Relationship Between Hematologic Inflammatory Markers and Glycemic Control in Type 2 Diabetes Mellitus Patients in a Tertiary Hospital in Nigeria.

INTRODUCTION: Hematologic inflammatory biomarkers derived from a full blood count (FBC) are elevated in Type 2 diabetes mellitus (DM). In low- and middle-income countries like Nigeria, a FBC is an affordable and easily available test, even in rural areas. Glycated hemoglobin (HbA1c), a measure of glycemic control, has been found to correlate with hematologic inflammatory markers. In Nigeria, where health care is expensive and patients essentially pay out of pocket, a more affordable and accessible alternative to HbA1c in determining glycemic control is needed. Therefore, this study aimed to determine the relationship between Hb A1c and hematologic inflammatory biomarkers, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and mean platelet volume (MPV), in predicting glycemic control. METHODS: This was a six-month study of 109 patients with Type 2 DM in a tertiary hospital in Lagos. The patients' HbA1c and FBC were measured. NLR, PLR, and MPV were derived from the FBC values. We categorized the patients based on glycemic control. Spearman correlation analysis was used to determine the relationship between HbA1c and the inflammatory biomarkers. RESULTS: There was no significant difference in NLR, PLR, and MPV between optimal and suboptimal controlled diabetic patients. Spearman's correlation analysis showed no significant association between NLR, PLR, MPV, and HbA1c in the patients (NLR: r=0.027, P=0.680; PLR: r=-0.091, P=0.356; MPV: r=-0.032, P=0.744). CONCLUSION: The inflammatory markers studied had no significant relationship with HbA1c and might not help monitor glycemic control in Type 2 DM patients.

The interplay between vitamin D status, subclinical inflammation, and prediabetes.

Vitamin D's role extends beyond classical calcium and phosphate homeostasis to encompass a pivotal influence on immune modulation and metabolic health. The mechanisms by which vitamin D exerts these effects involve its conversion to hormonally active calcitriol, which binds intracellular vitamin D receptors, initiating various downstream cascades. In this review, we tease out the evidence showing the relationship between vitamin D deficiency and prediabetes within the context of subclinical inflammation, with a special focus on the novel monocyte-to-HDL ratio (MHR), a novel inflammatory marker reflecting subclinical inflammation. This was based on a thorough literature review using reputable databases covering the period from 1980 to 2024. In light of this, we discuss calcitriol's anti-inflammatory effects and consequently link vitamin D deficiency to both overt and subclinical inflammation. Additionally, the utility of several biomarkers, notably MHR, in investigating this association is also discussed. We further reviewed the role of vitamin D deficiency in precipitating prediabetes and type 2 diabetes mellitus (T2DM) via insulin resistance, decreased insulin synthesis and secretion, and subclinical inflammation. Taken together, this mini review highlights that vitamin D deficiency is significantly associated with subclinical inflammation, playing a critical role in the development of prediabetes and the progression to T2DM. Addressing vitamin D deficiency through appropriate interventions may serve as a preventative measure against the development of prediabetes and T2DM.

Effects of subclinical mastitis on automatic milking system data, hematological and biochemical parameters, and milk composition in Holstein cows.

Objective: Subclinical mastitis decreases milk production and quality, despite the normal appearance of the mammary glands and milk. Herein, we aimed to investigate changes in factors monitored via automatic milking systems (AMS) prior to subclinical mastitis onset and identify differences in hematological and biochemical parameters and milk composition at subclinical mastitis onset. Methods: Thirty-two Holstein cows were divided into two groups according to somatic cell counts (SCC) from AMS and milk composition analysis and the California mastitis test (CMT): healthy cows (controls [CON], n=16, SCC <500×103 cells/ml and negative for CMT) and cows with subclinical mastitis (SCM, n=16, SCC ≥500×103 cells/ml and positive for CMT). Eventually, 121 milk samples from the CON ([mCON], n=60) and SCM ([mSCM], n=61) groups were obtained; SCM samples were categorized as those from non-inflamed (mNQ) or subclinically-inflamed (mIQ) quarters. We evaluated AMS factors; hematological, biochemical, and milk composition parameters; and bacterial isolation. Results: In cows with SCM, milk yield decreased and electrical conductivity (EC) changed before disease onset. Milk EC decreased in mNQ although increased in mIQ (p<0.05). The SCM group had higher globulin levels and lower basophil counts; albumin-to-globulin ratio; and total cholesterol, albumin, and blood urea nitrogen levels than the CON group (p<0.05). The mIQ group had higher SCC but lower levels of lactose and milk solids-not-fat than those in the mCON and mNQ groups (p<0.05). The mCON group had higher levels of milk non-protein nitrogen than the mNQ group (p<0.05). Opportunistic mastitis pathogens were isolated in the mIQ group. Conclusion: Changes in milk yield and EC measured using AMS occurred prior to subclinical mastitis, which may be associated with variation in basophil counts; albumin-to-globulin ratio; and total cholesterol, albumin, BUN, globulin, SCC, milk lactose, and milk solids-not-fat levels at disease onset. These findings provide new insights into early-stage subclinical mastitis.

Linking Non-alcoholic Fatty Liver Disease Severity With Metabolic Syndrome Features: An Integrative Study on Clinical and Radiological Fronts.

Introduction Non-alcoholic fatty liver disease (NAFLD) has become a widespread cause of chronic liver disease, ranging from simple steatosis to severe conditions like non-alcoholic steatohepatitis (NASH) and cirrhosis. Despite its similarity to alcohol-induced liver damage, NAFLD affects individuals with no significant alcohol consumption. This study explores the association between NAFLD, bone mineral density (BMD), insulin resistance, and subclinical inflammation, focusing on the Asian Indian population. The primary objective was to investigate the relationship between NAFLD and BMD, insulin levels, and markers of subclinical inflammation, hypothesizing that patients with NAFLD exhibit lower BMD, possibly linked to insulin resistance and inflammation. Methodology A cross-sectional study with 100 subjects aged 18-50 years (50 cases with NAFLD and 50 controls) was conducted. Exclusion criteria included excessive alcohol consumption, drug-induced fatty liver, severe organ dysfunction, infections, pregnancy, and acute or chronic illness. Data were collected through clinical examinations, anthropometric measurements, biochemical investigations, ultrasound diagnosis of NAFLD, and dual-energy X-ray absorptiometry (DEXA) scans for BMD assessment. Statistical analysis employed the chi-squared tests, t-tests, and Wilcoxon rank-sum tests. Results NAFLD patients had higher body mass index (BMI), waist-to-hip ratio, and markers of insulin resistance and inflammation compared to non-NAFLD controls. DEXA scans revealed significantly lower BMD in NAFLD cases, along with a higher prevalence of osteopenia. Positive correlations were observed between BMD and insulin resistance. The study contributes to understanding the link between NAFLD and lower BMD in the Asian Indian population, emphasizing the impact of insulin resistance and inflammation on bone health. The literature review supports the relevance of exploring NAFLD as an independent risk factor for low BMD. Conclusion This case-control study underscores the significant association between NAFLD and lower BMD in the Asian Indian population. Despite limitations, the findings highlight the importance of further research with larger samples and comprehensive assessments to elucidate the interplay between NAFLD, metabolic factors, and bone health.

Investigation of subclinical ocular inflammation in the aqueous humor of patients with myopia following bilateral sequential collamer lens implantation.

BACKGROUND: The aqueous humor, a transparent fluid secreted by the ciliary body, supports the lens of the eyeball. In this study, we analyzed the cytokine and chemokine profiles within the aqueous humor of the contralateral eye post-implantation of an implantable collamer lens (ICL) to evaluate potential subclinical inflammation in the second eye subsequent to ICL implantation in the first eye. METHODS: Aqueous humor samples were procured from both eyes of 40 patients (totaling 80 eyes) prior to bilateral ICL insertion. Subsequently, a comprehensive statistical analysis was conducted using the Luminex assay to quantify 30 different cytokines in these samples. RESULTS: Compared to the first eye, the aqueous humor of the second eye demonstrated decreased concentrations of IFN-γ (P = 0.038), IL-13 (P = 0.027), IL-17/IL-17 A (P = 0.012), and IL-4 (P = 0.025). No significant differences were observed in other cytokine levels between the two groups. Patients were then categorized based on the postoperative rise in intraocular pressure (IOP) in the first eye. The group with elevated IOP displayed elevated levels of EGF in the aqueous humor of the first eye (P = 0.013) and higher levels of PDGF-AB/BB in the aqueous humor of the second eye (P = 0.032) compared to the group with normal IOP. Within the elevated IOP group, the levels of EGF (P = 0.013) and IL-17/IL-17 A (P = 0.016) in the aqueous humor were lower in the second eye than in the first eye. In the normal IOP group, cytokine levels did not differ notably between eyes. CONCLUSION: Following sequential ICL implantation, it appears that a protective response may be activated to mitigate subclinical inflammation in the second eye induced by the initial implantation in the first eye. Additionally, the increase in IOP subsequent to surgery in the first eye may correlate with the presence of inflammatory mediators in the aqueous humor.

A Murine Model of Maternal Micronutrient Deficiencies and Gut Inflammatory Host-microbe Interactions in the Offspring.

BACKGROUND & AIMS: Micronutrient deficiency (MND) (ie, lack of vitamins and minerals) during pregnancy is a major public health concern. Historically, studies have considered micronutrients in isolation; however, MNDs rarely occur alone. The impact of co-occurring MNDs on public health, mainly in shaping mucosal colonization by pathobionts from the Enterobacteriaceae family, remains undetermined due to lack of relevant animal models. METHODS: To establish a maternal murine model of multiple MND (MMND), we customized a diet deficient in vitamins (A, B12, and B9) and minerals (iron and zinc) that most commonly affect children and women of reproductive age. Thereafter, mucosal adherence by Enterobacteriaceae, the associated inflammatory markers, and proteomic profile of intestines were determined in the offspring of MMND mothers (hereafter, low micronutrient [LM] pups) via bacterial plating, flow cytometry, and mass spectrometry, respectively. For human validation, Enterobacteriaceae abundance, assessed via 16s sequencing of 3-month-old infant fecal samples (n = 100), was correlated with micronutrient metabolites using Spearman's correlation in meconium of children from the CHILD birth cohort. RESULTS: We developed an MMND model and reported an increase in colonic abundance of Enterobacteriaceae in LM pups at weaning. Findings from CHILD cohort confirmed a negative correlation between Enterobacteriaceae and micronutrient availability. Furthermore, pro-inflammatory cytokines and increased infiltration of lymphocyte antigen 6 complex high monocytes and M1-like macrophages were evident in the colons of LM pups. Mechanistically, mitochondrial dysfunction marked by reduced expression of nicotinamide adenine dinucleotide (NAD)H dehydrogenase and increased expression of NAD phosphate oxidase (Nox) 1 contributed to the Enterobacteriaceae bloom. CONCLUSION: This study establishes an early life MMND link to intestinal pathobiont colonization and mucosal inflammation via damaged mitochondria in the offspring.

Circulating microRNAs and hepcidin as predictors of iron homeostasis and anemia among school children: a biochemical and cross-sectional survey analysis.

BACKGROUND: MicroRNAs (miRNAs) can control several biological processes. Thus, the existence of these molecules plays a significant role in regulating human iron metabolism or homeostasis. PURPOSE: The study aimed to determine the role of circulating microRNAs and hepcidin in controlling iron homeostasis and evaluating possible anemia among school children. METHODS: The study was based on a biochemical and cross-sectional survey study that included three hundred fifty school children aged 12-18 years old. RT-PCR and immunoassay analysis were accomplished to estimate iron concentration, Hgb, serum ferritin (SF), soluble transferrin receptor (sTfR), total body iron stores (TIBs), total oxidative stress (TOS), total antioxidant capacity (TAC), α-1-acid glycoprotein (AGP), high sensitive C-reactive protein (hs-CRP), and miRNAs; miR-146a, miR-129b, and miR-122 in 350 school adolescents. RESULTS: Iron disorders were cross-sectionally predicted in 28.54% of the study population; they were classified into 14.26% with ID, 5.7% with IDA, and 8.6% with iron overload. The overall proportion of iron depletion was significantly higher in girls (20.0%) than in boys (8.6%). MicroRNAs; miR-146a, miR-125b, and miR-122 were significantly upregulated with lower hepcidin expression in adolescence with ID and IDA compared to iron-overloaded subjects, whereas downregulation of these miRNAs was linked with higher hepcidin. Also, a significant correlation was recorded between miRNAs, hepcidin levels, AGP, hs-CRP, TAC, and other iron-related indicators. CONCLUSION: Molecular microRNAs such as miR-146a, miR-125b, and miR-122 were shown to provide an additional means of controlling or regulating cellular iron uptake or metabolism either via the oxidative stress pathway or regulation of hepcidin expression via activating genes encoding Hfe and Hjv activators, which promote iron regulation. Thus, circulating miRNAs as molecular markers and serum hepcidin could provide an additional means of controlling or regulating cellular iron and be associated as valuable markers in diagnosing and treating cases with different iron deficiencies.

The role of ultrasonographic synovial assessment in rheumatoid arthritis patients with concomitant fibromyalgia.

Objectives: This study aimed to compare the prevalence and musculoskeletal ultrasonography (US) findings of rheumatoid arthritis (RA) patients with concomitant fibromyalgia (FM) according to the 1990 American College of Rheumatology (ACR) FM classification criteria or the 2016 ACR FM diagnostic criteria. Patients and methods: This cross-sectional study included 63 patients (17 males, 46 females; mean age: 48.2±7.1 years; range, 18 to 62 years) with RA. Medical history and laboratory data were obtained from electronic records. Clinical examination, composite disease activity measures, functional status, and the German 7-joint ultrasound score were assessed to evaluate disease activity and synovial inflammation. The patients were divided into three groups: patients who met only the 2016 ACR criteria, patients who met only the 1990 ACR criteria, and patients who met both criteria. Results: In patients with RA, concomitant FM prevalence was 34.9% according to the 2016 ACR FM diagnostic criteria versus 23.8% according to the 1990 ACR FM classification criteria. Rheumatoid arthritis patients with FM had high tender joint count and disease activity scores, while musculoskeletal US findings were similar. Patients who met only the 2016 ACR FM diagnostic criteria had significantly higher gray-scale US and power Doppler US synovitis scores than patients who satisfied only ACR 1990 FM classification criteria (p=0.03 and p=0.02, respectively). Conclusion: Synovial inflammation is a prominent sign in RA patients diagnosed with FM according to the 2016 ACR FM diagnostic criteria. The higher disease activity seen in the presence of FM in RA patients is associated with FM rather than synovitis.

Immunological mechanisms of arterial damage in pediatric patients with primary hypertension.

Primary hypertension is a disease that is being diagnosed with increasing frequency in pediatric patients, and many of them are found to have hypertension-mediated organ damage (HMOD), including arterial damage. The pathophysiology of primary hypertension and the formation of HMOD is multifactorial. One mechanism studied in recent years is the subclinical inflammation accompanying the elevation of blood pressure. Experimental studies, studies in adults and children, revealed the involvement of immune mechanisms in the formation of vascular lesions in the course of primary hypertension. The paper summarizes the current knowledge on this subject and points to possible therapeutic targets. Particular emphasis is placed on data from pediatric patients with primary hypertension, as a relation between arterial damage (early vascular aging) and immune system activation had already been found in children. The correct identification of immunological mechanisms may not only broaden our understanding of primary hypertension as a disease but also, more importantly, lead to the most effective methods of its treatment.

Topical proactive therapy in dermatology. A scoping review.

The term 'proactive therapy' refers to a long-term management of clinically intact skin in previously disease-affected areas. This method was initially implemented in atopic dermatitis to maintain the remission and decrease the risk of exacerbations. Proactive therapy aims to limit the need for reactive treatment and improve the patients' quality of life. A proactive approach is likely to be adopted for other relapsing and inflammatory skin conditions in the future. This scoping review aims to identify dermatological conditions to be treated with the proactive approach, evaluate the available evidence for its efficacy and safety, as well as highlight the research gaps.

Time-Dependent Changes of Klotho and FGF-23 Levels after Kidney Transplantation: Role of Cold Ischemia Time, Renal Function and Graft Inflammation.

We investigated the evolution of serum klotho (s-Kl) and FGF-23 during the first two years post-kidney transplantation (KT), considering the cold ischemia time (CIT), glomerular filtration rate (GFR) and graft subclinical inflammation (SCI). We undertook a prospective, cohort, multicenter study of consecutive patients between April 2018 and January 2021 (with follow-up at 24 months). Subgroups were analyzed according to the median CIT (<14 vs. ≥14 h), the median GFR (≤40 vs. >40 mL/min/1.73 m2) and the presence of SCI at month 3. A total of 147 patients were included. s-Kl and fibroblast growth factor-23 (FGF-23) levels were measured at baseline and at months 3, 12 and 24. Graft biopsies (n = 96) were performed at month 3. All patients had low s-Kl levels at month 3. Patients with CIT < 14 h exhibited a significant increase in s-Kl at month 24. In patients with CIT ≥ 14 h, s-Kl at month 3 fell and lower s-Kl levels were seen at month 24. Patients with a GFR > 40 had a lesser decrease in s-Kl at month 3. FGF-23 fell significantly at months 3 and 12 in both GFR groups, a reduction maintained during follow-up. There were significant inter-group differences in s-Kl from months 3 to 24. CIT, GFR at 3 months and SCI were significantly associated with s-KI at month 3. A reduction in s-Kl at month 3 post-KT could be explained by longer CIT and delayed graft function as well as by impaired graft function. Early SCI may regulate s-Kl increase post-KT.

[Diabetes mellitus and the intestinal microbiome]. / A diabetes mellitus és a bélmikrobiom.

The intestinal microbiome plays an important role in the body's physiological processes. One of its most decisive roles is the production of short-chain fatty acids, which has crucial importance in the maintenance of an intact intestinal barrier and immune homeostasis. Dysbiosis in the microbiome caused by dietary habits, regular medication use, and other factors can result in damage to the barrier function, which triggers the translocation of lipopolysaccharides into the portal circulation. By maintaining subclinical inflammation, these can lead to the development of obesity, insulin resistance, and fatty liver. The entry of pathogenic bacteria into the portal circulation can cause beta cell destruction through molecular mimicry and consequent autoimmunity. Both mechanisms can lead to diabetes mellitus. The paper reviews the changes in the intestinal microbiome in type 1 and type 2 diabetes mellitus, detailing experimental and clinical data. It points out that even though our knowledge is not yet sufficient to help daily clinical practice, the expansion of data can help the prognostic use of some results. All this, however, requires further investigations and observations. Orv Hetil. 2023; 164(25): 981-987.

Factors associated with subclinical inflammation of wrist joints in rheumatoid arthritis patients with low or no disease activity- a RA ultrasound registry study.

BACKGROUND: To evaluate the factors to predict subclinical inflammation of wrist joints in patients with RA who are in clinical remission or low disease activity. METHODS: Gray scale and power Doppler ultrasound were performed on the dorsal radio-lunate of both wrists. The presence of synovitis, comorbidities, and use of disease modifying anti-rheumatic drugs were recorded. A Multivariable forward logistical regression model was used to identify factors associated with subclinical inflammation. RESULTS: There were 1248 patients (1010 females, 238 males; mean age: 60.0 ± 10.5 years ). 57.4% of patients in complete remission and low disease activity had sonographic inflammation. Multivariable forward logistic regression analysis indicated that male sex, smoking are positively associated with inflammation and that age, alcohol consumption, and use of methotrexate, glucocorticoid, or a biological therapy are negatively associated with inflammation. Use of biological agents decreased the risk of inflammation by 40.9%. CONCLUSIONS: There was evidence of subclinical inflammation in most patients who were in low or no disease activity, those with biological therapy had lower risk of subclinical inflammation.

Association Between Serum Bicarbonate Levels and Prediabetes and Subclinical Inflammation in Young Healthy Adults: A Cross-sectional Study.

Purpose: Low bicarbonate, a hallmark of metabolic acidosis is associated with various diseases. This study investigated associations between bicarbonate levels with prediabetes and subclinical inflammation among healthy young adults in Qatar. Patients and Methods: A cross-sectional study was carried out with 825 participants aged 18-40 years, devoid of any known comorbidities, using data from the Qatar Biobank. For each participant, blood samples were taken for measurements of bicarbonate, prediabetes, and subclinical inflammation biomarkers. Prediabetes was defined using HbA1c between 5.7 and 6.4% and subclinical inflammation was defined using monocyte to high density lipoprotein (HDL) cholesterol ratio (MHR). Associations between bicarbonate levels and the outcomes were analyzed using multivariable linear and logistic regression and then stratified by gender. Results: A total of 825 participants with mean age 29.2 years (5.9) of which 365 (44.2%) were males. After multivariable logistic regression, each unit increase in serum bicarbonate was associated with a 17% decreased risk of prediabetes (OR: 0.83, 95%CI: 0.70-0.99, p=0.034), in males but no association was observed for females. Similarly, after multivariable linear regression, a unit increase in serum bicarbonate was associated with a 0.18 unit decrease in MHR (beta -0.18, 95%CI: -0.29, -0.07, p=0.002), again with no association observed in females. Conclusion: In a healthy young adult population, higher serum bicarbonate levels were inversely associated with both prediabetes and subclinical inflammation in males, but not in females.

Exploratory analysis of the effect of a controlled lifestyle intervention on inflammatory markers - the Healthy Lifestyle Community Programme (cohort 2).

BACKGROUND: Chronic low-grade inflammation is associated with an increased risk of chronic disease and mortality. The objective of the study was to test the effect of a healthy lifestyle intervention on biomarkers of inflammation (among other risk markers). METHODS: We conducted a non-randomized controlled trial with mostly middle-aged and elderly participants from the general population in rural northwest Germany (intervention: n = 114; control: n = 87). The intervention consisted of a 1-year lifestyle programme focusing on diet (largely plant-based; strongest emphasis), physical activity, stress management, and social support. High-sensitivity C-reactive protein (hs-CRP) was assessed at baseline, 10 weeks, 6 months, and 1 year. Homocysteine (Hcy) was assessed at baseline, 10 weeks, and 1 year. Adiponectin (Apn) was assessed at baseline and 10 weeks. An exploratory analysis of these inflammatory markers assessing the between-group differences with ANCOVA was conducted. RESULTS: The 1-year trajectory of hs-CRP was significantly lower in the intervention group compared to control (between-group difference: -0.8 (95% CI -1.2, -0.3) mg/l; p = 0.001; adjusted for baseline). The 1-year trajectory of Hcy was non-significantly higher in the intervention compared to control (between-group difference: 0.2 (95% CI -0.3, 0.7) µmol/l; p = 0.439; adjusted for baseline). From baseline to 10 weeks, Apn decreased significantly more in the intervention group compared to control (between-group difference: -1.6 (95% CI -2.7, -0.5) µg/ml; p = 0.004; adjusted for baseline). CONCLUSIONS: Our study shows that healthy lifestyle changes can lower hs-CRP and Apn levels and are unlikely to significantly affect Hcy levels within 1 year. TRIAL REGISTRATION: German Clinical Trials Register (DRKS; reference: DRKS00018775 , registered 12 Sept 2019; retrospectively registered; www.drks.de ).

Can RDW be used as a screening test for subclinical inflammation in children with FMF? Is RDW related to MEFV gene mutations?

OBJECTIVE: Subclinical inflammation, an insidious feature of familial Mediterranean fever (FMF), can lead to life-threatening amyloidosis. We aimed to investigate acute phase reactants and complete blood count parameters to identify a useful marker for subclinical inflammation in children with FMF. A secondary aim was to identify an association between subclinical inflammation and specific Mediterranean fever (MEFV) gene mutations. METHODS: This study included 420 pediatric patients with FMF. Laboratory parameters of patients during the attack-free period and MEFV gene mutation analyses were recorded. RESULTS: Of the 420 patients, 88 (21%) had subclinical inflammation. Of those with subclinical inflammation, 48 (55%) had mutations in exon 10, 36 (41%) had M694V mutation, and 10 (11%) had M694V homozygous mutation. Red cell distribution width (RDW) value was higher in exon 10, M694V, and M694V homozygous mutations compared to other mutations. RDW was positively correlated with serum amyloid A (SAA) (r = 0.390, p = 0.0001). Analysis of a receiver-operating characteristic curve of RDW revealed that its optimal cut-off value for subclinical inflammation was 12.69%, its sensitivity was 64.10%, and its specificity was 50.90%. The area under the curve was 0.616 (p = 0.004, 95% confidence interval = 0.538-0.695). CONCLUSION: We suggest that RDW can be used as a screening test as a marker of subclinical inflammation. A high RDW value should alert the clinician about subclinical inflammation in FMF children's patients with M694V (heterozygous, homozygous, compound heterozygous) mutation. Key Points • Subclinical inflammation in FMF patients can lead to amyloidosis. • RDW can be a predictor of subclinical inflammation. • RDW can be used as a screening test for subclinical inflammation in FMF patients with M694V mutation.

TIMP-1 in the prognosis of patients who underwent coronary artery bypass surgery: a 12-year follow-up study.

Introduction: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been linked to clinical outcomes in patients with coronary artery disease (CAD). However, the prognostic value of TIMP-1 in patients with CAD who underwent coronary artery bypass grafting (CABG) has not been elucidated. We aimed to investigate the correlations of TIMP-1 with high-sensitivity C-reactive protein (hs-CRP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in the long-term prognosis of consecutive patients who underwent CABG. Methods: A total of 234 patients (age: 70.4 ± 10.5 years, 84.6% men) with CAD who underwent CABG were prospectively enrolled. Preoperative levels of MMPs, TIMP-1, hs-CRP, and NT-proBNP were recorded. Major adverse cardiovascular events (MACE) were defined as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. Results: During a median follow-up of 12.1 years, 120 deaths were recorded. The deceased were older, had more manifest acute coronary syndrome (ACS), a lower left ventricular ejection fraction (LVEF), and an estimated glomerular filtration rate (eGFR), but significantly higher MMP13, TIMP-1, hs-CRP, and NT-proBNP compared with the survivors. After adjusting for age, sex, manifest ACS, eGFR, LVEF, total cholesterol, and triglycerides, TIMP-1 (hazard ratio and 95% confidence intervals per SD: 1.506, 1.183-1.917), hs-CRP (1.349, 1.183-1.561), and NT-ProBNP (1.707, 1.326-2.199) were all independently associated with all-cause mortality. The mediation analysis revealed that the mortality risks of TIMP-1 were partially mediated by NT-proBNP (62.2%) and hs-CRP (25.3%). The associations of TIMP-1 with MACE were partially mediated by NT-proBNP (54.4%) but not hs-CRP. Conclusions: TIMP-1 was an independent predictor of long-term outcomes after CABG, with possible roles in subclinical inflammation and postoperative cardiac remodeling.

Heme Oxygenase-1 and Blood Bilirubin Are Gradually Activated by Oral D-Glyceric Acid.

It has been shown that small doses of oral D-glyceric acid (DGA) activate mitochondrial metabolism and reduce inflammation among 50-60-year-old healthy volunteers. The present results with the same small doses reveal that after a 4-day DGA regimen, a dose of DGA activated the HO-1 pathway acutely, while enhanced inflammatory status after the 4-day DGA regimen seemed to be able to downregulate the HO-1 pathway in non-acute measurement. Blood bilirubin was strongly upregulated towards the end of the altogether 21-day study period with positive associations towards improved inflammation and reduced blood triglycerides. After the 4-day DGA regimen, hepatic inflow of blood bilirubin with albumin as the carrier was clearly upregulated in the lower-aerobic-capacity persons. At the same time also, blood triglycerides were down, pointing possibly to the activation of liver fatty acid oxidation. The combination of activated aerobic energy metabolism with transient HO-1 pathway activation and the upregulation of blood bilirubin may reduce the risks of chronic diseases, especially in aging. Furthermore, there exist certain diseases with unsatisfactorily-met medical needs, such as fatty and cholestatic liver diseases, and Parkinson's disease, that can be possibly ameliorated with the whole-body mechanism of the action of the DGA regimen.

Treatment of early borderline lesions in low immunological risk kidney transplant patients: a Spanish multicenter, randomized, controlled parallel-group study protocol: the TRAINING study.

BACKGROUND: Subclinical inflammation, including borderline lesions (BL), is very common (30-40%) after kidney transplantation (KT), even in low immunological risk patients, and can lead to interstitial fibrosis/tubular atrophy (IFTA) and worsening of renal function with graft loss. Few controlled studies have analyzed the therapeutic benefit of treating these BL on renal function and graft histology. Furthermore, these studies have only used bolus steroids, which may be insufficient to slow the progression of these lesions. Klotho, a transmembrane protein produced mainly in the kidney with antifibrotic properties, plays a crucial role in the senescence-inflammation binomial of kidney tissue. Systemic and local inflammation decrease renal tissue expression and soluble levels of α-klotho. It is therefore important to determine whether treatment of BL prevents a decrease in α-klotho levels, progression of IFTA, and loss of kidney function. METHODS: The TRAINING study will randomize 80 patients with low immunological risk who will receive their first KT. The aim of the study is to determine whether the treatment of early BL (3rd month post-KT) with polyclonal rabbit antithymocyte globulin (Grafalon®) (6 mg/kg/day) prevents or decreases the progression of IFTA and the worsening of graft function compared to conventional therapy after two years post-KT, as well as to analyze whether treatment of BL with Grafalon® can modify the expression and levels of klotho, as well as the pro-inflammatory cytokines that regulate its expression. DISCUSSION: This phase IV investigator-driven, randomized, placebo-controlled clinical trial will examine the efficacy and safety of Grafalon® treatment in low-immunological-risk KT patients with early BL. TRIAL REGISTRATION: clinicaltrials.gov : NCT04936282. Registered June 23, 2021, https://clinicaltrials.gov/ct2/show/NCT04936282?term=NCT04936282&draw=2&rank=1 . Protocol Version 2 of 21 January 2022. SPONSOR: Canary Isles Institute for Health Research Foundation, Canary Isles (FIISC). mgomez@fciisc.org .

Long-term immunological outcomes of early subclinical inflammation on surveillance kidney allograft biopsies.

The long-term impact of early subclinical inflammation (SCI) through surveillance biopsy has not been well studied. To do this, we recruited a prospective observational cohort that included 1000 sequential patients who received a kidney transplant from 2013-2017 at our center. A total of 586 patients who underwent a surveillance biopsy in their first year post-transplant were included after excluding those with clinical rejections, and those who were unable to undergo a surveillance biopsy. Patients were classified based on their biopsy findings: 282 with NSI (No Significant Inflammation) and 304 with SCI-T (SCI and Tubulitis) which was further subdivided into 182 with SC-BLR (Subclinical Borderline Changes) and 122 with SC-TCMR (Subclinical T Cell Mediated Rejection, Banff 2019 classification of 1A or more). We followed the clinical and immunological events including Clinical Biopsy Proven Acute Rejection [C-BPAR], long-term kidney function and death-censored graft loss over a median follow-up of five years. Episodes of C-BPAR were noted at a median of two years post-transplant. Adjusted odds of having a subsequent C-BPAR was significantly higher in the SCI-T group [SC-BLR and SC-TCMR] compared to NSI 3.8 (2.1-7.5). The adjusted hazard for death-censored graft loss was significantly higher with SCI-T compared to NSI [1.99 (1.04-3.84)]. Overall, SCI detected through surveillance biopsy within the first year post-transplant is a harbinger for subsequent immunological events and is associated with a significantly greater hazard for subsequent C-BPAR and death-censored graft loss. Thus, our study highlights the need for identifying patients with SCI through surveillance biopsy and develop strategies to prevent further alloimmune injuries.