The environmental obesogen bisphenol A increases macrophage self-renewal.

Self-renewal of macrophages is important for the healthy development and replenishment of tissue-resident macrophage pools. How this mechanism is controlled by endocrine signals is still largely unexplored. Here, we show that the endocrine disruptor bisphenol A (BPA) increases macrophage self-renewal. This effect was associated with phosphorylation of extracellular signal-regulated kinase (ERK) and a slight increase in the expression of liver X receptor alpha (LXRα). We found that LXRα inhibition induced, while LXRα activation impeded, macrophage self-renewal. LXRα signaling hence may protect from excessive macrophage expansion. Self-renewing macrophages, however, had negligible LXRα expression when compared with quiescent macrophages. Accordingly, tissue-resident macrophage pools, which are dominated by quiescent macrophages, were rich in LXRα-expressing macrophages. Overall, we show that BPA increases macrophage self-renewal and that this effect, at least in part, can be inhibited by increasing LXRα expression. Since BPA is accumulated in the adipose tissue, it has the potential to increase self-renewal of adipose tissue macrophages, leading to a condition that might negatively impact adipose tissue health.

Changes and regulation of the C5a receptor on neutrophils during septic shock in humans.

During experimental sepsis, excessive generation of the anaphylatoxin C5a results in reduction of the C5a receptor (C5aR) on neutrophils. These events have been shown to result in impaired innate immunity. However, the regulation and fate of C5aR on neutrophils during sepsis are largely unknown. In contrast to 30 healthy volunteers, 60 patients in septic shock presented evidence of complement activation with significantly increased serum levels of C3a, C5a, and C5b-9. In the septic shock group, the corresponding decrease in complement hemolytic activity distinguished survivors from nonsurvivors. Neutrophils from patients in septic shock exhibited decreased C5aR expression, which inversely correlated with serum concentrations of C-reactive protein (CRP) and clinical outcome. In vitro exposure of normal neutrophils to native pentameric CRP led to a dose- and time-dependent loss of C5aR expression on neutrophils, whereas the monomeric form of CRP, as well as various other inflammatory mediators, failed to significantly alter C5aR levels on neutrophils. A circulating form of C5aR (cC5aR) was detected in serum by immunoblotting and a flow-based capture assay, suggestive of an intact C5aR molecule. Levels of cC5aR were significantly enhanced during septic shock, with serum levels directly correlating with lethality. The data suggest that septic shock in humans is associated with extensive complement activation, CRP-dependent loss of C5aR on neutrophils, and appearance of cC5aR in serum, which correlated with a poor outcome. Therefore, cC5aR may represent a new sepsis marker to be considered in tailoring individualized immune-modulating therapy.

Coaching to strengthen critical success factors in integrative care for chronic fatigue patients: the Patient Needs-Resources Model.

Theoretical and empirical studies discover that an integrative approach is particularly important in chronic disorders and multiple long-term conditions, such as chronic fatigue. Chronic fatigue syndrome (CFS) is a classic example of a potentially severe, multisystemic illness with a wide diversity of symptoms and the corresponding diagnostic complexity. The prevalence of CFS-like syndromes expanded in the context of the COVID-19 pandemic, increasing the disorder and treatment burden. Thus, this article aimed to draw attention to the possibilities to strengthen the integrative approach to diagnosing and treating chronic disorders and multiple long-term conditions. The main critical success factors identified for integrative approaches were: a holistic approach, that provides a more comprehensive diagnostic and personalized treatment strategy, a multidisciplinary team, and patient engagement. The strengths and weaknesses of these factors were explored and coaching was identified as a potential unifying and reinforcing element. Coaching has a wide spectrum of manifestations clearly representing a holistic approach, that has been successfully used in multidisciplinary team building. Moreover, coaching exposes support addressing the patient engagement issues identified by the Patient Needs-Resources Model (PN-R Model) such as low levels of self-efficacy, optimism, and subjective well-being. Coaching may assist patients to identify and prioritize their goals, becoming aware of their personal resources, developing strategies for managing symptoms, and building skills to increase their self-efficacy and active engagement in the treatment process. Therefore, the authors emphasize coaching as a perspective element of optimization of patient care, that requires additional theoretical and long-term empirical research.

Macrophage activation syndrome in a patient with pulmonary inflammatory myofibroblastic tumour.

We describe for the first time a case of macrophage activation syndrome (MAS) in a patient with a history of inflammatory myofibroblastic tumour (inflammatory pseudotumour, IPT) of the lung and thoracic spine. The patient was admitted to the intensive care unit with a history of prolonged remitting fever, hepatosplenomegaly, bilaterally enlarged thoracic lymph nodes and an acute severe inflammatory response syndrome (SIRS). Up-regulated cytokine production (e.g. IL-1ß and IL-6), increased levels of ferritin and circulating soluble interleukin-2 receptor (sIL-2R, sCD25) led to the differential diagnosis of MAS. Bone marrow aspiration, the main tool for a definite diagnosis, revealed macrophages phagocytosing haematopoietic cells. Immunosuppressive therapy with corticosteroids and cyclosporine was an effective treatment in this patient.

Preparation of cryofixed cells for improved 3D ultrastructure with scanning transmission electron tomography.

Scanning transmission electron tomography offers enhanced contrast compared to regular transmission electron microscopy, and thicker samples, up to 1 µm or more, can be analyzed, since the depth of focus and inelastic scattering are not limitations. In this study, we combine this novel imaging approach with state of the art specimen preparation by using novel light transparent sapphire specimen carrier for high-pressure freezing and a freeze substitution protocol for better contrast of membranes. This combination allows for imaging membranes and other subcellular structures with unsurpassed quality. This is demonstrated with mitochondria, where the inner and outer mitochondrial membranes as well as the membranes in the cristae appear in very close apposition with a minimal intermembrane space. These findings correspond well with old observations using freeze fracturing. In 880-nm thick sections of hemophagocytes, the three-dimensional structure of membrane sheets could be observed in the virtual sections of the tomogram. Microtubules, actin and intermediate filaments could be visualized within one sample. Intermediate filaments, however, could even be better observed in 3D using surface scanning electron tomography.

Development of a dendrimer PAMAM­based gold biochip for rapid and sensitive detection of endogenous IFN­Î³ and anti­IFN­Î³ IgG in patients with hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but severe disease characterized by immune hyperactivation and cytokine storm. Given the high mortality rate of HLH, there is a need for more effective diagnostic tools and treatments. The present study developed a dendrimer­based protein biochip for rapid, sensitive and simultaneous detection of serum interferon (IFN)­Î³ and endogenous anti­IFN­Î³ antibody (Ab) in patients with HLH. A gold biochip was modified with 1, 4­phenylene diisothiocyanate (PDITC), polyamidoamine (PAMAM) or PDITC­activated PAMAM. The optimal immobilization concentration for Ab capture and the reaction concentration for detecting Ab on the PDITC­activated PAMAM­modified biochip were 6.25 and 3.12 µg/ml, respectively; the limit of detection of IFN­Î³ protein was 50 pg/ml. The efficiency of the protein­probed biochip in detecting IFN­Î³ and anti­IFN­Î³ Ab in serum samples from 77 patients with HLH was evaluated; the positive rates for IFN­Î³ and anti­IFN­Î³ IgG Ab were 63.6% (49/77) and 61.0% (47/77), respectively. The present results demonstrated that the PDITC­activated PAMAM­modified biochip might be a sensitive tool for the specific detection of IFN­Î³ and anti­IFN­Î³ Ab in serum, and might have clinical applicability for the diagnosis of HLH.

Effect of major abdominal surgery on endotoxin release and expression of Toll-like receptors 2/4.

BACKGROUND: Surgery can cause endotoxemia, and endotoxin aggregates to Toll-like receptors and acts proinflammatory; repetitive endotoxin application can cause tolerance. The objective of the study is to characterize early inflammatory response and expression of TLR2/4 during major abdominal surgery. MATERIALS AND METHODS: A prospective controlled study of 20 patients with elective major abdominal surgery was performed. Blood samples were collected before and at a defined time after surgery. Endotoxemia, capability of plasma to inactivate endotoxin, cytokine release of LPS-stimulated mononuclear cells, quantitative TLR mRNA expression, and plasma concentrations of TNFalpha, IL-6, C-reactive protein (CRP), alpha(1)-acid glycoprotein, transferrin, and albumin were measured. RESULTS: Surgery caused endotoxemia (p = 0.053), and the capability of plasma to inactivate endotoxin was reduced (p = 0.0002). Two hours postoperatively, the plasma concentrations of TNFalpha and IL-6 peaked significantly, but the liberation capacity of mononuclear cells for cytokines (TNFalpha, IL-1beta, IL-6) was significantly reduced. The concentration of CRP and alpha(1)-acid glycoprotein peaked 48 h postoperatively, but those of transferrin and albumin were significantly decreased (p < 0.001, respectively). Median mRNA expression of TLR2 and TLR4 of mononuclear cells was not altered, and there was no obvious trend over time. CONCLUSION: Major abdominal surgery is associated with endotoxemia, reduced capability of plasma to inactivate endotoxin, cytokine kinetics resembling those of healthy man after experimentally given LPS, and substantial acute-phase reaction. The cytokine liberation of mononuclear cells suggests a state of postoperative endotoxin tolerance. Despite these substantial changes, trends in TLR2/4 expression are not obvious.

Trauma-induced systemic inflammatory response versus exercise-induced immunomodulatory effects.

Accidental trauma and heavy endurance exercise, both induce a kind of systemic inflammatory response, also called systemic inflammatory response syndrome (SIRS). Exercise-related SIRS is conditioned by hyperthermia and concomitant heat shock responses, whereas trauma-induced SIRS manifests concomitantly with tissue necrosis and immune activation, secondarily followed by fever. Inflammatory cytokines are common denominators in both trauma and exercise, although there are marked quantitative differences. Different anti-inflammatory cytokines may be involved in the control of inflammation in trauma- and exercise-induced stress. Exercise leads to a balanced equilibrium between inflammatory and anti-inflammatory responses. Intermittent states of rest, as well as anti-oxidant capacity, are lacking or minor in trauma but are high in exercising individuals. Regular training may enhance immune competence, whereas trauma-induced SIRS often paves the way for infectious complications, such as sepsis.

Development of a novel protein biochip enabling validation of immunological assays and detection of serum IgG and IgM antibodies against Treponema pallidum pathogens in the patients with syphilis.

In this study, we developed a novel protein biochip methodology that was characterized by dithiobis (succinimidyl undecanoate) (DSU) and specialized for detection of serum IgG and IgM antibodies against Treponema pallidum pathogens in the patients with syphilis, respectively. The biochips were validated by a dimension of atomic force microscope (AFM). The visualized detection limit of IgG antibody on the biochip was 0.39µg/ml. Finally, 286 serum samples from the patients with syphilis were simultaneously tested on the rTpN15-17-47 coated biochips. The results were evaluated in comparison with the assays of T. pallidum particle agglutination (TPPA) and the toluidine red unheated serum test (TRUST). The result demonstrated that the relative positive rate in the 286 patients by biochip was 99.0%, similar to that by TPPA (97.9%, P>0.05) and higher than that by TRUST, (76.2%, P<0.01). The detection specificities were 100% for the biochip and the TPPA and 97.0% for the TRUST. Thus, the protein biochip would provide a useful platform not only for enabling concurrent detection of the infectious antibodies directed against T. pallidum on a larger scale, but also for monitoring therapy modality of the disease.

A severe systemic presentation of pigmented villonodular synovitis in a child with underlying Chediak-Higashi syndrome.

Pigmented villonodular synovitis (PVNS), a condition of synovial hyperproliferation that mostly affects large joints, is rare in children and conventionally lacks systemic symptoms. This report describes a complex paediatric patient who underwent bone marrow transplantation to control the accelerated phase of the Chediak-Higashi syndrome. Diffuse PVNS developed in one knee 2.75 years later. Progression of PVNS was accompanied by the development of severe systemic symptoms, which resolved rapidly following subtotal surgical debridement. The patient remains well with minimal elevation of inflammatory marker levels 10.5 years later. As PVNS and Chediak-Higashi syndrome are both very rare diseases we propose a potential unifying hypothesis for this combination.

Association analysis of ERBB2 amplicon genetic polymorphisms and STARD3 expression with risk of gastric cancer in the Chinese population.

The purpose of this study was to investigate whether risk of gastric cancer (GC) was associated with single nucleotide polymorphisms (SNPs) in a gene cluster on the chromosome 17q12-q21 (ERBB2 amplicon) in the Chinese Han population. We detected twenty-six SNPs in this gene cluster containing steroidogenic acute regulatory-related lipid transfer domain containing 3 (STARD3), protein phosphatase 1 regulatory subunit 1B (PPP1R1B/DARPP32), titin-cap (TCAP), per1-like domain containing 1(PERLD1/CAB2), human epidermal growth factor receptor-2 (ERBB2/HER2), zinc-finger protein subfamily 1A 3 (ZNFN1A3/IKZF3) and DNA topoisomerase 2-alpha (TOP2A) genes in 311 patients with GC and in 425 controls by Sequenom. We found no associations between genetic variations and GC risk. However, haplotype analysis implied that the haplotype CCCT of STARD3 (rs9972882, rs881844, rs11869286 and rs1877031) conferred a protective effect on the susceptibility to GC (P=0.043, odds ratio [OR]=0.805, 95% confidence intervals [95% CI]=0.643-0.992). The STARD3 rs1877031 TC genotype endued histogenesis of gastric mucinous adenocarcinoma and signet-ring cell carcinoma (P=0.021, OR=2.882, 95% CI=1.173-7.084). We examined the expression of STARD3 in 243 tumor tissues out of the 311 GC patients and 20 adjacent normal gastric tissues using immumohistochemical (IHC) analysis and tissue microarrays (TMA). The expression of STARD3 was observed in the gastric parietal cells and in gastric tumor tissues and significantly correlated with gender (P=0.004), alcohol drinking (P<0.001), tumor location (P=0.007), histological type (P=0.005) and differentiation (P=0.023) in GC. We concluded that the combined effect of haplotype CCCT of STARD3 might affect GC susceptibility. STARD3 expression might be related to the tumorigenesis of GC in the Chinese population.

Genetic association of osteopontin (OPN) and its receptor CD44 genes with susceptibility to Chinese gastric cancer patients.

PURPOSE: (1) To investigate associations between single nucleotide polymorphisms (SNPs) in osteopontin (OPN) and its receptor-cluster of differentiation 44 (CD44) genes and gastric cancer susceptibility. (2) To explore the correlation of OPN and CD44 expression of gastric cancer. METHODS: We detected 26 SNPs of the genes in gastric cancer patients from the Chinese Han population by Sequenom technique and performed expression of OPN in combination with CD44 in 243 tissues samples of the cases by tissue microarray and immunohistochemistry (IHC). RESULTS: We found that the minor alleles of OPN rs4754C>T and OPN rs9138C>A remained strongly associated with decreased gastric cancer risk (P = 1.53 × 10(-4), odds ratio (OR) 0.642, 95 % confidence interval (CI) 0.511-0.808 and P = 1.59 × 10(-4), OR 0.642, 95 %CI 0.510-0.809). OPN variant rs1126772A>G and CD44 variant rs353639A>C significantly contributed to elevated risk of gastric cancer (P = 0.042, OR 1.279, 95 % CI 1.008-1.622 and P = 0.047, OR 1.334, 95 % CI 1.003-1.772). Haplotypes of OPN and CD44 variants significantly influenced risk of gastric cancer. Clinical data indicated that rs4754 and rs9138 of OPN were significantly associated with smoking (P = 0.029, OR 0.343, 95 % CI 0.127-0.926 and P = 0.029, OR 0.343, 95 %CI 0.127-0.926) and OPN rs1126772 revealed associations with tumor-node-metastasis (TNM) stage (P = 0.025, OR 1.765, 95 % CI 1.073-2.905) and tumor differentiation (P = 0.031, OR 1.722, 95 % CI 1.049-2.825). OPN expression was observed in 133 of the 243 cases (54.7 %) by IHC and was correlated with serosa invasion (P = 0.013), TNM stage (P = 0.003) and lymph node metastasis (P = 0.002). CD44 expression was found in 92 of the 243 cases (37.9 %) and was associated with tumor size (P = 0.005) and lymph node metastasis (P = 0.023), respectively. The OPN expression displayed a positive association with CD44 (P = 0.01, r s = 0.164). CONCLUSIONS: We found that the polymorphisms rs4754, rs9138 and rs1126772 of OPN gene and rs353639 of CD44 gene were significantly associated with gastric cancer. Our IHC data indicated that interaction of OPN and CD44 protein would promote progression and metastasis of gastric cancer.

Genetic analysis of ADIPOQ variants and gastric cancer risk: a hospital-based case-control study in China.

Single-nucleotide polymorphisms (SNPs) of adiponectin (ADIPOQ), adiponectin receptor 1 (ADIPOR1) and ADIPOR2 genes contribute to the risk and progression of cancers. Here, we investigated the associations between variants of these three genes and the risk of gastric cancer. We genotyped six ADIPOQ SNPs, nine ADIPOR1 SNPs and six ADIPOR2 SNPs using the Sequenom technique in a hospital-based case-control study of patients with gastric cancer and cancer-free controls in the Chinese Han population. We found associations of certain variants with location of gastric cancer. Rs16861205 with the minor allele A in ADIPOQ, rs10773989 with the minor allele C and rs1044471 with the minor allele T in ADIPOR2 presented significant associations with a decreased risk of cardia cancer (P = 0.024, OR 0.605, 95 % CI 0.390-0.938; P = 0.015, OR 0.699, 95 % CI 0.522-0.935; and P = 0.022, OR = 0.703, 95 % CI 0.519-0.951, respectively). ADIPOQ rs16861205 with minor allele A displayed an association with an increased risk of body cancer (P = 0.010, OR 1.821, 95 % CI 1.148-2.890). Further stratified analysis of the patients indicated that there were significant correlations for rs1342387A/G (P = 0.027) and rs16861205A/G (P = 0.000) with tumor location; rs16850799A/G (P = 0.004) and rs2058033C/A (P = 0.003) with invasion depth; rs16850799A/G (P = 0.019) with the tumor-node-metastasis stage; rs16850799A/G (P = 0.016), rs1501299A/C (P = 0.005) and rs1063538C/T (P = 0.017) with alcohol consumption; rs11612414A/G (P = 0.040) and rs12733285T/C (P = 0.005) with salted food; rs1063538C/T (P = 0.043) with family history of gastric cancer; and rs11612414A/G (P = 0.029) with gender. Adiponectin expression significantly correlated with gender (P = 0.014), alcohol consumption (P = 0.037), family history (P = 0.019) and invasion depth of primary tumor (P = 0.024). Our data suggested that variants of ADIPOQ may be genetic markers conferring susceptibility to gastric cancer subtypes. These findings need to be validated in a larger panel of samples from distinct populations.