0.025, for highest vs. lowest quartile of HOMA]. HIV status did not appear to substantially impact the relationship of HOMA with SCN. There was a small but statistically significant association of HOMA and reduced neuropsychological performance on the SCN test in this cohort of women.