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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., (© 2024. The Author(s).)

Background: An oral sodium phenylbutyrate and taurursodiol combination (PB and TURSO) significantly reduced functional decline in people living with amyotrophic lateral sclerosis (ALS) in the CENTAUR trial. Biomarkers linking clinical therapeutic effect with biological changes are of high interest in ALS. We performed analyses of neuroinflammatory biomarkers associated with ALS in the literature, including YKL-40 (also known as chitinase-3-like protein 1), chitinase 1 (CHIT1) and C reactive protein (CRP), in plasma samples collected in CENTAUR., Methods: Log10-transformed plasma biomarker measurements were analysed using a linear mixed-effects model. Correlation between paired biomarker concentrations and ALS Functional Rating Scale-Revised (ALSFRS-R) total scores was assessed via Pearson correlation coefficients., Results: By week 24, geometric least squares mean YKL-40 plasma concentration decreased by approximately 20% (p=0.008) and CRP by 30% (p=0.048) in the PB and TURSO versus placebo group. YKL-40 (r of -0.21; p<0.0001) and CRP (r of -0.19; p=0.0002) concentration correlated with ALSFRS-R total score. CHIT1 levels were not significantly different between groups., Conclusions: YKL-40 and CRP plasma levels were significantly reduced in participants with ALS receiving PB and TURSO in CENTAUR and correlated with disease progression. These findings suggest YKL-40 and CRP could be treatment-sensitive biomarkers in ALS, pending further confirmatory studies., Trial Registration Number: https://clinicaltrials.gov/study/NCT03127514., Competing Interests: Competing interests: RB reports receiving laboratory supplies from nVector for the biomarker assays used in these analyses; consulting fees from MT Pharma, RRD International, BrainStorm and Cell Therapeutics unrelated to this manuscript; consulting fees from Amylyx Pharmaceuticals, Inc., related to this manuscript; a pending patent with nVector; and stock options in nVector, AcuraStem and Aural Analytics. JA reports stock options in nVector. LM, JC and JT are full-time employees of and have stock option ownership in Amylyx. MC reports consulting fees from Lilly, Immunity Pharm Ltd, Orion, Cytokinetics, Wave Life Sciences, Takeda, Avexis, Biogen, Helixsmith, Sunovian Pharmaceuticals Inc., Disarm, ALSpharma, RRD International, Transposon, QurAlis, Regeneron Pharmaceuticals, AB Science, Locust Walk, NeuroSense Therapeutics, Faze Medicines, Arrowhead Pharmaceuticals, VectorY Therapeutics, Servier, Eledon Pharmaceuticals, Pasithea Therapeutics and Denali Therapeutics and stock in Praxis. SP reports research grants from Amylyx related to this manuscript; research grants from the National Institutes of Health, Alector Therapeutics, Biohaven, Cytokinetics, Anelixis Pharmaceuticals, Revalesio Corporation, UCB, Clene, Prilenia, Seelos Therapeutics, Calico and Denali Therapeutics unrelated to this manuscript; consulting fees from Frequency Therapeutics, SOLA Pharmaceuticals, Stealth BioTherapeutics, Orion, Roche, Janssen, Arrowhead and Amylyx; honoraria from Medscape; and board membership in the Association of Academic Physiatrists., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motor neurons, and there is currently a lack of reliable diagnostic biomarkers. This meta-analysis aimed to evaluate CHIT1, CHI3L1, and CHI3L2 levels in the cerebrospinal fluid (CSF) or blood and their diagnostic potential in ALS patients. A systematic, comprehensive search was performed of peer-reviewed English-language articles published before April 1, 2023, in PubMed, Scopus, Embase, Cochrane Library, and Web of Science. After a thorough screening, 13 primary articles were included, and their chitinases-related data were extracted for systematic review and meta-analysis. In ALS patients, the CSF CHIT1 levels were significantly elevated compared to controls with healthy control (HC) (SMD, 1.92; 95% CI, 0.78 - 3.06; P < 0.001). CHIT1 levels were elevated in the CSF of ALS patients compared to other neurodegenerative diseases (ONDS) control (SMD, 0.74; 95% CI, 0.22 - 1.27; P < 0.001) and exhibited an even more substantial increase when compared to ALS-mimicking diseases (AMDS) (SMD, 1.15; 95% CI, 0.35 - 1.94, P < 0.001). Similarly, the CSF CHI3L1 levels were significantly higher in ALS patients compared to HC (SMD, 3.16; 95% CI, 1.26 - 5.06, P < 0.001). CHI3L1 levels were elevated in the CSF of ALS patients compared to ONDS (SMD, 0.75; 95% CI, 0.32 - 1.19; P = 0.017) and exhibited a more pronounced increase when compared to AMDS (SMD, 1.92; 95% CI, 0.41 - 3.42; P < 0.001). The levels of CSF chitinases in the ALS patients showed a significant increase, supporting the role of CSF chitinases as diagnostic biomarkers for ALS., (© 2024. The Author(s).)

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., Competing Interests: Declaration of competing interest E.L. performs consultancy for Recordati, Chiesi, Kyowa Kirin, Advicenne, and was supported by a research grant from Horizon Pharma., (Copyright © 2024. Published by Elsevier Inc.)

The aim of our observational study was to derive a small set out of 92 repeatedly measured biomarkers with optimal predictive capacity for adverse clinical events in heart failure, which could be used for dynamic, individual risk assessment in clinical practice. In 250 chronic HFrEF (CHF) patients, we collected trimonthly blood samples during a median of 2.2 years. We selected 537 samples for repeated measurement of 92 biomarkers with the Cardiovascular Panel III (Olink Proteomics AB). We applied Least Absolute Shrinkage and Selection Operator (LASSO) penalization to select the optimal set of predictors of the primary endpoint (PE). The association between repeatedly measured levels of selected biomarkers and the PE was evaluated by multivariable joint models (mvJM) with stratified fivefold cross validation of the area under the curve (cvAUC). The PE occurred in 66(27%) patients. The optimal set of biomarkers selected by LASSO included 9 proteins: NT-proBNP, ST2, vWF, FABP4, IGFBP-1, PAI-1, PON-3, transferrin receptor protein-1, and chitotriosidase-1, that yielded a cvAUC of 0.88, outperforming the discriminative ability of models consisting of standard biomarkers (NT-proBNP, hs-TnT, eGFR clinically adjusted) - 0.82 and performing equally well as an extended literature-based set of acknowledged biomarkers (NT-proBNP, hs-TnT, hs-CRP, GDF-15, ST2, PAI-1, Galectin 3) - 0.88. Nine out of 92 serially measured circulating proteins provided a multivariable model for adverse clinical events in CHF patients with high discriminative ability. These proteins reflect wall stress, remodelling, endothelial dysfunction, iron deficiency, haemostasis/fibrinolysis and innate immunity activation. A panel containing these proteins could contribute to dynamic, personalized risk assessment.Clinical Trial Registration: 10/05/2013 https://clinicaltrials.gov/ct2/show/NCT01851538?term=nCT01851538&draw=2&rank=1 ., (© 2022. The Author(s).)

Background/aim: Chitotriosidase (ChT) is an enzyme secreted by activated macrophages and neutrophils in response to proinflammatory signals. There is growing evidence indicating that ChT activity reflects the systemic inflammatory status. This study aimed to investigate whether serum ChT activity increased in patients with psoriasis and related comorbidities., Materials and Methods: This cross-sectional study included 53 (28 with associated comorbidities and 25 without comorbidities) patients with psoriasis and 52 healthy volunteers. All participants underwent laboratory investigations for serum ChT levels, complete blood count, erythrocyte sedimentation rate, C-reactive protein, and serum lipid levels., Results: The patients with psoriasis showed significantly higher levels of ChT activity as compared to the healthy controls (23.5 ± 11.4 vs. 17.5 ± 10.4 μmol/mL/hour; p = 0.015). Additionally, the ChT activity was significantly higher in patients with comorbidities than in those without (p = 0.042)., Conclusion: Our data support the pathogenetic role of inflammatory processes induced by macrophage activation in patients with psoriasis and related comorbidities. We believe that high ChT activity in patients with psoriasis may serve as an early prediction of the possible related comorbidities., Competing Interests: None of the authors have any conflict of interest, all authors are in agreement with the content of the manuscript., (This work is licensed under a Creative Commons Attribution 4.0 International License.)

The previous studies have shown that plasma chitotriosidase (CHIT) levels increase in many diseases with inflammation. However, there are no reported studies investigating the relationship between CHIT and chronic heart failure (CHF) which is an inflammatory process. Therefore, we aimed to investigate the role of CHIT in diagnosis and severity of CHF in this study. 36 patients (50% male, mean age 63.17±10.18 years) with left ventricular ejection fraction <40% and 27 controls (44% male, mean age 61.33±8.73 years) were included in this study. Patients with CHF were divided into two groups as ischemic heart failure (IHF) and non-ischemic heart failure (NIHF) according to the underlying etiology. Plasma CHIT and N-terminal pro brain natriuretic peptide (NT-proBNP) levels were measured by ELISA method. Plasma CHIT and NT-proBNP levels were higher in patients with CHF than in controls (CHIT 931.25±461.39 ng/mL, 232.79±61.28 ng/mL, p<0.001; NT-proBNP, 595.31±428.11 pg/mL vs 78.13±30.47 pg/L; p<0.001). Also, the levels of these parameters increased in IHF compared with NIHF (CHIT, 1139.28±495.22 ng/mL, 671.22±237.21 ng/mL, p=0.002; NT-proBNP, 792.87±461.26 pg/mL vs 348.36±202.61 pg/mL, p=0.001) and there was a strong correlation between NT-proBNP and CHIT (r=0.969, p<0.001). According to this study findings, plasma CHIT level increases in CHF and its increased levels are correlated with NT-proBNP which is used diagnosis and prognosis of HF., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Adropin (AD), copeptin (CP), neprilysin (NEP) and chitotriosidase (CHIT1) have been associated with the regulation of vascular endothelial function. In this work, we analyzed the plasma concentrations of cytokines (AD, CP, NEP and CHIT1) in type 2 diabetic patients with or without retinopathy (DR) to predict the risk of DR for diabetic patients., Method: A total of 392 patients diagnosed as type 2 diabetes mellitus (T2DM) and 120 healthy volunteers as a control group were enrolled in this study. T2DM patients were divided into three groups: diabetes without retinopathy (NDR, n = 174) group, non-proliferative diabetic retinopathy (NPDR, n = 118) group and proliferative diabetic retinopathy (PDR, n = 100) group. The serum AD, CP, NEP and CHIT1 levels of subjects were detected by enzyme-linked immunosorbent assay (ELISA)., Results: We reported a significant decrease in AD and a significant increase in CP, NEP and CHIT1 in NDR as well as DR patients when compared with controls (p < 0.05), the lower level of AD and significantly higher levels of CP, NEP and CHIT1 were seen in DR patients compared to NDR group (p < 0.05), at the same time, we observed the lowest level of AD and the highest levels of CP, NEP and CHIT1 in the PDR group. Logistic regression analysis showed that AD was a protective factor for DR, conversely, CP, NEP and CHIT1 were the independent risk factors (p < 0.05). Moreover, receiver operating characteristic curve analyses indicated that CP had greater diagnosis capacity with an AUC (the areas under the ROC curve) of 0.901 than AD, NEP, CHIT1 for DR patients., Conclusion: The decreased AD level and the elevated CP, NEP and CHIT1 levels involved in vascular endothelial function may be evidence facilitating the presence of DR. Thereby they can be explored to use as promising non-invasive biomarkers for prediction of DR severity, distinguishing DR from diabetic patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Sarcoidosis is a systemic inflammatory disease characterized by development of granulomas in the affected organs. Sarcoidosis is often a diagnosis of exclusion, and traditionally used tests for sarcoidosis demonstrate low sensitivity and specificity. We propose that accuracy of diagnosis can be improved if biomarkers of altered lymphocyte populations and levels of signaling molecules involved in disease pathogenesis are measured for patterns suggestive of sarcoidosis. These distinctive biomarkers can also be used to determine disease progression, predict prognosis, and make treatment decisions. Many subsets of T lymphocytes, including CD8 + T-cells and regulatory T-cells, have been shown to be dysfunctional in sarcoidosis, and the predominant CD4 + T helper cell subset in granulomas appears to be a strong indicator of disease phenotype and outcome. Studies of altered B cell populations, B cell signaling molecules, and immune complexes in sarcoidosis patients reveal promising biomarkers as well as possible explanations of disease etiology. Furthermore, examined biomarkers raise questions about new treatment methods and sarcoidosis antigens.

Eliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) with extensive, intermediate, or poor CYP2D6-metabolizer phenotypes (90% of patients). We report real-world outcomes after 2 years of eliglustat therapy in the International Collaborative Gaucher Group Gaucher Registry (NCT00358943). As of January 2019, baseline and 2-year data (±1 year) were available for 231 eliglustat-treated GD1 patients: 19 treatment-naïve (zero splenectomized) and 212 ERT patients who switched to eliglustat (36 splenectomized). Most patients (89%) were from the United States, where eliglustat was first approved. In treatment-naïve patients, mean hemoglobin increased from 12.4 to 13.4 g/dL (P = .004, n = 18), mean platelet count increased from 113 to 156 × 10 9 /L (P < .001, n = 17); mean spleen volume decreased from 7.4 to 3.5 multiples of normal (MN) (P = .02, n = 7); mean liver volume remained normal (n = 7), and median spine Z-score was unchanged (-1.3 to -1.2, n = 6). In non-splenectomized switch patients, mean hemoglobin remained stable/non-anemic (n = 167); mean platelet count remained stable/normal (n = 165); mean spleen volume decreased from 3.3 to 2.8 MN (P < .001, n = 64); mean liver volume remained normal (n = 63), and median lumbar spine Z-score improved from -0.7 to -0.4 (P = .014, n = 68). In splenectomized switch patients, mean hemoglobin remained stable/non-anemic (n = 31); mean platelet count increased from 297 to 324 × 10 9 /L (non-significant, n = 29); mean liver volume remained normal (n = 13); median spine Z-score improved from -0.8 to -0.6 (non-significant, n = 11). Median chitotriosidase decreased in all groups (P < .01 for all). These real-world results are consistent with eliglustat clinical trial results demonstrating long-term benefit in treatment-naïve patients and stability in ERT switch patients., (© 2020 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Background: Chitinase activity is an important innate immune defence mechanism against infection that includes fungi. The 2 human chitinases: chitotriosidase (CHIT1) and acidic mammalian chitinase are associated to allergy, asthma, and COPD; however, their role in bronchiectasis and bronchiectasis-COPD overlap (BCO) is unknown., Research Question: What is the association between chitinase activity, airway fungi and clinical outcomes in bronchiectasis and bronchiectasis-COPD overlap?, Study Design and Methods: A prospective cohort of 463 individuals were recruited across five hospital sites in three countries (Singapore, Malaysia, and Scotland) including individuals who were not diseased (n = 35) and who had severe asthma (n = 54), COPD (n = 90), bronchiectasis (n = 241) and BCO (n = 43). Systemic chitinase levels were assessed for bronchiectasis and BCO and related to clinical outcomes, airway Aspergillus status, and underlying pulmonary mycobiome profiles., Results: Systemic chitinase activity is elevated significantly in bronchiectasis and BCO and exceed the activity in other airway diseases. CHIT1 activity strongly predicts bronchiectasis exacerbations and is associated with the presence of at least one Aspergillus species in the airway and frequent exacerbations (≥3 exacerbations/y). Subgroup analysis reveals an association between CHIT1 activity and the "frequent exacerbator" phenotype in South-East Asian patients whose airway mycobiome profiles indicate the presence of novel fungal taxa that include Macroventuria, Curvularia and Sarocladium. These taxa, enriched in frequently exacerbating South-East Asian patients with high CHIT1 may have potential roles in bronchiectasis exacerbations., Interpretation: Systemic CHIT1 activity may represent a useful clinical tool for the identification of fungal-driven "frequent exacerbators" with bronchiectasis in South-East Asian populations., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Nephropathic cystinosis, a hereditary lysosomal storage disorder caused by dysfunction of the lysosomal cotransporter cystinosin, leads to cystine accumulation and cellular damage in various organs, particularly in the kidney. Close therapeutic monitoring of cysteamine, the only available disease-modifying treatment, is recommended. White blood cell cystine concentration is the current gold standard for therapeutic monitoring, but the assay is technically demanding and is available only on a limited basis. Because macrophage-mediated inflammation plays an important role in the pathogenesis of cystinosis, biomarkers of macrophage activation could have potential for the therapeutic monitoring of cystinosis., Methods: We conducted a 2-year prospective, longitudinal study in which 61 patients with cystinosis who were receiving cysteamine therapy were recruited from three European reference centers. Each regular care visit included measuring four biomarkers of macrophage activation: IL-1 β , IL-6, IL-18, and chitotriosidase enzyme activity., Results: A multivariate linear regression analysis of the longitudinal data for 57 analyzable patients found chitotriosidase enzyme activity and IL-6 to be significant independent predictors for white blood cell cystine levels in patients of all ages with cystinosis; a receiver operating characteristic analysis ranked chitotriosidase as superior to IL-6 in distinguishing good from poor therapeutic control (on the basis of white blood cell cystine levels of <2 nmol 1/2 cystine/mg protein or ≥2 nmol 1/2 cystine/mg protein, respectively). Moreover, in patients with at least one extrarenal complication, chitotriosidase significantly correlated with the number of extrarenal complications and was superior to white blood cell cystine levels in predicting the presence of multiple extrarenal complications., Conclusions: Chitotriosidase enzyme activity holds promise as a biomarker for use in therapeutic monitoring of nephropathic cystinosis., (Copyright © 2020 by the American Society of Nephrology.)

Objective: To characterize subclinical abnormalities in asymptomatic heterozygote NPC1 mutation carriers as markers of neurodegeneration., Methods: Motor function, cognition, mood, sleep, and smell function were assessed in 20 first-degree heterozygous relatives of patients with Niemann-Pick disease type C (NPC) (13 male, age 52.7 ± 9.9 years). Video-oculography and abdominal ultrasound with volumetry were performed to assess oculomotor function and size of liver and spleen. NPC biomarkers in blood were analyzed. 18 F-fluorodesoxyglucose PET was performed (n = 16) to detect patterns of brain hypometabolism., Results: NPC heterozygotes recapitulated characteristic features of symptomatic NPC disease and demonstrated the oculomotor abnormalities typical of NPC. Hepatosplenomegaly (71%) and increased cholestantriol (33%) and plasma chitotriosidase (17%) levels were present. The patients also showed signs seen in other neurodegenerative diseases, including hyposmia (20%) or pathologic screening for REM sleep behavior disorder (24%). Cognitive function was frequently impaired, especially affecting visuoconstructive function, verbal fluency, and executive function. PET imaging revealed significantly decreased glucose metabolic rates in 50% of participants, affecting cerebellar, anterior cingulate, parieto-occipital, and temporal regions, including 1 with bilateral abnormalities., Conclusion: NPC heterozygosity, which has a carrier frequency of 1:200 in the general population, is associated with abnormal brain metabolism and functional consequences. Clinically silent heterozygous gene variations in NPC1 may be a risk factor for late-onset neurodegeneration, similar to the concept of heterozygous GBA mutations underlying Parkinson disease., (© 2020 American Academy of Neurology.)

Introduction: This study aimed to determine the association between plasma chitotriosidase activity and the clinical characteristics and exacerbation rate of COPD patients., Methods: The study comprised 97 patients with COPD. Their clinical characteristics and a history of exacerbations in the last 12 months were noted. Plasma chitotriosidase activity was determined. Patients were followed up for 12 months, and the number of moderate and severe exacerbations during this period was recorded., Results: Chitotriosidase activity positively correlated with patient age (rho = 0.217, p = 0.036) and inversely with CAT (rho = - 0.240, p = 0.020). There was no correlation with lung function. Chitotriosidase activity was significantly lower in patients with a history of ≥ 2 exacerbations compared to patients without a history of exacerbations (93 [38-312] vs. 264 [168-408] nmol/h/mL, p = 0.033). Overall, there was no difference in chitotriosidase activity between patients with or without observed exacerbations. Patients with a history of ≥ 1 exacerbation and ≥ 1 observed exacerbation had higher chitotriosidase activity compared to patients without further exacerbations (240 [144-456] vs. 52 [39-240] nmol/h/mL, p = 0.035). Multivariate analysis identified FEV 1 (HR 0.976, 95% CI 0.956-0.996, p = 0.016) and blood eosinophil percentage (HR 1.222, 95% CI 1.048-1.424, p = 0.011) as independent predictors of future exacerbations in the total patient population, while in patients with a history of ≥ 1 exacerbation ,the only independent predictor was chitotriosidase activity (HR per 10 nmol/h/mL 1.028, 95% CI 1.002-1.055, p = 0.037)., Conclusion: While mixed associations between chitotriosidase activity and clinical outcomes were seen, chitotriosidase activity could be a predictor of future exacerbations in patients with a history of ≥ 1 exacerbation in the past  12 months.

Objective: Amyotrophic lateral sclerosis (ALS) is a complex disease with numerous pathological mechanisms resulting in a heterogeneous patient population. Using biomarkers for particular disease mechanisms may enrich a homogeneous subset of patients. In this study, we quantified chitotriosidase (Chit-1) and chitinase-3-like protein 1 (CHI3L1), markers of glial activation, in cerebrospinal fluid (CSF) and plasma and determined the cell types that express CHI3L1 in ALS., Methods: Immunoassays were used to quantify Chit-1, CHI3L1 and phosphorylated neurofilament heavy chain levels in longitudinal CSF and matching plasma samples from 118 patients with ALS, 17 disease controls (DCs), and 24 healthy controls (HCs). Immunostaining was performed to identify and quantify CHI3L1-positive cells in tissue sections from ALS, DCs and non-neurological DCs., Results: CSF Chit-1 exhibited increased levels in ALS as compared with DCs and HCs. CSF CHI3L1 levels were increased in ALS and DCs compared with HCs. No quantitative differences were noted in plasma for either chitinase. Patients with ALS with fast-progressing disease exhibited higher levels of CSF Chit-1 and CHI3L1 than patients with slow-progressing disease. Increased numbers of CHI3L1-positive cells were observed in postmortem ALS motor cortex as compared with controls, and these cells were identified as a subset of activated astrocytes located predominately in the white matter of the motor cortex and the spinal cord., Conclusions: CSF Chit-1 and CHI3L1 are significantly increased in ALS, and CSF Chit-1 and CHI3L1 levels correlate to the rate of disease progression. CHI3L1 is expressed by a subset of activated astrocytes predominately located in white matter., Competing Interests: Competing interests: RB is founder of Iron Horse Diagnostics, Inc, a company commercialising assays for ALS and other neurological diseases., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Non-small cell lung cancer (NSCLC) is the main type of lung cancer, with a low 5-year survival rate because of the absence of effective clinical biomarkers for early diagnosis. Based on the immunosurveillance theory, we proposed that changes in the immune system are more pronounced than tumour-associated antigens during the early stage of cancer. Therefore, a new strategy was designed to screen early diagnostic biomarkers from peripheral leukocytes in early-stage NSCLCs with transcriptome sequencing. A total of 358 immune-related differentially expressed genes were identified between early-NSCLC patients and healthy individuals. Orosomucoid-1 (ORM1, a acute phase protein), the total ORM and chitotriosidase-1 (involved in degradation of chitobiose) were selected for further verification in 210 serum samples by western blotting, ELISA and nephelometry immunoassay (based on immuno-scatter turbidmetry). Receiver operating characteristic curve analysis show that ORM1 and total ORM have excellent diagnostic efficacies, with area under the curve of 0.862 and 0.920, respectively, which significantly distinguished very early-NSCLC (IA) from healthy samples. Flow cytometry results showed that CD15 + neutrophils made up 73% of ORM1 + peripheral leukocytes. In mouse lung cancer model, serum ORM1, but not liver ORM1, changed significantly in the early stage of NSCLC. ORM1 expression in peripheral leukocytes was regulated by TGF-β and mediated by the TGF-β/Smad signalling pathway. Our results indicated that combined ORM and TGF-β could be a promising clinical biomarker in the diagnosis of early NSCLC., (© 2019 Federation of European Biochemical Societies.)

Background: Serum chitotriosidase is a promising biomarker that has shown high specificity and sensitivity in patients with sarcoidosis. The aim of this study was to investigate correlations between serum chitotriosidase, clinical phenotypes, disease localizations and different radiological lung involvement and to identify clinical features associated with over-expression of chitotriosidase in a large cohort of sarcoidosis patients., Methods: Chitotriosidase activity was evaluated in a population of 694 consecutive patients (males 39%, age 55.8 ± 12.8 years). Clinical and respiratory functional characteristics, Clinical Outcome Scale (COS) classification, clinical phenotypes proposed by the GenPhenResA project, and radiological assessment, including CT scan, were collected. Serum sampling and clinical and functional assessments at follow-up were also included., Results: Significantly higher chitotriosidase activity was observed in sarcoidosis patients than in healthy controls (p < 0.0001). Evidence of lung fibrosis with reticular abnormalities and traction bronchiectasis at High resolution CT, presence of multiple extrapulmonary sarcoid localizations and increased 24-h urinary excretion of calcium were associated with significantly higher chitotriosidase activity (p < 0.005). Patients with remitted or minimal disease had lower values of chitotriosidase than patients with persistent disease. At follow-up, patients who required an increase in steroid dose showed an increase in its activity., Conclusions: Chitotriosidase is a reliable biomarker of sarcoidosis. It is increased in patients with sarcoidosis correlating with disease activity, severity and multiorgan dissemination. Steroid therapy tended to reduce chitotriosidase expression, however it responded in cases of disease relapse.

Establishing the diagnosis of sarcoidosis most often requires biopsy and histopathologic evaluation, since there is no single marker with sufficient specificity and sensitivity for the disease. Our aims were to determine and compare the diagnostic accuracies of several potential biomarkers and to develop a combined biomarker analysis tool for the diagnosis of sarcoidosis. 133 healthy individuals and 104 patients with suspected sarcoidosis and diagnostic thoracic surgery were enrolled into this study. Histopathologic results were contrasted to biomarker levels of chitotriosidase (CTO), serum amyloid-A (SAA), soluble interleukin-2 receptor (sIL-2R), lysozyme (LZM) or angiotensin converting enzyme (ACE). Sarcoidosis was confirmed by histopathology in 69 patients. CTO activity, sIL-2R concentration and ACE activity could discriminate between sarcoidosis and control patients, while SAA and LZM concentrations could not. A new combined parameter, which was derived from the multiplication of ACE by CTO activities (double product) showed the best diagnostic accuracy in this clinical study: (AUC = 0.898, sensitivity: 90.5%, specificity: 79.3%, positive and negative predictive values: 90.5% and 79.3%, respectively). Sarcoidosis can be diagnosed with the combined analysis of ACE and CTO activities more accurately than with single serum biomarkers in the absence of invasive biopsy in the majority of cases with pulmonary manifestation of sarcoidosis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Calcium metabolism alterations are quite common in sarcoidosis and have been correlated with disease activity., Objectives: The aim of the study was to investigate the clinical significance of calcium metabolism alterations in patients with chronic sarcoidosis. We paid particular attention to associations with specific disease phenotypes and chitotriosidase (CTO) expression., Methods: 212 chronic sarcoidosis patients (mean age 56.07 ± 12 years; 97 males) were retrospectively recruited. Demographic, clinical, functional, and radiological data, and serum-urinary calcium metabolism were entered into an electronical database for analysis. Levels of CTO and angiotensin-converting enzyme (ACE) were measured and bone mineral density and lung function tests were conducted., Results: Hypercalciuria and hypercalcemia were observed in 18.8 and 1.8% of patients, respectively. Urinary calcium levels correlated with CTO activity (r = 0.33, p = 0.0042). Patients with worsening persistent disease showed the highest levels of urinary calcium. Diffusing capacity of the lung for carbon monoxide (DLCO) percentage correlated inversely with urinary calcium (r = 0.1482; p = 0.0397)., Conclusions: Calcium metabolism alteration, particularly hypercalciuria, was observed in a significant percentage of patients of sarcoidosis. Urinary calcium was correlated with clinical status, DLCO, and serum CTO activity, suggesting its potential role as a biomarker of the activity and severity of sarcoidosis., (© 2020 S. Karger AG, Basel.)

Sepsis is a major cause of death in hospitalised patients accounting for mortality rates as high as 60% and, hence, is called 'a hidden public health disaster'. Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis is not a disease but is a clinical syndrome, where the initial features are nonspecific resulting in delayed diagnosis. Lack of specific laboratory tests to diagnose the syndrome adds to the diagnostic confusion. Failure to identify sepsis in the early stages itself delays effective treatment resulting in high morbidity and mortality. Various biomarkers and newer laboratory tests help to address these issues. However, to date there is no ideal test to diagnose sepsis. The most commonly used markers are C-reactive protein (CRP) and procalcitonin (PCT). There are around 180 biomarkers reported to be useful in sepsis. In addition to CRP and PCT, various emerging laboratory markers, such as like serum amyloid A, soluble triggering receptor expressed on myeloid cell-1, mannan and antimannan antibodies, and interferon γ inducible protein-10 etc., have been reviewed and their clinical usefulness discussed in this paper., Competing Interests: No conflict of interests declared

Several physiological and metabolic changes take place in dairy ruminants around parturition (late pregnancy, parturition, and early lactation). Dairy species are genetically selected for their higher milk production compared with non-dairy species. This fact causes a constant stress that impairs the immune status of the animal, with consequences for its welfare and performance. In the present study, we assessed the immune status of high-yield dairy sheep and goats by quantifying IgG and IgM concentrations, as well as chitotriosidase (ChT) and complement system [total complement system (TC) and alternative complement pathway (AC)] activity in blood plasma around parturition. We also measured IgG and IgM concentrations and ChT activity in colostrum and milk during the first 40 d postpartum. The lowest blood IgG concentration was at parturition in both species. We detected no differences in blood IgG concentrations between species. Blood IgM concentrations were constant in both species throughout the study period. However, blood IgM concentrations were greater in sheep than in goats. Blood ChT activity was greater in goats than in sheep, and both species showed constant activity of this enzyme throughout the study period. We observed no differences in complement system (TC and AC) activity between sheep and goats. In addition, both TC and AC activity were constant in both species throughout the experiment. In general, IgG and IgM concentrations were greater in sheep colostrum than in goat colostrum, but these differences disappeared after d 4 (IgG) and d 3 (IgM) postpartum. In both species, the highest IgG and IgM concentrations were measured in colostrum, gradually decreasing during the first days postpartum. Chitotriosidase activity decreased in both species from colostrum to milk, although goats always showed greater ChT activity than sheep. Both sheep and goats seemed to be more susceptible to infectious diseases around parturition. As well, goats showed greater ChT activity in blood, colostrum, and milk than sheep. This fact may give these animals additional protection against parasite and fungal infections., (Copyright © 2019 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Objective: To assess prognostic factors of antimelanoma differentiation-associated gene 5 antibody (anti-MDA5)-positive dermatomyositis/clinically amyopathic DM-associated interstitial lung disease (DM/CADM-ILD) and evaluate the use of serum chitotriosidase, a marker for macrophage activation, as a potential biomarker in anti-MDA5-positive DM/CADM-ILD., Methods: This retrospective study included 30 patients with anti-MDA5-positive DM/CADM-ILD. The clinical characteristics and laboratory findings at the time of diagnosis were analyzed. Serum chitotriosidase levels were measured in the 30 patients, in 21 healthy controls, and in 25 patients with anti-aminoacyl-tRNA synthetase antibody-positive (anti-ARS)-polymyositis (PM)/DM/CADM-ILD, and the potential of serum chitotriosidase as a prognostic biomarker in anti-MDA5-positive DM/CADM-ILD was assessed., Results: The median serum chitotriosidase level in patients with anti-MDA5-positive DM/CADM-ILD was 17.3 ng/ml, which was higher than that in healthy controls and anti-ARS-PM/DM/CADM-ILD (2.0 and 8.9 ng/ml, respectively). Of the 30 patients, 10 died of respiratory failure associated with DM/CADM-ILD deterioration. Cox hazard analysis demonstrated that higher serum chitotriosidase level and lower PaO 2 value were significant predictors of a poor outcome. Using optimal cutoff levels according to receiver-operating characteristic curve analyses, chitotriosidase ≥ 23.5 ng/ml, ferritin ≥ 800 ng/ml, and Krebs von den Lungen-6 ≥ 720 U/ml were significantly associated with a poor prognosis. Serum chitotriosidase levels were negatively correlated with PaO 2 and percentage predicted forced vital capacity. The survival rate was significantly poorer in patients with high chitotriosidase levels (≥ 23.5 ng/ml) than in those with low chitotriosidase levels (< 23.5 ng/ml)., Conclusion: Serum chitotriosidase may be a potential biomarker for predicting a poor prognosis in patients with anti-MDA5-positive DM/CADM-ILD.

Background: Despite the absence of endogenous chitin in humans, chitinases are present in the serum of healthy subjects and their levels are increased in a variety of chronic inflammatory conditions. It has been shown that chitotriosidase and structurally related chitinase-like protein-YKL-40 contribute to the pathogenesis of COPD. However, details regarding the relation of their systemic and local airways levels remain unknown., Objectives: To examine peripheral blood and sputum chitotriosidase and YKL-40 expression in smokers and patients with COPD., Methods: Forty patients with COPD, 20 healthy smokers and 10 healthy never-smokers were studied. Serum and induced sputum chitotriosidase protein and activity levels, YKL-40 concentrations, and their gene expression in sputum cells and peripheral blood mononuclear cells (PBMC) were evaluated., Results: Both chitotriosidase protein levels and activity were higher in sputum obtained from COPD subjects compared to healthy never-smokers ( P <0.05 and P <0.01, respectively). A similar pattern was observed for PBMC chitotriosidase mRNA expression ( P <0.001). YKL-40 serum concentrations were elevated in healthy smokers and COPD subjects compared to healthy never-smokers ( P <0.001 and P <0.01, respectively). In sputum, YKL-40 levels were increased in COPD compared to healthy never-smokers ( P <0.01). PBMC YKL-40 mRNA expression was increased in COPD and healthy smokers compared to healthy never-smokers ( P <0.0001). No associations were found between chitotriosidase or YKL-40 peripheral blood levels and sputum levels., Conclusions: Our results demonstrate that chitotriosidase and YKL-40 are overexpressed in peripheral blood and airways in both healthy smokers and COPD subjects which may indicate smoking-related activation of macrophages, neutrophils, and epithelial cells., Competing Interests: The authors report no conflicts of interest in this work.

Background: Niemann-Pick disease type C (NP-C) is an inherited neurodegenerative disease (1 per 100 000 newborns) caused by NPC proteins impairment that leads to unesterified cholesterol accumulation in late endosomal/lysosomal compartments. To date the NP-C diagnostics is usually based on cholesterol detection in fibroblasts using an invasive and time-consuming Filipin staining and we need more arguments to widely introduce oxysterols as a biomarkers in NP-C., Methods: Insofar as NP-C represents about 8% of all infant cholestases, in this prospective observational study we tried to re-assess the specificity plasma oxysterol and chitotriosidase as a biochemical screening markers of NP-C in children with cholestasis syndrome of unknown origin. For 108 patients (aged from 2 weeks to 7 years) the levels of cholestane-3β,5α,6β-triol (C-triol) and chitotriosidase (ChT) were measured. For patients with elevated C-triol and/or ChT the NPC1 and NPC2 genes were Sanger-sequenced and 47 additional genes (from the custom liver damage panel) were NGS-sequenced., Results: Increased C-triol level (> 50 ng/ml) was detected in 4 (of 108) infants with cholestasis syndrome of unknown origin, with following molecular genetic NP-C diagnosis for one patient. Plasma cholesterol significantly correlates with C-triol (p < 0.05). NGS of high C-triol infants identified three patients with mutations in JAG1 (Alagille syndrome) and ABCB11 (Byler disease) genes. Increased ChT activity was detected in 8 (of 108) patients with various aetiologies, including NP-C, Byler disease and biliary atresia., Conclusion: Combined analysis of ChT activity and C-triol levels is an effective method for identifying NP-C.

Background and Aims: Lysosomal acid lipase deficiency (LALD) leads to the accumulation of cholesteryl esters and/or triglycerides (TG) in lysosomes due to the lack of the enzyme codified by the LIPA gene. The most common symptoms are dyslipidaemia and hypertransaminasemia, together with manifestations common to other lysosomal storage disorders (LSDs), including visceromegalies and elevated plasma biomarkers. Alteration of the lipid-liver profile (LLP) has been widely applied as a criterion for LALD screening, but the usefulness of biomarkers has not yet been explored. Our purpose was to explore the utility of plasma chitotriosidase activity (ChT) and CCL18/PARC concentration in addition to LLP to identify LALD patients in an observational retrospective study of two different sample collections., Methods: Biological samples refining: Collection 1 (primary hypercholesterolemia suspected) included unrelated individuals with hyperlipidaemia and without LDLR, APOB and PCSK9 gene mutations (Set 1), and Collection 2 (LSD suspected) included individuals without definitive LSD diagnosis (Set 2). We assessed plasma LLP (total cholesterol and its fractions, TG concentration and transaminases activities), as well as plasma ChT and CCL18/PARC. All subjects with anomalous LLP and/or biomarker levels were LIPA sequenced., Results: Twenty-four subjects showed altered LLP and/or biomarkers. We identified two LALD patients (one homozygous and one compound heterozygous) and one carrier of a novel LIPA variant., Conclusions: The measurement of plasma ChT and CCL18/PARC combined with LLP will be a useful approach to identifying LALD patients in retrospective LALD patient studies., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: Sarcoidosis is a systemic granulomatous disease with unknown etiology. Many clinical presentations have been reported, and acute disease needs to be distinguished from subacute and chronic disease. The unpredictable clinical course of the disease prompted us to evaluate the clinical utility of biomarker serum detection in sarcoidosis follow-up., Methods: Serum concentrations of chitotriosidase, ACE, KL-6, and lysozyme were analyzed by different methods in a population of 74 sarcoidosis patients (46 on steroid therapy at sampling) regularly monitored at Siena Sarcoidosis Regional Referral Centre and in a group of controls with the aim of comparing their contribution to clinical management of sarcoidosis patients., Results: KL-6 concentrations were significantly elevated in sarcoidosis patients with lung fibrosis and were significantly correlated with DLco and CPI score, while chitotriosidase was significantly higher in patients with extrapulmonary localizations. With a cut-off value of 303.5 IU/ml, KL-6 showed the best sensitivity (78%), while chitotriosidase reported the best specificity (85%) among the biomarkers., Conclusions: KL-6 is a reliable biomarker of fibrotic lung involvement in sarcoidosis patients. Among biomarkers, KL-6 showed the best sensitivity and serum chitotriosidase the best specificity, even in patients on chronic steroid therapy, and seemed to correlate with extrapulmonary localizations.

Objective: To investigate the role of neuroinflammation in asymptomatic and symptomatic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mutation carriers., Methods: The neuroinflammatory markers chitotriosidase 1 (CHIT1), YKL-40 and glial fibrillary acidic protein (GFAP) were measured in cerebrospinal fluid (CSF) and blood samples from asymptomatic and symptomatic ALS/FTD mutation carriers, sporadic cases and controls by ELISA., Results: CSF levels of CHIT1, YKL-40 and GFAP were unaffected in asymptomatic mutation carriers (n=16). CHIT1 and YKL-40 were increased in gALS (p<0.001, n=65) whereas GFAP was not affected. Patients with ALS carrying a CHIT1 polymorphism had lower CHIT1 concentrations in CSF (-80%) whereas this polymorphism had no influence on disease severity. In gFTD (n=23), increased YKL-40 and GFAP were observed (p<0.05), whereas CHIT1 was nearly not affected. The same profile as in gALS and gFTD was observed in sALS (n=64/70) and sFTD (n=20/26). CSF and blood concentrations correlated moderately (CHIT1, r=0.51) to weak (YKL-40, r=0.30, GFAP, r=0.39). Blood concentrations of these three markers were not significantly altered in any of the groups except CHIT1 in gALS of the Ulm cohort (p<0.05)., Conclusion: Our data indicate that neuroinflammation is linked to the symptomatic phase of ALS/FTD and shows a similar pattern in sporadic and genetic cases. ALS and FTD are characterised by a different neuroinflammatory profile, which might be one driver of the diverse presentations of the ALS/FTD syndrome., Competing Interests: Competing interests: DRT received consultancies from Covance Laboratories (UK) and GE Healthcare (UK), received a speaker honorarium from GE Healthcare (UK), and collaborated with Novartis Pharma Basel (Switzerland).PO, PW, PS, SAS, FN, AEV, JDS, PMA, JK, AD, KFa, KFl, HJ, ML, KM, AK, JP, AS, DYH, JHW, ACL and MO report no competing interests., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Serum chitotriosidase activity (CHIT1) is a biomarker of macrophage activation with an important role in inflammation-induced tissue remodeling and fibrosis. Macrophages have been described to play a crucial role in regulating pathological erythropoiesis in polycythemia vera (PV). The aim of this study was to evaluate CHIT1 in patients diagnosed with Philadelphia-negative myeloproliferative neoplasms (MPNs)., Methods: Using fluorometric assay, we measured CHIT1 in 28 PV, 27 essential thrombocythemia (ET), 17 primary myelofibrosis (PMF), 19 patients with secondary myelofibrosis and in 25 healthy controls., Results: CHIT1 was significantly higher in PV (p < .001) and post-PV myelofibrosis (MF) transformation (post-PV MF) (p = .020), but not in ET (p = .080), post-ET MF transformation (p = .086), and PMF patients (p = .287), when compared to healthy controls. CHIT1 in PV was positively correlated with hemoglobin (p = .026), hematocrit (p = .012), absolute basophil count (p = .030) and the presence of reticulin fibrosis in the bone marrow (p = .023)., Discussion: A positive correlation between CHIT1 and these distinct laboratory PV features might imply macrophages closely related to clonal erythropoiesis as cells of CHIT1 origin. In addition, a positive association between CHIT1 and reticulin fibrosis might indicate its potential role in PV progression., Conclusion: CHIT1 might be considered as a circulating biomarker in PV. Additional studies are needed to clarify the role of CHIT1 in promoting disease progression and bone marrow fibrosis in PV.

Background: Gaucher disease is a rare pan-ethnic disorder which occurs due to an increased accumulation of undegraded glycolipid glucocerebroside inside the cells' lysosomes. A beta-Glucosidase (GBA) gene defect results in glucocerebrosidase enzyme deficiency. Though the disease is mainly diagnosed in childhood, the adult manifestation is often missed or identified late due to the failure to recognize the heterogeneous clinical presentation. The present study includes seven unrelated Indian adult patients (age range: 20-40 years) having splenomegaly, with or without hepatomegaly, cytopenia and bone abnormality., Methods: The biochemical investigation implicated measuring plasma chitotriosidase enzyme activity followed by confirmatory test of β-Glucosidase enzyme activity from the leukocytes. The molecular characterization involved patients' initial screening for the common Gaucher mutation (Leu444Pro). Later, all patients were subjected to whole GBA gene coding region study using bidirectional Sanger sequencing. The population screening for common Gaucher disease mutation (Leu444Pro) was executed in 1200 unrelated and healthy Indian subjects by Restriction Fragment Length Polymorphism-Polymerase Chain Reaction technique. The allele frequency was calculated using Hardy-Weinberg formula., Results: The biochemical analysis revealed a significant reduction in the β-Glucosidase activity in all the patients. Also, an elevated level of plasma Chitotriosidase activity in five patients supported their diagnosis of Gaucher disease. Sanger sequencing established four patients with homozygous variation and three patients with compound heterozygous variation in GBA gene. This study uncovers two missense variants (Ala448Thr and Val17Gly) not previously reported in Gaucher disease patients. Also the known mutations like Leu444Pro, Arg329Cys, Asp315Asn, Ser125Arg, and Arg395Cys were identified in these patients. The homology modeling suggested the destabilization of the protein structure due to novel variants. The Leu444Pro mutation screening in the Indian population spotted two people as a carrier. This emerged the carrier frequency of 1:600 along with wild-type allele frequency 0.97113 and mutant allele frequency 0.02887., Conclusions: The study reports novel and known variants identified in the GBA gene in seven adult patients. The given study is the first report on the carrier frequency of the Leu444Pro mutant allele in an Indian population which will help understanding the burden and susceptibility of Gaucher disease to affect next generation in India.

Olipudase alfa, a recombinant human acid sphingomyelinase (ASM), is an enzyme replacement therapy for the treatment of nonneurologic manifestations of acid sphingomyelinase deficiency (ASMD). This ongoing, open-label, long-term study (NCT02004704) assessed safety and efficacy of olipudase alfa following 30 months of treatment in five adult patients with ASMD. There were no deaths, serious or severe events, or discontinuations during 30 months of treatment. The majority of adverse events were mild and included headache, nausea, and abdominal pain. No patient developed anti-drug antibodies and there were no clinically significant adverse changes in vital signs, hematology, or cardiac safety parameters. Statistically significant reductions in liver (31%) and spleen (39%) volumes were maintained through 30 months of treatment. There was a mean increase in lung diffusing capacity of 35%, and clinically relevant improvements in infiltrative lung disease parameters. Lipid profiles improved in all patients. Improvements in bone mineral density of the spine were observed in some patients. Chitotriosidase in serum and lyso-sphingomyelin in dried blood spots decreased with olipudase alfa treatment, suggesting utility as biomarkers for monitoring treatment efficacy. Olipudase alfa is the first etiology-specific treatment in development for ASMD. This study demonstrates that treatment with olipudase alfa for 30 months is well-tolerated and associated with life-transforming sustained improvements in relevant disease clinical measures.

Objective: The aim of this work was to assess baseline serum levels of established biomarkers related to inflammation and oxidative stress in samples from alkaptonuric subjects enrolled in SONIA1 (n = 40) and SONIA2 (n = 138) clinical trials (DevelopAKUre project)., Methods: Baseline serum levels of Serum Amyloid A (SAA), IL-6, IL-1β, TNFα, CRP, cathepsin D (CATD), IL-1ra, and MMP-3 were determined through commercial ELISA assays. Chitotriosidase activity was assessed through a fluorimetric method. Advanced Oxidation Protein Products (AOPP) were determined by spectrophotometry. Thiols, S-thiolated proteins and Protein Thiolation Index (PTI) were determined by spectrophotometry and HPLC. Patients' quality of life was assessed through validated questionnaires., Results: We found that SAA serum levels were significantly increased compared to reference threshold in 57.5% and 86% of SONIA1 and SONIA2 samples, respectively. Similarly, chitotriosidase activity was above the reference threshold in half of SONIA2 samples, whereas CRP levels were increased only in a minority of samples. CATD, IL-1β, IL-6, TNFα, MMP-3, AOPP, thiols, S-thiolated protein and PTI showed no statistically significant differences from control population. We provided evidence that alkaptonuric patients presenting with significantly higher SAA, chitotriosidase activity and PTI reported more often a decreased quality of life. This suggests that worsening of symptoms in alkaptonuria (AKU) is paralleled by increased inflammation and oxidative stress, which might play a role in disease progression., Conclusions: Monitoring of SAA may be suggested in AKU to evaluate inflammation. Though further evidence is needed, SAA, chitotriosidase activity and PTI might be proposed as disease activity markers in AKU., (Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Background: Allergic asthma is a chronically relapsing inflammatory airway disease with a complex pathophysiology., Aim: This study was undertaken to investigate the potential contribution of NOD2 signaling, proinflammatory cytokines, chitotriosidase (CHIT1) activity, oxidative stress and DNA damage to atopic asthma pathogenesis, as well as to explore their possible role as surrogate noninvasive biomarkers for monitoring asthma severity., Methods: Sixty patients with atopic bronchial asthma who were divided according to asthma severity into 40 mild-moderate, 20 severe atopic asthmatics, in addition to thirty age-matched healthy controls were enrolled in this study. NOD2 expression in PBMCs was assessed by quantitative real-time RT-PCR. DNA damage indices were assessed by alkaline comet assay. Serum IgE, IL-17, IL-8 and 3-Nitrotyrosine levels were estimated by ELISA. Serum CHIT1and GST activities, as well as MDA levels, were measured., Results: NOD2 mRNA relative expression levels were significantly decreased in atopic asthmatic cases relative to controls with lower values among severe atopic asthmatics. On the other hand, IL-17 and IL-8 serum levels, CHIT1 activity, DNA damage indices and oxidative stress markers were significantly increased in atopic asthmatic cases relative to controls with higher values among severe atopic asthmatics. The change in these parameters correlated significantly with the degree of decline in lung function., Conclusion: The interplay between NOD2 signaling, proinflammatory cytokines, CHIT1 activity, heightened oxidative stress and DNA damage orchestrates allergic airway inflammation and thus contributing to the pathogenesis of atopic asthma. These parameters qualified for measurement as part of new noninvasive biomarker panels for monitoring asthma severity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In the spleens of Gaucher disease mice and patients, there is a striking elevation of expression of glycoprotein non-Metastatic Melanoma B (gpNMB). We conducted a study in a large cohort of patients with Gaucher disease to assess the utility of serum levels of soluble fragment of gpNMB as a biomarker of disease activity. There was >15-fold elevation of gpNMB in sera of untreated patients with Gaucher disease. gpNMB levels correlated with overall disease severity as well as the severity of individual organ compartments: liver, spleen, bone and hematological disease. Imiglucerase enzyme replacement therapy resulted in significant reduction of gpNMB. Serum levels of gpNMB were highly correlated with accumulation of bioactive lipid substrate of Gaucher disease, glucosylsphingosine as well as established biomarkers, chitotriosidase and chemokine, CCL18. Our results suggest utility of gpNMB as a biomarker of Gaucher disease to monitor individual patients and cohorts of patients for disease progression or response to therapy. Investigation of gpNMB in Gaucher disease pathophysiology is likely to illuminate our understanding disease mechanisms., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Here, we report a patient with Niemann-Pick disease type B, with early severe onset of disease and pulmonary involvement, treated with hematopoietic stem cell transplant (HSCT) from a bone marrow matched unrelated donor. We confirm that HSCT is feasible and potentially beneficial for patients with severe phenotype. Noteworthy, we discussed the potential usefulness of the activity of peripheral chitotriosidase for the longitudinal evaluation of HSCT success and effectiveness., (© 2017 Wiley Periodicals, Inc.)

Background: Intravenous enzyme replacement therapy is a first-line therapy for Gaucher disease type 1, and substrate reduction therapy represents an oral treatment alternative. Both enzyme replacement therapy and substrate reduction therapy are generally used as monotherapies in Gaucher disease. However, one randomized study and several case reports have described combination therapy over short time periods., Case Presentation: We report two female Gaucher disease type 1 patients of mainly Anglo-Saxon descent, where combined enzyme replacement therapy and miglustat substrate reduction therapy were administered to overcome refractory clinical symptoms. The first patient was diagnosed at age 17 and developed Gaucher disease-related bone manifestations that worsened despite starting imiglucerase enzyme replacement therapy. After switching to miglustat substrate reduction therapy, her bone symptoms improved, but she developed tremors and eventually switched back to enzyme replacement therapy. Miglustat was later recommenced in combination with ongoing enzyme replacement therapy due to continued bone pain, and her bone symptoms improved along with maintained visceral manifestations. Enzyme replacement therapy was subsequently tapered off and the patient has since been successfully maintained on miglustat. The second patient was diagnosed aged 3, and commenced imiglucerase enzyme replacement therapy aged 15. After 9 years on enzyme replacement therapy she switched to miglustat substrate reduction therapy and her core symptoms were maintained/stable for 3 years. Imiglucerase enzyme replacement therapy was later added as a boost to therapy and her symptoms were subsequently maintained over a 2.3-year period. However, miglustat was discontinued due to her relocation, necessitating an increase in enzyme replacement therapy dose. Overall, both patients benefited from combination therapy., Conclusion: While the majority of Gaucher disease type 1 patients will not need treatment with both substrate reduction therapy and enzyme replacement therapy, the current case reports demonstrate that judicious use of combination therapy may be of benefit in some cases.

The relationship between chronic hemolysis with subsequent iron overload, inflammation, and premature atherosclerosis has been documented in hemolytic anemias, particularly β-thalassemia. However, no such relationship has been established in sickle cell disease (SCD). We sought to evaluate SCD as a risk factor for early vascular insult by measuring carotid intima-media thickness (CIMT) and plasma chitotriosidase and to assess the role of the latter as a potential quantitative indicator of vascular inflammation and atherogenesis. Thirty SCD pediatric patients (3-18 years) and 30 matched controls were enrolled. Full clinical history, with hematological and biochemical parameters, was evaluated. CIMT and chitotriosidase activity were also assessed for all study participants. CIMT values were significantly higher in SCD patients (median 0.42; range 0.32-0.6 mm) compared to controls (0.36; 0.34-0.45 mm), P = 0.03. CIMT correlated positively with age (r = 0.460, P = 0.011), and total number of vascular incidents necessitating hospital admission (r = 0.439, P = 0.015). Similarly, chitotriosidase activity was significantly higher among SCD patients (median 59.6; range 7.3-512 nmol/ml plasma/h) compared to controls (32.7; 6.8-63.1 nmol/ml plasma/h), P < 0.001, and showed a positive correlation with serum ferritin (r = 0.517, P = 0.003) and CIMT (r = 0.535, P = 0.002). SCD children are at risk of developing premature atherogenic changes. Plasma chitotriosidase and CIMT may represent useful predictors of these changes.

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., (© 2017 by the Association of Clinical Scientists, Inc.)

Aims: Chitotriosidase, is a macrophage sourced enzyme which shows high activity during the course of various storage disorders such as Gaucher's Disease. The aforementioned macrophage sourced enzyme, which has a role in basic immune response, is also high in patients with diabetes. This study was designed to determine the chitotriosidase activities in patients with diabetes and the relationship between the complication of diabetes and chitotriosidase activity., Materials Methods: This study included 76 patients with type2 diabetes mellitus and 76 healthy subjects. The chitotriosidase activity of all serum samples were determined by fluorometric method., Results and Conclusion: The chitotriosidase activity of patients having complications (neuropathy or nephropathy) were statistically significantly higher (p<0.05) than those of the controls. When the chitotriosidase activity of patients was evaluated regarding their glycosylated hemoglobin (HbA1c) levels, a progressive increase in chitotriosidase activity was observed in patients. The chitotriosidase activity of patients having higher HbA1c>10% levels was statistically significant higher than those of the control group's (p<0.05). It is shown that chitotriosidase activity might be a marker for some complications and is closely related to HbA1c levels., (Copyright © 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Gaucher disease (GD) is caused by mutations on the gene encoding for the lysosomal enzyme glucocerebrosidase. Type I GD (GD1) patients present anemia, hepatosplenomegaly and bone alterations. In spite of treatment, bone alterations in GD patients persist, including poor bone mineral density (BMD). Mechanisms leading to bone damage are not completely understood, but previous reports suggest that osteoclasts are involved. Chitotriosidase (CHIT) is the most reliable biomarker used in the follow up of patients, although its correlation with bone status is unknown. The aim of this work was to study the pro-osteoclastogenic potential in patients and to evaluate its correlation with CHIT activity levels and clinical parameters. PBMCs from treated patients and healthy controls were cultured in the presence of M-CSF, and mature osteoclasts were counted. BMD, blood CHIT activity and serum levels of CTX, BAP, and cytokines were evaluated in patients. We found that blood CHIT activity and osteoclast differentiation were significantly increased in patients, but no correlation between them was observed. Interestingly, osteoclast numbers but not CHIT, presented a negative correlation with BMD expressed as Z-score. CTX, BAP and serum cytokines involved in bone remodeling were found altered in GD1 patients. These results show for the first time a correlation between osteoclast differentiation and BMD in GD1 patients, supporting the involvement of osteoclasts in the bone pathology of GD1. Our results also suggest that an altered immune response may play an important role in bone damage., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Cancer progression has been associated with altered immune cell function and activation. Neopterin, which is secreted by interferon-γ stimulated macrophages, exhibits an association with multiple cancer types and metastatic disease. Chitotriosidase, which is secreted by chronically activated macrophages and granulocyte-macrophage colony-stimulating factor stimulated neutrophils has not been studied in the setting of cancer., Objective: The goal of this discovery study was to screen chitotriosidase for diagnostic capacity in detecting cancer and compare its operating characteristics with those of neopterin., Methods: Serum from subjects with breast (n= 66) or prostate (n= 70) cancer, and from 204 subjects free of malignant disease were studied. Chitotriosidase was measured by enzyme activity assay, while neopterin was measured by a competitive enzyme immunoassay. Statistical analyses included group comparisons by Mann Whitney U test, diagnostic capacity by receiver operating characteristics (ROC) curve analysis and biomarker associations with physiologic and clinical measures by Spearman correlation., Results: Chitotriosidase activity was significantly higher in both cancer types compared with gender matched controls, though only in breast cancer was the diagnostic capacity significant (area under the ROC curve of 0.97 ± 0.01). In contrast, neopterin was significantly elevated in prostate cancer and exhibited discriminatory capacity (area under the ROC curve of 0.76 ± 0.05). Age, BMI, % body fat and metastasis were variables that correlated with neopterin, but not chitotriosidase levels., Conclusions: The operating characteristics of serum chitotriosidase were different from neopterin and further analysis of chitotriosidase as a biomarker for breast cancer is warranted.

Chitotriosidase, an enzyme secreted by activated macrophages, is widely used as a biomarker for therapeutic monitoring and patient follow-up in Gaucher disease (GD), a lysosomal disorder caused by an inherited deficiency of glucocerebrosidase. We analyzed the long-term evolution of chitotriosidase aiming to establish an accurate model that describes the influence of enzyme replacement therapy (ERT) and the impact of several covariates. A total of 55 patients with non-neuronopathic (type 1) GD were followed for almost 17 years (during a maximum of 7.57 and 8.96 years, before and after the onset of ERT, respectively). Plasma chitotriosidase activity, measured yearly before the onset of ERT and at 6-month intervals after the initiation of ERT, was analyzed as a function of several covariates (age at diagnosis and at ERT initiation, nature of the most frequent genotypes, spleen status and the occurrence of bone complications). The evolution of chitotriosidase was approximated by a sigmoidal function, which allows the calculation of predicted values, based on several parameters inferred from our data. Splenectomy and the occurrence of bone complications significantly delayed the decline in chitotriosidase activity and induced higher mean residual values after long-term (4-9 years) ERT. Likewise, patients who started ERT infusions under 15 years of age had significantly higher mean residual chitotriosidase activities. The influence of other covariates did not reach statistical significance. In conclusion, we propose a novel model describing the evolution of chitotriosidase, allowing more accurate treatment adjustments, according to the variations of this biomarker.

Background: Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by deficiency in acid beta-glucosidase. GD exhibits a wide clinical spectrum of disease severity with an unpredictable natural course. Plasma chitotriosidase activity and CC chemokine ligand 18 (CCL18) have been exchangeably used for monitoring GD activity and response to enzyme replacement therapy in conjunction with clinical assessment. Yet, a large-scale head-to-head comparison of these two biomarkers is currently lacking. We propose a collaborative systematic review with meta-analysis of individual participant data (IPD) to compare the accuracy of plasma chitotriosidase activity and CCL18 in assessing type I (i.e., non-neuropathic) GD severity., Methods: Eligible studies include cross-sectional, cohort, and randomized controlled studies recording both plasma chitotriosidase activity and CCL18 level at baseline and/or at follow-up in consecutive children or adult patients with type I GD. Pre-specified surrogate outcomes reflecting GD activity include liver and spleen volume, hemoglobin concentration, platelet count, and symptomatic bone events with imaging confirmation. Primary studies will be identified by searching Medline (1995 onwards), EMBASE (1995 onwards), and Cochrane Central Register of Controlled Trials (CENTRAL). Electronic search will be complemented by contacting research groups in order to identify unpublished relevant studies. Where possible, IPD will be extracted from published articles. Corresponding authors will be invited to collaborate by supplying IPD. The methodological quality of retrieved studies will be appraised for each study outcome, using a checklist adapted from the Quality Assessment of Diagnostic Accuracy Studies-2 tool. The primary outcome will be a composite of liver volume >1.25 multiple of normal (MN), spleen volume >5 MN, hemoglobin concentration <11 g/dL, or platelet count <100 × 10 9 /L. Effect size estimates for biomarker comparative accuracy in predicting outcomes will be reported as differences in areas under receiver operating characteristic curves along with 95% confidence intervals. Effect size estimates will be reported as (weighted) mean differences along with 95% confidence intervals for each biomarker according to outcomes. IPD meta-analysis will be conducted with both one- and two-stage approaches., Discussion: Valid and precise accuracy estimates will be derived for CCL18 relative to plasma chitotriosidase activity in discriminating patients according to GD severity., Systematic Review Registration: PROSPERO 2015 CRD42015027243.

Objectives: Gaucher's disease type 1 (GD1) pathophysiology includes an imbalance on brain-derived neurotrophic factor (BDNF) levels and in the inflammatory system. However, the pathways involved remain poorly understood. The hypothesis of this study is that epigenetic mechanisms might be involved, at least partially, in this phenomenon., Design and Methods: This study investigated the BDNF modulation, global histone H4 acetylation and pro- and anti-inflammatory cytokines levels in the peripheral blood of GD1 patients (n=10) when compared with control samples (CS) (n=11)., Results: The results showed a significant increase in Chitotriosidase (CT) (p=0.019) and decreased β-glucosidase (GBA) activities (p=0.001) in GD1 samples when compared to CS, for GD1 diagnostic confirmation. Reduced levels of BDNF (p=0.004) and elevated levels of TNF-α (p=0.017) and IL-4 (p=0.035) were also found in the GD group. No significant differences were observed in IL-6 or IL-17a levels between groups (p>0.05). Finally, a trend on higher global histone H4 acetylation levels (p=0.054) was observed in the control group when compared to GD1 individuals., Conclusions: Combined, these results suggest inflammatory cytokines imbalance, reduced BDNF levels and global histone H4 hypoacetylation status in GD type 1 physiopathology. These preliminary findings may open new avenues to introduce therapies and strategies in the preventive management and treatment of this population., (Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive neurodegenerative disease caused by mutations in either the NPC1 or NPC2 genes. The diagnosis of NP-C remains challenging due to the non-specific, heterogeneous nature of signs/symptoms. This study assessed the utility of plasma chitotriosidase (ChT) and Chemokine (C-C motif) ligand 18 (CCL18)/pulmonary and activation-regulated chemokine (PARC) in conjunction with the NP-C suspicion index (NP-C SI) for guiding confirmatory laboratory testing in patients with suspected NP-C., Methods: In a prospective observational cohort study, incorporating a retrospective determination of NP-C SI scores, two different diagnostic approaches were applied in two separate groups of unrelated patients from 51 Spanish medical centers (n = 118 in both groups). From Jan 2010 to Apr 2012 (Period 1), patients with ≥2 clinical signs/symptoms of NP-C were considered 'suspected NP-C' cases, and NPC1/NPC2 sequencing, plasma chitotriosidase (ChT), CCL18/PARC and sphingomyelinase levels were assessed. Based on findings in Period 1, plasma ChT and CCL18/PARC, and NP-C SI prediction scores were determined in a second group of patients between May 2012 and Apr 2014 (Period 2), and NPC1 and NPC2 were sequenced only in those with elevated ChT and/or elevated CCL18/PARC and/or NP-C SI ≥70. Filipin staining and 7-ketocholesterol (7-KC) measurements were performed in all patients with NP-C gene mutations, where possible., Results: In total across Periods 1 and 2, 10/236 (4%) patients had a confirmed diagnosis o NP-C based on gene sequencing (5/118 [4.2%] in each Period): all of these patients had two causal NPC1 mutations. Single mutant NPC1 alleles were detected in 8/236 (3%) patients, overall. Positive filipin staining results comprised three classical and five variant biochemical phenotypes. No NPC2 mutations were detected. All patients with NPC1 mutations had high ChT activity, high CCL18/PARC concentrations and/or NP-C SI scores ≥70. Plasma 7-KC was higher than control cut-off values in all patients with two NPC1 mutations, and in the majority of patients with single mutations. Family studies identified three further NP-C patients., Conclusion: This approach may be very useful for laboratories that do not have mass spectrometry facilities and therefore, they cannot use other NP-C biomarkers for diagnosis.

Acid Ceramidase Deficiency (Farber disease, FD) is an ultra-rare Lysosomal Storage Disorder that is poorly understood and often misdiagnosed as Juvenile Idiopathic Arthritis (JIA). Hallmarks of FD are accumulation of ceramides, widespread macrophage infiltration, splenomegaly, and lymphocytosis. The cytokines involved in this abnormal hematopoietic state are unknown. There are dozens of ceramide species and derivatives, but the specific ones that accumulate in FD have not been investigated. We used a multiplex assay to analyze cytokines and mass spectrometry to analyze ceramides in plasma from patients and mice with FD, controls, Farber patients treated by hematopoietic stem cell transplantation (HSCT), JIA patients, and patients with Gaucher disease. KC, MIP-1α, and MCP-1 were sequentially upregulated in plasma from FD mice. MCP-1, IL-10, IL-6, IL-12, and VEGF levels were elevated in plasma from Farber patients but not in control or JIA patients. C16-Ceramide (C16-Cer) and dhC16-Cer were upregulated in plasma from FD mice. a-OH-C18-Cer, dhC12-Cer, dhC24:1-Cer, and C22:1-Cer-1P accumulated in plasma from patients with FD. Most cytokines and only a-OH-C18-Cer returned to baseline levels in HSCT-treated Farber patients. Sphingosines were not altered. Chitotriosidase activity was also relatively low. A unique cytokine and ceramide profile was seen in the plasma of Farber patients that was not observed in plasma from HSCT-treated Farber patients, JIA patients, or Gaucher patients. The cytokine profile can potentially be used to prevent misdiagnosis of Farber as JIA and to monitor the response to treatment. Further understanding of why these signaling molecules and lipids are elevated can lead to better understanding of the etiology and pathophysiology of FD and inform development of future treatments., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Acute kidney injury is a common complication after cardiac surgery with cardiopulmonary bypass. The authors evaluated the effects of normothermic cardiopulmonary bypass on renal blood flow, glomerular filtration rate, renal oxygen consumption, and renal oxygen supply/demand relationship, i.e., renal oxygenation (primary outcome) in patients undergoing cardiac surgery., Methods: Eighteen patients with a normal preoperative serum creatinine undergoing cardiac surgery procedures with normothermic cardiopulmonary bypass (2.5 l · min · m) were included after informed consent. Systemic and renal hemodynamic variables were measured by pulmonary artery and renal vein catheters before, during, and after cardiopulmonary bypass. Arterial and renal vein blood samples were taken for measurements of renal oxygen delivery and consumption. Renal oxygenation was estimated from the renal oxygen extraction. Urinary N-acetyl-β-D-glucosaminidase was measured before, during, and after cardiopulmonary bypass., Results: Cardiopulmonary bypass induced a renal vasoconstriction and redistribution of blood flow away from the kidneys, which in combination with hemodilution decreased renal oxygen delivery by 20%, while glomerular filtration rate and renal oxygen consumption were unchanged. Thus, renal oxygen extraction increased by 39 to 45%, indicating a renal oxygen supply/demand mismatch during cardiopulmonary bypass. After weaning from cardiopulmonary bypass, renal oxygenation was further impaired due to hemodilution and an increase in renal oxygen consumption, accompanied by a seven-fold increase in the urinary N-acetyl-β-D-glucosaminidase/creatinine ratio., Conclusions: Cardiopulmonary bypass impairs renal oxygenation due to renal vasoconstriction and hemodilution during and after cardiopulmonary bypass, accompanied by increased release of a tubular injury marker.

Background: The variants of neuronopathic Gaucher disease may be viewed as a clinical phenotypic continuum divided into acute and chronic forms. The chronic neuronopathic form of Gaucher disease is characterized by a later onset of neurological symptoms and protracted neurological and visceral involvement. The first-choice treatment for nonneuronopathic Gaucher disease is enzyme replacement therapy with recombinant analogues of the deficient human enzyme glucocerebrosidase. Enzyme replacement therapy has been shown to improve hematological and bone manifestations associated with Gaucher disease, but, as with most proteins, recombinant enzymes cannot cross the blood-brain barrier, which prevents effects on neurological manifestations. Substrate reduction therapy with miglustat (N-butyldeoxynojirimycin) inhibits glucosylceramide synthase, which catalyzes the first step in glycosphingolipid synthesis. Because miglustat can cross the blood-brain barrier, it has been suggested that, combined with enzyme replacement therapy, it might be effective in treating neurological symptoms in patients with neuronopathic Gaucher disease., Case Presentation: We report observed effects of combined enzyme replacement therapy and substrate reduction therapy in a 7-year-old Caucasian boy with neuronopathic Gaucher disease who was homozygous for L444P mutations. He had received enzyme replacement therapy from the age of 18 months, and concomitant miglustat treatment was commenced, with dosing according to body surface area uptitrated over 1 month with dietary modifications when he reached the age of 30 months. He experienced mild diarrhea after commencing miglustat therapy, which decreased in frequency/severity over time. His splenomegaly was reduced, and his hematological values and plasma angiotensin-converting enzyme activity normalized. Plasma chitotriosidase also showed substantial and sustained decreases. After 5 years of combination therapy, the patient showed no signs of neurological impairment., Conclusions: This case supports the concept that oral miglustat in combination with intravenous enzyme replacement therapy may be beneficial in preventing neurological signs in patients with chronic neuronopathic Gaucher disease. The importance of dietary modifications has also been confirmed. Further follow-up studies are needed to better define the therapeutic effect of combined treatment in this Gaucher disease subtype.

Sarcoidosis is a systemic granulomatous disease of unknown etiology. Recent studies demonstrated that its pathogenesis is related with enhanced oxidative stress (protein carbonylation and lipid peroxidation) and alterations in the circulating lipid profile. Alterations of lipid metabolism (including the reduction in high-density lipoprotein cholesterol levels and apolipoprotein A1 concentrations) induce plasma membrane, bronchial and lung capillary endothelial cell damage in sarcoidosis patients. Dyslipidemia is associated with increased oxidative stress, diminished overall antioxidative protection and increased risk for atherosclerosis. Very recently increased cardiovascular biomarkers (in particular alterations of lipoprotein A and d-dimer concentrations) were observed in sarcoidosis patients, mainly in those with a high risk of atherosclerosis. Chitotriosidase, a biomarker of sarcoidosis activity and macrophage activation, is increased in serum and bronchoalveolar lavage fluid of patients with sarcoidosis as well as in patients with atherosclerosis. Lipidomics and other recent methodologies allowed the discovery of proteins involved in lipid metabolism and sarcoidosis pathogenesis, such as serum amyloid A, a biomarker of sarcoidosis activity, involved in innate immune response, inflammation and apolipoprotein metabolism. In this review lipid metabolism alteration and atherosclerosis risk in sarcoidosis patients were discussed in order to contribute to this novel and interesting research topic., (© 2017 S. Karger AG, Basel.)