Increased levels of calprotectin in obesity are related to macrophage content: impact on inflammation and effect of weight loss

Calprotectin has been recently described as a novel marker of obesity. The aim of this study was to determine the circulating concentrations and expression levels of calprotectin subunits (S100A8 and S100A9) in visceral adipose tissue (VAT), exploring its impact on insulin resistance and inflammation and the effect of weight loss. We included 53 subjects in the study. Gene expression levels of the S100A8/A9 complex were analyzed in VAT as well as in both adipocytes and stromovascular fraction cells (SVFCs). In addition, circulating calprotectin and soluble receptor for the advanced glycation end product (sRAGE) concentrations were measured before and after weight loss achieved by Roux-en-Y gastric bypass (RYGB) (n = 26). Circulating concentrations and VAT expression of S100A8/A9 complex were increased in normoglycemic and type 2 diabetic obese patients (P < 0.01) and associated with markers of inflammation (P < 0.01). Oppositely, concentrations of sRAGE were significantly lower (P < 0.001) in both obese groups compared to lean volunteers. Elevated calprotectin levels in obese patients decreased (P < 0.00001) after RYGB, whereas sRAGE concentrations tended to increase. Calprotectin was mainly expressed by SVFCs, and its expression was significantly correlated (P < 0.01) with mRNA levels of the monocyte-macrophage-related molecules macrophage-specific antigen CD68 (CD68), monocyte chemotactic protein 1 (MCP1), integrin α-M (CD11B), and NADPH oxidase 2 (NOX2). Tumor necrosis factor-α treatment significantly enhanced (P < 0.05) the mRNA levels of S100 calcium-binding protein A8 (S100A8) of human visceral adipocytes. The increased levels of calprotectin in obesity and obesity-associated type 2 diabetes, its positive association with inflammation as well as the higher expression levels in the SVFCs in VAT suggests a potential role of this protein as a chemotactic factor in the recruitment of macrophages to VAT, increasing inflammation and the development of obesity-associated comorbidities.     

Myeloablative therapy against high risk Ewing's sarcoma: A single institution experience and literature review

Background

Attempts to improve survival outcomes of patients with high risk Ewing''s sarcoma (ES) have focused on chemotherapy dose intensification strategies.

Aim

The objective of this study is to retrospectively evaluate clinical characteristics and outcome of pediatric patients with high risk ES treated at a single institution.

Materials and methods

From 1995 to 2008, seventeen patients (male:female, 14:3) were treated with dose-intensive therapy in our institution. Median age at diagnosis was 10 years (range: 2–15). Seven patients had metastases at diagnosis (lung in 6 cases and bone in one case). Eleven patients presented with unresectable disease. Fifteen (88.2%) received the Spanish Society of Pediatric Oncology protocol which includes six cycles of vincristine, doxorubicin, ifosfamide and etoposide. Two out of the six cases that were resectable received postoperative radiation. In addition, eleven patients received definitive radiation therapy. Finally, twelve (70.5%) out of 17 patients received myeloablative therapy with melphalan/etoposide. The rest of patients (N = 5) received busulfan/melphalan.

Results

Median follow-up was 78 months (range: 15–155 months). Initial responses were complete in all patients, but 9 of them developed progression disease. Seven patients became long-term event-free survivors. No patient died of toxicity after transplantation. The 2- and 5-year overall survival rates for all patients were 93% and 73%, respectively. Event-free survival rates were 74% and 54% at 2 and 5 years, respectively.

Conclusion

This single-institution experience suggests that myeloablative therapy against high risk ES is effective and safe.     

Evaluación del sufrimiento en la demencia avanzada

Introduction

At the end stage of life of dementia, medical comorbidities are associated with a high degree of patient suffering. The aim of this study was to assess the relationship between the lack of symptoms of discomfort and the level of patient suffering. The relationship with psychological distress and caregiver burden was also clarified.

Material and methods

This study included patients with advanced dementia according to the criteria of the Hospice Enrolment Criteria for End-stage Dementia patients. Patient suffering was assessed with Mini-Suffering State Examination (MSSE). The caregivers were scored by Zarit caregiver burden scale (ZR), and the General Health Questionnaire of Goldberg (GHQ-28). Central tendency and correlation tests were used in the statistical analysis.

Results

The study recorded data from 71 patients. In the comorbidity of medical symptoms associated with advanced dementia, pneumonia (Spearman's rho: −0.29; P=.01), and malnutrition (Spearman's rho: −0.25; P=.03), showed a significant association with the total scale score of MSSE. There were no significant correlations between patient suffering and caregiver psychological distress (r: 0.11; P=.37), or caregiver burden (r: 0.13; P=.32).

Conclusions

The identification of suffering in patients with advanced dementia is recognised by specific symptoms, such as pneumonia and malnutrition. The caregiver’ psychological distress of the caregiver was shown to be unrelated to patient suffering as measured by MSSE.     

Endophilin,Lamellipodin, and Mena cooperate to regulate F‐actin‐dependent EGF‐receptor endocytosis

The epidermal growth factor receptor (EGFR) plays an essential role during development and diseases including cancer. Lamellipodin (Lpd) is known to control lamellipodia protrusion by regulating actin filament elongation via Ena/VASP proteins. However, it is unknown whether this mechanism supports endocytosis of the EGFR. Here, we have identified a novel role for Lpd and Mena in clathrin‐mediated endocytosis (CME) of the EGFR. We have discovered that endogenous Lpd is in a complex with the EGFR and Lpd and Mena knockdown impairs EGFR endocytosis. Conversely, overexpressing Lpd substantially increases the EGFR uptake in an F‐actin‐dependent manner, suggesting that F‐actin polymerization is limiting for EGFR uptake. Furthermore, we found that Lpd directly interacts with endophilin, a BAR domain containing protein implicated in vesicle fission. We identified a role for endophilin in EGFR endocytosis, which is mediated by Lpd. Consistently, Lpd localizes to clathrin‐coated pits (CCPs) just before vesicle scission and regulates vesicle scission. Our findings suggest a novel mechanism in which Lpd mediates EGFR endocytosis via Mena downstream of endophilin.     

A Single Immunization with MVA Expressing GnGc Glycoproteins Promotes Epitope-specific CD8+-T Cell Activation and Protects Immune-competent Mice against a Lethal RVFV Infection

Background

Rift Valley fever virus (RVFV) is a mosquito-borne pathogen causing an important disease in ruminants often transmitted to humans after epizootic outbreaks in African and Arabian countries. To help combat the spread of the disease, prophylactic measures need to be developed and/or improved.

Methodology/Principal Findings

In this work, we evaluated the immunogenicity and protective efficacy of recombinant plasmid DNA and modified vaccinia virus Ankara (rMVA) vectored vaccines against Rift Valley fever in mice. These recombinant vaccines encoded either of two components of the Rift Valley fever virus: the viral glycoproteins (Gn/Gc) or the nucleoprotein (N). Following lethal challenge with live RVFV, mice immunized with a single dose of the rMVA-Gn/Gc vaccine showed no viraemia or clinical manifestation of disease, but mounted RVFV neutralizing antibodies and glycoprotein specific CD8+ T-cell responses. Neither DNA-Gn/Gc alone nor a heterologous prime-boost immunization schedule (DNA-Gn/Gc followed by rMVAGn/Gc) was better than the single rMVA-Gn/Gc immunization schedule with regards to protective efficacy. However, the rMVA-Gn/Gc vaccine failed to protect IFNAR^−/− mice upon lethal RVFV challenge suggesting a role for innate responses in protection against RVFV. Despite induction of high titer antibodies against the RVFV nucleoprotein, the rMVA-N vaccine, whether in homologous or heterologous prime-boost schedules with the corresponding recombinant DNA vaccine, only conferred partial protection to RVFV challenge.

Conclusions/Significance

Given the excellent safety profile of rMVA based vaccines in humans and animals, our data supports further development of rMVA-Gn/Gc as a vaccine strategy that can be used for the prevention of Rift Valley fever in both humans and livestock.     

Spanish juniper gain expansion opportunities by counting on a functionally diverse dispersal assemblage community

Seed dispersal is typically performed by a diverse array of species assemblages with different behavioral and morphological traits which determine dispersal quality (DQ, defined as the probability of recruitment of a dispersed seed). Fate of ecosystems to ongoing environmental changes is critically dependent on dispersal and mainly on DQ in novel scenarios. We assess here the DQ, thus the multiplicative effect of germination and survival probability to the first 3 years of life, for seeds dispersed by several bird species (Turdus spp.) and carnivores (Vulpes vulpes, Martes foina) in mature woodland remnants of Spanish juniper (Juniperus thurifera) and old fields which are being colonized by this species. Results showed that DQ was similar in mature woodlands and old fields. Germination rate for seeds dispersed by carnivores (11.5%) and thrushes (9.12%) was similar, however, interacted with microhabitat suitability. Seeds dispersed by carnivores reach the maximum germination rate on shrubs (16%), whereas seeds dispersed by thrushes did on female juniper canopies (15.5) indicating that each group of dispersers performed a directed dispersal. This directional effect was diluted when survival probability was considered: thrushes selected smaller seeds which had higher mortality in the seedling stage (70%) in relation to seedlings dispersed by carnivores (40%). Overall, thrushes resulted low‐quality dispersers which provided a probability or recruitment of 2.5%, while a seed dispersed by carnivores had a probability of recruitment of 6.5%. Our findings show that generalist dispersers (i.e., carnivores) can provide a higher probability of recruitment than specialized dispersers (i.e., Turdus spp.). However, generalist species are usually opportunistic dispersers as their role as seed dispersers is dependent on the availability of trophic resources and species feeding preferences. As a result, J. thurifera dispersal community is composed by two functional groups of dispersers: specialized low‐quality but trustworthy dispersers and generalist high‐quality but opportunistic dispersers. The maintenance of both, generalist and specialist dispersers, in the dispersal assemblage community assures the dispersal services and increases the opportunities for regeneration and colonization of degraded areas under a land‐use change scenario.