Impact of serum chitotriosidase activity on tuberculosis treatment response: single center study from Serbia.

BACKGROUND: The aim of our study was to investigate serum chitotriosidase level in tuberculosis patients, its relationship with microbiological and clinical parameters, and response to treatment. MATERIALS AND METHODS: This longitudinal panel study included 149 patients with confirmed TB disease. Serum chitotriosidase activity was measured at the beginning and the end of treatment. Factors associated with chitotriosidase activity were explored using univariate and multivariable logistic regression analysis. RESULTS: Out of 149 study participants, 71(47.7%) were female. The mean age was 53.0 (SD = 18.2). Majority of cases were new 118(79.2), predominantly 145 (97.3%) having pulmonary tuberculosis. More than half of the patients were sputum smear positive 91 (61.1%) while culture positive in 146 (98%) of them. According to radiological findings, cavitary lesions were found in 92 (63.4%) patients. Anti TB treatment was associated with significant decrease in serum chitotriosidase level (< 0.001). New TB treatment (OR = 4.41%;95% CI = 1.20-9.89), and cavitary lesions (OR = 3.86;95%CI = 0,59-26.57) were found to be significantly associated with decrease of chitotriosidase activity. CONCLUSIONS: The results of our study showed that serum chitotriosidase values are strong biomarkers for starting anti TB treatment and for treatment monitoring, since decrease in serum chitotriosidase level can predict favorable treatment response in patients with tuberculosis. Further studies are needed to explore these, and other factors associated with chitotriosidase activity among tuberculosis patients.

Hematopoietic stem cell transplantation or enzyme replacement therapy in Gaucher disease type 3.

Gaucher disease (GD) is a lysosomal storage disorder with glucocerebroside accumulation in the macrophages. The disease is divided into three types based on neurocognitive involvement with GD1 having no involvement while the acute (GD2) and chronic (GD3) are neuronopathic. The non-neurological symptoms of GD3 are well treated with enzyme replacement therapy (ERT) which has replaced hematopoietic stem cell transplantation (HSCT). ERT is unable to prevent neurological progression as the enzyme cannot cross the blood-brain barrier. In this retrospective study, we report the general, neurocognitive, and biochemical outcomes of three siblings with GD3 after treatment with ERT or HSCT. Two were treated with HSCT (named HSCT1 and HSCT2) and one with ERT (ERT1). All patients were homozygous for the c.1448 T > C, (p.Leu483Pro) variant in the GBA1 gene associated with GD3. ERT1 experienced neurocognitive progression with development of seizures, oculomotor apraxia, perceptive hearing loss and mental retardation. HSCT1 had no neurological manifestations, while HSCT2 developed perceptive hearing loss and low IQ. Chitotriosidase concentrations were normal in plasma and cerebrospinal fluid (CSF) for HSCT1 and HSCT2, but both were markedly elevated in ERT1. We report a better neurological outcome and a normalization of chitotriosidase in the two siblings treated with HSCT compared to the ERT-treated sibling. With the advancements in HSCT over the past 25 years, we may reconsider using HSCT in GD3 to achieve a better neurological outcome and limit disease progression.

Characteristics of Patients with Sarcoidosis with Emphasis on Acute vs. Chronic Forms-A Single Center Experience.

Sarcoidosis is a granulomatous disease of unknown etiology that can affect almost any organ. Although the acute form can have spontaneous regression, a certain number of patients can have a chronic form, which leads to an increase in mortality and a decrease in the quality of life. Considering that the risk factors are still unknown, we wanted to compare the characteristics of patients with acute and chronic forms of sarcoidosis in Serbia in order to determine significant differences between them with hopes of contributing to everyday clinical practice. A total of 2380 patients treated in our clinic were enrolled in this study. They were separated into the following two groups: 1126 patients with acute form and 1254 patients with chronic form. They were further compared by gender, smoking status, radiological status, exposition, biomarkers for sarcoidosis, organ involvement, and other comorbidities; the distribution of patients according to regions of Serbia was also noted. Statistical significance was found in radiological findings (p < 0.001), biomarkers (calcium in 24 h urine p < 0.001; chitotriosidase p = 0.001), and the affliction of organs (p < 0.001). The differences noted in this paper could help improve our understanding of this disease.

The Exploitation of the Glycosylation Pattern in Asthma: How We Alter Ancestral Pathways to Develop New Treatments.

Asthma has reached epidemic levels, yet progress in developing specific therapies is slow. One of the main reasons for this is the fact that asthma is an umbrella term for various distinct subsets. Due to its high heterogeneity, it is difficult to establish biomarkers for each subset of asthma and to propose endotype-specific treatments. This review focuses on protein glycosylation as a process activated in asthma and ways to utilize it to develop novel biomarkers and treatments. We discuss known and relevant glycoproteins whose functions control disease development. The key role of glycoproteins in processes integral to asthma, such as inflammation, tissue remodeling, and repair, justifies our interest and research in the field of glycobiology. Altering the glycosylation states of proteins contributing to asthma can change the pathological processes that we previously failed to inhibit. Special emphasis is placed on chitotriosidase 1 (CHIT1), an enzyme capable of modifying LacNAc- and LacdiNAc-containing glycans. The expression and activity of CHIT1 are induced in human diseased lungs, and its pathological role has been demonstrated by both genetic and pharmacological approaches. We propose that studying the glycosylation pattern and enzymes involved in glycosylation in asthma can help in patient stratification and in developing personalized treatment.

Assessing Chitinases and Neurofilament Light Chain as Biomarkers for Adult-Onset Leukodystrophies.

Leukodystrophies represent a large and complex group of inherited disorders affecting the white matter of the central nervous system. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare leukodystrophy which still needs the proper identification of diagnostic, prognostic, and monitoring biomarkers. The aim of this study was to determine the diagnostic and prognostic value of chitinases and neurofilament light chain as biomarkers for ALSP. A cross-sectional study was performed to analyze cerebrospinal fluid levels of chitinases (chitotriosidase and chitinase 3-like 2) and neurofilament light chain in five different groups: (i) normal health individuals; (ii) patients with definitive diagnosis of ALSP and genetic confirmation; (iii) asymptomatic patients with CSF1R variants; (iv) patients with other adult-onset leukodystrophies; and (v) patients with amyotrophic lateral sclerosis (external control group). Chitinase levels showed a statistical correlation with clinical assessment parameters in ALSP patients. Chitinase levels were also distinct between ALSP and the other leukodystrophies. Significant differences were noted in the levels of chitinases and neurofilament light chain comparing symptomatic (ALSP) and asymptomatic individuals with CSF1R variants. This study is the first to establish chitinases as a potential biomarker for ALSP and confirms neurofilament light chain as a good biomarker for primary microgliopathies.

Enhanced levels of fractalkine and HSP60 in cerebrospinal fluid of sporadic amyotrophic lateral sclerosis patients.

Amyotrophic Lateral Sclerosis (ALS) is a multifactorial neurodegenerative disorder with a significant contribution of non-cell autonomous mechanisms to motor neuronal degeneration. Amongst a plethora of molecules, fractalkine (C-X3-C motif chemokine ligand 1), and Heat Shock Protein 60 (HSP60), are key modulators of microglial activation. The contribution of these molecules in Sporadic ALS (SALS) remains unexplored. To investigate this, fractalkine levels were estimated in Cerebrospinal fluid (CSF) of SALS patients (ALS-CSF; n = 44) by Enzyme-linked Immunosorbent Assay (ELISA) and correlated with clinical parameters including disease severity and duration. CSF HSP60 levels were estimated by Western blotting (ALS-CSF; n = 19). Also, CSF levels of Chitotriosidase-1 (CHIT-1), a microglia-specific neuroinflammatory molecule, were measured and its association, if any, with fractalkine and HSP60 was investigated. Both fractalkine and HSP60 levels were significantly elevated in ALS-CSF. Similar to our earlier observation, CHIT-1 levels were also upregulated. Fractalkine showed a moderate negative correlation with the ALS-Functional Rating Scale (ALSFRS) score indicating its significant rise in mild cases which plateaued in cases with high disease severity. However, no obvious correlation was found between fractalkine, HSP60, and CHIT-1. Our study hints that high fractalkine levels in mild cases might be conferring neuroprotection by combating microglial activation and highlights its importance as a novel therapeutic target for SALS. On the other hand, significantly enhanced levels of HSP60, a pro-inflammatory molecule, hint towards its role in accentuating microgliosis, although, it doesn't act synergistically with CHIT-1. Our study suggests that fractalkine and HSP60 act independently of CHIT-1 to suppress and accentuate neuroinflammation, respectively.

Plasma chitotriosidase enzyme activity as a novel therapeutic monitor for cysteamine treatment in nephropathic cystinosis: A retrospective validation study.

BACKGROUND: Cystine-depleting therapy in nephropathic cystinosis is currently monitored via the white blood cell cystine assay, although its application and usefulness are limited by practical and technical issues. Therefore, alternative biomarkers that are widely available, more economical and less technically demanding, while reliably reflecting long-term adherence to cysteamine treatment, are desirable. Recently, we proposed chitotriosidase enzyme activity as a potential novel biomarker for the therapeutic monitoring of cysteamine treatment in cystinosis. In this study, we aimed to validate our previous findings and to confirm the value of chitotriosidase in the management of cystinosis therapy. MATERIALS & METHODS: A retrospective study was conducted on 12 patients treated at the National Institutes of Health Clinical Center and followed up for at least 2 years. Plasma chitotriosidase enzyme activity was correlated with corresponding clinical and biochemical data. RESULTS: Plasma chitotriosidase enzyme activity significantly correlated with WBC cystine levels, cysteamine total daily dosage and a Composite compliance score. Moreover, plasma chitotriosidase was a significant independent predictor for WBC cystine levels, and cut-off values were established in both non-kidney transplanted and kidney transplanted cystinosis patients to distinguish patients with a good versus poor compliance with cysteamine treatment. Our observations are consistent with those of our previous study and validate our findings. CONCLUSIONS: Chitotriosidase enzyme activity is a valid potential alternative biomarker for monitoring cysteamine treatment in nephropathic cystinosis patients. SYNOPSIS: Chitotriosidase enzyme activity is a valid potential alternative biomarker for monitoring cysteamine treatment in nephropathic cystinosis patients.

[The survival prediction of hospitalized patients with COVID-19: the role of chitotriosidase level in peripheral blood].

AIM: To assess the relationship between plasma chitotiosidase (CHIT) level and mortality in hospitalized patients with COVID-19. MATERIALS AND METHODS: 347 hospitalized patients with COVID-19 were enrolled in our single-center cohort prospective observational study. On the first day of hospitalization the patients were assessed by the level of CHIT in the venosus blood to addition to default laboratory examinations. The primary endpoint was all-cause death. The survival after hospital discharge were assessed via phone calls on 90 and 180 days since inclusion to the study (NCT04752085). RESULTS: Our study included 347 patients. The first symptoms appeared in 7 days [5; 7] before hospitalization; 283 (84.3%) patients had less than 50% of the involvement of the lung tissue to the inflammation process (CT 0-2); 36 (10.4%) patients had died since the start of our investigation; 30 (83.3%) of them died during hospitalization, others -no later than 60 days; 68 (19%) people didn't answer during phone call. The survivor's activity of the enzyme in the deceased was significantly lower in compare to deceased patients (90.5 [40.2; 178.0] nmol/h/mL vs 180.0 [77.2; 393.2] nmol/h/mL; p=0.001). Survivor of the patients with a higher level of the activity of the CHIT (more than 171 nmol/h/mL) was statically significantly lower. CONCLUSION: Rising of the CHIT's activity more than 171 nmol/h/mL might be an early independent predictor of the bad prognosis of the patients, who were hospitalized with COVID-19 infection.

Lack of Association between Serum Chitotriosidase Activity and Arterial Stiffness in Type 2 Diabetes without Cardiovascular Complications.

Chitotriosidase (CHIT), a mammalian chitinase secreted by neutrophils and activated macrophages, is increased in both cardiovascular disease (CVD) and type 2 diabetes (T2D). Arterial stiffness rises early in T2D and increases the risk of CVD. The aim of this study is to evaluate CHIT activity as an early biomarker of arterial stiffness in people with T2D free from overt vascular complications. In this cross-sectional study, arterial stiffness as measured using standard pulse wave velocity (PWV) was evaluated in 174 people with T2D without overt vascular disease. Then, we measured CHIT serum activity with an electrochemiluminescence assay in two subgroups of participants: 35 with the highest (high-PWV) and 40 with the lowest (low-PWV) PWV values. CHIT activity was no different between the low-PVW and high-PWV groups (12.7 [9.6-17.9] vs. 11.4 [8.8-15.0] nmol/mL/h, respectively). Compared with the low-PWV group, the high-PWV participants were older (p < 0.001); had a longer duration of diabetes (p = 0.03); higher ankle-brachial index ABI (p = 0.04), systolic blood pressure (p = 0.002), diastolic blood pressure (p = 0.005), fasting blood glucose (p = 0.008), and HbA1c (p = 0.005); and lower eGFR (p = 0.03) and body mass index (BMI) (p = 0.01). No association was present with sex, duration of diabetes, age, BMI, peripheral blood pressure, laboratory parameters, and glucose-lowering medications or ongoing antihypertensive therapy. Although no association was found, this study provides novel data about the association of CHIT activity with CVD, focusing on a specific outcome (arterial stiffness) in a well-defined population of subjects with T2D without established CVD.

Long-Term Evaluation of Biomarkers in the Czech Cohort of Gaucher Patients.

A personalized treatment decision for Gaucher disease (GD) patients should be based on relevant markers that are specific to GD, play a direct role in GD pathophysiology, exhibit low genetic variation, reflect the therapy, and can be used for all patients. Thirty-four GD patients treated with enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) were analyzed for platelet count, chitotriosidase, and tartrate-resistant acid phosphatase activity in plasma samples, and quantitative measurement of Lyso-Gb1 was performed in dried blood spots. In our ERT and SRT study cohorts, plasma lyso-GL1 correlated significantly with chito-triosidase (ERT: r = 0.55, p < 0.001; SRT: r = 0.83, p < 0.001) and TRAP (ERT: r = 0.34, p < 0.001; SRT: r = 0.88, p < 0.001), irrespective of treatment method. A platelet count increase was associated with a Lyso-Gb1 decrease in both treatment groups (ERT: p = 0.021; SRT: p = 0.028). The association of Lyso-Gb1 with evaluated markers was stronger in the SRT cohort. Our results indicate that ERT and SRT in combination or in a switch manner could offer the potential of individual drug effectiveness for particular GD symptoms. Combination of the key biomarker of GD, Lyso-Gb1, with other biomarkers can offer improved response assessment to long-term therapy.

Effectiveness and Safety of Eliglustat Treatment in Gaucher Disease: Real-life Unicentric Experience.

PURPOSE: The therapy and management of Gaucher disease (GD) have radically changed with the use of substrate reduction therapy, of which eliglustat is the most widely known drug, allowing it to overcome the limits of enzyme replacement therapy (ERT). The rarity of GD and the limited use of eliglustat outside clinical trials require further study of its strengths and weaknesses. METHODS: In this study, we evaluated the effectiveness and safety of eliglustat in a cohort of 12 patients with GD followed up in our center, reporting a reduction in both chitotriosidase (394.3 vs 181.1 nmol/h/mL, P = 0.027) and glucosylsphingosine values (45.1 vs 18.9 ng/mL, P <0.001) after at least 12 months of therapy compared with baseline, regardless of patient demographic characteristics and GD characteristics. FINDINGS: There were no drug-related serious adverse effects and no drug-related cardiac events. Most adverse events were mild and transient, mainly dyspepsia and abdominal pain. Of interest, we reported an absence of statistical difference in terms of response regarding glucosylsphingosine reduction in relation to naive or prior exposure to ERT (P = 0.296), which was confirmed also when patients were placed in naive and treated groups for <5 vs >5 years (P = 0.667). IMPLICATIONS: The use of eliglustat immediately after diagnosis may guarantee the best treatment for patients with milder phenotypes or with aggressive disease after an initial stabilization with ERT compared with ERT, which cannot adequately remove the disease burden despite the apparent response, thus potentially reducing future complications caused by substrate deposits.

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.

Chitinase Signature in the Plasticity of Neurodegenerative Diseases.

Several reports have pointed out that Chitinases are expressed and secreted by various cell types of central nervous system (CNS), including activated microglia and astrocytes. These cells play a key role in neuroinflammation and in the pathogenesis of many neurodegenerative disorders. Increased levels of Chitinases, in particular Chitotriosidase (CHIT-1) and chitinase-3-like protein 1 (CHI3L1), have been found increased in several neurodegenerative disorders. Although having important biological roles in inflammation, to date, the molecular mechanisms of Chitinase involvement in the pathogenesis of neurodegenerative disorders is not well-elucidated. Several studies showed that some Chitinases could be assumed as markers for diagnosis, prognosis, activity, and severity of a disease and therefore can be helpful in the choice of treatment. However, some studies showed controversial results. This review will discuss the potential of Chitinases in the pathogenesis of some neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, to understand their role as distinctive biomarkers of neuronal cell activity during neuroinflammatory processes. Knowledge of the role of Chitinases in neuronal cell activation could allow for the development of new methodologies for downregulating neuroinflammation and consequently for diminishing negative neurological disease outcomes.

A 20-Year Longitudinal Study of Plasma Chitotriosidase Activity in Treated Gaucher Disease Type 1 and 3 Patients-A Qualitative and Quantitative Approach.

Chitotriosidase is an enzyme produced and secreted in large amounts by activated macrophages, especially macrophages loaded with phagocytozed glycosphingolipid in Gaucher disease. Macrophages phagocytose decayed blood cells that contain a lot of sphingolipid-rich cell membranes. In Gaucher disease, due to a deficit in beta-glucocerebrosidase activity, the phagocytozed substrate glucocerebroside cannot undergo further catabolism. In such a situation, macrophages secrete chitotriosidase in proportion to the degree of overload. Gaucher disease (GD) is a recessively inherited disorder resulting in storage of glucosylceramide (GlcCer) in lysosomes of tissue macrophages. It is directly caused by the deficiency of beta-glucocerebrosidase (GBA) activity. Chitotriosidase has been measured systematically each year in the same group of 49 patients with type 1 and 3 GD for over 20 years. Our analysis showed that chitotriosidase is very sensitive biomarker to enzyme replacement therapy (ERT). The response to treatment introduction is of an almost immediate nature, lowering pathologically high chitotriosidase levels by a factor of 2 in a time scale of 8 months, on average. Long term enzyme replacement therapy (ERT) brings chitotriosidase activity close to reference values. Finally, reducing the dose of ERT quickly boosts chitotriosidase activity, but restoring the initial dose of treatment brings chitotriosidase level of activity back onto the decreasing time trajectory.

Exploratory Evaluation of Neopterin and Chitotriosidase as Potential Circulating Biomarkers for Colorectal Cancer.

Chronic inflammation is demonstrated to play a direct role in carcinogenesis. Our exploratory study aimed to assess the potential added value of two inflammation biomarkers, chitotriosidase and neopterin, in follow-up evaluation of patients with colorectal cancer (CRC). An observational exploratory study was conducted. Patients with CRC and matched controls (1:1, age, sex, and living environment) were evaluated. The patients with CRC (CRC group) and controls were assessed at baseline (before surgical intervention for patients with CRC). Patients with CRC were also evaluated at 1-year follow-up. Significantly more patients with blood group A (54.5% vs. 25.0%) and smokers (50.0% vs. 22.7%) were in the CRC group. The serum values of chitotriosidase and neopterin were higher in CRC patients than in controls, but only neopterin reached the conventional level of statistical significance (p-value = 0.015). The circulating chitotriosidase and neopterin values decreased significantly at 1-year follow-up (p-value < 0.0001). Patients with higher N- and M-stage showed statistically significant higher levels of chitotriosidase and neopterin at baseline and 1-year follow-up (p-values < 0.03). Circulating chitotriosidase levels also showed statistically significant differences regarding baseline and 1-year follow-up on patients with CRC and different differentiation grades (p-values < 0.02). The circulating levels of neopterin significantly decreased at 1-year follow-up, indicating its potential as a prognostic marker. The circulating values of chitotriosidase and neopterin exhibit significant differences in patients with than without recurrences. Our results support further evaluation of chitotriosidase and neopterin as prognostic markers in patients with CRC.

Inhibition of Macrophage-Specific CHIT1 as an Approach to Treat Airway Remodeling in Severe Asthma.

Chitotriosidase (CHIT1) is an enzyme produced by macrophages that regulates their differentiation and polarization. Lung macrophages have been implicated in asthma development; therefore, we asked whether pharmacological inhibition of macrophage-specific CHIT1 would have beneficial effects in asthma, as it has been shown previously in other lung disorders. CHIT1 expression was evaluated in the lung tissues of deceased individuals with severe, uncontrolled, steroid-naïve asthma. OATD-01, a chitinase inhibitor, was tested in a 7-week-long house dust mite (HDM) murine model of chronic asthma characterized by accumulation of CHIT1-expressing macrophages. CHIT1 is a dominant chitinase activated in fibrotic areas of the lungs of individuals with fatal asthma. OATD-01 given in a therapeutic treatment regimen inhibited both inflammatory and airway remodeling features of asthma in the HDM model. These changes were accompanied by a significant and dose-dependent decrease in chitinolytic activity in BAL fluid and plasma, confirming in vivo target engagement. Both IL-13 expression and TGFß1 levels in BAL fluid were decreased and a significant reduction in subepithelial airway fibrosis and airway wall thickness was observed. These results suggest that pharmacological chitinase inhibition offers protection against the development of fibrotic airway remodeling in severe asthma.

SMPD1 gene variants in patients with ß-Thalassemia major.

BACKGROUND: ß-thalassemia major and Niemann-Pick diseases have similar clinical and laboratory findings. We aimed to investigate the effects of sphingomyelin phosphodiesterase 1 (SMPD1) gene variants on the clinical and laboratory findings in patients with ß-thalassemia major. METHODS AND RESULTS: This study included 45 patients who were followed up for ß-thalassemia major in our clinic. Plasma chitotriosidase, leukocyte acid sphingomyelinase, liver enzymes, ferritin, hemogram, biochemical parameters, SMPD1 gene variant analysis, cardiac T2* MRI, and liver R2 MRI were assessed in all patients. The SMPD1 gene c.132_143del, p.A46_L49del (c.108GCTGGC[4] (p.38AL[4])) (rs3838786) variant was detected in 9 of 45 (20.0%) patients. Plasma chitotriosidase, ferritin, acetyl aminotransferase, and alanine aminotransferase levels were significantly higher in patients with the gene variant than in those without (p < 0.05). Leukocyte acid sphingomyelinase levels were significantly lower in patients with the gene variant than in those without (p < 0.05). CONCLUSION: These results imply that the clinical and laboratory findings and some features of disease progression in patients with ß-thalassemia major are similar to those of Niemann-Pick disease. They also suggest that SMPD1 gene c.132_143del, p.A46_L49del (c.108GCTGGC[4] (p.38AL[4])) (rs3838786) variant may underlie these clinical findings in patients with ß-thalassemia major.

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.

A sex-stratified analysis of neuroimmune gene expression signatures in Alzheimer's disease brains.

Alzheimer's disease (AD) is the most common form of progressively disabling dementia. The chitinases CHI3L1 and CHI3L2 have long been known as biomarkers for microglial and astrocytic activation in neurodegeneration. Here, we collected microarray datasets from the National Center for Biotechnology Information (NCBI) brain samples of non-demented controls (NDC) (n = 460), and of deceased patients with AD (n = 697). The AD patients were stratified according to sex. Comparing the high CHI3L1 and CHI3L2 expression group (75th percentile), and low CHI3L1 and CHI3L2 expression group (25th percentile), we obtained eight signatures according to the sex of patients and performed a genomic deconvolution analysis using neuroimmune signatures (NIS) belonging to twelve cell populations. Expression analysis revealed significantly higher CHI3L1 and CHI3L2 expression in AD compared with NDC, and positive correlations of these genes with GFAP and TMEM119. Furthermore, deconvolution analysis revealed that CHI3L1 and CHI3L2 high expression was associated with inflammatory signatures in both sexes. Neuronal activation profiles were significantly activated in AD patients with low CHI3L1 and CHI3L2 expression levels. Furthermore, gene ontology analysis of common genes regulated by the two chitinases unveiled immune response as a main biological process. Finally, microglia NIS significantly correlated with CHI3L2 expression levels and were more than 98% similar to microglia NIS determined by CHI3L1. According to our results, high levels of CHI3L1 and CHI3L2 in the brains of AD patients are associated with inflammatory transcriptomic signatures. The high correlation between CHI3L1 and CHI3L2 suggests strong co-regulation.