OBJECTIVE

To identify molecular alterations associating with in vivo exposure of prostate carcinoma to chemotherapy and assess functional roles modulating tumor response and resistance.

METHODS

Patients with high-risk localized prostate cancer (tumor-node-metastasis>>or= T(2b) or prostate-specific antigen>>or= 15 ng/mL or Gleason glade>>or= 4+3) were enrolled into a phase II clinical trial of neoadjuvant chemotherapy with docetaxel and mitoxantrone followed by prostatectomy. Pretreatment prostate tissue was acquired by needle biopsy and posttreatment tissue was acquired by prostatectomy. Prostate epithelium was captured by microdissection, and transcript levels were quantitated by cDNA microarray hybridization. Gene expression changes associated with chemotherapy were determined by a random variance t test. Several were verified by quantitative reverse transcription PCR. In vitro analyses determining the influence of growth differentiation factor 15 (GDF15) on chemotherapy resistance were done.

RESULTS

Gene expression changes after chemotherapy were measured in <em>31</em> patients who completed four cycles of neoadjuvant chemotherapy. After excluding genes shown previously to be influenced by the radical prostatectomy procedure, we identified 51 genes with significant transcript level alterations following chemotherapy. This group included several cytokines, including GDF15, chemokine (C-X-C motif) ligand 10, and <em>interleukin</em> receptor 1beta. Overexpression of GDF15 or exposure of prostate cancer cell lines to exogenous recombinant GDF15 conferred resistance to docetaxel and mitoxantrone.

CONCLUSIONS

Consistent molecular alterations were identified in prostate cancer cells exposed to docetaxel and mitoxantrone chemotherapy. These alterations include transcripts encoding cytokines known to be regulated through the nuclear factor-kappaB pathway. Chemotherapy-induced cytokines and growth factors, such as GDF15, contribute to tumor cell therapy resistance and may serve as targets to improve responses.

Gp130-like receptor (GPL) is a newly identified cytokine receptor. A recent study reported the involvement of GPL, together with OSMR, in the formation of the receptor complex for IL-<em>31</em>, a novel immune cytokine with a skin tropism. In the present work, we analyzed the signaling properties of IL-<em>31</em> in glioblastoma and melanoma tumor cells. We demonstrate that in response to IL-<em>31</em>, its receptor complex recruits Jak1, Jak2, STAT1, -3, -5 signaling pathways, as well as the Pi3 kinase / AKT cascade. SHP-2 and Shc adapter molecules are also recruited and contribute to an increased activation of the MAP kinase pathway in response to IL-<em>31</em>. Different responses were observed depending on the expression of short or long GPL receptor isoform within the studied cell lines. We show that the short form of GPL receptor exerts a profound inhibitory effect on the signaling of IL-<em>31</em> and behaves as a dominant negative receptor.

OBJECTIVE

Several lines of evidence show that selenium (Se) has potential protective effects in osteoarthritis (OA), however the exact mechanism is still unclear. As interleukin-1β (IL-1β) is one of the key proinflammatory cytokines contributing to the progression in OA, we investigated the effect of Se in neutralizing the inflammatory effects of IL-1β on nitric oxide (NO) and prostaglandin E₂ (PGE₂) production, and the signaling pathways involved.

METHODS

Isolated primary human chondrocytes were pretreated with selenomethionine (SeMet) (0.5 μM SeMet) for 24 h then co-treated without or with IL-1β (10 pg/ml or 50 pg/ml) for another 24 h followed by RNA isolation. Gene expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2) was determined by quantitative Real Time-Polymerase Chain Reaction. Culture media concentrations of NO and PGE₂ were determined by nitrite (NO₂⁻) assay and immunoassay respectively. For analysis of cell signaling pathways, chondrocytes were pretreated with SeMet then stimulated with IL-1β for 0-45 min. The activity of IL-1β signaling pathways was determined by Western blot screening of phosphorylation states of signal transduction proteins.

RESULTS

SeMet inhibited chondrocyte gene expression of IL-1β induced iNOS (31-54%, P=0.031) and COX2 (50-65%, P=0.031) with corresponding reductions in both NO (19-47%, P=0.031) and PGE₂ (24-32%, P=0.031) production. Pretreatment with SeMet attenuated IL-1β induced activation of p38 MAPK (39%, P=0.039) but not the extracellular signal-regulated kinase pathways (ERK) 1/2, c-Jun N-terminal kinases (JNK) or nuclear factor κB (NFκB).

CONCLUSIONS

This study elucidates one potential protective mechanism of Se, namely through the alteration of cell signaling and downstream transcription of pro-inflammatory effects of IL-1β.

OBJECTIVE

Interleukin-1beta plays an important role in inflammation and gastric physiology. Polymorphisms of the IL1B gene have been associated with gastric atrophy and increased cancer risk, especially in Helicobacter pylori-infected subjects. The aim of this study was to evaluate the relationship between IL1B and IL1 receptor antagonist gene polymorphisms and the risk of multifocal atrophic gastritis in African Americans and Caucasians.

METHODS

Genomic DNA was extracted from gastric biopsies of 269 adult outpatients (172 African Americans and 97 Caucasians) undergoing diagnostic upper gastrointestinal endoscopy. Histological diagnosis was evaluated according to the updated Sydney System and H. pylori status was assessed by Steiner silver stain. Polymorphisms of the IL1B gene (-511, -31, and +3954) and the IL1 receptor antagonist were investigated by PCR-RFLP. Logistic regression models were used to identify variables associated with multifocal atrophic gastritis in terms of odds ratios and 95% confidence intervals.

RESULTS

Considering subjects with normal histology and nonatrophic gastritis as controls, a significant association was found between IL1B+3954T carrier and multiatrophic gastritis (OR 2.23, 95% CI 1.28, 3.88). Analyses stratified by ethnic group demonstrated similar associations in both African Americans (OR 2.23, 95% CI 1.14, 4.37) and Caucasians (OR 2.04, 95% CI 0.74, 5.65). A positive but not significant association was found between the allele 2 of the IL1RN and the presence of multifocal atrophic gastritis. The remaining proinflammatory polymorphisms were not associated with this precancerous lesion.

CONCLUSIONS

Our results suggest that the presence of IL1B+3954T allele is a risk marker for multifocal atrophic gastritis in the population studied.

OBJECTIVE

The Charlson comorbidity index (CCI) is a commonly used scale for assessing morbidity, but its role in assessing mortality in hemodialysis patients is not clear. Age, a component of CCI, is a strong risk factor for morbidity and mortality in chronic diseases and correlates with comorbidities. We hypothesized that the Charlson comorbidity index without age is a strong predictor of mortality in hemodialysis patients.

METHODS

A 6-year cohort of 893 hemodialysis patients was examined for an association between a modified CCI (without age and kidney disease) (mCCI) and mortality.

RESULTS

Patients were 53±15 years old (mean±SD), had a median mCCI score of 2, and included 47% women, <em>31</em>% African Americans and 55% diabetics. After adjusting for case-mix and nutritional and inflammatory markers including C-reactive protein and <em>interleukin</em>-6, 2nd (mCCI: 1-2), 3rd (mCCI=3), and 4th (mCCI: 4-9) quartiles compared to 1st (mCCI=0) quartiles showed death hazard ratios (95% confidence intervals) of 1.43 (0.92-2.23), 1.70 (1.06-2.72), and 2.33 (1.43-3.78), respectively. The mCCI-death association was robust in non-African Americans. The CCI-death association linearity was verified in cubic splines. Each 1 unit higher mCCI score was associated with a death hazard ratio of 1.16 (1.07-1.27).

CONCLUSIONS

CCI independent of age is a robust and linear predictor of mortality in hemodialysis patients, in particular in non-African Americans.

Areas where Plasmodium falciparum transmission is holoendemic are characterized by high rates of pediatric severe malarial anemia (SMA) and associated mortality. Although the etiology of SMA is complex and multifactorial, perturbations in inflammatory mediator production play an important role in the pathogenic process. As such, the current study focused on identification of inflammatory biomarkers in children with malarial anemia. Febrile children (3 to 30 months of age) presenting at Siaya District Hospital in western Kenya underwent a complete clinical and hematological evaluation. Children with falciparum malaria and no additional identifiable anemia-promoting coinfections were stratified into three groups: uncomplicated malaria (hemoglobin [Hb] levels of ≥11.0 g/dl; n = <em>31</em>), non-SMA (Hb levels of 6.0 to 10.9 g/dl; n = 37), and SMA (Hb levels of <6.0 g/dl; n = 80). A Luminex hu25-plex array was used to determine potential biomarkers (i.e., <em>interleukin</em> 1β [IL-1β], IL-1 receptor antagonist [IL-1Ra], IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-15, IL-17, tumor necrosis factor alpha [TNF-α], alpha interferon [IFN-α], IFN-γ, granulocyte-macrophage colony-stimulating factor [GM-CSF], macrophage inflammatory protein 1 alpha [MIP-1α], MIP-1β, IFN-inducible protein of 10 kDa [IP-10], monokine induced by IFN-γ [MIG], eotaxin, RANTES, and monocyte chemoattractant protein 1 [MCP-1]) in samples obtained prior to any treatment interventions. To determine the strongest biomarkers of anemia, a parsimonious set of predictor variables for Hb was generated by least-angle regression (LAR) analysis, controlling for the confounding effects of age, gender, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and sickle cell trait, followed by multiple linear regression analyses. IL-12p70 and IFN-γ emerged as positive predictors of Hb, while IL-2R, IL-13, and eotaxin were negatively associated with Hb. The results presented here demonstrate that the IL-12p70/IFN-γ pathway represents a set of biomarkers that predicts elevated Hb levels in children with falciparum malaria, while activation of the IL-13/eotaxin pathway favors more profound anemia.

BACKGROUND

Overweight and obesity have been associated with better survival in patients with chronic obstructive pulmonary disease (COPD). On the other hand, excess body weight is associated with abnormal metabolic and inflammatory profiles that define the metabolic syndrome and predispose to cardiovascular diseases. This study was undertaken to evaluate the impact of overweight and obesity on the prevalence of the metabolic syndrome and on the metabolic and inflammatory profiles in patients with COPD.

METHODS

Twenty-eight male patients with COPD were divided into an overweight/obese group [ n = 16, body mass index (BMI) = 33.5 +/- 4.2 kg/m(2)] and normal weight group (n = 12, BMI = 21.1 +/- 2.6 kg/m(2)). Anthropometry, pulmonary function and body composition were assessed. The metabolic syndrome was diagnosed according to waist circumference, circulating levels of triglyceride and high-density lipoprotein cholesterol levels, fasting glycemia and blood pressure. C-reactive protein, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), leptin and adiponectin plasma levels were measured.

RESULTS

Airflow obstruction was less severe in overweight/obese compared with normal weight patients (forced expiratory volume(1): 51 +/- 19% versus 31 +/- 12% predicted, respectively, P < 0.01). The metabolic syndrome was diagnosed in 50% of overweight/obese patients and in none of the normal weight patients. TNF-alpha, IL-6 and leptin were significantly higher in overweight/obese patients whereas the adiponectin levels were reduced in the presence of excess weight.

CONCLUSIONS

The metabolic syndrome was frequent in overweight/obese patients with COPD. Obesity in COPD was associated with a spectrum of metabolic and inflammatory abnormalities.

Chronic heart failure is a state of immune activation, and endotoxin is a potential trigger for cytokine production. Our aim was to study whether immune activation and endotoxemia occur in adults with congenital heart disease. We prospectively measured tumor necrosis factor (TNF)-alpha, soluble TNF receptors (sTNFR-1, sTNFR-2), <em>interleukin</em>-6, <em>interleukin</em>-10, endotoxin, and soluble CD14 levels in 52 consecutive adults with congenital heart disease (age 34 +/- 2 years [mean +/- SEM]) and 18 healthy controls (age <em>31</em> +/- 1 years). A variety of congenital heart lesions were studied: single ventricle physiology (n = 15), systemic right ventricle (n = 7), tetralogy of Fallot (n = 20), and "other" congenital heart disease (n = 10). Patients were subgrouped into asymptomatic (New York Heart Association [NYHA] class I, n = 11), mild (NYHA class II, n = 30), and moderate/severe (NYHA class III/IV, n = 11) categories. Patients had elevated TNF and <em>interleukin</em>-6 levels compared with controls (TNF 2.8 vs 2.1 pg/ml, p <0.05; <em>interleukin</em>-6 8.5 vs 5.7 pg/ml, p <0.001). TNF levels were higher in patients with moderate/severe symptoms compared with patients who were asymptomatic or had mild symptoms (p <0.05). Soluble TNFR-1 levels related directly to the degree of systemic ventricular impairment (p <0.05). There were no significant differences in sTNFR-1, sTNFR-2, <em>interleukin</em>-10, or sCD14 levels between patients and controls. Endotoxin levels were greater in patients with congenital heart disease versus controls (0.40 vs 0.26 endotoxin units/ml, p <0.0001). Thus, adults with congenital heart disease have elevated levels of inflammatory cytokines and bacterial endotoxin, which relate to functional status. Congenital heart disease in adults may be amenable to novel anti-inflammatory therapies in selected patients.

BACKGROUND

Patients co-infected with advanced HIV and tuberculosis are at risk of tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) and death soon after initiation of antiretroviral therapy (ART). Tuberculosis-associated IRIS has been associated with quicker recovery of cellular immune responses after ART initiation and early mortality with slower recovery of these responses. We aimed to assess whether patients who have these outcomes have distinct immunological profiles before and after ART initiation.

METHODS

We undertook this prospective cohort study at 22 public clinics and the main public hospital in Gaborone, Botswana, in ART-naive adults (aged ≥21 years) with advanced HIV (CD4 cell counts ≤125 cells per μL) and pulmonary tuberculosis. We obtained data for clinical variables and for levels of 29 plasma biomarkers, quantified by Luminex assay. We classified patients as having tuberculosis-associated IRIS, early mortality, or survival without a diagnosis of tuberculosis-associated IRIS (controls), on the basis of outcomes recorded in the 6 months after ART initiation. We used rank-sum or χ(2) tests, and logistic regression with odds ratios (OR) and 95% CIs, to assess the association between variables measured before and 4 weeks after ART initiation with death and tuberculosis-associated IRIS, compared with controls.

RESULTS

Between Nov 12, 2009, and July 3, 2013, we enrolled 201 participants. <em>31</em> (15%) patients left the study before ART initiation, leaving 170 (85%) patients for analysis. Patients with tuberculosis-associated IRIS had reduced pre-ART concentrations of several pro-inflammatory biomarkers, including <em>interleukin</em> (IL)-6 (adjusted OR per 1 log10 increase 0·40 [95% CI 0·18-0·89]). However, patients with early death had increased pre-ART concentrations of inflammatory biomarkers, including monocyte chemoattractant protein-1 (adjusted OR 9·0 [95% CI 1·0-80·0]) and tumour necrosis factor (TNF)α (7·8 [1·1-55·2]). At week 4 after ART initation, tuberculosis-associated IRIS was independently associated with greater increases in several inflammatory biomarkers, including IL-6 (adjusted OR 1·7 [95% CI 1·2-2·5]) and TNFα (1·5 [1·0-2·2]), versus controls. Death was likewise associated with greater increases in systemic inflammatory markers, including granulocyte colony-stimulating factor (adjusted OR 2·8 [95% CI 1·3-6·1]), IL-12p40 (1·8 [1·0-3·4]), and IL-15 (2·0 [1·1-3·7]), versus controls. However, changes in CD4 cell count during ART, which were similar between controls and patients with tuberculosis-associated IRIS (p=0·45), were substantially lower in patients who died (p=0·006).

CONCLUSIONS

Distinct immunological profiles before and after ART initiation characterise patients with advanced HIV and tuberculosis who have tuberculosis-associated IRIS and death. Interventions that decrease inflammation while promoting cellular immune recovery during ART should be considered in patients co-infected with HIV and tuberculosis.

BACKGROUND

National Institutes of Health and the Penn Center for AIDS Research.

BACKGROUND: Inflammatory mechanisms in heart disease are of great interest. The proinflammatory cytokine <em>interleukin</em> (IL) 6 has been linked to increased morbidity in unstable angina pectoris and depressed myocardial function in heart failure (HF). METHODS: We studied the relation of IL-6 levels to C-reactive protein (CRP), infarction size, left ventricular function, and HF in acute myocardial infarction (MI) and after hospital discharge in <em>31</em> consecutive patients (19 males, mean age 69+/-13 years). Blood sampling for IL-6 was performed on admittance, four times on day 1, twice on day 2, and once daily on days 3-5, and 6 and 12 weeks later. Clinical signs of HF were evaluated daily during hospitalization and after 6 and 12 weeks. Echocardiography was performed on day 3 and at 6 weeks. RESULTS: IL-6 showed a curved time course with elevated levels already on admittance (mean+/-S.D. 19.3+/-26.9 ng/l), thereafter increasing to a peak on days 1 and 2 (maximum 68.5+/-152.9 ng/l), and then declining rapidly to lower, although not normalized, levels during hospitalization and at 6 and 12 weeks. CRP showed a similar time pattern, but with a later peak and a seemingly less rapid decline in levels. Mean levels of IL-6 and CRP on days 1-5 correlated highly (r=0.794, p<0.0001). IL-6 and infarction size did not correlate. HF during hospitalization and at 6 weeks was not related to IL-6; however, patients with HF at 12 weeks had higher IL-6 levels, both at 6 and 12 weeks. Patients on ACE inhibitors or diuretics at discharge had higher IL-6 levels at 6 weeks. IL-6 during hospitalization was not related to LVF; yet, patients with depressed LVF in the hospital and at 6 weeks had higher IL-6 levels at 6 and 12 weeks. CONCLUSIONS: IL-6 in acute MI shows a curved time course and is highly correlated to CRP. It peaks on days 1 and 2 and remains elevated even after 12 weeks. Increased IL-6 levels after hospital discharge are associated with HF and depressed LVF. Whether anti-inflammatory agents will influence left ventricular dysfunction and outcome postacute MI has yet to be determined.

<AbstractText>Obesity is associated with an increased risk of breast cancer, including the estrogen receptor (ER)-positive subtype in postmenopausal women. Whether excess adiposity is associated with increased risk in women with a normal body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is unknown.</AbstractText><AbstractText>To investigate the association between body fat and breast cancer risk in women with normal BMI.</AbstractText><AbstractText>This ad hoc secondary analysis of the Women's Health Initiative (WHI) clinical trial and observational study cohorts was restricted to postmenopausal participants with a BMI ranging from 18.5 to 24.9. Women aged 50 to 79 years were enrolled from October 1, 1993, through December <em>31</em>, 1998. Of these, 3460 participants underwent body fat measurement with dual-energy x-ray absorptiometry (DXA) at 3 US designated centers with follow-up. At a median follow-up of 16 years (range, 9-20 years), 182 incident breast cancers had been ascertained, and 146 were ER positive. Follow-up was complete on September 30, 2016, and data from October 1, 1993, through September 30, 2016, was analyzed August 2, 2017, through August 21, 2018.</AbstractText><AbstractText>Body fat levels were measured at baseline and years 1, 3, 6, and 9 using DXA. Information on demographic data, medical history, and lifestyle factors was collected at baseline. Invasive breast cancers were confirmed via central review of medical records by physician adjudicators. Blood analyte levels were measured in subsets of participants.</AbstractText><AbstractText>Among the 3460 women included in the analysis (mean [SD] age, 63.6 [7.6] years), multivariable-adjusted hazard ratios for the risk of invasive breast cancer were 1.89 (95% CI, 1.21-2.95) for the highest quartile of whole-body fat and 1.88 (95% CI, 1.18-2.98) for the highest quartile of trunk fat mass. The corresponding adjusted hazard ratios for ER-positive breast cancer were 2.21 (95% CI, 1.23-3.67) and 1.98 (95% CI, 1.18-3.<em>31</em>), respectively. Similar positive associations were observed for serial DXA measurements in time-dependent covariate analyses. Circulating levels of insulin, C-reactive protein, <em>interleukin</em> 6, leptin, and triglycerides were higher, whereas levels of high-density lipoprotein cholesterol and sex hormone-binding globulin were lower in those in the uppermost vs lowest quartiles of trunk fat mass.</AbstractText><AbstractText>In postmenopausal women with normal BMI, relatively high body fat levels were associated with an elevated risk of invasive breast cancer and altered levels of circulating metabolic and inflammatory factors. Normal BMI categorization may be an inadequate proxy for the risk of breast cancer in postmenopausal women.</AbstractText><AbstractText>ClinicalTrials.gov identifier: NCT00000611.</AbstractText>

Aims: This study aimed to make a comparison between the clinical laboratory-related factors, complete blood count (CBC) indices, cytokines, and lymphocyte subsets in order to distinguish severe coronavirus disease 2019 (COVID-19) cases from the non-severe ones.

<strong class="sub-title"> Materials and methods: </strong> Relevant studies were searched in PubMed, Embase, Scopus, and Web of Science databases until March <em>31</em>, 2020. Cochrane's Q test and the I² statistic were used to determine heterogeneity. We used the random-effect models to pool the weighted mean differences (WMDs) and 95% confidence intervals (CIs).

Key findings: Out of a total of 8557 initial records, 44 articles (50 studies) with 7865 patients (ranging from 13 to 1582), were included. Our meta-analyses with random-effect models showed a significant decrease in lymphocytes, monocyte, CD4+ T cells, CD8+ T cells, CD3 cells, CD19 cells, and natural killer (NK) cells and an increase in the white blood cell (WBC), neutrophils, neutrophil to lymphocyte ratio (NLR), C-reactive protein (CRP)/hs-CRP, erythrocyte sedimentation rate (ESR), ferritin, procalcitonin (PCT), and serum amyloid A (SAA), interleukin-2 (IL-2), IL-2R, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (INF-γ) in the severe group compared to the non-severe group. However, no significant differences were found in IL-1β, IL-17, and CD4/CD8 T cell ratio between the two groups.

Significance: Decrease in total lymphocytes and lymphocyte subsets as well as the elevation of CRP, ESR, SAA, PCT, ferritin, and cytokines, but not IL-1β and IL-17, were closely associated with COVID-19 severity, implying reliable indicators of severe COVID-19.

Keywords: COVID-19; Cytokine; Laboratory findings; Lymphocyte subsets; Meta-analysis; Novel coronavirus; SARS-CoV-2.

Background: Prognostic factors for the Coronavirus disease 2019 (COVID1-9) are not well established. This study aimed to summarize the available data on the association between the severity of COVID-19 and common hematological, inflammatory and biochemical parameters.

Methods: EMBASE, MEDLINE, Web of sciences were searched to identify all published studies providing relevant data. Random-effects meta-analysis was used to pool effect sizes.

<strong class="sub-title"> Results: </strong> The bibliographic search yielded 287 citations, <em>31</em> of which were finally retained. Meta-analysis of standardized mean difference (SMD) between severe and non-severe COVID-19 cases showed that CK-MB (SMD = 0.68,95%CI: 0.48;0.87; <i>P-value:</i>< 0.001), troponin I (SMD = 0.71, 95%CI:0.42;1.00; <i>P-value:</i>< 0.001), D-dimer (SMD = 0.54,95%CI:0.<em>31</em>;0.77; <i>P-value:</i>< 0.001), prothrombin time (SMD = 0.48, 95%CI:0.23;0.73; <i>P-value:</i> < 0.001), procalcitonin (SMD = 0.72, 95%CI: 0.34;1,11; <i>P-value:</i>< 0.001), <em>interleukin</em>-6 (SMD = 0.93, 95%CI: 0.25;1.61;<i>P-value:</i> 0.007),C-reactive protein (CRP) (SMD = 1.34, 95%CI:0.83;1.86; <i>P-value:</i>< 0.001), ALAT (SMD = 0.53, 95%CI: 0.34;0,71; <i>P-value:</i>< 0.001), ASAT (SMD = 0.96, 95%CI: 0.58;1.34; <i>P-value:</i> < 0.001), LDH (SMD = 1.36, 95%CI: 0.75;1.98; <i>P-value:</i>< 0.001), CK (SMD = 0.48, 95%CI: 0.10;0.87; <i>P-value:</i>0.01), total bilirubin (SMD = 0.32, 95%CI: 0.18;0.47;<i>P-value:</i> < 0.001), γ-GT (SMD = 1.03, 95%CI: 0.83;1.22; <i>P-value:</i> < 0.001), myoglobin (SMD = 1.14, 95%CI: 0.81;1.47; <i>P-value:</i>< 0.001), blood urea nitrogen (SMD = 0.32, 95%CI: 0.18;0.47;<i>P-value:</i>< 0.001) and Creatininemia (SMD = 0.18, 95%CI: 0.01;0.35; <i>P-value:</i>0.04) were significantly more elevated in severe cases, in opposition to lymphocyte count (SMD = -0.57, 95%CI:-0.71; - 0.42; <i>P-value:</i> < 0.001) and proportion of lymphocytes (SMD = -0.81, 95%CI: - 1.12; - 0.49; <i>P-value:</i>< 0.001) which were found to be significantly lower in severe patients with other biomarker such as thrombocytes (SMD = -0.26, 95%CI: - 0.48; - 0.04; <i>P-value:</i>0.02), eosinophils (SMD = - 0.28, 95%CI:-0.50; - 0.06; <i>P-value:</i>0.01), haemoglobin (SMD = -0.20, 95%CI: - 0.37,-0.03; <i>P-value:</i>0.02), albuminemia (SMD-1.67,95%CI -2.40; - 0.94; <i>P-value:</i>< 0.001), which were also lower. Furthermore, severe COVID-19 cases had a higher risk to have lymphopenia (RR =1.66, 95%CI: 1.26;2.20; <i>P-value</i>:0.002), thrombocytopenia (RR = 1.86, 95%CI: 1.59;2.17; <i>P-value</i>: < 0.001), elevated procalcitonin level (RR = 2.94, 95%CI: 2.09-4.15; <i>P-value</i>:< 0.001), CRP (RR =1.41,95%CI: 1.17-1.70; <i>P-value</i>:0.003), ASAT(RR =2.27, 95%CI: 1.76;2.94; <i>P-value</i>:< 0.001), CK(RR = 2.61, 95%CI: 1.35;5.05; <i>P-value</i>: 0.01), Creatininemia (RR = 3.66, 95%CI: 1.53;8.81; <i>P-value</i>: 0.02) and LDH blood level (RR = 2.03, 95%CI: 1.42;290; <i>P-value</i>: 0.003).

Conclusion: Some inflammatory (procalcitonin, CRP), haematologic (lymphocyte, Thrombocytes), and biochemical (CK-MB, Troponin I, D-dimer, ASAT, ALAT, LDH, γ-GT) biomarkers are significantly associated with severe COVID-19. These biomarkers might help in prognostic risk stratification of patients with COVID-19.

Keywords: COVID-19; Meta-analysis; Prognostic biomarkers.

We studied <em>31</em> blunt trauma victims, Injury Severity Score (ISS) mean 14 (9-57), for the pattern of release of C-reactive protein (CRP) and cytokine <em>interleukin</em>-6 (IL-6). Blood samples were taken on admission (within 6 hours of injury), as well as at 24 hours, and 3, 5 and 7 days. Serum CRP and IL-6 were measured by ELISA. Subsequent surgical events and sepsis were noted. Serum IL-6 levels on admission were considerably higher (median 135 pg mL-1) than our laboratory reference range (< 5 pg mL-1), slowly returning towards reference values during the study. Serum CRP levels were similar to laboratory normal values on admission (median 8.5 mg L-1 vs 7.5 mg L-1), reaching peak values (median 110 mg L-1) after 3 days. There was a correlation between IL-6 release and ISS but not between CRP and ISS. Patients undergoing surgery showed further increases in IL-6 and CRP levels postoperatively. Of 24 surgical patients, 9 developed postoperative sepsis. In blunt trauma patients, early assessment of the markers CRP or IL-6 were not useful for the diagnosis of sepsis. Levels of CRP following accidental or surgical trauma should be assessed with caution.

Animal studies have shown that an acute stressor in close temporal proximity to immune challenge can enhance the response to delayed-type hypersensitivity and antibody response to vaccination. The current study examined the effects of acute exercise or mental stress prior to influenza vaccination on the subsequent antibody response to each of the three viral strains. Sixty young healthy adults (<em>31</em> men, 29 women) were randomly allocated to one of three task conditions: dynamic exercise, mental stress, or control. After an initial baseline, participants completed their allocated 45 min task and then received the influenza vaccine. Plasma cortisol and <em>interleukin</em>-6 were determined at the end of baseline, after the task, and after 60 min recovery. Antibody titres were measured pre-vaccination and at 4 weeks and 20 weeks post-vaccination follow-ups. For the A/Panama strain, women in both the exercise and mental stress conditions showed higher antibody titres at both 4 and 20 weeks than those in the control condition, while men responded similarly in all conditions. <em>Interleukin</em>-6 at +60 min recovery was found to be a significant predictor of subsequent A/Panama antibody response in women. In line with animal research, the current study provides preliminary evidence that acute stress can enhance the antibody response to vaccination in humans.

BACKGROUND

The effectiveness of intra-articular platelet-rich plasma (PRP) injections has been evaluated in knee chondroplasty and osteoarthritis (OA); however, little evidence of its efficacy in hip OA exists.

OBJECTIVE

To compare the therapeutic efficacy of autologous PRP, hyaluronic acid (HA), or a combination of both (PRP+HA) in hip OA.

METHODS

Randomized controlled trial; Level of evidence, 1.

METHODS

Patients aged between 18 and 65 years who were treated with outpatient surgery and who had hip OA and pain intensity at baseline of >20 on a 100-mm visual analog scale (VAS) were recruited for this study. Exclusion criteria were extensive surgery; presence of excessive deformities; or rheumatic, infective, cardiovascular, or immune system disorders. The primary outcome measure was a change in pain intensity as assessed by the VAS at 2, 6, and 12 months after treatment. Secondary outcome measures were the Harris Hip Score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and concentration of growth factors in PRP and their correlation with clinical outcomes. Clinical outcomes were evaluated by assessors and collectors blinded to the type of treatment administered.

RESULTS

A total of 111 patients were randomly assigned to 3 groups and received 3 weekly injections of either PRP (44 patients), PRP+HA (<em>31</em> patients), or HA (36 patients). At all follow-ups, the PRP group had the lowest VAS scores. In particular, at 6-month follow-up, the mean VAS score was 21 (95% CI, 15-28) in the PRP group, 35 (95% CI, 26-45) in the PRP+HA group, and 44 (95% CI, 36-52) in the HA group (P < .0005 [PRP vs HA] and P = .007 [PRP vs PRP+HA]; F = 0.663). The WOMAC score of the PRP group was significantly better at 2-month follow-up (mean, 73; 95% CI, 68-78) and 6-month follow-up (mean, 72; 95% CI, 67-76) but not at 12-month follow-up. A significant, "moderate" correlation was found between <em>interleukin</em>-10 and variations of the VAS score (r = 0.392; P = .040). Significant improvements were achieved in reducing pain and ameliorating quality of life and functional recovery.

CONCLUSIONS

Results indicated that intra-articular PRP injections offer a significant clinical improvement in patients with hip OA without relevant side effects. The benefit was significantly more stable up to 12 months as compared with the other tested treatments. The addition of PRP+HA did not lead to a significant improvement in pain symptoms.

Chronic inflammation has been implicated as a cofactor in the development of several human cancers. <em>Interleukin</em>-1beta is a key pro-inflammatory cytokine. We have previously shown associations between polymorphisms at position -511 and -<em>31</em> in the promoter of the IL1B gene and risk of non-small cell lung cancer. In this study we investigated the functional role of the -<em>31</em> T/C SNP in the regulation of the IL1B gene. The -<em>31</em> T/C polymorphism is located in the core promoter and may affect the binding of transcription factors and thereby promoter activity. We therefore established a promoter reporter assay to explore the impact of the promoter variants on the expression of the gene. In the present study, we show that expression from the T-variant of the promoter was higher (p<0.001) than from the C-variant, in A549 cells. Electrophoretic mobility shift assays revealed differential binding of proteins to a promoter fragment containing the SNP. Interestingly, a highly specific complex formed on the C-variant that was not present on the T-variant. Supershift experiments implicated binding of both the CCAAT-enhancer binding protein beta (C/EBPbeta, also called NF-IL6) transcription factor and the TATA-box binding protein (TBP) to the SNP region. Due to the high frequency of this SNP, differences in IL1B gene expression caused by the variants may have significant biological impact in the population.

Affinity chromatography and reverse-phase high-performance liquid chromatography was used to purify a soluble <em>interleukin</em> 1 beta (IL-1 beta) specific binding protein from the supernatant of a human B cell line, Raji. The purified protein specifically bound 125I IL-1 beta forming a 60-kD complex in nonreducing conditions and a 70-kD complex in reducing conditions. Binding was found to be displaceable by mature human and murine IL-1 beta and human <em>31</em>-kD IL-1 beta propeptide, but not displaceable by human and murine IL-1 alpha or human IL-1 receptor (IL-1R) antagonist. Ligand blotting revealed a 47-kD molecule that specifically bound IL-1 beta. Measurement of binding affinity of the cell surface Raji IL-1R (Kd = 2.2 nm) and the Raji soluble (s)IL-1R (Kd = 2.7 nm) demonstrated a similar affinity for 125I IL-1 beta. Purified sIL-1R inhibited binding of IL-1 beta to cell lines with both type I (80 kD) and type II (65 kD) IL-1Rs, but did not interfere with IL-1 alpha binding. This natural sIL-1R may function as an important regulatory molecule of IL-1 beta in vivo.

The aim of this study was to assess monocyte/macrophage function, as defined by lipopolysaccharide (LPS)-induced production of tumour necrosis factor (TNF)-alpha, <em>interleukin</em> (IL)-10 and interferon (IFN)-gamma by stimulated whole blood cultures in patients with colorectal carcinoma before and after surgical resection. Forty colorectal cancer patients prior to surgery and <em>31</em> healthy controls were studied. Heparinized venous blood was taken from colorectal cancer patients prior to surgery and from healthy controls. Serial samples were obtained at least 3-6 weeks post-operatively. Blood was stimulated with LPS for 24 h and supernatants were assayed for TNF-alpha, IFN-gamma and IL-10 by enzyme-linked immunosorbent assay. LPS-induced production of TNF-alpha and of IFN-gamma was reduced in patients with colorectal carcinoma compared to controls (TNF-alpha, 11,269 pg/ml(-1) ¿12,598¿; IFN-gamma, 0.00 pg/ml(-1) ¿226¿; median ¿IQR¿) (TNF-alpha, 20,576 pg/m(-1) ¿11,637¿, P < 0.0001; IFN-gamma, 1,048 ¿2,428¿, P = 0.0051, Mann-Whitney U-test). Production in patients after surgery had increased (TNF-alpha: 17,620 pg/ml(-1) ¿7,986¿; IFN-gamma. 410 pg/ml(-1) ¿2,696¿; mean ¿s.d.¿) and were no longer significantly reduced when compared to controls (TNF-alpha, P = 0.28; IFN-gamma, P = 0.76). Production of TNF-alpha and IFN-gamma prior to surgery were reduced to a greater extent in patients with Dukes' stage C tumours compared to those with Dukes' stage A and B stage. There was no difference in IL-10 production between any group. Monocytes/macrophages from patients with colorectal carcinoma are refractory to LPS stimulation as reflected by reduction in TNF-alpha and IFN-gamma production and this is more pronounced in patients with advanced stage tumours. This suppression is not mediated by IL-10 and disappears following surgical resection of the tumour. This provides evidence for tumour induced suppression of immune function in patients with colorectal cancer and identifies a potential therapeutic avenue.

This study tested the hypothesis that the inflammatory cytokine, <em>interleukin</em>-6, contributes to the hypertensive response to acute psychosocial stress, caused by switching male mice to a cage previously occupied by a different male mouse. Male C57BL6 (WT) and <em>interleukin</em>-6 (IL-6) knockout (KO) mice were implanted with biotelemetry devices to monitor mean arterial pressure, heart rate, and motor activity in the unrestrained state. Baseline mean arterial pressure was 98+/-1 and 103+/-1 for WT and IL-6 KO mice. Cage switch increased mean arterial pressure by 42+/-2 mm Hg in WT mice, but this was blunted significantly in KO mice (<em>31</em>+/-3 mm Hg peak increase). Area under the curve for the first 90 minutes also was significantly less. Heart rate and motor activity increased similarly, and there also were no differences in the increases in plasma renin activity or plasma norepinephrine concentration between WT and KO mice. Thus, the acute hypertensive response to psychosocial stress depends significantly on IL-6, and the effect appears to be specific for blood pressure rather than to a global impairment in the response to stress. However, because perfusion of the isolated mesenteric bed with phenylephrine and chronic infusion of angiotensin II caused similar responses in WT and IL-6 KO mice, it is clear that future studies are needed to determine to what extent the acute blood pressure effect of IL-6 is stress-specific.

BACKGROUND

Recent evidence suggests that atherosclerosis is a chronic inflammatory process. In this study, we examined several markers of inflammation in men with coronary heart disease (CHD) and appropriate controls.

METHODS

The concentrations of C-reactive protein (CRP), serum amyloid A (SAA), <em>interleukin</em>-6 (IL-6), and soluble intracellular adhesion molecule (sICAM-1) were examined in 100 men with angiographically documented CHD and 100 age-, gender-, and smoking-matched controls with no history of CHD. We assessed the association of these markers with severity of disease as indicated by >50% obstruction in one vessel (n = 30), two vessels (n = 39), or three vessels (n = <em>31</em>).

RESULTS

Significant increases were noted in serum CRP (median for cases vs controls, 3.4 vs 1.5 mg/L; P <0.0001), SAA (5.9 vs 3.7 mg/L; P <0.005), and IL-6 (2.3 vs 1.7 ng/L; P <0. 013) in patients with CHD compared with controls. These differences remained significant after correction for age, smoking, hypertension, diabetes, and lipid and homocysteine concentrations. Plasma sICAM-1 was not significantly different between the two groups (335 vs 339 microg/L). No significant correlation was seen between these markers and the severity of coronary disease.

CONCLUSIONS

Concentrations of CRP, SAA, and IL-6 were increased in patients with CHD but failed to correlate with severity of coronary disease. These markers might reflect the diffuse atherosclerotic process in the vascular system rather than the degree of localized obstruction from coronary lesions.

OBJECTIVE

Recent research implicated place of an immune mechanism in the pathophysiology of obsessive-compulsive disorder (OCD). Despite increasing evidence involvement of cytokine release in OCD, results of the studies are inconsistent. The aim of this study was to evaluate the plasma levels of the cytokines; tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in OCD patients.

METHODS

Plasma concentrations of TNF-alpha and IL-6 were measured in 31 drug-free outpatients with OCD, and 31-year age and sex-matched healthy controls. TNF-alpha and IL-6 concentrations in blood were determined by enzyme-linked immunosorbent assay (ELISA).

RESULTS

Both TNF-alpha and IL-6 levels showed statistically significant increases in OCD patients compared to controls (P < .000, P < .001, resp.). In addition, the age of onset was negatively correlated with TNF-alpha level (r = -.402, P = .025) and duration of illness was weakly correlated with IL-6 levels (r: .357; P: .048) in patients group.

CONCLUSIONS

OCD patients showed increases in TNF-alpha and IL-6 levels compared to the healthy controls. This study provides evidence for alterations in the proinflammatory cytokines which suggest the involvement of the immune system in the pathophysiology of OCD.

Previous work has demonstrated an increase in the production of granulocyte-macrophage colony-stimulating factor (GM-CSF) by monocytes derived from asthmatic individuals. We have suggested that monocytes and macrophages enhance airways inflammation by augmented cytokine production. We tested this hypothesis by measuring the production of GM-CSF and macrophage-derived cytokines, namely <em>interleukin</em>-1 beta (IL-1 beta), tumour necrosis factor-alpha (TNF-alpha) and <em>interleukin</em>-8 (IL-8), from unstimulated and lipopolysaccharide (LPS)-stimulated peripheral blood monocytes and alveolar macrophages in <em>31</em> asthmatic and 11 normal, control subjects. The basal production of GM-CSF was four fold higher in the monocytes of asthmatic individuals, but there was no significant difference in the basal production of TNF-alpha, IL-1 beta and IL-8. After stimulation with LPS, asthmatic monocytes produced twofold more GM-CSF and fourfold more IL-1 beta than the monocytes from control subjects. Unstimulated macrophages from asthmatic subjects produced significantly less GM-CSF and TNF-alpha than macrophages from controls, and there was no difference in either IL-1 beta or IL-8 production. When stimulated by LPS, macrophages from asthmatic subjects produced twofold more GM-CSF, threefold more TNF-alpha and fourfold more IL-8. The levels of IL-8 produced by both monocytes and macrophages were at least 20 fold higher than those of the other cytokines measured. There is selectivity in the upregulation of cytokine production by monocytes and macrophages in asthma.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND

With concerns about the disastrous health and economic consequences caused by the influenza pandemic, comprehensively understanding the global host response to influenza virus infection is urgent. The role of microRNA (miRNA) has recently been highlighted in pathogen-host interactions. However, the precise role of miRNAs in the pathogenesis of influenza virus infection in humans, especially in critically ill patients is still unclear.

METHODS

We identified cellular miRNAs involved in the host response to influenza virus infection by performing comprehensive miRNA profiling in peripheral blood mononuclear cells (PBMCs) from critically ill patients with swine-origin influenza pandemic H1N1 (2009) virus infection via miRNA microarray and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) assays. Receiver operator characteristic (ROC) curve analysis was conducted and area under the ROC curve (AUC) was calculated to evaluate the diagnostic accuracy of severe H1N1 influenza virus infection. Furthermore, an integrative network of miRNA-mediated host-influenza virus protein interactions was constructed by integrating the predicted and validated miRNA-gene interaction data with influenza virus and host-protein-protein interaction information using Cytoscape software. Moreover, several hub genes in the network were selected and validated by qRT-PCR.

RESULTS

Forty-one significantly differentially expressed miRNAs were found by miRNA microarray; nine were selected and validated by qRT-PCR. QRT-PCR assay and ROC curve analyses revealed that miR-<em>31</em>, miR-29a and miR-148a all had significant potential diagnostic value for critically ill patients infected with H1N1 influenza virus, which yielded AUC of 0.9510, 0.8951 and 0.8811, respectively. We subsequently constructed an integrative network of miRNA-mediated host-influenza virus protein interactions, wherein we found that miRNAs are involved in regulating important pathways, such as mitogen-activated protein kinase signaling pathway, epidermal growth factor receptor signaling pathway, and Toll-like receptor signaling pathway, during influenza virus infection. Some of differentially expressed miRNAs via in silico analysis targeted mRNAs of several key genes in these pathways. The mRNA expression level of tumor protein T53 and transforming growth factor beta receptor 1 were found significantly reduced in critically ill patients, whereas the expression of Janus kinase 2, caspase 3 apoptosis-related cysteine peptidase, <em>interleukin</em> 10, and myxovirus resistance 1 were extremely increased in critically ill patients.

CONCLUSIONS

Our data suggest that the dysregulation of miRNAs in the PBMCs of H1N1 critically ill patients can regulate a number of key genes in the major signaling pathways associated with influenza virus infection. These differentially expressed miRNAs could be potential therapeutic targets or biomarkers for severe influenza virus infection.