Association between Human Leukocyte Antigen and End-Stage Renal Disease in Patients from Transylvania, Romania.

End-stage renal disease (ESRD) is the final stage of chronic kidney disease. This study explored the association between human leukocyte antigen (HLA) and ESRD. The interaction between genetic and environmental factors may also play a role in the development of ESRD. The study included 2392 ESRD patients who were awaiting renal transplantation. Blood samples were genotyped by SSOP and SSP-PCR methods. Multivariate logistic regression analysis showed that HLA-A*11 (p = 0.027), HLA-A*34 (p = 0.017), HLA-A*69 (p = 0.012), HLA-B*41 (p < 0.001), HLA-B*50 (p = 0.004), HLA-DRB1*10 (p = 0.027), and HLA-DRB1*14 (p = 0.004) were positively associated with ESRD (OR > 1); HLA-DRB1*07 (p < 0.001), HLA-DRB1*08 (p = 0.005), and HLA-DRB1*13 (p < 0.001) were protective against ESRD (OR < 1); and the three-locus haplotype HLA-A*02-B*41-DRB1*03, containing one susceptible allele, was strongly associated with ESRD (p < 0.001, OR = 3.15). In conclusion, this retrospective analysis of HLA typing in patients with ESRD of various etiologies suggests that molecular data on the HLA polymorphism should be collected in order to identify high-risk ESRD patients and to improve graft survival after kidney transplantation.

Waist to height ratio in nonalcoholic fatty liver disease - Systematic review and meta-analysis.

BACKGROUND AND AIMS: Current nonalcoholic fatty liver disease (NAFLD) guidelines do not provide any recommendations regarding the waist-to-height ratio (WHtR), a simple obesity metric calculated by dividing waist circumference by height. Therefore, we performed a systematic review and meta-analysis aiming to evaluate WHtR in NAFLD. METHODS: We performed a systematic electronic search on PubMed, Embase, and Scopus, identifying observational studies assessing WHtR in NAFLD. QUADAS-2 tool was used to evaluate the quality of included studies. The two main statistical outcomes were the area under the curve (AUC) and the mean difference (MD). RESULTS: We included a total of 27 studies in our quantitative and qualitative synthesis, with a total population of 93,536 individuals. WHtR was significantly higher in NAFLD patients compared to controls with an MD of 0.073 (95% CI 0.058 - 0.088). This was also confirmed after conducting a subgroup analysis according to the hepatic steatosis diagnosis method, for ultrasound (MD 0.066 [96% CI 0.051 - 0.081]) and transient elastography (MD 0.074 [96% CI 0.053 - 0.094]). Moreover, NAFLD male patients presented significantly lower WHtR compared to female patients (MD -0.022 [95% CI -0.041 - -0.004]). The AUC of WHtR for predicting NAFLD was 0.815 (95% CI 0.780 - 0.849). CONCLUSIONS: WHtR is considerably higher in NAFLD patients compared to controls. Female NAFLD patients present higher WHtR compared to NAFLD male patients. In comparison to other presently suggested scores and markers, the WHtR's accuracy in predicting NAFLD is considered acceptable.

Chitotriosidase and Neopterin as Two Novel Potential Biomarkers for Advanced Stage and Survival Prediction in Gastric Cancer-A Pilot Study.

Gastric cancer is the fifth type of neoplasia most frequently diagnosed and the fourth cause of death among other cancers. Prevalence is around two times higher for males than females. Chitotriosidase and neopterin are two molecular biomarkers with potential diagnostic and prognostic use in malignant pathology. We conducted a longitudinal prospective cohort study on thirty-nine patients with gastric adenocarcinoma, with a male-to-female ratio of 1.78 and an average age of 64.3 ± 9.97 years. No statistically significant differences in biomarker levels at presentation were observed between curative-intent surgery (28 patients) and advanced cases, suited only for palliative procedures (11 patients). Biomarker values were not significantly different for the advanced T stage and the presence of metastasis (p > 0.05-Mann Whitney test). The patients that died in the first 30 days after surgery did not present significantly different values at baseline, in comparison with those that had longer survival times, though a significant cut-off value was observed for chitotriosidase activity at 310 nmol/mL/h [AUC (area under the curve) = 0.78; 95% CI (0.61-0.92)]. The cut-off values corresponding to death after the first year, tumor invasion, and metastasis were not statistically significant. In the COX multivariate model, neopterin did not validate itself as a prognostic biomarker, however, chitotriosidase activity before surgery was significantly associated with overall survival (HR = 1.0038, p = 0.03). We conclude that chitotriosidase may have the potential to improve the prognostic model for gastric adenocarcinoma.

Chitotriosidase and Neopterin as Potential Biomarkers for the Evaluation of Complicated Cholecystitis-A Pilot Study.

Gallstones are a common surgical pathology. Laparoscopic cholecystectomy represents the elective treatment. Complicated cases can increase the rate of conversion, the duration, and the difficulty of the intervention, along with the hospitalization period. A prospective cohort study was conducted on 51 patients with gallstones. Only subjects with normal renal, pancreatic, and hepatic functions were included. The severity of cholecystitis was evaluated by considering the ultrasound examination, intraoperative findings, and pathology report. We evaluated two potential biomarkers, namely neopterin and chitotriosidase, by comparing their levels before and after the intervention for chronic (n = 36) and complicated (n = 15) cases, as well as their eventual association with the hospitalization period. Subjects with complicated cholecystitis had significantly higher (p = 0.01) neopterin levels at presentation (16.82 nmol/L vs. 11.92 nmol/L, median values), but the differences in chitotriosidase activity between complicated (170.00 nmol/mL/h) and chronic (160.00 nmol/mL/h) cases were not significant (p = 0.66). Patients with neopterin levels above the cut-off value 14.69 nmol/L had a 3.34 times higher risk of complicated cholecystitis. Twenty-four hours after the laparoscopic cholecystectomy, the differences in neopterin level and chitotriosidase activity between chronic and complicated cases were not significant. A significant decrease in chitotriosidase activity was observed after the intervention, only for complicated cases (190 nmol/mL/h vs. 145 nmol/mL/h, p = 0.007); for neopterin, the postoperative decrease was not statistically significant (19.42 nmol/L vs. 10.92 nmol/L, p = 0.06). No significant association with the hospitalization period was observed. Neopterin may be a useful biomarker for complicated cholecystitis, and chitotriosidase may have prognostic utility in early patient follow-up.

Exploratory Longitudinal Analysis of the Circulating CHIT1 Activity in Pediatric Patients with Obesity.

Macrophage activation and cytokine release play a pivotal role in inflammation-mediated metabolic disturbances in obesity. The proinflammatory macrophage secretes human chitotriosidase (CHIT1). The expression of the CHIT1 in visceral adipose tissue is associated with cytokine production. Our study aimed to assess whether the CHIT1 circulating activity, as a macrophage activation indicator, reflects the change of the adiposity level and the insulin resistance (IR) in children with obesity. We longitudinally (median follow-up period of 7 months; IQR [5 to 8.5] and {2 to 13} months) evaluated the CHIT1 circulating activity, the adiposity level (waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WtHR), and body mass index (BMI)-for-age z score), and two surrogate markers of IR (Homeostatic Model Assessment for Insulin Resistance, HOMA-IR and the triglycerides-to-high density lipoprotein cholesterol ratio, TG/HDLc) in 29 pediatric patients (16 girls and 13 boys) with obesity. We found a significant reduction in CHIT1 circulating activity (Wilcoxon test, p = 0.015) and a decrease in TG/HDLc at the follow-up evaluation (Wilcoxon test, p < 0.001). Indicators of adiposity were positively correlated with HOMA-IR at baseline, among which WC was the sole indicator associated with HOMA-IR (Spearman's rank correlation coefficients, p < 0.05) at follow-up. Human chitotriosidase has the potential to be a valuable measure of the progression of subclinical inflammation in children with obesity. Subclinical inflammation, as expressed by the circulating CHIT1 activity, progresses independently of the abdominal adiposity, as measured by the clinical indicators, and is associated with a change in insulin resistance.

Evaluation of Circulating Chitotriosidase Activity in Children with Obesity.

Childhood obesity progresses to metabolic disturbances via low-grade inflammation. Identifying novel molecules that reflect the activity of the immune responses is critical in understanding its underlying pathogenesis. Our exploratory study aimed to evaluate the change of chitotriosidase (CHIT1) plasma activity according to Body Mass Index (BMI)-for-age z score in pediatric patients. The study evaluated 68 children consisting of 47.1% girls with a mean age of 12.47 ± 3.71 years and 52.9% boys with a mean age of 11.93 ± 3.18 years. The effect of the most frequent CHIT1 gene variants, the 24 base pair duplication (dup24) and G102S polymorphism, upon the association between circulating CHIT1 activity and the obesity level, was also investigated. A significantly higher logCHIT1 plasma activity was found in children with extreme obesity than in children with overweight (p = 0.048 for the uncorrected CHIT1 and 0.026 for the corrected CHIT1). The BMI-for-age z score significantly (p = 0.031) predicts increased CHIT1 activity in children with overweight, obesity, and extreme obesity after controlling for the two gene variants, age, gender, and time since weight gain. Dup24 and G102S polymorphism were significant independent predictors (p-values < 0.002) for the change of CHIT1 plasma activity. Circulating CHIT1 might be an accurate indicator of inflammation in children with obesity. Its role and the effect of the dup24 and G102S variants on the CHIT1 activity should be validated in a larger cohort.

Non-Coding RNAs: Prevention, Diagnosis, and Treatment in Myocardial Ischemia-Reperfusion Injury.

Recent knowledge concerning the role of non-coding RNAs (ncRNAs) in myocardial ischemia/reperfusion (I/R) injury provides new insight into their possible roles as specific biomarkers for early diagnosis, prognosis, and treatment. MicroRNAs (miRNAs) have fewer than 200 nucleotides, while long ncRNAs (lncRNAs) have more than 200 nucleotides. The three types of ncRNAs (miRNAs, lncRNAs, and circRNAs) act as signaling molecules strongly involved in cardiovascular disorders (CVD). I/R injury of the heart is the main CVD correlated with acute myocardial infarction (AMI), cardiac surgery, and transplantation. The expression levels of many ncRNAs and miRNAs are highly modified in the plasma of MI patients, and thus they have the potential to diagnose and treat MI. Cardiomyocyte and endothelial cell death is the major trigger for myocardial ischemia-reperfusion syndrome (MIRS). The cardioprotective effect of inflammasome activation in MIRS and the therapeutics targeting the reparative response could prevent progressive post-infarction heart failure. Moreover, the pharmacological and genetic modulation of these ncRNAs has the therapeutic potential to improve clinical outcomes in AMI patients.

Evaluation of Chitotriosidase and Neopterin as Biomarkers of Microvascular Complications in Patients with Type 1 Diabetes Mellitus.

The chronic complications of diabetes mellitus (DM) are accompanied by inflammatory manifestations. Our study aimed to evaluate a possible association between the inflammatory status (reflected by serum chitotriosidase and neopterin) and the timely evolution and occurrence of chronic microvascular complications in patients with type 1 DM. This observational, cross-sectional study included 82 type 1 DM patients from the Centre for Diabetes, Nutrition and Metabolic Diseases, Cluj-Napoca, Romania. Our results demonstrated a link between the extent of inflammation, evaluated by the enzymatic activity of circulating chitotriosidase, and the onset of microvascular complications, especially diabetic neuropathy and retinopathy. Chitotriosidase enzymatic activity showed an ascending evolution over time. In non-smoking patients, the increase in chitotriosidase activity was correlated with the extent of microalbuminuria and the decline of glomerular filtration rate, while in smokers, only the presence of a positive correlation between chitotriosidase activity and disease progression was noticed. According to our results, the time span between the moment of diagnosis and the onset of microvascular complications was longer in non-smokers than in smokers. These results also imply that increased chitotriosidase activity may be a predictor of endothelial dysfunction in type 1 DM.

Implications of Long Non-Coding RNAs in Age-Altered Proteostasis.

This review aims to summarize the current knowledge on how lncRNAs are influencing aging and cancer metabolism. Recent research has shown that senescent cells re-enter cell-cycle depending on intrinsic or extrinsic factors, thus restoring tissue homeostasis in response to age-related diseases (ARDs). Furthermore, maintaining proteostasis or cellular protein homeostasis requires a correct quality control (QC) of protein synthesis, folding, conformational stability, and degradation. Long non-coding RNAs (lncRNAs), transcripts longer than 200 nucleotides, regulate gene expression through RNA-binding protein (RBP) interaction. Their association is linked to aging, an event of proteostasis collapse. The current review examines approaches that lead to recognition of senescence-associated lncRNAs, current methodologies, potential challenges that arise from studying these molecules, and their crucial implications in clinical practice.

Diagnostic and prognostic value of microRNAs for Alzheimer's disease: a comprehensive meta-analysis.

BACKGROUND AND AIMS: Recent research has shown that microRNAs (miRNAs), a class of sequences regulating gene expression without undergoing translational processes, have been accepted as novel biomarkers of diseases. In the present meta-analysis, our main objective was to evaluate the diagnostic value of miRNAs expressed in different body fluids for Alzheimer's disease (AD), more exactly to analyze the discriminative value of miRNAs between AD and control subjects. METHODS: Medline and EMBASE were searched for articles written in English, and because the result reporting modalities were extremely different in the studies included in the analysis, the current article comprises 2 meta-analyses, each of them using different statistical indicators. The first meta-analysis reviewed 10 studies, which were required to provide sufficient information to allow the calculation of AUC or Cohen's d for size effect. We proposed a second meta-analysis, starting from the drawbacks identified in this first approach, which used different statistical indicators (fold change) provided by other studies (8 studies). RESULTS: The present study offers an encouraging role of miRNA families in diagnosing AD. The heterogeneity of miRNA expression between the hippocampus, CSF and peripheral blood, the small sample size of each research study, as well as the different methods for miRNA detection remain the main obstacles in interpreting these results. CONCLUSIONS: There is a need (in a future perspective) to establish the right miRNA combinations as potent diagnostic biomarkers for AD.

Relation between serum cotinine levels and trophic lesions in patients with critical limb ischemia: a pilot study.

Aim: To evaluate if smoking, quantified by the serum cotinine levels, is related to the evolution of patients with critical limb ischemia (CLI).Method: A pilot study was conducted on CLI patients who addressed at the Second Surgery Clinic of the Emergency County Hospital, Cluj-Napoca, Romania between November 2015 and December 2016. The sample of patients was split into two groups using the threshold of 15 ng/mL for the serum level of cotinine (low cotinine level - LCL vs. high cotinine level - HCL). Furthermore, the ROC analysis was conducted to identify the threshold of cotinine level able to discriminate between CLI patients with and without trophic lesions.Results: The mean age of patients was 60.7 ± 10.5 years with a significantly higher percentage of male patients (84%). A significant association was identified between urban origin and serum cotinine level, which is related to the increased number of cigarettes smoked per day among urban participants. Excepting necrectomy and toe disarticulation, no differences were found between LCL and HCL group regarding symptoms, signs or comorbidities. In smokers with CLI (38/43), a serum cotinine cut-off of 9.765 ng/mL was observed on eight out of 10 CLI patients with necrectomy and five out of 28 patients without necrectomy.Conclusion: Our study showed higher serum cotinine levels associated with a higher number of smoked cigarettes and necrectomy in patients with CLI. The serum cotinine could be a fair screening test for necrectomy in smokers CLI patients.

Natural products with anti-aging potential: Affected targets and molecular mechanisms.

In recent years, there has been a great deal of attention toward the molecular machinery relevant to age-related progression controlled through the external intervention of polyphenols- an epigenetic-modulating diet. Natural products modulate cellular longevity through histone post-translational modification and can also induce the upregulation of autophagy, thus reducing the level of acetyl coenzyme A (AcCoA). In addition, the effect of caloric restriction (CR) on cancer-related chronic inflammation is of great significance in aging. In line with this, SIRT1 protein levels are expanded in response to calorie restriction mimetics (CRM), in this way acting as autophagy inducers relevant to cancer prevention.

Evaluation of Chitotriosidase as a Marker of Inflammatory Status in Critical Limb Ischemia.

BACKGROUND: Chitotriosidase is an enzyme secreted by activated macrophages. This study aims to investigate the usefulness of circulating chitotriosidase activity as a marker of inflammatory status in patients with critical limb ischemia (CLI). MATERIALS AND METHODS: An observational gender-matched case-control study was conducted on patients hospitalized with the primary diagnosis of CLI, as well as a control group. The control group consisted of healthy volunteers. RESULTS: Forty-three patients were included in each group. Similar demographic characteristics (median age of 60-62 years and overweight) were observed in both groups. Chitotriosidase activity ranged from 110 nmol/ml/hr to 1530 nmol/ml/hr in the CLI group and from 30 nmol/ml/hr to 440 nmol/ml/hr in the control group; demonstrating significantly elevated values in the CLI group (p<0.001). Median plasma chitotriosidase activity was significantly elevated in smokers compared with non-smokers in both groups (p<0.05). However, this activity had higher values in CLI than in control subjects. Receiver operating characteristic (ROC) analysis was then performed in order to verify the diagnostic accuracy of chitotriosidase as an inflammatory biomarker in CLI. CONCLUSION: Circulating chitotriosidase is a test which can potentially be used for the monitoring of CLI patients without other inflammatory conditions. However, the interpretation of elevated values must take into account the inflammatory response induced by tobacco exposure.

Non-coding RNAs, the Trojan horse in two-way communication between tumor and stroma in colorectal and hepatocellular carcinoma.

In a continuous and mutual exchange of information, cancer cells are invariably exposed to microenvironment transformation. This continuous alteration of the genetic, molecular and cellular peritumoral stroma background has become as critical as the management of primary tumor progression events in cancer cells. The communication between stroma and tumor cells within the extracellular matrix is one of the triggers in colon and liver carcinogenesis. All non- codingRNAs including long non-coding RNAs, microRNAs and ultraconserved genes play a critical role in almost all cancers and are responsible for the modulation of the tumor microenvironment in several malignant processes such as initiation, progression and dissemination. This review details the involvement of non codingRNAs in the evolution of human colorectal carcinoma and hepatocellular carcinoma in relationship with the microenvironment. Recent research has shown that a considerable number of dysregulated non- codingRNAs could be valuable diagnostic and prognostic biomarkers in cancer. Therefore, more in-depth knowledge of the role non- codingRNAs play in stroma-tumor communication and of the complex regulatory mechanisms between ultraconserved genes and microRNAs supports the validation of future effective therapeutic targets in patients suffering from hepatocellular and colorectal carcinoma, two distinctive entities which share quite a lot common non-coding RNAs.

Inflamma-miRs in Aging and Breast Cancer: Are They Reliable Players?

Human aging is characterized by chronic low-grade inflammation known as "inflammaging." Persistent low-level inflammation also plays a key role in all stages of breast cancer since "inflammaging" is the potential link between cancer and aging through NF-kB pathways highly influenced by specific miRs. Micro-RNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at a posttranscriptional level. Inflamma-miRs have been implicated in the regulation of immune and inflammatory responses. Their abnormal expression contributes to the chronic pro-inflammatory status documented in normal aging and major age-related diseases (ARDs), inflammaging being a significant mortality risk factor in both cases. Nevertheless, the correct diagnosis of inflammaging is difficult to make and its hidden contribution to negative health outcomes remains unknown. This methodological work flow was aimed at defining crucial unanswered questions about inflammaging that can be used to clarify aging-related miRNAs in serum and cell lines as well as their targets, thus confirming their role in aging and breast cancer tumorigenesis. Moreover, we aim to highlight the links between the pro-inflammatory mechanism underlying the cancer and aging processes and the precise function of certain miRNAs in cellular senescence (CS). In addition, miRNAs and cancer genes represent the basis for new therapeutic findings indicating that both cancer and ARDs genes are possible candidates involved in CS and vice versa. Our goal is to obtain a focused review that could facilitate future approaches in the investigation of the mechanisms by which miRNAs control the aging process by acting as efficient ARDs inflammatory biomarkers. An understanding of the sources and modulation of inflamma-miRs along with the identification of their specific target genes could enhance their therapeutic potential.

Contribution of the IL-17/IL-23 axis to the pathogenesis of inflammatory bowel disease.

Inflammatory bowel diseases (IBDs) are chronic disorders of modern society, requiring management strategies aimed at prolonging an active life and establishing the exact etiology and pathogenesis. These idiopathic diseases have environmental, genetic, immunologic, inflammatory, and oxidative stress components. On the one hand, recent advances have shown that abnormal immune reactions against the microorganisms of the intestinal flora are responsible for the inflammation in genetically susceptible individuals. On the other hand, in addition to T helper cell-type (Th) 1 and Th2 immune responses, other subsets of T cells, namely regulatory T cells and Th17 maintained by IL-23 are likely to develop IBD. IL-23 acts on innate immune system members and also facilitates the expansion and maintenance of Th17 cells. The IL-17/IL-23 axis is relevant in IBD pathogenesis both in human and experimental studies. Novel biomarkers of IBD could be calprotectin, microRNAs, and serum proinflammatory cytokines. An efficient strategy for IBD therapy is represented by the combination of IL-17A and IL-17F in acute IL-17A knockout TNBS-induced colitis, and also definite decrease of the inflammatory process in IL-17F knockout, DSS-induced colitis have been observed. Studying the correlation between innate and adaptive immune systems, we hope to obtain a focused review in order to facilitate future approaches aimed at elucidating the immunological mechanisms that control gut inflammation.

Is interleukin-17 a proatherogenic biomarker?

The importance of chronic inflammation in atherogenesis and cytokine involvement in all stages of atherosclerotic plaque development is now obvious. Our approach of the significant cytokines involved in atherogenesis or cardiovascular diseases is based on a correlation between clinical research and experiments on animal models. The contribution of IL-17 in atherogenesis remains controversial. In this study we investigated the role of IL-17 in cardiovascular diseases and in atherosclerosis associated with pathological aging. We performed a case-control study, enrolling subjects aged over 65 years in both groups. We included 40 patients with cardiovascular disorders and 10 healthy volunteers. IL-17 levels were measured in the serum of patients and healthy controls, along with serum total cholesterol and triglycerides. Significantly higher levels of IL-17 were obtained in patients compared to healthy controls (p<0.001). The level of this biomarker correlated significantly with two biochemical parameters - serum total cholesterol and triglycerides (the Pearson coefficient showed statistical significance, p=0.033, respectively p=0.043). We did not find any correlation between IL-17 and these two parameters in the control group. Our study is useful in understanding the physiopathological implications of IL-17 in the atherogenesis process. This could represent a starting point for future studies, including research regarding the therapeutic potential of IL-17 in pathological aging.