Structural basis for surface activation of the classical complement cascade by the short pentraxin C-reactive protein.

Human C-reactive protein (CRP) is a pentameric complex involved in immune defense and regulation of autoimmunity. CRP is also a therapeutic target, with both administration and depletion of serum CRP being pursued as a possible treatment for autoimmune and cardiovascular diseases, among others. CRP binds to phosphocholine (PC) moieties on membranes to activate the complement system via the C1 complex, but it is unknown how CRP, or any pentraxin, binds to C1. Here, we present a cryoelectron tomography (cryoET)-derived structure of CRP bound to PC ligands and the C1 complex. To gain control of CRP binding, a synthetic mimotope of PC was synthesized and used to decorate cell-mimetic liposome surfaces. Structure-guided mutagenesis of CRP yielded a fully active complex able to bind PC-coated liposomes that was ideal for cryoET and subtomogram averaging. In contrast to antibodies, which form Fc-mediated hexameric platforms to bind and activate the C1 complex, CRP formed rectangular platforms assembled from four laterally associated CRP pentamers that bind only four of the six available globular C1 head groups. Potential residues mediating lateral association of CRP were identified from interactions between unit cells in existing crystal structures, which rationalized previously unexplained mutagenesis data regarding CRP-mediated complement activation. The structure also enabled interpretation of existing biochemical data regarding interactions mediating C1 binding and identified additional residues for further mutagenesis studies. These structural data therefore provide a possible mechanism for regulation of complement by CRP, which limits complement progression and has consequences for how the innate immune system influences autoimmunity.

Effects of low-dose acetylsalicylic acid on the inflammatory response to experimental sleep restriction in healthy humans.

BACKGROUND: Sleep deficiencies, such as manifested in short sleep duration or insomnia symptoms, are known to increase the risk for multiple disease conditions involving immunopathology. Inflammation is hypothesized to be a mechanism through which deficient sleep acts as a risk factor for these conditions. Thus, one potential way to mitigate negative health consequences associated with deficient sleep is to target inflammation. Few interventional sleep studies investigated whether improving sleep affects inflammatory processes, but results suggest that complementary approaches may be necessary to target inflammation associated with sleep deficiencies. We investigated whether targeting inflammation through low-dose acetylsalicylic acid (ASA, i.e., aspirin) is able to blunt the inflammatory response to experimental sleep restriction. METHODS: 46 healthy participants (19F/27M, age range 19-63 years) were studied in a double-blind randomized placebo-controlled crossover trial with three protocols each consisting of a 14-day at-home monitoring phase followed by an 11-day (10-night) in-laboratory stay (sleep restriction/ASA, sleep restriction/placebo, control sleep/placebo). In the sleep restriction/ASA condition, participants took low-dose ASA (81 mg/day) daily in the evening (22:00) during the at-home phase and the subsequent in-laboratory stay. In the sleep restriction/placebo and control sleep/placebo conditions, participants took placebo daily. Each in-laboratory stay started with 2 nights with a sleep opportunity of 8 h/night (23:00-07:00) for adaptation and baseline measurements. Under the two sleep restriction conditions, participants were exposed to 5 nights of sleep restricted to a sleep opportunity of 4 h/night (03:00-07:00) followed by 3 nights of recovery sleep with a sleep opportunity of 8 h/night. Under the control sleep condition, participants had a sleep opportunity of 8 h/night throughout the in-laboratory stay. During each in-laboratory stay, participants had 3 days of intensive monitoring (at baseline, 5th day of sleep restriction/control sleep, and 2nd day of recovery sleep). Variables, including pro-inflammatory immune cell function, C-reactive protein (CRP), and actigraphy-estimated measures of sleep, were analyzed using generalized linear mixed models. RESULTS: Low-dose ASA administration reduced the interleukin (IL)-6 expression in LPS-stimulated monocytes (p<0.05 for condition*day) and reduced serum CRP levels (p<0.01 for condition) after 5 nights of sleep restriction compared to placebo administration in the sleep restriction condition. Low-dose ASA also reduced the amount of cyclooxygenase (COX)-1/COX-2 double positive cells among LPS-stimulated monocytes after 2 nights of recovery sleep following 5 nights of sleep restriction compared to placebo (p<0.05 for condition). Low-dose ASA further decreased wake after sleep onset (WASO) and increased sleep efficiency (SE) during the first 2 nights of recovery sleep (p<0.001 for condition and condition*day). Baseline comparisons revealed no differences between conditions for all of the investigated variables (p>0.05 for condition). CONCLUSION: This study shows that inflammatory responses to sleep restriction can be reduced by preemptive administration of low-dose ASA. This finding may open new therapeutic approaches to prevent or control inflammation and its consequences in those experiencing sleep deficiencies. TRIAL REGISTRATION: ClinicalTrials.gov NCT03377543.

In which common chronic conditions can (or cannot) obesity and lifestyle factors explain higher concentrations of C-reactive protein?

AIM: Elevated C-reactive protein (CRP), a marker of inflammation, is common in many chronic conditions. We aimed to examine to what extent elevated CRP in chronic conditions could be explained by concurrent adiposity. MATERIALS AND METHODS: This cross-sectional study analysed UK Biobank data on 10 chronic conditions reported at baseline. Linear regression models explored the extent to which CRP concentrations were elevated in each condition, unadjusted; adjusted for sociodemographic confounders and lifestyle and body mass index (BMI) in a series of models; or adjusted for BMI and waist circumference together or for adiposity alone. RESULTS: After exclusion of participants with a potential acute infection at baseline, we tested the association in 292 772 UK Biobank participants. Linear regression showed that elevated CRP concentration was associated with all included conditions. After adjustment for sociodemographic confounders, lifestyle and BMI, chronic kidney disease, heart failure, liver disease, psoriasis, rheumatoid arthritis and chronic obstructive pulmonary disease were still associated with elevated CRP. In contrast, the association between prevalent diabetes, prior myocardial infarction (MI), hypertension and sleep apnoea and CRP could be mostly explained by adiposity alone. For example, the 42% higher CRP concentrations in diabetes compared to those without diabetes in the unadjusted model (lnCRP ß: 0.35; 95% confidence interval [CI]: 0.32-0.37, p < 0.001) were completely attenuated after adjustment for BMI (lnCRP ß: -0.07; 95% CI: -0.09-0.05, p < 0.001). CONCLUSIONS/INTERPRETATION: In diabetes, MI, hypertension and sleep apnoea and elevated CRP appears to be accounted for by the greater adiposity typically evident in these conditions. However, for the other conditions, systemic inflammation cannot be explained by excess adiposity alone.

Drainage fluid LDH and neutrophil to lymphocyte ratio as biomarkers for early detecting anastomotic leakage in patients undergoing colorectal surgery.

OBJECTIVES: In this study, we investigated the role of several circulating and drainage fluid biomarkers for detecting postoperative complications (PCs) and anastomotic leakage (AL) in patients undergoing colorectal surgery. METHODS: All consecutive patients undergoing colorectal surgery between June 2018 and April 2020 were prospectively considered. On postoperative days (POD) 1, 3, and 5, we measured lactate dehydrogenase (LDH) in drainage fluid, C-reactive protein (CRP) in serum and drainage fluid, and neutrophil to lymphocyte ratio (NLR). RESULTS: We enrolled 187 patients. POD1 patients with AL had higher serum CRP levels, while on POD3 and on POD5 higher NLR and serum CRP. LDH and CRP in drainage fluid were also significantly higher at both time points. The area under the curves (AUCs) of serum and drainage fluid CRP were 0.752 (0.629-0.875) and 0.752 (0.565-0.939), respectively. The best cut-off for serum and drainage fluid CRP was 185.23 and 76 mg/dL, respectively. The AUC of NLR on POD3 was 0.762 (0.662-0.882) with a sensitivity and specificity of 84 and 63 %, respectively, at a cut-off of 6,6. Finally, drainage fluid LDH showed the best diagnostic performance for AL, with an AUC, sensitivity, and specificity of 0.921 (0.849-0.993), 82 %, and 90 % at a cut-off of 2,186 U/L. Trends in serum parameters between patients with or without PCs or AL were also evaluated. Interestingly, we found that NLR decreased faster in patients without PCs than in patients with PCs and patients with AL. CONCLUSIONS: Drainage fluid LDH and NLR could be promising biomarkers of PCs and AL.

An anti-inflammatory response of an organic food intervention by reducing pesticide exposures in children of Cyprus: A cluster-randomized crossover trial.

Organic food consumption in children has been shown to reduce the body burden of chemical pesticides. However, there is little evidence of human health benefits associated with the consumption of organic foods. The objectives were to i) determine the effectiveness of an organic food intervention treatment in reducing the magnitude of an inflammation biomarker (C-reactive protein, CRP) in children (10-12 years) and ii) assess the association between the urinary biomarkers of exposure to pesticides and CRP. This work was part of the ORGANIKO cluster-randomized cross-over trial entailing a 40-day organic food treatment in healthy children. Urinary biomarkers of exposure to pesticides and inflammation (CRP) were measured using tandem mass spectrometry and ELISA immunoassay, respectively. Linear mixed-effect regression models of CRP were used to account for the effect and duration of organic food treatment. Multiple comparisons were handled using Benjamini-Hochberg correction. Results supported an anti-inflammatory effect of organic food treatment in children, albeit with mixed results, depending on the creatinine adjustment method; biomarker levels were divided by urinary creatinine (method a1), or urinary creatinine was used as a fixed effect variable (a2). In the a1 method, a time-dependent reduction for creatinine-adjusted CRP (ß = -0.019; 95% CI: -0.031, -0.006; q = 0.045) was observed during the organic food intervention period. A statistically significant association (ß = 0.104; 95% CI: 0.035, 0.173; q = 0.045) was found between the biomarker of pyrethroids exposure (3-PBA) and CRP inflammatory biomarker, but not for 6-CN. In the a2 method, similar trend of time-dependent reduction for creatinine-adjusted CRP (ß = -0.008; 95% CI: -0.021, 0.004; p = 0.197) was observed during the organic food intervention period, but did not reach statistical significance (q > 0.05); the associations of pyrethroid and neonicotinoid biomarkers with CRP were not statistically significant (q > 0.05). More studies are warranted to sufficiently understand the potential anti-inflammatory response of an organic food treatment.

Body composition markers are associated with changes in inflammatory markers but not vice versa: A bi-directional longitudinal analysis in a population-based sample.

BACKGROUND AND AIM: Growing body of evidence consistently link obesity and inflammation, Although the direction of the association is still unclear. We aimed to investigate longitudinal associations of body anthropometric, composition and fat distribution parameters with inflammatory markers and vice versa. METHOD AND RESULTS: We used data from 2464 individuals of the SHIP-TREND cohort with a median follow-up of 7 years. Linear regression models adjusted for confounders were used to analyze associations of standardized body composition markers derived from classic anthropometry, bioelectrical impedance analysis (BIA) and magnetic resonance imaging (MRI) at baseline with changes in inflammatory markers (C-reactive protein (CRP), white blood cell (WBC), fibrinogen) and vice versa. Higher level of anthropometric markers at baseline were associated with an increase in the change of inflammatory markers. A 13.5 cm higher waist circumference (WC), 16.0 kg body weight and 7.76 % relative fat mass (FM) at baseline was associated with a change in CRP of 0.52 mg/L (95 % confidence interval [CI]: 0.29 to 0.74), 0.51 mg/L (95 % CI: 0.29; 0.74) and 0.58 mg/L (95 % CI: 0.34; 0.82) respectively. Absolute FM showed the strongest association with changes in serum fibrinogen levels (ß for 8.69 kg higher FM: 0.07 g/L; 95 % CI: 0.05; 0.09). Baseline inflammatory markers were only associated with changes in hip circumference. CONCLUSION: Our study indicates the importance of anthropometric, body composition and fat distribution markers as a risk factor for the development of inflammation. To prevent inflammatory-related complications, important is to take measures against the development of obesity.

Metabolic syndrome increases osteoarthritis risk: findings from the UK Biobank prospective cohort study.

OBJECTIVE: The association between Metabolic Syndrome (MetS), its components, and the risk of osteoarthritis (OA) has been a topic of conflicting evidence in different studies. The aim of this present study is to investigate the association between MetS, its components, and the risk of OA using data from the UK Biobank. METHODS: A prospective cohort study was conducted in the UK Biobank to assess the risk of osteoarthritis (OA) related to MetS. MetS was defined according to the criteria set by the International Diabetes Federation (IDF). Additionally, lifestyle factors, medications, and the inflammatory marker C-reactive protein (CRP) were included in the model. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI). The cumulative risk of OA was analyzed using Kaplan-Meier curves and log-rank tests. To explore potential nonlinear associations between MetS components and OA risk, a restricted cubic splines (RCS) model was employed. In addition, the polygenic risk score (PRS) of OA was calculated to characterize individual genetic risk. RESULTS: A total of 45,581 cases of OA were identified among 370,311 participants, with a median follow-up time of 12.48 years. The study found that individuals with MetS had a 15% higher risk of developing OA (HR = 1.15, 95%CI:1.12-1.19). Additionally, central obesity was associated with a 58% increased risk of OA (HR = 1.58, 95%CI:1.5-1.66), while hyperglycemia was linked to a 13% higher risk (HR = 1.13, 95%CI:1.1-1.15). Dyslipidemia, specifically in triglycerides (HR = 1.07, 95%CI:1.05-1.09) and high-density lipoprotein (HR = 1.05, 95%CI:1.02-1.07), was also found to be slightly associated with OA risk. When stratified by PRS, those in the high PRS group had a significantly higher risk of OA compared to those with a low PRS, whereas no interaction was found between MetS and PRS on OA risks. Furthermore, the presence of MetS significantly increased the risk of OA by up to 35% in individuals with elevated CRP levels (HR = 1.35, 95% CI:1.3-1.4). CONCLUSION: MetS and its components have been found to be associated with an increased risk of OA, particularly in individuals with elevated levels of CRP. These findings highlight the significance of managing MetS as a preventive and intervention measure for OA.

The association between dental caries and serum crp in the us adult population: evidence from NHANES 2015-2018.

BACKGROUND: Dental caries remains one of the most prevalent diseases worldwide, affecting 29.4% of the global population. Despite numerous efforts to diagnose, predict, and prevent dental caries, the incidence continues to rise. Salivary biomarkers provide a non-invasive means for early detection of various oral conditions. C-reactive protein (CRP) is a key marker, elevated in both oral and general inflammatory conditions such as diabetes, periodontitis and oral squamous cell carcinoma. Considering the emerging connection between oral and systemic health, it is worth exploring the various factors associated with this widespread disease. This study investigates the association between CRP levels and dental caries in the United States population, utilizing data from the National Health and Nutrition Examination Survey (NHANES). METHODS: The study analyzed data from the 2015-2018 NHANES cycles, focusing on a nationally representative sample of individuals aged 30 years and above. Weighted multivariable negative binomial and logistic regression analyses were employed to explore the relationship between dental caries and CRP levels, adjusting for age, gender, race, education level, diabetes status, and gum disease. RESULTS: The results of the negative binomial regression analysis demonstrated a positive association between higher CRP levels and an increased mean number of dental caries (Adjusted Mean Ratio [AMR] = 1.7; 95% CI: 1.3 - 2; P: < 0.001). The logistic regression analysis showed that individuals with higher CRP levels have a 50% increase in the odds of developing dental caries (AOR: 1.5, CI: 1.2 - 1.9; P: < 0.01). CONCLUSION: The results of this cross-sectional study of the U.S. population highlight the positive association between high CRP levels and increased dental caries. These findings contribute to the growing body of evidence supporting the integration of oral and systemic health care. Further research is necessary to deepen our understanding of the mechanistic relationship between CRP levels and dental caries.

Serum Procalcitonin, Hematology Parameters, and Cell Morphology in Multiple Clinical Conditions and Sepsis.

BACKGROUND: The clinical value of procalcitonin (PCT) in infection diagnosis and antibiotic stewardship is still unclear. This study aimed to investigate the association between serum PCT and different clinical conditions as well as other infectious/inflammatory parameters in different septic patients in order to elucidate the value of PCT detection in infection management. METHODS: Chemiluminescence immunoassay was used for serum PCT analysis. Hematology analysis was used for complete blood cell count. Digital automated cell morphology analysis was used for blood cell morphology examination. Blood, urine, and stool cultures were performed according to routine clinical laboratory standard operating procedures. C-reactive protein (CRP) was analyzed by immunoturbidimetry. Erythrocyte sedimentation rate test was performed using natural sedimentation methods. RESULTS: Outpatients, ICU patients, and patients under 2 years of age with respiratory infections had higher serum PCT levels. Septic patients had the highest-serum PCT levels and other infection indexes. PCT levels in the blood, urine, and stool culture-positive patients were significantly higher than in culture-negative patients. The neutrophil granulation and reactive lymphocytes were observed together with the PCT-level increments in different septic patients, and these alterations were lessened after treatment. There was no significant change in monocyte morphology between pre- and posttreatment septic patients. CONCLUSIONS: Serum PCT is associated with neutrophil cytotoxicity and lymphocyte morphology changes in sepsis; thus, the combination of neutrophil and lymphocyte digital cell morphology evaluations with PCT detection may be a useful examination for guiding the clinical management of sepsis.

Systemic Lupus Erythematosus and Cytokine Storm.

Systemic lupus erythematosus (SLE) is the prototype of autoimmune diseases and can manifest with a plethora of clinical signs and symptoms associated with a myriad of laboratory abnormalities. An infrequent but potentially lethal complication of SLE is macrophage activation syndrome (MAS). The diagnosis of MAS in SLE can be very challenging due to similarities in presentation of both flares and infections, such as fever, lymphadenopathy, splenomegaly, and cytopenias. These aggravating factors contribute to the increased risk of poor outcomes in SLE-associated MAS. Indeed, at the moment MAS remains invariably lethal if untreated and still has a high mortality rate with treatment. In this chapter, we discuss several aspects of MAS in the context of SLE and in particular, the pathogenesis of MAS in SLE, how MAS presents in pediatric versus adult SLE, and, finally, MAS treatment in SLE and future directions.

Correlation between the C-reactive protein (CRP)-albumin-lymphocyte (CALLY) index and the prognosis of gastric cancer patients after gastrectomy: a systematic review and meta-analysis.

The C-Reactive Protein (CRP)-Albumin-Lymphocyte (CALLY) index is an established immuno-nutritional scoring system. We screened relevant literature from the major databases up until May, 2024, and extracted the data for analysis. A total of 2829 gastric cancer (GC) patients from six studies were included in this meta-analysis, the results of which revealed that the CALLY index was an independent prognostic factor for OS and RFS in both univariate analyses and multivariate analyses, and that a high CALLY index was a favorable prognostic factor. Moreover, GC patients in the high CALLY index group seemed to have better 5-year OS and 5-year RFS than those in the low CALLY index group. There was a higher proportion of patients with T1 status in the high CALLY index group than in the low CALLY index group. However, the opposite results were found in the analyses of lymph node metastasis positivity, lymph-vascular invasion positivity, postoperative complications, differentiated histological type, anastomotic leakage, and adjuvant chemotherapy. The present meta-analysis concluded that the CALLY index was a simple and useful independent prognostic biomarker for GC patients after gastrectomy.

Vitamin D and CRP are associated in hospitalized inflammatory bowel disease (IBD) patients in Shanghai.

BACKGROUND AND OBJECTIVES: Patients with inflammatory bowel disease (IBD) are more likely to be confirmed with vitamin D deficiency. However, the association between inflammation and vitamin D remains unclear. The purpose of this study was to evaluate the association between inflammation and vitamin D in hospitalized patients with IBD. METHODS AND STUDY DESIGN: All the participants were recruited from one teaching hospital from June 2018 to October 2022. Inflammation was evaluated by serum concentration of C-reactive protein (CRP), using an immunoturbidimetric method at admission. We further divided the participants into five groups based on serum CRP levels: <5, 5-9.9, 10-19.9, 20-39.9, and >40mg/L. Serum 25-hydroxy-vitamin D (25-(OH)-D) was assessed by liquid chromatography tandem mass spectrometry. Addi-tional information, including age, sex, body mass index (BMI), IBD (ulcerative colitis vs. Crohn's disease) subtype, was abstracted from medical records. RESULTS: This study included 1,989 patients with IBD (average age was 39.4 years, 33.8% of them were women, 1,365 CD and 624 UC patients). The median CRP was 5.49 mg/L (range of quartiles: 1.64~19.5 mg/L) and the prevalence of 25-(OH)-D deficiency was 69.8%. CRP was significantly associated with serum level of 25-(OH)-D. The difference in 25-(OH)-D was -4.28 ng/ml (-5.27 ng/ml, -3.31 ng/ml) between two extremist CRP groups after adjustment of potential covariates (age, sex, BMI, type of IBD, dietary type, season, and lymphocyte count). Subgroup analysis in sex, type of IBD, and age, were similar to the main analysis results. CONCLUSIONS: There was a negative association between CRP levels and vitamin D in hospitalized patients with IBD.

Association of mTOR Pathway and Conformational Alterations in C-Reactive Protein in Neurodegenerative Diseases and Infections.

Inflammatory biomarkers have been very useful in detecting and monitoring inflammatory processes along with providing helpful information to select appropriate therapeutic strategies. C-reactive protein (CRP) is a nonspecific, but quite useful medical acute inflammatory biomarker and is associated with persistent chronic inflammatory processes. Several studies suggest that different levels of CRP are correlated with neurological disorders such as Alzheimer's disease (AD). However, dynamics of CRP levels have also been observed in virus/bacterial-related infections leading to inflammatory responses and this triggers mTOR-mediated pathways for neurodegeneration diseases. The biophysical structural transition from CRP to monomeric CRP (mCRP) and the significance of the ratio of CRP levels on the onset of symptoms associated with inflammatory response have been discussed. In addition, mTOR inhibitors act as immunomodulators by downregulating the expression of viral infection and can be explored as a potential therapy for neurological diseases.

Use of C-reactive protein to guide the antibiotic therapy in hospitalized patients: a systematic review and meta-analysis.

BACKGROUND: C-reactive protein (CRP) is an inflammatory protein used in clinical practice to identify and monitor inflammatory and infectious processes. Recent data suggest CRP might be useful in guiding antibiotic therapy discontinuation among critical care patients. This meta-analysis analyzed the benefits and risks of CRP-guided protocols to guide antibiotic therapy in hospitalized patients in comparison with standard treatment. METHODS: Studies were searched in four databases: CENTRAL, Medline, Embase and LILACS. The search was performed until Jan 25th, 2023. The reference lists of the articles retrieved and related review studies were hand-screened to find eligible trials that might have been missed. Primary endpoints included the duration of antibiotic therapy for the index episode of infection. The secondary endpoint was the all-cause hospital mortality and infection relapses. The risk of bias was evaluated using the Cochrane Risk of Bias 2.0 tool. Random effects were used to pool the mean differences and odds ratio of individual studies. The protocol was registered in PROSPERO (CRD42021259977). RESULTS: The search strategy retrieved 5209 titles, out of which three studies met the eligibility criteria and were included in this meta-analysis. 727 adult patients were analyzed, of whom 278 were included in the intervention group and 449 were included in the control group. 55,7% of all patients were women. Meta-analysis indicated that experimental groups (CRP-guided) had a lower duration of antibiotic therapy (days) [MMD = -1.82, 95%IC -3.23; -0.40]; with no difference in mortality [OR = 1.19 95%IC 0.67-2.12] or in the occurrence of infection relapse [OR = 3.21 95%IC 0.85-12.05]. CONCLUSION: The use of CRP-guided protocol reduces the total amount of time required for antibiotic therapy when compared to standard protocols of treatment in hospitalized patients with acute bacterial infection. We did not observe statistical differences regarding mortality and infection relapse rates.

Effects of fermented dairy products on inflammatory biomarkers: A meta-analysis.

AIM: Fermented dairy products (FDPs) are made from raw milk under the action of specific microorganisms by lactic acid bacteria fermentation or co-fermentation of lactic acid bacteria, bifidobacteria, and yeast. The aim of this study was to explore the effects of FDPs on inflammatory biomarkers. DATA SYNTHESIS: A comprehensive search was conducted on four electronic databases, including PubMed, Web of Science, Embase, and the Cochrane Library. Finally, fourteen trials (15 arms) were included in this meta-analysis: yogurt (n = 9), fermented milk (n = 4), and kefir (n = 2). Additionally, the random effects model or fixed-effects model was used to pool the study results. Firstly, the analysis indicated that FDPs' supplementation decreased the levels of C-reactive protein (CRP) (SMD = -0.21; 95% CI: -0.40, -0.02; P = 0.033) and increased interferon-gamma (IFN-γ) levels (SMD = 0.12; 95% CI: 0.01, 0.23; P = 0.033). Furthermore, we obtained some statistically significant results in the following subgroups: CRP decreased in participants with metabolic diseases. IFN-γ increased in the intervention that lasted ≥12 weeks, Asian, yogurt, and healthy population. Finally, there was no significant effect on tumor necrosis factor-alpha, interleukin (IL)-6, IL-10, and IL-2. CONCLUSIONS: FDPs reduced CRP and increased IFN-γ, but they had no effect on other inflammatory markers. The results showed that the consumption of FDPs was slightly associated with reduced inflammation, but because of the limited literature, these results should be interpreted with caution.

Thymic function and survival at advance ages in nursing home residents from Southern Italy.

BACKGROUND: Immunosenescence is a complex process characterized by an age-related remodelling of immune system. The prominent effects of the immunosenescence process is the thymic involution and, consequently, the decreased numbers and functions of T cells. Since thymic involution results in a collapse of the T-cell receptor (TCR) repertoire, a reliable biomarker of its activity is represented by the quantification of signal joint T-cell receptor rearrangement excision circles (sjTRECs) levels. Although it is reasonable to think that thymic function could play a crucial role on elderly survival, only a few studies investigated the relationship between an accurate measurement of human thymic function and survival at old ages. METHODS AND FINDINGS: By quantifying the amount sjTRECs by real-time polymerase chain reaction (PCR), the decrease in thymic output in 241 nursing home residents from Calabria (Southern Italy) was evaluated to investigate the relationship between thymic function and survival at old ages. We found that low sjTREC levels were associated with a significant increased risk of mortality at older ages. Nursing home residents with lower sjTREC exhibit a near 2-fold increase in mortality risk compared to those with sjTREC levels in a normal range. CONCLUSION: Thymic function failure is an independent predictor of mortality among elderly nursing home residents. sjTREC represents a biomarker of effective ageing as its blood levels could anticipate individuals at high risk of negative health outcomes. The identification of these subjects is crucial to manage older people's immune function and resilience, such as, for instance, to plan more efficient vaccinal campaigns in older populations.

C-reactive protein as a prognostic predictor for non-muscle invasive bladder cancer after intravesical bacillus Calmette-Guérin therapy: A Japan Urological Oncology Group study analysis.

OBJECTIVE: To investigate the involvement of pretreatment C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR) in the prognosis of patients who underwent intravesical bacillus Calmette-Guérin (BCG) therapy for non-muscle invasive bladder cancer (NMIBC). METHODS: The clinicopathological data of 1709 patients with NMIBC who underwent initial intravesical BCG therapy after transurethral resection of bladder tumor were retrospectively analyzed to evaluate the outcome of intravesical BCG therapy in a multicenter study conducted by the Japan Urological Oncology Group. The prognoses of these patients were analyzed to determine whether the biomarkers (CRP and NLR) could predict the efficacy of intravesical BCG therapy. Patients were divided into two groups according to the pretreatment CRP and NLR, with cutoff values defined as CRP ≥ 0.5 mg/dl and NLR ≥ 2.5, based on several previous reports. RESULTS: In the univariable analysis, CRP ≥ 0.5 mg/dl was significantly associated with intravesical recurrence, cancer-specific survival, and bladder cancer (BC) progression, while NLR ≥ 2.5 was not significantly associated with patient prognosis. In the multivariable analysis, CRP ≥ 0.5 mg/dl was significantly associated with intravesical recurrence and BC progression. The concordance index was used to examine the accuracy in predicting recurrence and progression events. While CRP was slightly, though not statistically significant, inferior to the European Association of Urology risk classification, the combination of them showed improved predictive accuracy. CONCLUSION: This study suggests that CRP can be a prognostic factor after intravesical BCG therapy and may provide useful data for determining treatment and follow-up strategies for patients with NMIBC.

COVID-19 Biomarkers at the Crossroad between Patient Stratification and Targeted Therapy: The Role of Validated and Proposed Parameters.

Clinical knowledge about SARS-CoV-2 infection mechanisms and COVID-19 pathophysiology have enormously increased during the pandemic. Nevertheless, because of the great heterogeneity of disease manifestations, a precise patient stratification at admission is still difficult, thus rendering a rational allocation of limited medical resources as well as a tailored therapeutic approach challenging. To date, many hematologic biomarkers have been validated to support the early triage of SARS-CoV-2-positive patients and to monitor their disease progression. Among them, some indices have proven to be not only predictive parameters, but also direct or indirect pharmacological targets, thus allowing for a more tailored approach to single-patient symptoms, especially in those with severe progressive disease. While many blood test-derived parameters quickly entered routine clinical practice, other circulating biomarkers have been proposed by several researchers who have investigated their reliability in specific patient cohorts. Despite their usefulness in specific contexts as well as their potential interest as therapeutic targets, such experimental markers have not been implemented in routine clinical practice, mainly due to their higher costs and low availability in general hospital settings. This narrative review will present an overview of the most commonly adopted biomarkers in clinical practice and of the most promising ones emerging from specific population studies. Considering that each of the validated markers reflects a specific aspect of COVID-19 evolution, embedding new highly informative markers into routine clinical testing could help not only in early patient stratification, but also in guiding a timely and tailored method of therapeutic intervention.

Oxidative stress status and vitamin D levels of asymptomatic to mild symptomatic COVID-19 infections during the third trimester of pregnancy: A retrospective study in Metz, France.

It is believed that the subtle equilibrium between tolerance and immunity during the unique biological state of pregnancy, which is characterized by further physiological and hormonal changes, rends pregnant women more vulnerable to coronavirus disease 2019 (COVID-19). In this retrospective study, confirmed COVID-19-positive pregnant women (n = 15) during their third trimester, comprising asymptomatic (n = 7) and mild symptomatic (n = 8), and healthy pregnant controls (n = 20), were enrolled between June 1, 2020 and  June 1, 2021 from the Hospital CHR Metz-Thionville in Metz, France. Vitamin D concentrations, C-reactive protein (CRP), and oxidative stress markers including superoxide dismutase (SOD), catalase (CAT), reduced (GSH) and oxidized (GSSG) glutathione levels, hydrogen peroxide (H2 O2 ), and the total antioxidant capacity, measured the ferric reducing ability of plasma (FRAP), were evaluated in the serum of patients and controls. Results showed that all pregnant women (patients and controls) enrolled in this study were vitamin D deficient (<20 ng/ml). However, mild COVID-19 pregnant women were severely vitamin D deficient (<12 ng/ml), which may suggest a link between vitamin D deficiency and the symptomatology of COVID-19 illness in singleton pregnancy. No differences between the levels of CRP and the majority of the studied oxidative stress markers in COVID-19-positive pregnant women (asymptomatic and/or mildly symptomatic patients) versus COVID-19-negative pregnant women were found, suggesting the absence or a low magnitude of oxidative stress in pregnant women with COVID-19. This may also explain the absence of severe courses of COVID-19 infection. More studies are warranted to investigate the role of vitamin D supplementation and antioxidant-rich diets in the prevention against severe forms of COVID-19 in pregnant women.

Association of childhood maltreatment history with salivary interleukin-6 diurnal patterns and C-reactive protein in healthy adults.

Childhood maltreatment has been associated with increased inflammation, as indicated by elevated levels of proinflammatory markers such as interleukin-6 (IL-6) and C-reactive protein (CRP). Studies in humans show that secretion of IL-6 follows a clear circadian rhythm, implying that its disturbed rhythm represents an important aspect of dysregulated inflammatory system. However, possible alterations in diurnal secretion patterns of IL-6 associated with childhood maltreatment have not been studied. Here we investigated this association in 116 healthy adults. Diurnal levels of IL-6 were examined using saliva samples collected at 5 times a day across 2 consecutive days. Salivary CRP levels were also determined by averaging measurements at 2 times a day for 2 days. Different types of childhood maltreatment were assessed with the Childhood Trauma Questionnaire (CTQ). CTQ total and emotional abuse scores were significantly correlated with smaller IL-6 diurnal variation as indexed by lower standard deviation across the measurement times (p = 0.024 and p = 0.008, respectively). Individuals with emotional abuse, as defined by a cut-off score of CTQ, showed flatter IL-6 rhythm than those without (p = 0.031). These results, both correlation and group comparison, remained significant after controlling for age, sex, and body mass index. Childhood maltreatment was not associated with total output of IL-6 or CRP. Our findings indicate that childhood trauma can have a long-term negative effect on the circadian rhythm of inflammatory system. The findings are consistent with those of previous studies on adulthood trauma, suggesting that the disrupted IL-6 rhythmicity may be associated with a broad range of trauma-related conditions.