CD14 recycling modulates LPS-induced inflammatory responses of murine macrophages.

TLR4 is activated by the bacterial endotoxin lipopolysaccharide (LPS) and triggers two proinflammatory signaling cascades: a MyD88-dependent one in the plasma membrane, and the following TRIF-dependent one in endosomes. An inadequate inflammatory reaction can be detrimental for the organism by leading to sepsis. Therefore, novel approaches to therapeutic modulation of TLR4 signaling are being sought after. The TLR4 activity is tightly connected with the presence of CD14, a GPI-anchored protein that transfers LPS monomers to the receptor and controls its endocytosis. In this study we focused on CD14 trafficking as a still poorly understood factor affecting TLR4 activity. Two independent assays were used to show that after endocytosis CD14 can recycle back to the plasma membrane in both unstimulated and stimulated cells. This route of CD14 trafficking can be controlled by sorting nexins (SNX) 1, 2 and 6, and is important for maintaining the surface level and the total level of CD14, but can also affect the amount of TLR4. Silencing of these SNXs attenuated especially the CD14-dependent endosomal signaling of TLR4, making them a new target for therapeutic regulation of the inflammatory response of macrophages to LPS.

Changes in surrogate markers of intestinal epithelial injury and microbial translocation in young and older men during prolonged occupational heat stress in temperate and hot conditions.

PURPOSE: Exertional heat stress can cause damage to the intestinal epithelium and disrupt gastrointestinal barrier integrity, leading to microbial translocation (MT) linked to the development of heat stroke. This study aimed to assess age-related differences in markers of intestinal epithelial injury and MT following non-heat stress and high-heat stress exercise in healthy young and older men. METHODS: Markers of intestinal epithelial injury (intestinal fatty acid-binding protein-'IFABP') and MT (soluble cluster of differentiation 14-'sCD14'; and lipopolysaccharide-binding protein-'LBP') were assessed in healthy young (18-30 y, n = 13) and older (50-70 y) men (n = 12). Blood samples were collected before, after 180 min of moderate-intensity (metabolic rate: 200 W/m2) walking and following 60 min recovery in either a non-heat stress [temperate: 21.9 °C, 35% relative humidity (RH)] or high-heat stress (hot: 41.4 °C, 35% RH) environment. RESULTS: There were no differences in IFABP and sCD14 between the young and older groups in the temperate condition, while LBP was greater in the older group (+ 0.66 ug/mL; + 0.08 to + 1.24 ug/mL). In the hot condition, the older group experienced greater increases in IFABP compared to the young group (+ 712 pg/mL/hr; + 269 to + 1154 pg/mL/hr). However, there were no clear between-group differences for sCD14 (+ 0.24 ug/mL/hr, - 0.22 to + 0.70 ug/mL/hr) or LBP (+ 0.86 ug/mL/hr, - 0.73 to + 2.46 ug/mL/hr). CONCLUSION: While older men may experience greater intestinal epithelial injury following exercise in the heat; this did not lead to a greater magnitude of microbial translocation relative to their younger counterparts.

Soluble Factors CD14, CD163, and Migration Inhibitory Factor Are Associated with Endometriosis-Related Infertility.

OBJECTIVES: Myeloid cell-derived factors contribute to the immunopathology of endometriosis. Soluble CD14 (sCD14), CD163 (sCD163), and MIF serve as in vivo markers of myeloid function. However, these soluble molecules are largely unexplored in women with endometriosis-related infertility cases. We investigated three soluble markers, namely sCD14, sCD163, and MIF, in cases of infertility associated with endometriosis and correlated its level to the stage of endometriosis. DESIGN: Eighty-seven women newly diagnosed with endometriosis or other benign gynecologic control cases linked to infertility were prospectively recruited and underwent diagnostic laparoscopy. PARTICIPANTS: Forty-four patients with endometriosis were included in this study, comprising 19 patients with early-endometriosis (stages I and II) and 25 late-endometriosis (stages III and IV) based on the revised American Society for Reproductive Medicine (rASRM) classification. The remaining 43 patients constituted a control group with infertility due to other causes. METHODS: The levels of sCD14, sCD163, and MIF in serum and peritoneal fluid were assessed using ELISA. RESULTS: Endometriosis women exhibited significantly higher serum levels of sCD163 and MIF levels compared to the control group. Both sCD163 and MIF levels displayed a positive correlation with the rASRM adhesion score. Moreover, the MIF level in serum had a positive correlation with the rASRM endometriosis score. In receiver operating characteristic analysis, serum sCD163 and MIF could significantly discriminate endometriosis and non-endometriosis in infertility cases. LIMITATIONS: Some limitations of the current study deserve to be underlined. First, the sensitive ELISA method was the sole-validated tool for detecting the markers in patient samples. Second, healthy or fertile women were not involved as the control group. CONCLUSIONS: The elevated systemic levels of sCD163 and MIF correlated with the severity of endometriosis. These soluble molecules have a potential diagnostic capacity as a non-invasive biomarker. Furthermore, our data warrants future studies on the underlying mechanism of sCD163 and MIF in endometriosis-related infertility.

Comparison of Integrase Strand Transfer Inhibitors (INSTIs) and Protease-Boosted Inhibitors (PIs) on the Reduction in Chronic Immune Activation in a Virally Suppressed, Mainly Male Population Living with HIV (PLWH).

Background and Objectives: The success of combined antiretroviral therapy (cART) has led to a dramatic improvement in the life expectancy of people living with HIV (PLWH). However, there has been an observed increase in cardiometabolic, bone, renal, hepatic, and neurocognitive manifestations, as well as neoplasms, known as serious non-AIDS events/SNAEs, compared to the general population of corresponding age. This increase is linked to a harmful phenomenon called inflammaging/immunosenescence, which is driven by chronic immune activation and intestinal bacterial translocation. In this study, we examined immunological and metabolic parameters in individuals receiving current cART. Materials and Methods: The study was conducted at Laiko General Hospital in Athens, Greece. Plasma concentrations of sCD14, IL-6, SuPAR, I-FABP, and LBP were measured in virally suppressed PLWH under cART with at least 350 CD4 lymphocytes/µL. We compared these levels between PLWH receiving integrase strand transfer inhibitors (INSTIs) and protease inhibitors (PIs) and attempted to correlate them with chronic immune activation and metabolic parameters. Results: Data from 28 PLWH were analyzed, with a mean age of 52 and 93% being males. Among the two comparison groups, IL-6 levels were higher in the PIs group (5.65 vs. 7.11 pg/mL, p = 0.03). No statistically significant differences were found in the other measured parameters. A greater proportion of PLWH under INSTIs had normal-range LBP (33% vs. 0%, p = 0.04). When using inverse probability of treatment weighting, no statistically significant differences in the measured parameters were found between the two groups (sCD14 p = 0.511, IL-6 p = 0.383, SuPAR p = 0.793, I-FABP p = 0.868, and LBP p = 0.663). Glucose levels were found to increase after viral suppression in the entire sample (92 mg/dL vs. 98 mg/dL, p = 0.009). Total (191 mg/dL vs. 222 mg/dL, p = 0.005) and LDL cholesterol (104 mg/dL vs. 140 mg/dL, p = 0.002) levels were higher in the PIs group. No significant differences were observed in liver and renal function tests. Conclusions: Further investigation is warranted for PLWH on cART-containing INSTI regimens to explore potential reductions in chronic immune activation and intestinal bacterial translocation.

Characteristics and clinical significance of plasma IL-18, sCD14, and sCD163 levels in patients with HIV-1 infection.

Biomarkers of monocyte-macrophages activation and inflammation in plasma such as interleukin-18 (IL-18), soluble leukocyte differentiation antigen 14 (sCD14), and sCD163 are associated with disease severity and prognosis in HIV-1 infected patients, however, their relationships with efficacy of antiretroviral therapy (ART) need further investigation. We aimed to characterize and explore the clinical significance of plasma IL-18, sCD14, and sCD163 in this population. This was a retrospective cohort study consisting of HIV-1 infected patients enrolled in a randomized, controlled, open-label, noninferiority trial (ALTERLL study), with follow-up time points including initiation of ART (baseline), 12-, 24- and 48-weeks of treatment. Plasma levels of IL-18, sCD14, and sCD163 were measured using the enzyme-linked immunosorbent assay method. Viral suppression was defined as HIV-1 RNA < 20 copies/ml. Among the 193 studied patients (median age of 29.0 years, 180 males), IL-18 and sCD163 had U-shaped regression curves and sCD14 had an inverted U-shaped regression curve while the virus was decreased and immune function recovered. Patients with higher levels of IL-18 or lower levels of sCD163 at baseline were less likely to achieve viral suppression at Week 12 or Week 24 of treatment, respectively. In multivariate analysis, baseline sCD163 ≤ 500 pg/ml (adjusted odds ratio 0.33, 95% confidence interval 0.16-0.68) was independently associated with a lower rate of viral suppression at Week 24 of treatment. In conclusion, we demonstrated different dynamic changes among IL-18, sCD14, and sCD163 after ART. Baseline sCD163 level could be a potential predictor of early virological response to ART. Further validation and mechanistic research are needed.

Impact of the first-line antiretroviral therapy on soluble markers of inflammation in cohort of human immunodeficiency virus type 1 in Moroccan patients: a prospective study.

Chronic inflammation and immune activation are a hallmark of HIV-1 infection. In this study, we assessed inflammation biomarkers in a cohort of people living with HIV-1 (PLWH) before and after long-term suppressive combined antiretroviral therapy (cART). A single-center prospective cohort study was conducted to assess inflammatory biomarkers in 86 cART-naive PLWH and after receiving suppressive cART and 50 uninfected controls. Tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and soluble CD14 (sCD14) were measured using enzyme-linked immunosorbent assay (ELISA). No significant difference was found in IL-6 levels between cART-naïve PLWH and controls (p = 0.753). In contrast, TNF-α level showed a significant difference between cART naïve-PLWH and controls (p = 0.019). Interestingly, IL-6 and TNF-α levels were significantly decreased in PLWH after cART (p < 0.0001). The sCD14 showed no significant difference between cART-naïve patients and controls (p = 0.839) and similar levels were observed in pre- and post-treatment (p = 0.719). Our results highlight the critical importance of early treatment to reduce inflammation and its consequences during HIV infection.

Microbial translocation is associated with advanced liver fibrosis among people with HIV.

BACKGROUND: The prevalence of liver complications is increasing among people living with HIV, and microbial translocation (MT) might play a vital role. We conducted a prospective cohort study to evaluate the association between plasma biomarkers of MT and liver fibrosis (LF) among people living with HIV in southwest China. METHOD: A total of 665 people living with HIV were enrolled at baseline and had at least one follow-up visit during the 3-year study period. We calculated the Liver Fibrosis Index (FIB-4) to evaluate LF and measured plasma soluble CD14 (sCD14) and lipopolysaccharide-binding protein (LBP) as surrogate biomarkers for MT. We used ordinal logistic regression to investigate correlates of LF at baseline and used a linear mixed model to examine the association between dynamic changes in MT biomarkers and LF. RESULTS: Of the participants, 61 (9.17%) had advanced LF (FIB-4 >3.25), and 193 (29.02%) had moderate LF (1.45 ≤ FIB-4 ≤ 3.25). Patients with advanced LF had higher plasma levels of sCD14 and LBP than those with moderate or no LF, both at baseline and at follow-up. The following factors were significantly associated with advanced LF: the highest quartile of LBP (adjusted odds ratio [aOR] = 1.69; 95% confidence interval [CI] 1.02~2.81), current intravenous drug use (aOR = 1.82; 95% CI 1.06~3.12), baseline CD4 <200 cells/µl (aOR = 3.25; 95% CI 2.13~4.95), hepatitis C virus coinfection (aOR = 2.52; 95% CI 1.41~4.51) and age >50 years (aOR = 32.66; 95% CI 15.89~66.36). LF progression (increasing FIB-4) was significantly associated with increasing sCD14 level (ß = 1.11; 95% CI 0.97~1.26; p < 0.001) with covariate adjustment. CONCLUSION: The significant relationship between MT and LF may reveal pathogenic mechanisms and potential intervention targets of liver complications among people living with HIV in China.

Perinatal presepsin assessment: a new sepsis diagnostic tool?

Perinatal sepsis constitutes a medical emergency and is still one of the major causes of mortality and morbidity. The possibility of an early diagnosis of sepsis is still debated and controversial. In particular, clinical symptoms can be hidden by the association of sepsis with other perinatal diseases and/or by therapeutic strategies performed. In this context, there is evidence that the accuracy of standard of care diagnostic parameters (i.e. blood culture, C-reactive protein, procalcitonin) can be biased by additional confounding factors (gestational age, birth-weight, acute-chronic hypoxia). Therefore, the inclusion in clinical daily practice of new biomarkers of sepsis is of utmost importance. Of a panel of biomarkers, Presepsin (P-SEP) plays an important role in the development and response of the immune system and as an early marker of sepsis both in adult and pediatric patients. Therefore, in the present review we aim to offer an overview of the role of P-SEP in the early detection of perinatal sepsis as a trustworthy marker according to actual statements of official international institutions. Future perspectives regard the possibility of a longitudinal non-invasive biological fluids P-SEP assessment thus limiting the sample stress in high risk newborns.

The potential of soluble CD14 in discriminating nonalcoholic steatohepatitis from nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Although various noninvasive markers and prediction formulas for nonalcoholic steatohepatitis (NASH) have been reported, they are of value only in the diagnosis of the advanced fibrosis stage of NASH. In this study, we evaluated soluble CD14 (sCD14) as a diagnostic marker for discriminating NASH from nonalcoholic fatty liver disease (NAFLD) using an animal model and clinical specimens. METHODS: Serum sCD14 levels were measured in samples derived from mice with diet-induced NASH and patients using an enzyme-linked immunosorbent assay. Our cohort enrolled 126 patients with liver needle biopsy-proven NAFLD. RESULTS: The intestinal defense mechanism in NASH model mice was altered as a consequence of the unique gut environment. Elevated serum levels of sCD14 were observed in mice with diet-induced NASH, and the condition of the liver was exacerbated as a result of exposure to gut-derived endotoxin. We confirmed that the serum sCD14 levels in NAFL patients significantly differed from those in NASH patients. The area under the curve for distinguishing between NAFL and NASH was 0.891. Moreover, we found that serum sCD14 levels were weakly correlated with the inflammation grade based on the NAFLD activity score (NAS), the grade of fibrosis according to the Brunt fibrosis classification, and a positive correlation with the grade of ballooning based on NAS in patients with NAFLD. CONCLUSION: sCD14 could be a useful pathophysiological marker and diagnostic adjunct distinguishing NASH from NAFLD. The use of sCD14 may allow the screening and identification of high-risk groups for NASH development and support early therapeutic interventions.

The Diagnostic Value of Presepsin in Acute Appendicitis and Reference Ranges for Healthy Children.

OBJECTIVE: This study aimed to investigate the diagnostic value of presepsin, a new inflammatory marker for paediatric appendicitis, and to determine a reference range of presepsin for children. METHODS: This single-center prospective study was conducted in our paediatric emergency department between 1 February 2021 and 1 July 2021. Patients aged 0-18 years diagnosed with acute appendicitis, which was pathologically confirmed, and healthy volunteers in the same age group were included in the study. Serum presepsin levels were analysed using an enzyme-linked immunosorbent assay reader. In addition to presepsin, other acute-phase reactants, paediatric appendicitis scores and imaging methods were evaluated. RESULTS: There were 94 patients in the acute appendicitis group and 102 healthy volunteers in the control group. Median values were compared between the two groups, and no statistically significant differences were found (p = 0.544). In addition, no statistically signivficant differences in presepsin levels were found between the acute and perforated appendicitis groups (p = 0.344). The median (IQ1-IQ3) reference range for presepsin in healthy children was 0.9950 (0.7575-1.610) ng/mL. CONCLUSION: Presepsin is not a suitable marker for the diagnosis of acute appendicitis. We observed that serum presepsin levels were not elevated in paediatric appendicitis, which is a local infection, in contrast to previous studies.

Longitudinal Assessment of Multiple Immunological and Inflammatory Parameters during Successful DAA Therapy in HCV Monoinfected and HIV/HCV Coinfected Subjects.

In the direct-acting antiviral (DAA) era, it is important to understand the immunological changes after HCV eradication in HCV monoinfected (mHCV) and in HIV/HCV coinfected (HIV/HCV) patients. In this study, we analyzed sub-populations of monocytes, dendritic cells (DCs), T-lymphocytes and inflammatory biomarkers following initiation of DAA in 15 mHCV and 16 HIV/HCV patients on effective antiretroviral therapy at baseline and after sustained virological response at 12 weeks (SVR12). Fifteen age- and sex-matched healthy donors (HD) were enrolled as a control group. Activated CD4+ and CD8+ T-lymphocytes, mDCs, pDCs, MDC8 and classical, non-classical and intermediate monocytes were detected using flow cytometry. IP-10, sCD163 and sCD14 were assessed by ELISA while matrix metalloproteinase-2 (MMP-2) was measured by zymography. At baseline, increased levels of IP-10, sCD163 and MMP-2 were found in both HIV/HCV and mHCV patients compared to HD, whereas sCD14 increased only in HIV/HCV patients. After therapy, IP-10, sCD163 and sCD14 decreased, whereas MMP-2 persistently elevated. At baseline, activated CD8+ T-cells were high in HIV/HCV and mHCV patients compared to HD, with a decrease at SVR12 only in HIV/HCV patients. Activated CD4+ T-cells were higher in HIV/HCV patients without modification after DAAs therapy. These results suggest complex interactions between both viruses and the immune system, which are only partially reversed by DAA treatment.

Abnormal Levels of Some Biomarkers of Immune Activation Despite Very Early Treatment of Human Immunodeficiency Virus.

BACKGROUND: Despite early antiretroviral therapy (ART), ART-suppressed people with human immunodeficiency virus (HIV) (PWH) remain at higher risk for infections and infection-related cancers than the general population. The immunologic pathways that remain abnormal in this setting, potentially contributing to these complications, are unclear. METHODS: ART-suppressed PWH and HIV-negative controls, all cytomegalovirus seropositive and enriched for HIV risk factors, were sampled from an influenza vaccine responsiveness study. PWH were stratified by timing of ART initiation (within 6 months of infection [early ART] vs later) and nadir CD4+ T-cell count among later initiators. Between-group differences in kynurenine-tryptophan (KT) ratio, interferon-inducible protein 10, soluble CD14 and CD163, soluble tumor necrosis factor receptor 2, interleukin 6, and soluble urokinase plasminogen activator receptor were assessed after confounder adjustment. RESULTS: Most participants (92%) were male, reflecting the demographics of early-ART initiators in San Francisco. Most biomarkers were higher among later-ART initiators. Participants in the early-ART group achieved near-normal soluble tumor necrosis factor receptor 2, interleukin 6, and soluble urokinase plasminogen activator receptor levels, but substantially higher KT ratio than those without HIV after confounder adjustment (P = .008). Soluble CD14, soluble CD163, and interferon-inducible protein 10 trended similarly. CONCLUSIONS: While early-ART initiators restore near-normal levels of many inflammatory markers, the kynurenine pathway of tryptophan catabolism remains abnormally high. Because this pathway confers adaptive immune defects and predicts tuberculosis and cancer progression, this it may contribute to persistent risks of these complications in this setting.

Correlation of marker periodontopathogenic bacteria with the immune component sCD14 secretion level in inflammatory periodontal diseases.

Lipopolysaccharide of the cell wall of gram-negative bacteria is a highly active biological substance: its interaction with toll-like receptors-4 (TLR-4) of myeloid cells leads to the activation of a cascade of inflammatory reactions, which is accompanied by the release of the soluble CD14 receptor (sCD14), which can be considered not only as a marker of cell activation by endotoxin, but also as a marker of microbial translocation. The aim of the work was to assess the prognostic significance of the sCD14 level in the samples of the periodontal pocket in inflammatory periodontal diseases and the relationship of its secretion with marker periodontopathogens. For the study, washes were obtained from the periodontal pocket (88 samples in total) from patients with chronic periodontitis and intact periodontium. The sCD14 content was determined by ELISA; during real-time PCR, the marker periodontopathogens Aggregatibacter actinomycetemcomitans, Tannerella forsythia, Treponema denticola, Porphyromonas gingivalis, Prevotella intermedia, and Candida albicans were isolated. The study revealed differences in the level of sCD14 secretion by groups: in chronic periodontitis, its content was 8,5 times higher than in the control group and amounted to 17,2±4,06 ng/ml (p=0,006). The frequency of detecting genes of periodontal pathogenic bacteria was 89,3% in patients with periodontitis and 31,25% in the group with intact periodontium. An interesting dependence of the detection of periodontal pathogenic bacteria in the group of patients with chronic periodontitis was established depending on the content of sCD14. Thus, at high concentrations of soluble coreceptor, a greater number of periodontopathogenic bacteria of the I and II orders were released. Thus, in inflammatory periodontal diseases, the processes of sCD14 synthesis change, which is probably due to the colonization of periodontal pathogenic bacteria and the action of their toxins and aggression factors. The relationship of marker periodontopathogens with the level of secretion of the immune component sCD14 and its effect on the structure of the periodontal index reflect shifts in the processes of reparative regeneration of the oral mucosa and the regulation of local immunity in response to microbial invasion.

Serum sCD14, PGLYRP2 and FGA as potential biomarkers for multidrug-resistant tuberculosis based on data-independent acquisition and targeted proteomics.

Multidrug-resistant tuberculosis (MDR-TB), defined as tuberculosis (TB) resistant to at least isoniazid and rifampicin, is a major concern of TB control worldwide. However, the diagnosis of MDR-TB remains a huge challenge to its prevention and control. To identify new diagnostic methods for MDR-TB, a mass spectrometry strategy of data-independent acquisition and parallel reaction monitoring was used to detect and validate differential serum proteins. The bioinformatic analysis showed that the functions of differential serum proteins between the MDR-TB group and the drug-sensitive tuberculosis group were significantly correlated to the complement coagulation cascade, surface adhesion and extracellular matrix receptor interaction, suggesting a disorder of coagulation in TB. Here, we identified three potential candidate biomarkers such as sCD14, PGLYRP2 and FGA, and established a diagnostic model using these three candidate biomarkers with a sensitivity of 81.2%, a specificity of 90% and the area under the curve value of 0.934 in receiver operation characteristics curve to diagnose MDR-TB. Our study has paved the way for a novel method to diagnose MDR-TB and may contribute to elucidate the mechanisms underlying MDR-TB.

Influence of HIV-1 V2 sequence variability on bacterial translocation in antiretroviral naïve HIV-1 infected patients.

HIV-1 V2 domain binds α4ß7, which assists lymphocyte homing to gut-associated lymphoid tissue. This triggers bacterial translocation, thus contributing to immune activation. We investigated whether variability of V2 179-181 binding site could influence plasma levels of lipopolysaccharide (LPS) and soluble cluster of differentiation 14 (sCD14), markers of microbial translocation/immune activation. HIV gp120 sequences from antiretroviral naïve patients were analyzed for V2 tripeptide composition, length, net charge, and potential N-linked-glycosylation sites. LPS and sCD14 plasma levels were quantified. Clinical/immuno-virologic data were retrieved. Overall, 174 subjects were enrolled, 8% with acute infection, 71% harboring a subtype B. LDV179-181 was detected in 41% and LDI in 27%. No difference was observed between levels of LPS or sCD14 according to different mimotopes or according to other sequence characteristics. By multivariable analysis, only acute infection was significantly associated with higher sCD14 levels. In conclusion, no association was observed between V2 tripeptide composition and extent of bacterial translocation/immune activation.

Monocyte activation, HIV, and cognitive performance in East Africa.

Chronic inflammation associated with monocyte activation has been linked to HIV-related cognitive outcomes in resource-rich settings. Few studies have investigated this relationship in the African context where endemic non-HIV infections may modulate effects. We characterized immune activation biomarkers in Kenyan and Ugandan participants in relation to neuropsychological testing performance (NTP) from the African Cohort Study (AFRICOS). We focused on activation markers associated with monocytes (sCD14, sCD163, neopterin), T cells (HLA-DR+CD38+ on CD4+ and CD8+ T lymphocytes), and microbial translocation (intestinal fatty acid-binding protein, I-FABP). The HIV-infected (n = 290) vs. HIV-uninfected (n = 104) groups were similar in age with mean (SD) of 41 (9.5) vs. 39 (9.9) years, respectively (p = 0.072). Among HIV-infected participants, the mean (SD) current CD4+ count was 402 (232); 217 (75%) were on combination antiretroviral therapy (cART) and 199 (69%) had suppressed plasma HIV RNA. sCD14 was inversely correlated to NTP (r = - 0.14, p = 0.037) in models that included both HIV-infected and uninfected individuals, adjusted for HIV status and research site, whereas sCD163 was not (r = 0.041, p = 0.938). Neither of the T cell activation markers correlated with NTP. In the HIV-infected group, I-FABP was inversely associated with NTP (r = - 0.147, p = 0.049), even among those with suppressed plasma virus (r = - 0.0004, p = 0.025). Among the full group, HIV status did not appear to modulate the effects observed. In this cohort from East Africa, sCD14, but not sCD163, is associated with cognitive performance regardless of HIV status. Findings among both HIV-infected and HIV-uninfected groups is supportive that HIV and non-HIV-related inflammatory sources contribute to cognitive performance in this setting.

Evaluation of the clinical diagnostic value of traditional inflammatory markers and novel biomarkers in intracellular bacterial bloodstream infections.

OBJECTIVES: The clinical symptoms of the patients with intracellular bacterial bloodstream infections (Intra-bac BSIs) are atypical, and no early and accurate diagnostic biomarkers exist, which can easily lead to misdiagnosis, inappropriate and delayed treatment. Therefore, it is imperative to find novel biomarkers to help clinical diagnosis of Intra-bac BSIs. The present study was initiated to evaluate the diagnostic values of traditional inflammatory biomarkers (PCT, WBC and NEU% in identifying the patients with Intra-bac BSIs, and to further explore into the possibility of using suPAR and sCD14-ST as novel biomarkers for Intra-bac BSIs. METHODS: A multi-center retrospective study was conducted in three teaching hospitals in Chongqing. A total of 146 cases with BSIs, including 73 cases with Intra-bac BSIs and 73 cases with extracellular bacterial BSIs (Extra-bac BSIs) were enrolled in the retrospective study. We then prospectively enrolled 34 patients with Intra-bac BSIs, 34 patients with Extra-bac BSIs, 34 patients with viral infection and with normal medical examination results as a control group for further detection of sCD14-ST and suPAR by ELISA. RESULTS: PCT levels, WBC counts and NEU% in patients with Intra-bac BSIs were not increased or minimally increased, they were significantly lower than that with Extra-bac BSIs (P < 0.05), especially those with the Brucella bacterial BSIs, demonstrated a respective negative rate of 84% and 92% for PCT and WBC counts. In the prospective study, the levels of suPAR and sCD14-ST in both the Intra-bac BSIs and the Extra-bac BSIs groups were significantly higher than those in the viral infection group and normal control group (P < 0.05). The areas under the curve (AUC) of Intra-bac BSIs were 0.830 for suPAR, and 0.855 for sCD14-ST. The sensitivity, specificity, Youden's index for suPAR and sCD14-ST were respectively 76.5%, 88.2%, 0.647 and 94.1%, 64.7%, 0.588. CONCLUSIONS: Our multi-center study demonstrated that while the traditional inflammatory markers such as PCT, WBC counts, NEU% could not be served as promising diagnostic markers for Intra-bac BSIs; CRP can help guide the diagnosis of Intra-bac BSIs; Both suPAR and sCD14-ST could be considered as novel diagnostic biomarkers for Intra-bac BSIs as they showed good diagnostic accuracies in Intra-bac BSIs, especially suPAR.

High-Dose Neonatal Vitamin A Supplementation to Bangladeshi Infants Increases the Percentage of CCR9-Positive Treg Cells in Infants with Lower Birthweight in Early Infancy, and Decreases Plasma sCD14 Concentration and the Prevalence of Vitamin A Deficiency at Two Years of Age.

BACKGROUND: Vitamin A (VA) stores are low in early infancy and may impair development of the immune system. OBJECTIVE: This study determined if neonatal VA supplementation (VAS) affects the following: 1) development of regulatory T (Treg) cells; 2) chemokine receptor 9 (CCR9) expression, which directs mucosal targeting of immune cells; and 3) systemic endotoxin exposure as indicated by changed plasma concentrations of soluble CD14 (sCD14). Secondarily, VA status, growth, and systemic inflammation were investigated. METHODS: In total, 306 Bangladeshi infants were randomly assigned to receive 50,000 IU VA or placebo (PL) within 48 h of birth, and immune function was assessed at 6 wk, 15 wk, and 2 y. Primary outcomes included the following: 1) peripheral blood Treg cells; 2) percentage of Treg, T, and B cells expressing CCR9; and 3) plasma sCD14. Secondary outcomes included the following: 4) VA status measured using the modified relative dose-response (MRDR) test and plasma retinol; 5) infant growth; and 6) plasma C-reactive protein (CRP). Statistical analysis identified group differences and interactions with sex and birthweight. RESULTS: VAS increased (P = 0.004) the percentage of CCR9+ Treg cells (13.2 ± 1.37%) relative to PL (9.17 ± 1.15%) in children below the median birthweight but had the opposite effect (P = 0.04) in those with higher birthweight (VA, 9.13 ± 0.89; PL, 12.1 ± 1.31%) at 6 and 15 wk (values are combined mean ± SE). VAS decreased (P = 0.003) plasma sCD14 (1.56 ± 0.025 mg/L) relative to PL (1.67 ± 0.032 mg/L) and decreased (P = 0.034) the prevalence of VA deficiency (2.3%) relative to PL (9.2%) at 2 y. CONCLUSIONS: Neonatal VAS enhanced mucosal targeting of Treg cells in low-birthweight infants. The decreased systemic exposure to endotoxin and improved VA status at 2 y may have been due to VA-mediated improvements in gut development resulting in improved barrier function and nutrient absorption. This trial was registered at clinicaltrials.gov as NCT01583972 and NCT02027610.

No evidence of a synergistic effect of HIV infection and diabetes mellitus type 2 on fat distribution, plasma adiponectin or inflammatory markers.

BACKGROUND: Altered fat distribution and chronic inflammation are found in both persons living with HIV (PLWH) and persons with diabetes mellitus type 2 (DM2) and are known risk factors for cardiovascular diseases (CVD). We aimed to investigate if a synergistic effect of HIV infection and DM2 was found on fat distribution and inflammation. METHODS: A cross-sectional study was performed including PLWH with HIV RNA < 200 copies/mL (18 with DM2 (HIV + DM2+), 18 without DM2 (HIV + DM2-)) and controls (19 with DM2 (controls with DM2) and 25 without DM2 (healthy controls). We measured fat distribution using dual-energy X-ray absorptiometry scan. Plasma concentrations of adiponectin, interleukin-6 (IL-6), tumor necrosis factor-alfa (TNF- α) and soluble CD14 (sCD14) was measured using snap-frozen plasma. RESULTS: HIV + DM2+ and HIV + DM2- had comparable trunk/limb fat ratio. In contrast, HIV + DM2+ had a higher trunk/ limb fat ratio than controls with DM2 and healthy controls (p = 0.013 and p < 0.001, respectively). However, HIV + DM2+ and controls with DM2 had comparable amount of trunk fat mass (kg) (p = 0.254). A lower concentration of plasma adiponectin and higher concentration of IL-6 was found in HIV + DM2+ than in HIV + DM2-(p = 0.037 and p = 0.039) and in healthy controls (p = 0.001 and p = 0.012). In contrast, plasma adiponectin and IL-6 concentrations were comparable in HIV + DM2+ and controls with DM2 (p = 0.345 and p = 0.825). Concentration of sCD14 was comparable in HIV + DM2+ and HIV + DM2-(p = 0.850), but elevated in HIV + DM2+ compared to controls with DM2 (p < 0.001) and healthy controls (p = 0.007). No statistical interactions were found between HIV infection and DM2 for any of the depending variables. CONCLUSION: A synergistic effect of HIV and DM2 was not found for any of the outcomes. However, HIV + DM2+ had features related to both HIV infection and DM2 with a high trunk/limb ratio, high trunk fat mass, low concentration of plasma adiponectin and elevated concentrations of IL-6 and sCD14. This could contribute to elevated risk of CVD.

The limits and potentials of presepsin in orthopaedic surgery: state of the art and future directions.

Presepsin, i.e. the soluble cluster of differentiation 14-SubType (sCD14-ST), is an emerging biomarker for the diagnosis and evaluation of sepsis and infection. In 2004, Yaegashi et al. originally described presepsin as a potential biomarker; since then, several studies have investigated the role of presepsin in different infectious conditions, including neonatal sepsis, severe acute pancreatitis, infections in patients with haematological malignancies, severe community-acquired pneumonia, pacemaker and implantable cardioverter-defibrillator (ICD) pocket infections, surgical site infections (SSIs) and periprosthetic joint infects (PJIs). Moreover, presepsin has been also studied in the risk stratification in cardiac surgery patients, and as a biomarker in the perioperative management of patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA). This review aims to summarize the current knowledge about presepsin, focusing on the limits and potentials that the use of this biomarker could have in daily clinical practice. Presepsin is could be useful in daily clinical practice in orthopaedic surgery in the diagnosis and prevention of SSIs and PJIs. It is a cost-effective biomarker, but to improve its accuracy, it is important to carefully recalculate presepsin circulating values in patients with chronic kidney disease. However, further studies with larger patients' samples are needed to better validate the use of this biomarker in orthopaedics. In the future, synovial fluid presepsin might be a useful biomarker in the diagnosis of septic arthritis and PJIs.