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Clinica Chimica Acta

Current research reports and chronological list of recent articles..




The international scientific journal Clinica Chimica Acta publishes original Research Communications in the field of clinical chemistry and laboratory medicine, defined as the application of chemistry, biochemistry, immunochemistry, biochemical aspects of hematology, toxicology, and molecular biology to the study of human disease in body fluids, cells or tissues.

The publisher is Elsevier. The copyright and publishing rights of specialized products listed below are in this publishing house. This is also responsible for the content shown.

To search this web page for specific words type "Ctrl" + "F" on your keyboard (Command + "F" on a Mac). Then: type the word you are searching for in the window that pops up!

Additional research articles see Current Chemistry Research Articles. Magazines with similar content (clinical chemistry):

 - Clinical Biochemistry.

 - Clinical Chemistry and Laboratory Medicine.

 - Clinical Chemistry Online.

 - Clinical Science.

 - Clinical Toxicology.

 - Journal of Medicinal Chemistry.

 - Journal of Laboratory Medicine.



Clinica Chimica Acta - Abstracts



Head-to-head comparison of plasma cTnI concentration values measured with three high-sensitivity methods in a large Italian population of healthy volunteers and patients admitted to emergency department with acute coronary syndrome: A multi-center study

Publication date: September 2019

Source: Clinica Chimica Acta, Volume 496

Author(s): Aldo Clerico, Andrea Ripoli, Martina Zaninotto, Silvia Masotti, Veronica Musetti, Marcello Ciaccio, Rosalia Aloe, Sara Rizzardi, Ruggero Dittadi, Cinzia Carrozza, Tommaso Fasano, Marco Perrone, Antonio de Santis, Concetta Prontera, Daniela Riggio, Cristina Guiotto, Marco Migliardi, Sergio Bernardini, Mario Plebani

Abstract
Background

The study aim is to compare cTnI values measured with three high-sensitivity (hs) methods in apparently healthy volunteers and patients admitted to emergency department (ED) with acute coronary syndrome enrolled in a large multicentre study.

Methods

Heparinized plasma samples were collected from 1511 apparently healthy subjects from 8 Italian clinical institutions (mean age: 51.5 years, SD: 14.1 years, range: 18–65 years, F/M ratio:0.95). All volunteers denied chronic or acute diseases and had normal values of routine laboratory tests. Moreover, 1322 heparinized plasma sample were also collected by 9 Italian clinical institutions from patients admitted to ED with clinical symptoms typical of acute coronary syndrome. The reference study laboratory assayed all plasma samples with three hs-methods: Architect hs-cTnI, Access hs-cTnI and ADVIA Centaur XPT methods. Principal Component Analysis (PCA) was also used to analyze the between-method differences among hs-cTnI assays.

Results

On average, a between-method difference of 31.2% CV was found among the results of hs-cTnI immunoassays. ADVIA Centaur XPT method measured higher cTnI values than Architect and Access methods. Moreover, 99th percentile URL values depended not only on age and sex of reference population, but also on the statistical approach used for calculation (robust non-parametric vs bootstrap).

Conclusions

Due to differences in concentrations and reference values, clinicians should be advised that plasma samples of the same patient should be measured for cTnI assay in the same laboratory. Specific clinical studies are needed to establish the most appropriate statistical approach to calculate the 99th percentile URL values for hs-cTnI methods.


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Lysosomal enzyme activities as possible CSF biomarkers of synucleinopathies

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Silvia Paciotti, Leonardo Gatticchi, Tommaso Beccari, Lucilla Parnetti

Abstract

Mutations on the GBA gene, encoding for the lysosomal enzyme β-glucocerebrosidase (GCase), have been identified as the most common genetic risk factor involved in the development of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), indicating a direct contribution of this enzyme to the pathogenesis of synucleinopathies.

Decreased GCase activity has been observed repeatedly in brain tissues and biological fluids of both GBA mutation carrier and non-carrier PD and DLB patients, suggesting that lower GCase activity constitutes a typical feature of these disorders.

Additional genetic, pathological and biochemical data on other lysosomal enzymes (e.g., Acid sphingomyelinase, Cathepsin D, α-galactosidase A and β-hexosaminidase) have further strengthened the evidence of a link between lysosomal dysfunction and synucleinopathies.

A few studies have been performed for assessing the potential value of lysosomal enzyme activities in cerebrospinal fluid (CSF) as biomarkers for synucleinopathies. The reduction of GCase activity in the CSF of PD and DLB patients was validated in several of them, whereas the behaviour of other lysosomal enzyme activities was not consistently reliable among the studies. More in-depth investigations on larger cohorts, following stringent standard operating procedures should be committed to really understand the diagnostic utility of lysosomal enzymes as biomarkers for synucleinopathies. In this review, we reported the evidences of the association between the defective function of lysosomal proteins and the pathogenesis of synucleinopathies, and examined the role of lysosomal enzyme activities in CSF as reliable biomarkers for the diagnosis of PD and related neurodegenerative disorders.


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Association of circulating growth differentiation factor-15, Krüppel-like factor 4 and growth arrest-specific 6 with coronary artery disease

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Huan Liu, Yong-nan Lyu, Di Li, Yan Cui, Wen Dai, Yan Li

Abstract
Background

Current assessment tools for patients with acute chest pain are either traumatic (coronary angiography) or unreliable (measurement of cardiac troponin concentrations). We investigated whether the novel cardiovascular stress markers, serum growth differentiation factor-15 (GDF-15), Krüppel-like factor 4 (KLF4) and growth arrest-specific 6 (gas6) may be useful biomarkers of coronary artery disease (CAD).

Methods

A total of 350 male patients were enrolled, 198 with CAD and 152 controls, based on coronary angiography. GDF-15, KLF4 and gas6 concentrations were measured using commercial enzyme-linked immunosorbent assay kits. Multivariate logistic regression and multivariate linear regression were performed to evaluate potential associations of GDF-15, KLF4 and gas6 with risk of CAD or CAD severity.

Results

Serum GDF-15, KLF4 and gas6 concentrations were significantly higher in male patients with CAD than in control subjects (P < .05), and they correlated significantly with involvement of coronary vessels (P < .05). After adjusting for confounding factors, we found that circulating GDF-15 concentrations remained positively associated with the presence of CAD (odds ratio [OR] per 1-standard deviation [SD] increase, 3.182; 95% confidence interval [CI] 1.586 to 6.382; P = .001), as did KLF4 concentrations (OR per 1-SD increase, 13.05; 95% CI 2.940 to 57.921, P = .001). Moreover, circulating GDF-15 concentrations were positively associated with the Gensini score (estimated SD change per 1-SD increase, 22.091; 95% CI 9.147 to 35.035, P = .001), as were KLF4 concentrations (estimated SD change per 1-SD increase, 27.996; 95% CI 10.082 to 45.910, P = .002). Gas6, in contrast, showed no relationship to presence of CAD or Gensini score.,

Conclusions

In this case-control study, increased concentrations of circulating GDF-15 and KLF4 were significantly associated with the presence and severity of CAD.


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Higher plasma C-type lectin-like receptor 2 concentrations for prediction of higher risk of 30-day mortality in isolated severe blunt traumatic brain injury

Publication date: September 2019

Source: Clinica Chimica Acta, Volume 496

Author(s): Mi Guo, Han Zhang, Qing-Wei Lv, Hang-Bin Huang, Liang-Jun Shen

Abstract
Background

Platelet activation is implicated in secondary brain injury following traumatic brain injury (TBI). C-type lectin-like receptor 2 (CLEC-2) is extensively expressed on platelets and participates in platelet activation. We investigate dthe prognostic significance of plasma CLEC-2 in TBI patients.

Methods

One hundred and six patients with isolated severe blunt TBI and 106 healthy controls were prospectively investigated. Plasma CLEC-2 concentrations were detected and Glasgow coma scale (GCS) scores were recorded. The relationship between plasma CLEC-2 concentrations and 30-day mortality in addition to overall survival was determined using multivariate models.

Results

Patients exhibited a substantially higher concentration of plasma CLEC-2 than healthy controls. Among patients, plasma CLEC-2 concentrations were remarkably increased in the GCS scores- and Rotterdam computerized tomography classification- dependent manner. As compared with survivors within posttraumatic 30 days, plasma CLEC-2 concentrations were remarkably raised in non-survivors. Rising plasma CLEC-2 concentration was independently associated with an enhanced risk of 30-day mortality and short overall survival time. Plasma CLEC-2 concentrations had a significantly high area under receiver operating characteristic curve for predicting 30-day mortality.

Conclusions

Incremental plasma CLEC-2 concentrations are intimately related to increasing trauma severity, in close association with increased 30-day death, indicating the prognostic role of plasma CLEC-2 in TBI.


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Procalcitonin: Between evidence and critical issues

Publication date: September 2019

Source: Clinica Chimica Acta, Volume 496

Author(s): Elena Aloisio, Alberto Dolci, Mauro Panteghini

Abstract

Sepsis is a life-threatening organ dysfunction caused by a dysregulated response of the host to infection. It represents one of the major health care problems worldwide. Unfortunately, the diagnosis of sepsis is challenging for many reasons, including a lack of a sufficiently sensitive and specific diagnostic test. When procalcitonin (PCT) was discovered, it was thought that it could become the best test for identifying patients with sepsis. From the evidence sources in the available literature, it is now clear that the power of PCT in differentiating infectious from non-infectious forms of systemic inflammatory response syndrome in adults, and in stratifying morbidity and mortality risk, is limited. Nevertheless, PCT determination can be a useful tool for diagnosing late-onset neonatal sepsis, bacterial meningitis and other forms of organ-related bacterial infections and, above all, it can be used for guiding antibiotic stewardship in critical patients. The real impact of this application of PCT testing, however, still needs to be clearly defined. Laboratories should offer unrestricted PCT testing only to intensive care units (as an aid in decision for continuing or stopping antibiotics) and pediatric wards. For all other clinical wards, the laboratory should guide PCT requests and give them support towards the most appropriate approach to testing.


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Barricor blood collection tubes are equivalent to PST for a variety of chemistry and immunoassay analytes except for lactate dehydrogenase

Publication date: September 2019

Source: Clinica Chimica Acta, Volume 496

Author(s): Joshua E. Raizman, Bobbi Lynn Goudreau, Anna K. Füzéry, George S. Cembrowski

Abstract
Introduction

The BD Barricor tube uses a novel mechanical separator designed to eliminate gel artifacts, decrease cellular contamination, and improve stability. Here, we evaluated the Barricor tube as a possible replacement for PST using Beckman Coulter analyzers under both optimal, alternative, and suboptimal centrifugation conditions based on BD recommendations.

Methods

Paired PST and Barricor samples were collected from 4 local hospitals and processed based on site-specific preanalytical systems involving automated or manual centrifugation. Centrifugation conditions ranged from 1912 ×g for 10 min (suboptimal), 2060 g for 10 min (alternative), and 4000 ×g for 3 or 10 min (optimal). Tube volume (4.5 vs. 5.5 ml) was also assessed. Forty-three chemistry and immunochemistry analytes were measured on Beckman Coulter DxC and DxI analyzers.

Results

Using an automated preanlaytical system with suboptimal spin conditions, no bias between PST and Barricor was observed for all analytes tested except lactate dehydrogenase (LD). Further investigation revealed significant increase in LD when Barricor was spun for 10 min at 1912, 2060 and 4000 ×g, ranging from +7.4–19.4% vs. PST across the entire measurement interval (87–493 U/l). Smaller tube volume was also associated with higher LD. Differences in LD occurred despite no change in other hemolysis markers such as potassium, phosphate, and AST.

Conclusions

LD is most sensitive to varying centrifugation conditions (time and speed) in Barricor tubes. We recommend that BD centrifugation protocols should be closely evaluated to determine if Barricor is equivalent to PST under local preanalytical configurations.


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Howard Morris: ‘Dynamic scientist; inspiring leader and thoroughly good person’

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s):


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Key questions about the future of laboratory medicine in the next decade of the 21st century: A report from the IFCC-Emerging Technologies Division

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Ronda F. Greaves, Sergio Bernardini, Maurizio Ferrari, Paolo Fortina, Bernard Gouget, Damien Gruson, Tim Lang, Tze Ping Loh, Howard A. Morris, Jason Y. Park, Markus Roessler, Peng Yin, Larry J. Kricka

Abstract

This review advances the discussion about the future of laboratory medicine in the 2020s. In five major topic areas: 1. the “big picture” of healthcare; 2. pre-analytical factors; 3. Analytical factors; 4. post-analytical factors; and 5. relationships, which explores a next decade perspective on laboratory medicine and the likely impact of the predicted changes by means of a number of carefully focused questions that draw upon predictions made since 2013. The “big picture” of healthcare explores the effects of changing patient populations, the brain-to-brain loop, direct access testing, robots and total laboratory automation, and green technologies and sustainability. The pre-analytical section considers the role of different sample types, drones, and biobanks. The analytical section examines advances in point-of-care testing, mass spectrometry, genomics, gene and immunotherapy, 3D-printing, and total laboratory quality. The post-analytical section discusses the value of laboratory medicine, the emerging role of artificial intelligence, the management and interpretation of omics data, and common reference intervals and decision limits. Finally, the relationships section explores the role of laboratory medicine scientific societies, the educational needs of laboratory professionals, communication, the relationship between laboratory professionals and clinicians, laboratory medicine financing, and the anticipated economic opportunities and outcomes in the 2020's.


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The VLDL receptor plays a key role in the metabolism of postprandial remnant lipoproteins

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Katsuyuki Nakajima, Yoshiharu Tokita, Akira Tanaka, Sadao Takahashi

Abstract

A new concept to account for the process of postprandial remnant lipoprotein metabolism is proposed based on the characteristics of lipoprotein particles and their receptors. The characteristics of remnant lipoprotein (RLP) were investigated using an immuno-separation method. The majority of the postprandial lipoproteins increased after fat intake was shown to be VLDL remnants, not chylomicron (CM) remnants, based on the significantly high ratio of apoB100/apoB48 in the RLP and the high degree of similarity in the particle size of the apoB48 and apoB100 carrying lipoproteins, which fluctuate in parallel during a 6 h period after fat intake. The VLDL receptor was discovered as a receptor for TG-rich lipoprotein metabolism and is located in peripheral tissues such as skeletal muscle, adipose tissue, etc., but not in the liver. Postprandial VLDL particles are strongly bound and internalized into cells expressing the VLDL receptor. Ligands that bind to VLDL receptor, such as LPL and Lp(a), present in RLP. The presence of various specific ligands in VLDL remnants may enhance the capacity for binding to the VLDL receptor, which play the role primarily for energy delivery to the peripheral tissues, but is also a causal factor in atherogenic diseases when excessively and/or continuously remained in plasma.


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Diagnosis associated with Tau higher than 1200 pg/mL: Insights from the clinical and laboratory practice

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): S. Lehmann, C. Paquet, C. Malaplate-Armand, E. Magnin, S. Schraen, M. Quillard-Muraine, O. Bousiges, C. Delaby, J. Dumurgier, J. Hugon, B. Sablonnière, F. Blanc, D. Wallon, A. Gabelle, J.L. Laplanche, E. Bouaziz-Amar, K. Peoc'h, ePLM Group

Abstract
Context

Cerebrospinal fluid (CSF) biomarkers are valuable tools for the diagnosis of neurological diseases. We aimed to investigate within a retrospective multicentric study the final diagnosis associated with very high CSF Tau levels and to identify patterns of biomarkers that would differentiate them in clinical practice, to help clinical biologists into physicians' counseling.

Patients and methods

Within the national multicentric network ePLM, we included 1743 patients from January 1, 2008, to December 31, 2013, with CSF biomarkers assayed by the same Innotest assays (protein Tau, phospho-Tau [pTau], and Aβ 1-42). We identified 205 patients with protein Tau concentration higher than 1200 pg/mL and final diagnosis.

Results

Among those patients, 105 (51.2%) were suffering from Alzheimer's disease, 37 (18%) from sporadic Creuztfeldt-Jakob disease, and 63 (30.7%) from other neurological diseases including paraneoplastic/ central nervous system tumor, frontotemporal dementia, other diagnoses, amyloid angiopathy, Lewy body dementia, and infections of the central nervous system. Phospho-Tau, Aβ1-42 and Aβ1-42/pTau values differed significantly between the three groups of patients (p < .001). An Aβ1-42/pTau ratio between 4.7 and 9.7 was suggestive of other neurological diseases (threshold in AD: 8.3). CSF 14-3-3 was useful to discriminate Alzheimer's disease from Creuztfeldt-Jakob disease in case of Aβ1-42 concentrations <550 pg/mL or pTau>60 pg/mL.

Conclusion

This work emphasizes the interest of a well-thought-out interpretation of CSF biomarkers in neurological diseases, particularly in the case of high Tau protein concentrations in the CSF.


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Parkinson's and Lewy body dementia CSF biomarkers

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Lucilla Parnetti, Silvia Paciotti, Lucia Farotti, Giovanni Bellomo, Federica Nicoletta Sepe, Paolo Eusebi

Abstract

The clinical diagnosis of Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) is challenging due to highly variable clinical presentation and clinical and pathological overlap with other neurodegenerative diseases. Since cerebrospinal fluid (CSF) mirrors the pathological changes taking place in the brain, it represents a promising source of biomarkers.

With respect to classical AD biomarkers, low CSF Aβ42 levels have shown a robust prognostic value in terms of development of cognitive impairment in PD and DLB. In the differential diagnosis between AD and DLB, a potential role of t-tau, p-tau and Aβ42/Aβ38 ratio has been demonstrated. Regarding CSF α-synuclein (α-syn) species, lower levels of total α-synuclein (t-α-syn) and higher concentration of oligomeric-α-synuclein (o-α-syn) and phosphorylated α-synuclein (p-α-syn) have been observed in PD. Furthermore, the detection of “pro-aggregating” α-synuclein has enabled the discrimination of patients affected by synucleinopathies with high sensitivity and specificity. New promising biomarkers are emerging: GCase activity (reduced in PD and DLB patients vs. controls), CSF/serum albumin ratio (increased in PD and DLB), fatty-acid-binding protein (increased in AD and DLB vs. PD), visinin-like protein-1 (increased in AD vs. DLB) and monoamines (useful in differential diagnosis among PD and DLB). These encouraging results need to be confirmed by future studies.


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A post-hoc subgroup analysis assessing acute cardiac biomarker profiles in female cancer patients during adjuvant therapy

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Katharine Mackett, Sukhbinder Dhesy-Thind, Elysia K. Donovan, Som Mukherjee, Anand Swaminath, Darryl P. Leong, Sachi Voruganti, Jonathan Sussman, James Wright, Gordon Okawara, Graham Fraser, Stephen Sagar, Louise Bordeleau, Peter M. Ellis, Hal Hirte, Peter A. Kavsak


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Measurement of calcineurin activity in peripheral blood mononuclear cells by ultra-high performance liquid chromatography-tandem mass spectrometry. Renal transplant recipients application (pharmacodynamic monitoring)

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Pere Fontova, Raül Rigo-Bonnin, Anna Vidal-Alabró, Gema Cerezo, Oriol Bestard, Josep M. Cruzado, Joan Torras, Josep M. Grinyó, Núria Lloberas

Abstract
Background

Therapeutic drug monitoring of calcineurin inhibitor, tacrolimus (TAC), is routinely used in post-transplantation. Currently, measurement of calcineurin activity has been proposed as a promising clinical tool to evaluate efficacy and to optimize drug dosing. The main aim of our study was to develop a method to measure phosphatase calcineurin activity (CNA) in peripheral blood mononuclear cells (PBMCs) by ultra-high performance liquid chromatography-tandem mass spectrometry and to validate it following FDA and EMA guidelines.

Methods

This methodology is based on monitoring the Ca2+-dependent dephosphorylation of a phosphopeptide substrate. CNA was evaluated in 5 healthy volunteers and in 5 renal transplant patients receiving twice-daily formulation of TAC before drug intake. Moreover, we studied pharmacodynamic effect of TAC and blood concentrations of TAC in different drug dose intervals (0, 1, 3, 6 and 12 h).

Results

Our results showed linearity in the range 0.04–2.00 μM with a lower limit of quantification of 0.04 μM. Coefficients of variation and absolute relative biases were <4.3% and 10.3%, respectively. The mean recovery for peptide was 91.6 ± 4.0%. Matrix effect study displayed ion suppression, and no carry-over and interferences were observed. There were no differences in CNA between healthy and TAC-treated patients. Furthermore, CNA showed maximum inhibition at 1 h after drug intake when TAC reached the highest blood concentration.

Conclusions

This method improves the extraction phase of PBMCs and achieves faster determination compared to other techniques, bringing us closer to be applied in daily laboratory practice.

Graphical abstract

Unlabelled Image


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Quantification of NETs formation in neutrophil and its correlation with the severity of sepsis and organ dysfunction

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Sanni Kumar, Ena Gupta, Sanket Kaushik, Vijay Kumar Srivastava, Juhi Saxena, Sudhir Mehta, Anupam Jyoti

Abstract
Background

Previous study from this lab has discerned oxidative, nitrosative stress and their relationship with cytokines contributing to the severity of sepsis and organ dysfunction. Cytokines are known to induce neutrophil extracellular traps (NETs) formation via free radicals generation. Hyper-activation of neutrophil leads to the increased NETs formation or ineffective clearance of NETs would likely increase the risk of auto-antibody generation against NETs components and being partly responsible for the sepsis severity and organ dysfunction. The present study was undertaken to further assess the status of NETs formation and their correlation with severity of sepsis, with the cytokines and organ dysfunction.

Methods

The level of NETs formation, DNA release, elastase release, and inflammatory cytokines was determined in 80 sepsis patients and 45 healthy volunteers. Their linearity with organ parameters and associations with sepsis severity were also assessed.

Results

NETs formation experiment was carried out and it was significantly higher in sepsis (70%) compared to control (30%). NETs % were positively correlated with severity of sepsis and organ dysfunction. Pearson's correlation coefficient demonstrated a direct relation between NETs components and organ parameters with Sepsis severity scores.

Conclusion

NETs formation is significantly higher due to which it is contributing to the sepsis severity and organ failure.


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Evaluation of reproducibility of the cTnT immunoassay using quality control samples

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Rudina Ndreu, Veronica Musetti, Silvia Masotti, Martina Zaninotto, Concetta Prontera, Giancarlo Zucchelli, Mario Plebani, Aldo Clerico, on behalf of the Italian Society of Clinical Biochemistry (SIBioC), the Italian Section of the European Ligand Assay Society (ELAS)


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Validation and implementation of the fifth-generation high sensitivity Troponin T (hs-TnT) assay at a large teaching county hospital. A laboratory-driven multi-speciality effort

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Ibrahim A. Hashim, Rebecca Vigen, Fernabelle Fernandez, Amy Yu, Bryan Bertulfo, Lorie Thibodeaux, Sandeep R. Das, Deborah Diercks, James A. de Lemos, Patricia Kutscher

Abstract

We describe the validation and implementation of the new 5th generation high sensitivity Troponin T assay (Roche Diagnostics®). In addition to the assay improved sensitivity, the numerical values, reporting units, reference intervals, and critical limits are markedly different. We describe the use of clinical correlation as the basis for implementation and validation of the fifth-generation hs-TnT assay at a large teaching county hospital.


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Why harmonization is essential to realize the manifesto for the future of laboratory medicine

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): W. Greg Miller, Mario Plebani


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Soluble neural cell adhesion molecule and behavioural recovery in minimally conscious patients undergoing transcranial direct current stimulation

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Nicole Ziliotto, Giovanna Marchetti, Sofia Straudi, Veronica Tisato, Susanna Lavezzi, Fabio Manfredini, Nino Basaglia, Francesco Bernardi

Abstract
Background

Transcranial direct current stimulation (tDCS) is used for therapeutic purpose in severely brain-injured patients. The relationship between the recovery after tDCS and potential biomarkers in plasma has been limitedly investigated in patients with minimal conscious state (MCS).

Objective

To investigate soluble neuronal adhesion molecule (sNCAM) plasma levels in relation to tDCS and recovery processes in MCS.

Methods

sNCAM was measured in plasma before (T−1,T0), during (T1) and after (T2, T3) tDCS sessions in eight patients with a post traumatic etiology and at least one year of chronic state.

Results

While sNCAM levels were highly correlated overtime, no significant difference was observed in relation to tDCS. An inverse relation was observed between sNCAM levels at baseline and the tDCS long-lasting effects (T−1, r = −0.852, p = 0.007; T0, r = −0.787, p = 0.020).

Conclusions

This exploratory research suggests the sNCAM levels, potentially associated with tDCS outcomes, as a candidate biomarker of neurobiological after-effects in MCS patients.


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C-peptide and insulin assays with the Mindray CL-2000i: Precision and comparability with different methods

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Chiara Cosma, Andrea Padoan, Aldo Clerico, Mario Plebani

Abstract
Background

C-peptide and insulin are widely used in clinical practice for the diagnosis for several conditions, including hypoglycaemia and diabetes. However, the lack of method harmonization represents an important analytical limitation. Aims of this study were to evaluate new Mindray CL-2000i C-peptide and insulin methods for precision and comparability with Tosoh AIA-CL2400 and Siemens Immulite 2000 systems.

Methods

Mindray CL-2000i precision was evaluated by the CLSI EP15-A3 protocol and compared with the manufacturer's claimed values. A series of one hundred sixty-five specimens were used for comparing C-peptide and immunoreactive insulin (IRI) between Mindray CL-2000i, Tosoh AIA-CL2400 and Siemens Immulite 2000.

Results

Mindray CL-2000i repeatability results were 1.7% and 1.35% for C-peptide and 2.1% and 1.2% for IRI. Intermediate precisions were 2.6% and 1.4% for C-peptide and 4.6% and 2.3% for IRI. For C-peptide, Mindray CL-2000i performed similarly to Tosoh AIA-CL2400; for IRI a good agreement between Mindray C-2001 and Siemens Immulite 2000was found.

Conclusions

Mindray CL-2000i shows a low imprecision while a satisfactory for IRI between Mindray 2000i and Siemens Immulite 2000 was onbserved. Overall, results emphasize the need for standardization/harmonization efforts for both C-peptide and IRI measurement.


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Serum levels of trace elements in children born after assisted reproductive technology

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Xin-ru Xia, Shi-Wen Jiang, Yuan Zhang, You-fang Hu, Hong-gang Yi, Jie Liu, Nan-nan Zhao, Juan Chen, Li Gao, Yu-gui Cui, Jia-yin Liu

Abstract
Introduction

The health and development of newborn children born via assisted reproductive technology (ART), as well as their health in adulthood, have raised great concern. This study was designed to investigate whether ART children have differences in the levels of trace elements compared with naturally conceived children.

Methods

This study included those ART children and controls aged 1 to 12 years assessed with a follow-up protocol. Serum levels of the trace elements zinc, copper, iron, calcium, magnesium and lead were determined and analyzed.

Results

There were no significant differences in age, gender or body weight between the ART and control groups. There were no significant differences in the rates of deficiency or excess of trace elements between the two groups. Serum lead levels in children born via ART were significantly higher than those in the controls, whereas the levels of zinc and iron were significantly decreased in the ART group, although these levels were still within the normal ranges.

Discussion

These results indicate the need to monitor the blood levels of zinc, iron and lead in ART children aged 1–6 years old. These findings contribute to our understanding on the long-term safety of ART and may facilitate screening for potential diseases related to trace elements.


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Ectopic expression of factor VIII in MSCs and hepatocytes derived from rDNA targeted hESCs

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Qianru Sun, Xionghao Liu, Yong Wu, Wenbin Niu, Panpan Long, Jing Liu, Ming Lei, Youjin Hu, Lingqian Wu, Zhuo Li, Desheng Liang

Abstract

Hemophilia A is an X-linked recessive bleeding disorder caused by FVIII gene deficiency, which may result in spontaneous joint hemorrhages or life-threatening bleeding. Currently, cell-based gene therapy via ex vivo transduction of transplantable cells with integrating gene-expressing vectors offers an attractive treatment for HA. In present study, we targeted an expression cassette of B-domain-deleted FVIII into the ribosomal DNA (rDNA) locus of human embryonic stem cells (hESCs) by transfection with a nonviral targeting plasmid pHrn. The targeted hESCs clone could be expanded and retained the main pluripotent properties of differentiation into three germ layers both in vitro and in vivo. Importantly, under defined induction conditions, the targeted hESCs could differentiated into functional mesenchymal stem cells (MSCs) and hepatocytes, as validated by relevant specific cell markers and functional examination. Tumorgenesis assay demonstrated that these cells are relatively safe for future applications. Analysis on gene expression revealed that exogenous FVIII mRNA and FVIII proteins were both present in differentiated MSCs and hepatocytes. These results indicated that through gene targeting at hESCs rDNA locus a persistent cell source of transplantable genetic-modified cells can be accomplished for HA therapy.


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Intraoperative ultrasound-assisted enucleation of residual fibroids following laparoscopic myomectomy

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Yan Hao, Si-Jing Li, Ping Zheng, Xia Wu, Jie Sheng, Dong-Lan Yuan, Qi Zhou, Wei Wei, Ai-Hong Duan, Qing-Qing Wu, Dan Lu

Abstract
Aim

To investigate if intraoperative ultrasounds by laparoscopic and transvaginal ultrasonography (LUS and TVS) could improve enucleating the residual fibroids following laparoscopic myomectomy (LM).

Methods

From March to December 2016, 78 women with uterine fibroids underwent LM, LUS and TVS were applied to detect residual fibroids and to guide surgeons to enucleate them after the visible fibroids were removed during LM operation.

Results

The total number of residual fibroids found by LUS was 140, and the total number found by TVS was 127 following LM (P = 0.03). LUS is statistically superior to TVS in the detection of residual fibroids in the anterior wall (P = 0.004), in the detection of intramural fibroids (P = 0.002), and in the detection of fibroids with a diameter ranging from 0.5 to 1 cm (P = 0.002). According to the total number of enucleated fibroids by LM, patients were divided into three groups (Group 1: 2 to 4, Group 2: 5 to 7 and Group 3: ≥8 fibroid counts). The percentages of patients in each group with residual fibroids at the end of surgery were 22.2%, 51.9% and 66.7% respectively.

Conclusions

Both LUS and TVS are beneficial to surgical treatment of fibroids by assisting enucleation of residual fibroids following LM, while LUS is more effective in localizing residual fibroids than TVS.


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Effect of Hyperin and Icariin on steroid hormone secretion in rat ovarian granulosa cells

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Xiaowei Nie, Wenjie Sheng, Daorong Hou, Qiang Liu, Ronggen Wang, Yong Tan

Abstract
Aim of the study

This study was designed to investigate the effect of different concentrations of Hyperin and Icariin (ICA)on proliferation and the secretion of estrogen (E2), and progesterone (P) in granulosa cells, and to explore the effect of Hyperin and Icariin on the expression of CYP17 and CYP19.

Materials and methods

Rat ovary granulosa cells were cultured in vitro and treated with different concentrations of Hyperin and Icariin. The proliferation of ovarian granulosa cells was measured with the MTT assay. The concentration of estradiol was measured with a magnetic particle-based enzyme-linked immunosorbent assay (ELISA) kit. The CYP17 and CYP19 mRNA expression was detected by quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR). The CYP17 and CYP19 protein expression was determined with Western blotting.

Results

Hyperin (50 μg/l) and Icariin (10 μg/l) significantly increased proliferation of ovarian granulosa cells and secretion of estrogen and progesterone. Hyperin and Icariin stimulated the mRNA and protein expression of CYP17 and CYP19.

Conclusions

These results showed that Hyperin and Icariin can promote the secretion of E2 and P through up-regulation of CYP17 and CYP19. Frequently used Chinese herbs like Cuscuta Chinensis Lam and Epimedium Brevicornu maxim, which contain Hyperin and Icariin, could improve the ovarian endocrine function through these effects.


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A homozygous <em>ABCB4</em> mutation causing an LPAC syndrome evolves into cholangiocarcinoma

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Boudour Khabou, Ayman Trigui, Tahya Sellami Boudawara, Leila Keskes, Hassen Kamoun, Véronique Barbu, Faiza Fakhfakh

Abstract

Low phospholipid-associated cholelithiasis (LPAC) is characterized by the association of ABCB4 mutations and low biliary phospholipid concentration with symptomatic and recurring cholelithiasis. In the present study, we reported a case of a 63-year-old woman, who presented a biliary pain beginning at the age of 30, recurrent after cholecystectomy, along with “comet-tail shadows” revealed by ultrasonography thus, fulfilling the diagnosis of LPAC. This disease evolved into a cholangiocarcinoma. To understand the molecular basis of this phenotype, we performed the ABCB4 gene sequencing, followed by in silico analysis and Q-RT-PCR assay. The results displayed a homozygous missense sequence variation (c.140G > A, p.Arg47Gln), predicted as pathogenic according to MutPred. Accordingly, this gave rise to a decreased hepatic ABCB4 mRNA level and structural alterations of the mutated protein. Eventually, we reported, here, the first description of an ABCB4 missense mutation (p.Arg47Gln) at homozygous state in a Tunisian LPAC syndrome. An elucidation of its functional consequences was performed. Besides, this case suggests that the delayed diagnosis of LPAC syndrome and the lack of UDCA treatment may contribute in the development of complications, such as cholangiocarcinoma.


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Serum albumin saturation test based on non-esterified fatty acids imbalance for clinical employment

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Cassiano Felippe Gonçalves-de-Albuquerque, Marcos Roberto Colombo Barnese, Mariana Alves Soares, Mauro Velho Castro-Faria, Adriana Ribeiro Silva, Hugo Caire de Castro-Faria-Neto, Patrícia Burth, Mauricio Younes-Ibrahim

Abstract

Fatty acids are fundamental as energy and structural source to the human cells. They are not usually found free in human circulation. Alteration in fatty acids metabolism is linked to diseases such as diabetes, preeclampsia, heart disease, and some infectious diseases. Increased levels of non-esterified fatty acids (NEFA) may cause cell dysfunction and lipotoxicity. Since physiologically fatty acids are transported bound to albumin, we propose here a simple and cheap test that consists of albumin isoelectric focusing determination to measure the potential systemic NEFA cytotoxicity. For validation of this method, albumin isoelectric focusing in 51 serum samples from 40 critically ill patients and 11 controls was compared with NEFA/albumin ratios measured by HPLC. We called this approach an albumin saturation test. This test may indicate to physicians the potential NEFA lipotoxicity guiding them throughout better patient management. The albumin saturation test can point out serum albumin-NEFA saturation through a cheap assay that could be performed by any care facility.


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Small but non-negligible discrepancy between subgroup and single CKD-EPI equation to calculate the estimated glomerular filtration rate

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Tae-Dong Jeong


Datum:


Comparison of liquid chromatography with tandem mass spectrometry and ion-exchange chromatography by post-column ninhydrin derivatization for amino acid monitoring

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Andraz Smon, Vanja Cuk, Jernej Brecelj, Simona Murko, Urh Groselj, Mojca Zerjav Tansek, Tadej Battelino, Barbka Repic Lampret

Abstract
Objectives

Precise quantification of amino acids (AAs) is mandatory for successful diagnosis and monitoring of patients with metabolic diseases. We compared ion-exchange chromatography (IEC) and liquid chromatography with tandem mass spectrometry (LC-MS/MS), the two methods most commonly used in clinical laboratories for the quantification of AAs in physiological samples.

Design & methods

123 apparently healthy children were selected for the study. The plasma samples for LC-MS/MS were prepared accordingly to the aTRAQ Kit for Physiological Fluids on Sciex 3200 Qtrap, for IEC according to the protocol from Pickering laboratories on the AA analyzer Pinnacle PCX. Results were interpreted using the Pearson correlation coefficient and the percent difference Bland-Altman test.

Results

The Spearman correlation coefficients of the 14 AAs that we evaluated varied from 0.67 in Tau to 0.89 in Leu and Thr. The mean differences in measurements (IEC compared to LC-MS/MS) of 11 AAs complied with our acceptance criterion of <15%, the differences of Ser and Tyr were higher (19.5% and −19.0%, respectively), and the measured concentrations of Cit were much lower in LC-MS/MS than IEC (31% difference).

Conclusion

The two methods are sufficiently comparable for most AAs and the reference values for individual AAs did not have to be refined, with the exception of citrulline. For the monitoring of patients on therapy (e.g. patients with phenylketonuria), it is still advisable to always use the same analytical method for the quantification of AAs.


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Evaluation of analytical factors associated with targeted <em>MEFV</em> gene sequencing using long-range PCR/massively parallel sequencing of whole blood DNA for molecular diagnosis of Familial Mediterranean fever

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Takayuki Ishige, Sakae Itoga, Kenji Kawasaki, Emi Utsuno, Minako Beppu, Setsu Sawai, Motoi Nishimura, Tomohiko Ichikawa, Fumio Nomura, Kazuyuki Matsushita

Abstract
Background

Long-range PCR (LR-PCR) is used to enrich the target regions of the genome. This study aimed to establish the pipeline of targeted gene sequencing using LR-PCR and massively parallel sequencing (MPS).

Methods

The 14-kb-long MEFV gene, including the entire coding exons, was selected as a target gene and amplified using LR-PCR. The evaluated analytical factors were as follows: LR-PCR conditions, three types of post-PCR cleanup methods, and two types of MPS library preparation methods.

Results

With regard to LR-PCR conditions, Tks Gflex DNA polymerase at 7-min (30-s/kb) annealing/extension with 100-ng genomic DNA input had the highest yield. Regarding post-PCR purification methods, the magnetic beads-based method had high recovery and purity. In the MPS library preparation methods, the ligation-based method had a higher base coverage in the target (94.58%), uniformity of base coverage (99.95%), and target bases with no strand bias (97.40%). The exonic variants determined by Sanger sequencing were detected by both ligation- and transposon-based methods.

Conclusions

Various analytical factors were evaluated, and the pipeline of targeted gene sequencing using LR-PCR and MPS was established. These data can enable the optimization of targeted gene sequencing using LR-PCR and MPS in the clinical laboratory.


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A novel low-cost approach for the semi-quantitative analysis of carbohydrate-deficient transferrin (CDT) based on fluorescence resonance energy transfer (FRET)

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Giacomo Musile, Elio Franco De Palo, Sergey Alexandrovich Savchuk, Ksenia Shestakova, Federica Bortolotti, Franco Tagliaro

Abstract
Background and aim

The increase of the carbohydrate-deficient transferrin (CDT) as results of an heavy intake of alcohol for at least two weeks, is a well-known biochemical modification since the middle ‘70s. Notwithstanding the first commercial kit for the diagnosis of chronic alcohol abuse based on this biomarker was commercially accessible already thirty years ago, only expensive analytical methods are currently available for its determination. The present paper shows a new approach intrinsically sensitive and specific, based on a specific derivatization of transferrin, and not requiring sophisticated instrumentation.

Methods

The proposed procedure is based on a selective chelation of terbium (III) by transferrin followed by detection using an characteristic Fluorescence Resonance Transfer Energy (FRET) phenomenon (ex 298 nm - em 550 nm).

Results

The proposed procedure showed a limit of detection of 2.5 pmol/mL and a reproducibility intra-day and inter-days <15% and 20%, respectively. The results obtained analyzing 40 serum samples using the developed method, were compared with those obtained with HPLC-Vis and an R2 = 0.8854 was found.

Conclusions

Considering its main features (low-cost, ease of operation, minimum need of instrumentation) the present method is suitable for application in screening contexts and in non-strictly regulated environments (e.g. clinical diagnosis) as well as in developing countries or remote areas.


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Urinary neutrophil gelatinase-associated lipocalin as a biomarker of acute kidney injury in sepsis patients in the emergency department

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Hee Su Park, Jong Won Kim, Kyeong Ryong Lee, Dae Young Hong, Sang O Park, Sin Young Kim, Jin Young Kim, Sang Kuk Han

Abstract
Background

Plasma neutrophil gelatinase-associated lipocalin (NGAL) is a useful biomarker for predicting acute kidney injury (AKI). The purpose of this study was to evaluate the diagnostic performance of urinary NGAL in predicting AKI in sepsis patients in the emergency department.

Methods

A total of 140 patients were enrolled. We compared serum procalcitonin and urinary NGAL concentrations between patients with local infection, sepsis, and septic shock, and between patients who did and did not develop AKI with sepsis. Receiver-operating characteristic curve analysis was used to evaluate the ability to predict AKI in sepsis patients.

Results

Both serum procalcitonin and urinary NGAL concentrations were significantly higher in the sepsis and septic shock groups than in the local infection group (both p < 0.001). In sepsis patients, serum procalcitonin and urinary NGAL concentrations were higher in AKI patients than in those without AKI (p = 0.006, p < 0.001, respectively). The area under the curve for predicting of AKI was higher for a urinary NGAL of 0.820 (95% confidence interval (CI) 0.721–0.895) than for a serum procalcitonin concentration of 0.76 (95% CI 0.597–0.800).

Conclusion

Urinary NGAL concentration may predict AKI in patients with sepsis in the emergency department.


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Comprehensive immune complexome analysis detects disease-specific immune complex antigens in seminal plasma and follicular fluids derived from infertile men and women

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Naoko Murakami, Michio Kitajima, Kaname Ohyama, Nozomi Aibara, Ken Taniguchi, Mian Wei, Yuriko Kitajima, Kiyonori Miura, Hideaki Masuzaki

Abstract
Background

Autoimmune reactions and subsequent inflammation may underlie spermatogenic dysfunction and endometriosis-related infertility. The aim of this study is to identify disease-specific antigens in immune complexes (ICs) in seminal plasma (SP) and in follicular fluid (FF).

Methods

Immune complexome analysis, in which nano-liquid chromatography-tandem mass spectrometry is employed to comprehensively identify antigens incorporated into ICs in biological fluids, was performed for specimens collected from infertile couples undergoing assisted reproduction. Forty-two male patients consisting of subjects with oligozoospermia (n = 6), asthenozoospermia (n = 8), and normal semen analysis (n = 28). Fifty-eight female patients consisting of subjects with ovarian endometriosis (n = 10) and control women without disease (n = 48).

Results

Four disease-specific antigens were identified in subjects with oligozoospermia, while five disease-specific antigens were detected in subjects with asthenozoospermia, some of which are involved in sprematogenesis. Eight antigens were detected only in subjects with endometriosis.

Conclusion

Functional characteristics of disease-specific antigens were found to correspond to the pathogenesis of male and female infertility. The formation of ICs may contribute to spermatogenic dysfunction and endometriosis-related infertility via loss of function of the related proteins. Immune complexome analysis is expected to be a valuable tool for the investigation of novel diagnostic methods and treatment strategies for infertility.


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What information can be obtained from the tears of a patient with primary open angle glaucoma?

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Svetlana Tamkovich, Alina Grigor'eva, Alena Eremina, Alexey Tupikin, Marcel Kabilov, Valerii Chernykh, Valentin Vlassov, Elena Ryabchikova

Abstract

Since tears are a biological fluid, they have a potential diagnostic value for ophthalmic diseases. The aim of this study was to compare tear supernatants and pellets obtained from patients suffering from primary open angle glaucoma (POAG) and healthy persons (HPs) using transmission electron microscopy (TEM) and molecular biological methods.

Tear supernatants and pellets were prepared using ultrafiltration and ultracentrifugation and were examined by negative staining and immunogold labelling TEM. DNA of the pellets was isolated, quantified and sequenced using a MiSeq (Illumina, USA) genomic sequencer with the Reagent Kit v3 (600 cycles, Illumina, USA). MicroRNA was isolated and quantified from the pellets; miR-146b, miR-16 and miR-126 were detected using TaqMan MicroRNA Assays (Applied Biosystems, USA).

TEM of tear supernatants from both POAG patients and HPs revealed identical constituents: spherical or cup-shaped vesicles, “non-vesicles”, cell debris and macromolecular aggregates. Pellets of POAG patients and HPs contained small extracellular vesicles (sEVs) non-labelled vesicles and “non-vesicles”; pellets of sick persons also contained sEVs with “a capsule”. POAG-patient tear pellets showed elevated concentrations of genomic ds-DNA and SINE-repeats, and different expressions of miR-146b, miR-16 and miR-126 and a different set of bacterial DNA in comparison with pellets obtained from the tears of HPs.

The data obtained indicate that the tears of HPs and POAG patients could serve as an object for TEM studies and as a source of sEV-containing preparations (pellets), which, in turn, could be used for the isolation and study of genomic ds-DNA and RNA. Our data provide the basis for using tears for diagnostic applications.


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Analytical performance evaluation of the Elecsys® Troponin T Gen 5 STAT assay

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Robert L. Fitzgerald, Judd E. Hollander, W. Frank Peacock, Alexander T. Limkakeng, Nancy Breitenbeck, Kareen Blechschmidt, Michael Laimighofer, Christopher deFilippi

Abstract
Background

We report the analytical performance of the Elecsys® Troponin T Gen 5 STAT (TnT Gen 5 STAT; Roche Diagnostics) assay.

Methods

Measuring limits/ranges were determined in lithium-heparin plasma samples per Clinical and Laboratory Standards Institute (CLSI) EP17-A2. Precision was evaluated per CLSI EP05-A2 using lithium-heparin plasma/quality control samples on cobas e 411/cobas e 601 analyzers; two duplicated runs per day for 21 days (n = 84). Cross-reactivity with other troponin forms and interference from endogenous substances/drugs was tested; recovery criterion for no cross-reactivity was within ±10%.

Results

Coefficients of variation (CV) for repeatability/intermediate precision were 0.7–5.6%/1.4–10.3% (cobas e 411; mean cardiac troponin T [cTnT]: 7.3–9341 ng/L) and 0.7–3.0%/1.5–6.4% (cobas e 601; mean cTnT: 7.4–9455 ng/L). There was no cross-reactivity with skeletal muscle troponin T (≤ 10,000 ng/L), skeletal muscle troponin I (≤ 100,000 ng/L), cardiac troponin I (≤ 10,000 ng/L), or human troponin C (≤ 80,000 ng/L). No interference was observed with biotin (≤ 20 ng/mL) or 34 drugs.

Conclusion

The TnT Gen 5 STAT assay demonstrated a CV of <10% at the 99th percentile upper reference limit, meeting precision requirements (Fourth Universal Definition of Myocardial Infarction) for high-sensitivity troponin assays.


Datum:


False decrease of high-sensitivity cardiac troponin T assay in pneumatic tube system samples

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Jia Wei, Yi-ning Wu, Yun Ling, Xiao-ting Chen, Qiong Zhu, Jian Xu

Abstract
Background

The pneumatic tube system (PTS) is widely established in clinical laboratories. We aimed to evaluate the impacts of PTS on high-sensitivity cardiac troponin T (hs-cTnT) assays.

Methods

The hemolysis distribution of hs-cTnT PTS specimens from emergency department (ED) were determined by hemolysis index (HI). Grouped samples from 15 healthy volunteers were delivered to the laboratory via manual delivery (MD) or PTS. Interference studies were conducted to access the influence of different hemolysis degrees on hs-cTnT assays.

Results

7.26% PTS specimens from ED were hemolyzed in clinic. Compared with MD samples, we found highly elevated free plasma hemoglobin (Hb) in PTS samples. Hs-cTnT was interfered negatively with free Hb (R = -0.625, P < .001), and it was also validated in interference studies (R ≥ -0.820, all P ≤ .001). Clinically significant bias occurred in each hs-cTnT concentration at 100 mg/dl free Hb (Bias≥ − 13.85%, all P < .05). Moreover, bias of hs-cTnT assays at 50 mg/dl free Hb was approaching 10%, especially at 30 ng/l hs-cTnT concentration (Bias: -11.72%, P < .001).

Conclusions

PTS could increase the frequency of specimen hemolysis which might cause false decrease in hs-cTnT assays. Hence, clinicians should be aware of the increased measurement bias in hs-cTnT from hemolyzed PTS samples with free Hb ≥50 mg/dl.


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Evaluation of Martin's equation for LDL-C estimation in type 2 diabetes mellitus Egyptian patients

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Marwa M. Esawy, Marwa A. Shabana, Mahmoud M. Magdy

Abstract
Introduction

Type 2 Diabetes Mellitus has characteristic dyslipidemia. Low-density lipoprotein cholesterol (LDL-C) measurement plays a role in cardiovascular risk assessment and management. Friedewald equation (FE) has several limitations. This study aims to evaluate the effectiveness of Martin equation (ME) in Egyptian patients, especially those with type 2 diabetes.

Methods

A cross-sectional study was conducted on 454 diabetic and non-diabetic patients who were referred to the internal medicine outpatient clinic. Lipid profile was assessed by Cobas 8000 Modular Analyzer.

Results

The LDL-C was estimated by both FE and ME. In diabetic patients, LDL-C estimated by FE was underestimated with a bias of −3.9 ± 5.3 mg/dL (p = .04). But LDL-C estimated by ME was not significantly different compared to directly measured LDL-C. FE underestimate LDL-C with a bias of −4.6 ± 6.4 mg/dL (p = .042) in uncontrolled diabetic patients. A non-significant difference in both uncontrolled patients and controlled ones was detected by ME. FE had lower sensitivity and specificity (80% and 88.9 respectively) compared to the ME (95.9% sensitivity, and 95.6% specificity). ME was not influenced by triglyceride levels (p = .34).

Conclusion

The ME improves concordance of calculated LDL-C with a direct LDL-C assay in Egyptian diabetic patients.


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Clinical and molecular characteristics of carnitine-acylcarnitine translocase deficiency: Experience with six patients in Guangdong China

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Chengfang Tang, Sichi Liu, Meigui Wu, Suifang Lin, Yunting Lin, Ling Su, Jinfeng Zhang, Yi Feng, Yonglan Huang

Abstract

Carnitine-acylcarnitine translocase deficiency (CACTD) is a rare autosomal recessive disorder of mitochondrial fatty acid oxidation that occurs due to mutations in the SLC25A20 gene. Severe CACTD results in neonatal or infantile sudden death. Herein, we reported six patients with CACTD diagnosed based on biochemical and molecular findings from 5 unrelated families in Guangdong from 2016 to 2017. Among them, five patients presented with hypotonia, nonketotic hypoglycemia, and arrhythmia 2 days after birth, while the other patient presented with respiratory distress, hypotonia, and arrhythmia. Five of the patients died in the neonatal period. Blood acylcarnitine concentrations determination from dried blood spots (DBS) were measured by tandem mass spectrometry (MS/MS). The SLC25A20 and CPT2 gene sequences were analyzed by direct Sanger sequencing. SLC25A20 gene analysis revealed a c.199-10T>G (IVS2-10T>G) homozygous variants in four unrelated patients and a novel mutation c.199-10T>G/c.719-8_c.719-1dupCCCACAG compound heterozygous variants in twins. This report describes the clinical characteristics, biochemical findings and molecular analysis of SLC25A20 gene of patients with CACTD in Guangdong. And our results show that the c.199-10T>G is likely the most common variant of CACTD in Guangdong population as it accounts for 83% (10/12) of the observed mutant alleles. Individuals with the c.199-10T>G genotype had a severe CACTD phenotype.


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Donor-specific circulating cell free DNA as a noninvasive biomarker of graft injury in heart transplantation

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Hada Celicia Macher, Noelia García-Fernández, Alejandro Adsuar-Gómez, Manuel Porras-López, Antonio González-Calle, José Noval-Padillo, Juan Miguel Guerrero, Patrocinio Molinero, José Miguel Borrego-Domínguez, Ángel Herruzo-Avilés, Amalia Rubio

Abstract
Background

Considerable effort has been exerted to develop noninvasive diagnostic biomarkers that might replace or reduce the need to perform endomyocardial biopsies. In this context, graft DNA circulating on transplant recipients has been proposed as a potential biomarker of organ rejection or cellular graft injury.

Methods

We propose a digital PCR (dPCR) method based on the amplification of ten specific InDels sufficiently sensitive to detect small amounts of specific donor circulating DNA diluted on the host cell free DNA (cfDNA). We obtained 23 informative mismatches from 30 host and donor organ biopsy pairs.

Results

Patients without heart-related complications showed a high increase in the specific genomic marker levels during the first 24 h after transplantation that dropped to the basal levels on days 3–4 post-surgery. In contrast, patients with complications presented a significantly lagged decay pattern from day one after transplantation. A specific donor cfDNA increase was detected in one patient two days before rejection diagnosis, diminishing the basal levels after successful immunotherapy. A cfDNA increase was also observed during graft injury due to heart damage.

Conclusion

These results suggest that cfDNA monitoring of transplanted patients may be a useful tool to detect and probably anticipate graft rejection.


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Serum netrin-1 serves as a prognostic biomarker of aneurysmal subarachnoid hemorrhage

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Jiang-Li Chen, Dong-Hai Yuan, Shao-Jun Yang, Chao Gu, Hai-Song Zhou, Gao-Feng Shao

Abstract
Background

Netrin-1 exhibits anti-inflammatory properties. Netrin-1 could alleviate brain injury of subarachnoid hemorrhage (SAH) rat. This study was designed to discern the utility of serum netrin-1 as a biomarker for assessing the severity and prognosis of patients with aneurysmal SAH.

Methods

Netrin-1 concentrations were gauged in serum from 104 patients and 104 controls. Hemorrhagic clinical and radiological severity was assessed utilizing World Federation of Neurological Surgeons (WFNS) score, modified Fisher score, and Hunt Hess score. Glasgow Outcome Scale (GOS) score was recorded at 6 months after SAH. GOS score of 1–3 was considered as a poor outcome.

Results

Patients showed substantially lower serum netrin-1 concentrations than controls (median, 237.9 pg/ml; interquartile range, 189.6–271.2 pg/ml vs. median, 815.4 pg/ml; interquartile range, 581.8–990.4 pg/ml). Netrin-1 concentrations were independently correlated with WNFS score, modified Fisher score, Hunt Hess score and serum C-reactive protein concentrations (t = −4.667, −3.792, −4.304 and − 3.549 respectively). Area under ROC curve was 0.837 (95% CI, 0.752–0.902) for predicting 6-month poor prognosis. Serum netrin-1 concentrations <229.3 pg/ml emerged as an independent prognostic predictor (odds ratio, 14.316; 95% confidence interval, 5.032–40.726).

Conclusions

Serum netrin-1 might represent a potential biomarker for reflecting severity, inflammation and prognosis of human aneurysmal SAH.


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Serum lipoprotein-associated phospholipase A2 as a promising prognostic biomarker in association with 90-day outcome of acute intracerebral hemorrhage

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Lin Bian, Lian-Gang Mao, Yi Sun, Feng Shen, Jun-Feng Chen, Zheng Liu, Wei Zhou

Abstract
Background

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is reflective of vascular inflammation and plays a role in the pathophysiology of cerebrovascular disease. We determine usefulness of serum Lp-PLA2 as a prognostic biomarker for intracerebral hemorrhage (ICH).

Methods

In this prospective, observational study, serum Lp-PLA2 concentrations were detected among 164 patients with acute spontaneous basal ganglia hemorrhage and 164 healthy controls. Using multivariate analysis, we analyzed its association with poor outcome (modified Rankin Scale >2) at poststroke 90 days and hemorrhagic severity indicated by National Institutes of Health Stroke Scale (NIHSS) score and hematoma volume.

Results

Serum Lp-PLA2 concentrations were remarkably higher in patients than in controls. Lp-PLA2 concentrations were independently correlated with NIHSS score (t = 5.095, P < .001) and hematoma volume (t = 2.850, P = .005). At 90-day follow-up, 85 patients (51.8%) had poor outcome. Under receiver operating characteristic curve, serum Lp-PLA2 showed a significant prognostic discriminatory capability (AUC, 0.813; 95% CI, 0.744–0.869). Serum Lp-PLA2 concentrations ≥304 ng/ml was an independent predictor associated with poor outcome (OR 7.052; 95% CI 1.971–25.228).

Conclusions

Rising serum Lp-PLA2 concentrations are closely hemorrhagic severity and clinical outcomes after ICH, substantializing serum Lp-PLA2 as a potential prognostic biomarker of ICH.


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Simultaneous quantification of 48 plasma amino acids by liquid chromatography-tandem mass spectrometry to investigate urea cycle disorders

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Min-Zhi Peng, Yan-Na Cai, Yong-Xian Shao, Lu Zhao, Min-Yan Jiang, Yun-Ting Lin, Xi Yin, Hui-Ying Sheng, Li Liu

Abstract

Urea cycle disorders (UCD) are inborn errors of ammonia detoxification in which early diagnosis and treatment are critical to prevent metabolic emergencies. Unfortunately, the diagnosis was often and pronounced delayed. To improve diagnosis, we developed herein a liquid chromatography-tandem mass spectrometry method to investigate the disturbance of amino acid profile caused by UCD. The method enabled absolute quantification of 48 amino acids (AAs) within 20 min. Only 2.5 μL plasma was required for the analysis. The lower limits of quantification for most AAs were 0.01 μmol/L. Method accuracies ranged from 89.9% to 113.4%. The within- and between-run coefficients of variation were 0.8–7.7% and 2.6–14.5%, respectively. With this method, age-specific reference values were established for 42 AAs by analyzing 150 samples from normal controls, and patients with different subtypes of UCD were successfully distinguished. The data of patients revealed that UCD not only disturbed the metabolism of urea cycle AAs and induced accumulation of ammonia detoxification AAs, but also interfered the metabolism of some nervous system related AAs, such as pipecolic acid and N-acetylaspartic acid. This data may provide new insight into pathogenesis for UCD.


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Comparison of non-fasting LDL-C levels calculated by Friedewald formula with those directly measured in Chinese patients with coronary heart disease after a daily breakfast

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Qiu-zhen Lin, Yan-qiao Chen, Li-Ling Guo, Qun-Yan Xiang, Feng Tian, Tie Wen, Ling Liu

Abstract
Background

LDL-C level can be measured by direct methods (LDL-CM) or calculated by Friedewald formula (LDL-CC). The aim of this study was to investigate the difference between LDL-CM and LDL-CC after a daily breakfast in Chinese patients with coronary heart disease (CHD).

Methods

Three hundred and three inpatients, including 203 CHD patients (CHD group) and 100 non-CHD controls (CON group), were enrolled in this study. Serum levels of blood lipid parameters, including LDL-CC and LDL-CM, at 0, 2 and 4 h (h) were monitored after a daily breakfast in all subjects.

Results

LDL-CM was significantly higher than LDL-CC in fasting state in each group and at 4 h postprandially in CHD group (P < .05). Postprandial LDL-CM and LDL-CC significantly decreased in each group (P < .05). Postprandial decline in LDL-CM was significantly greater than that of LDL-CC (P < .05). For CHD patients taking statins for ≥1 month before admission, non-fasting percent attainment of LDL-CM or LDL-CC was significantly higher than its fasting value, especially at 4 h (P < .05). The percent deviation of LDL-CM from 1.8 mmol/L at 4 h was significantly different from its fasting value. However, there was no significant difference in percent deviation of LDL-CC from 1.8 mmol/L between fasting and non-fasting states.

Conclusions

It indicated that the clinical monitoring of non-fasting LDL-C level in CHD patients could be relatively complex, and the judgement may depend not only on the method to acquire LDL-C level, but also on the evaluation method.


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Association of IL-10 to coronary disease severity in patients with metabolic syndrome

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Ana Letícia Vargas Barcelos, Eduardo Aires de Oliveira, Gabriela Viegas Haute, Bruna Pasqualotto Costa, Leonardo Pedrazza, Márcio Vinícius Fagundes Donadio, Jarbas Rodrigues de Oliveira, Luiz Carlos Bodanese

Abstract
Background

Metabolic syndrome (MetS) is a group of risk factors that increase the risk for heart disease. Little is known about the role of IL-10 in the severity of coronary artery disease (CAD) in patients with MetS. We investigated plasma levels of IL-10 and other pro-inflammatory cytokines in patients with MetS with or without severe CAD.

Methods

Cross-sectional study with healthy and MetS individuals. IL-10 and other pro-inflammatory interleukins were analyzed in 90 subjects divided into 3 groups: group 1 (n = 30), patients with MetS without severe CAD; group 2 (n = 30), patients with MetS and severe CAD (history of myocardial infarction or revascularization performed through surgery or percutaneous transluminal coronary angioplasty with or without stent placement); and group 3 (n = 30), healthy individuals.

Results

Levels of IL-12 (p = .018), TNF-α (p = .007) and IL-6 (p = .010) were significantly higher in group 1 when compared to group 3 (p = .003; p = .002; p = .001, respectively). In addition, group 1 presented significantly higher levels of IL-12 (p = .019), TNF-α (p = .026) and IL-6 (p = .020) when compared to group 2. IL-10 levels were significantly higher in group 1 (p = .003) when compared to group 2 (p = .014) and group 3 (p < .001). Only the level of IL-10 was significant to explain the presence of severe CAD, as a protective factor (OR: 0.896; 95%CI: 0.818–0.981) in the logistic regression model.

Conclusions

Higher IL-10 levels in patients with MetS are associated with lower incidence of severe CAD, suggesting a protective effect through its anti-inflammatory activity even in the presence of higher levels of pro-inflammatory cytokines.


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Estimating the glomerular filtration rate and tubular dysfunction in an elderly population with normoalbuminuria in China

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Huabin Wang, Yingjie Lou, Yongjun Ma, Xiaoyun Shan

Abstract
Background

The prevalence and clinical risk factors of normoalbuminuric renal impairment have not yet been investigated in elderly Chinese populations. To clarify this, we conducted survey research on an elderly Chinese community population.

Methods

A total of 691 elderly community participants were included in this study. Normoalbuminuria was defined as a urinary albumin to creatinine ratio (ACR) <30 mg/g in morning urine. The estimated glomerular filtration rate (eGFR) and urinary alpha-1-microglobulin to creatinine ratio (MCR) were evaluated to assess normoalbuminuric kidney impairment in this elderly population.

Results

Among the whole cohort, 30.25% had albuminuria, 8.68% showed reduced eGFR and 49.78% had increased MCR. Normoalbuminuric subjects also showed a high prevalence of low eGFR and increased MCR (6.02% for reduced eGFR and 37.55% for increased MCR). Among the normoalbuminuric participants, the highest prevalence of increased MCR was found in the subjects with diabetes (50%), whereas the highest prevalence of low eGFR was found in women (8.11%). There was no significant difference in ln-MCR values between normoalbuminuric subjects with eGFR>60 and < 60 ml/min/1.73 m2. Age, gender, diabetes and hypertension were all independent risk factors of increased MCR. Diabetes and hypertension showed no statistical influence on decreased eGFR,whereas gender carried the highest risk for reduced eGFR.

Conclusions

Albuminuria may have limited utility as a screening marker of renal injury, as a considerable proportion of the elderly population have renal impairment despite normoalbuminuria. Rather than focusing solely on patients with diabetes or hypertension, normoalbuminuric renal impairment should be given more attention within the overall elderly population.


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Study on urine metabolic profiling and pathogenesis of hyperlipidemia

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Liu Yang, Zhu Li, Yanqi Song, Yijia Liu, Huan Zhao, Yuechen Liu, Tianpu Zhang, Yu Yuan, Xuemeng Cai, Shuo Wang, Pengwei Wang, Shan Gao, Lin Li, Yubo Li, Chunquan Yu

Abstract
Background

As a recognized risk factor for cardiovascular disease (CVD), hyperlipidemia (HLP) has developed into a high incidence disease that seriously threatens human health. Finding a new target for effective treatment of HLP will be a powerful way to reduce the incidence of CVD. The purpose of this study was to find potential biomarkers in urine of HLP patients and analyze their metabolic pathways to study the pathogenesis of HLP.

Methods

An UPLC-Q-TOF/MS technology was used to detect the metabolites in urine of 60 HLP patients and 60 normal controls. Based on PLS-DA pattern recognition, potential biomarkers related to HLP were screened out.

Results

22 potential biomarkers related to HLP were identified, which involved amino acid metabolism, fatty acid metabolism, nucleotide metabolism, steroid hormone metabolism and intestinal flora metabolism, and their possible pathogenesis was found to be related to inflammatory reaction and oxidative stress.

Conclusion

The non-targeted metabolomic method based on UPLC-Q-TOF/MS technology can effectively identify potential biomarkers in the urine of HLP patients and explore the possible pathogenesis. Our research will lay a foundation for finding new targets for the treatment of HLP and provide a basis for clinical research on the treatment of HLP.


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Quantitative proteomics of changes in succinylated proteins expression profiling in left appendages tissue from valvular heart disease patients with atrial fibrillation

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Fan Bai, Tao Tu, Fen Qin, Yingxu Ma, Na Liu, Yaozhong Liu, Xiaobo Liao, Shenghua Zhou, Qiming Liu

Abstract
Background

Previous studies have suggested that proteomic modifications are closely associated with cardiovascular diseases. The aim of this study was to identify potential mechanisms by profiling the changes in succinylated protein expression in left appendage tissues from patients with valvular heart disease and atrial fibrillation (AF).

Methods

Using dimethyl labeling for relative and absolute quantification-coupled high-performance liquid chromatography-tandem mass spectrometry, we analyzed the proteomics profiles and succinylation events in 18 left atrial appendage tissue samples from patients who underwent cardiac valvular surgery, including nine patients with permanent AF and nine patients with sinus rhythm (SR).

Results

In total, after setting the quantification ratio > 1.3 and < 1:1.3 representing the up- and downregulated cutoff values, respectively, 132 proteins were classified as targets of upregulation and 117 proteins as targets of downregulation. Within these proteins, 246 sites exhibited upregulated succinylation and 45 sites exhibited downregulated succinylation. Protein–protein interaction networks showed that the proteins exhibiting lysine succinylation and AF status were highly enriched in energy metabolism, extracellular matrix-related, and cellular structure-related proteins. These results were confirmed by western blot.

Conclusions

The differences in succinylation level of energy metabolism-related proteins indicates the possible involvement of these proteins in AF of valvular heart disease patients, and provide insight for further analysis of their biological functions.


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Increased plasma sestrin2 concentrations in patients with chronic heart failure and predicted the occurrence of major adverse cardiac events: A 36-month follow-up cohort study

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Haixiong Wang, Na Li, Xin Shao, Jun Li, Liping Guo, Xingyan Yu, Yuehui Sun, Jinlin Hao, Huaimin Niu, Jie Xiang, Xiaofang Li, Xuebin Han

Abstract
Background

Previous study had demonstrated that sestrin2 (Sesn2) expression was increased in human failing heart. Although, the circulating Sesn2 concentrations in patients with chronic heart failure (CHF) remains unknown. This study investigated plasma Sesn2 concentrations in patients with CHF and the role between Sesn2 and the occurrence of major adverse cardiac events.

Methods

A total of 80 control subjects and 220 CHF patients were enrolled and the Sesn2 concentrations of each sample were measured. Additionally, the occurrence of major adverse cardiac events in each CHF patient were followed prospectively for 36 months.

Results

Increased plasma Sesn2 concentrations were found in CHF patients and gradually increased from New York Heart Association (NYHA) functional class II to IV. The Sesn2 concentrations were positively correlated with N-terminal B-type natriuretic peptide (NT-pro BNP) but negatively correlated with left ventricular ejection fraction (LVEF) in CHF patients. The ROC curve suggested that Sesn2 had a certain value in predicting major adverse cardiac events during CHF patients, although, the predictive role of Sesn2 is not as good as NT-pro BNP. In addition, the multivariate Cox hazard analysis was performed after the CHF patients were divided into 3 groups (low, middle, and high) base on the plasma Sesn2 concentrations category, and the results showed that both high and middle Sesn2 concentrations increased the incidence of major adverse cardiac events when compared with low Sesn2 group. Furthermore, CHF patients with major adverse cardiac events showed higher Sesn2 concentrations when compared with CHF without major adverse cardiac events. The Kaplan-Meier analysis was performed after the CHF patients were divided into 2 groups according to the median Sesn2 concentrations and the results revealed that patients with high Sesn2 concentrations had a higher risk of major adverse cardiac events compared with those with low Sesn2.

Conclusions

Plasma Sesn2 concentrations were increased in CHF patients and positively correlated with the severity of CHF. Increased Sesn2 concentrations significantly increased the occurrence of major adverse cardiac events and suggested poor outcome in CHF patients.


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MicroRNA-34a suppresses human lens epithelial cell proliferation and migration via downregulation of c-Met

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Dong Feng, Ning Zhu, Chenying Yu, Dinghua Lou

Abstract

MicroRNAs (miRNAs) are endogenously expressed, non-coding, small RNAs which inhibit protein translation through binding to target mRNAs. Recent studies have demonstrated that miRNAs participate in the regulation of a variety of cell structures and functions including those for cell proliferation and migration. MicroRNA-34a (miR-34a), a potential effector of the p53 tumor suppressor gene, is extensively studied for its suppression of cell growth. In the present study, we investigated the function of miR-34a in human lens epithelial cells. Following confirming that miR-34a expression was increased in a P53 dependent manner in human lens epithelial cells after treatment with doxorubicin, we demonstrated that overexpression of miR-34a in the human lens epithelial cell line HLE B3 led to a significant decrease in cell proliferation and migration, with the use of MTS and transwell migration assays. Moreover, HGF enhanced the proliferation and migration of human lens epithelial cells. miR-34a was found to downregulate the expression of c-Met protein by Western blotting. Furthermore, overexpression of miR-34a downregulated the levels of phosphorylated Akt, phosphorylated ERK1/2 and other cell cycle regulators. miR-34a expression was significantly reduced in posterior capsule opacification (PCO) clinical samples. These results demonstrate that miR-34a may act as a suppressor in PCO by regulating human lens epithelial cell proliferation and migration through downregulation of c-Met.


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Analysis of serum Haptoglobin using glycoproteomics and lectin immunoassay in liver diseases in Hepatitis B virus infection

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): K. Dalal, B. Dalal, S. Bhatia, A. Shukla, A. Shankarkumar

Abstract
Background

Hepatocellular carcinoma (HCC) due to Hepatitis B viral (HBV) infection is a major cause in Asia-Pacific countries. Its early detection is of paramount importance using a marker having both sensitivity and specificity. The present study promises diagnostic and prognostic markers by the identification of site-specific glycoforms on Haptoglobin (Hp) using LC-MS/MS and lectin ELISA in liver diseased conditions in HBV infection.

Methods

Three groups of patients: chronic, liver cirrhosis and HCC with HBV infection along with controls were enrolled. Hp was purified using affinity column chromatography and, peptide sequence, N-glycosylation site, glycan composition and glycoforms were identified using mass spectrometry. Quantitative lectin ELISA was used to measure levels of fucosylation on Hp in liver diseases due to HBV.

Results

Hp levels were significantly lower in HCC when compared with Non-HCC cases (p < .05). Fucosylated glycoforms were significantly increased at site Asn184, Asn207 and Asn211 in liver diseased stages versus controls. A significant association was observed between the Fuc-Hp/Hp Elisa index and, advanced liver disease stages and controls using lectin Elisa (p < .001).

Conclusion

Quantitation of fucosylation levels on Hp protein using Lectin ELISA may be useful glycobiomarker either alone or in combination (AFP + DCP + FucHp; AUC = 0.94) in HBV HCC diagnosis in clinical practice.

Graphical abstract

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Gene expression patterns associated with human placental trophoblast differentiation

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Shi-Wen Jiang, Wei Zhou, Jianhao Wang, Lauren M. Little, Lynn Leaphart, Jacob Jay, Eseosaserea Igbinigie, Haibin Chen, Jinping Li

Abstract

Cell fusion is a hallmark of placental trophoblast cell differentiation and the mature syncytiotrophoblasts play essential roles for fetal-maternal exchange and production of pregnancy-related hormones. Using a well-established in vitro trophoblast differentiation model, we performed a microarray analysis on mRNA expression in trophoblast and syncytiotrophoblast cell cultures. Dramatic changes in gene expression patterns were detected during trophoblast differentiation. Real-time PCR analysis confirmed the reliability of the microarray data. As many as 3524 novel and known genes have been found to be up- or down-regulated for >2-fold. A number of cell cycle regulator including CDC6, CDC20, Cyclins B2, L1 and E2, were down-regulated in the syncytiotrophoblast, providing a mechanism for the loss of mitotic activity during trophoblast differentiation. Further characterization on the identified genes may lead to better understanding of placental patho-physiology in obstetric diseases such as preeclampsia.


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A simple method to allow for guanine-cytosine amplification error in prenatal DNA screening for trisomy 18

Publication date: September 2019

Source: Clinica Chimica Acta, Volume 496

Author(s): Nicholas J. Wald, Jonathan P. Bestwick, King Wai Lau, Wayne J. Huttly, Weilin Ke, Ray Cheng, Robert W. Old

Abstract
Background

A source of error in prenatal screening for trisomies is PCR amplification error associated with guanine-cytosine (GC) content of DNA fragments in maternal plasma. We describe a simple method of allowing for this.

Methods

Data from a Reflex DNA screening programme (67 trisomy 18 and 83 unaffected pregnancies) were used to compare the ratio of chromosome 18 DNA fragment counts to chromosome 8 DNA fragment counts (because chromosome 8 has a similar GC content to chromosome 18) with the percentage of chromosome 18 DNA counts using counts from all autosomes in the denominator, with and without an all autosome correction for the GC content of the DNA fragments.

Results

A chromosome 18 to 8 ratio of DNA fragment counts was more discriminatory than the percentage of all autosome counts arising from chromosome 18 without, or with an all autosome correction for GC content bias. It achieves a high screening performance, eg. for a 0.25% false-positive rate, a 97% detection rate instead of 49% without a correction for GC content, and 91% with an all autosome correction for GC content.

Conclusion

Consideration can be given to using the ratio of chromosome 18 DNA fragment counts to chromosome 8 DNA fragment counts in cell-free DNA prenatal screening for trisomy 18, avoiding the need for more complex methods of making a correction for the GC content currently used.


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Evaluation of 99th percentile and reference change values of the hs-cTnI method using ADVIA Centaur XPT platform: A multicenter study

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Aldo Clerico, Silvia Masotti, Veronica Musetti, Andrea Ripoli, Rosalia Aloe, Martina Di Pietro, Sara Rizzardi, Ruggero Dittadi, Cinzia Carrozza, Lucia Belloni, Marco Perrone, Tommaso Fasano, Simone Canovi, Antonio de Santis, Concetta Prontera, Cristina Guiotto, Domenico Cosseddu, Marco Migliardi, Sergio Bernardini

Abstract
Background

According to quality specifications required by international guidelines, the evaluation of the 99th URL value is a very difficult task that is usually beyond the capacity of a single laboratory. The aims of this article are to report and discuss the results of a multicenter study concerning the evaluation of the 99th percentile URL and reference change (RCV) of the ADVIA Centaur High-Sensitivity Troponin I (TNIH), recently distributed to the Italian clinical laboratories.

Materials and methods

The reference population evaluated with ADVIA XPT method for the calculation of cTnI reference distribution parameters consisted of 1325 healthy adults subjects (age range from 18 to 86 years), including 653 women (mean age 50.7 years, SD 14.5 years) and 672 men (mean age 50.9 years, SD 13.8 years), well matched for both age (P = .8112) and sex (F/M = 0.97).

Results

cTnI distribution values of reference population was highly skewed, while log-transformed cTnI values roughly approximated a log-normal distribution. Men have higher cTnI values than women throughout all the adult lifespan. Moreover, the subjects with age ≤ 55 years had significantly lower cTnI values than those with age > 55 years (p < .0001). Of note, 62% of women and 77% of men had equal or higher than cTnI values than the LoD value of the method (i.e., 2.2 ng/L).

Conclusions

The results of the present study demonstrate that the ADVIA Centaur High-Sensitivity Troponin I using the XPT automated platform fits both the criteria and quality specifications required by the most recent international guidelines for high-sensitivity methods for cTnI assay.


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Quality control optimization part I: Metrics for evaluating predictive performance of quality control

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Robert L. Schmidt, Lauren N. Pearson

Abstract
Background

Quality control (QC) policies are usually designed using power curves. This type of analysis reasons from a cause (a shift in the assay results) to an effect (a signal from the QC monitoring process). End users face a different problem: they must reason from an effect (QC signal) to a cause. It would be helpful to have metrics that evaluated QC policies from an end-user perspective.

Methods

We developed a simple dichotomous model based on classification of assay errors. Errors are classified as important or unimportant based on a critical shift size, defined as Sc. Using this scheme, we show how QC policies can be analyzed using common accuracy metrics such as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). We explore the impact of design choices (QC limits, number of repeats) on these performance measures in a number of different contexts.

Results

PPV varies widely (1% to 100%) depending on context. NPV also varies (40% to 100%) but is less sensitive to context than PPV. There are many contexts in which QC policies have low predictive values. In such cases, performance (PPV, NPV) can be improved by adjusting the QC limits or the number of repeats at each QC event.

Conclusion

The effectiveness of QC can be improved by considering the context in which the QC policy will be applied. Using simple assumptions, common accuracy metrics can be used to evaluate QC policy performance.


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A comparative study of viscoelastic hemostatic assays and conventional coagulation tests in trauma patients receiving fibrinogen concentrate

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Henry T. Peng, Bartolomeu Nascimento, Homer Tien, Jeannie Callum, Sandro Rizoli, Shawn G. Rhind, Andrew Beckett

Abstract
Background

Both thrombelastography (TEG) and rotational thromboelastometry (ROTEM) have been investigated for diagnosis of coagulopathy and guidance of resuscitation in trauma and surgery. Given similarities between the two systems, it is important to determine whether one is superior to the other and how comparable they are to conventional coagulation tests (CCTs). Therefore, we conducted a comparative study of functional fibrinogen and coagulation assays using TEG and ROTEM and CCTs to determine their capability to monitor coagulation profiles, diagnose coagulopathy and predict blood transfusion requirements in trauma patients.

Methods

Blood samples were collected from 45 patients at admission and during 48-h hospitalization as part of a randomized control trial on early fibrinogen replacement in trauma. Functional fibrinogen (FF) TEG, ROTEM FIBTEM and EXTEM, and CCTs were performed and compared.

Results

We found significant differences between the placebo and fibrinogen groups over hospitalization time in FF TEG MA, ROTEM CT, MCF and LI30. FF TEG MA and ROTEM FIBTEM MCF mirrored plasma fibrinogen profiles, reached a maximum difference between the two groups 1–3 h after fibrinogen administration. In comparison, CCTs detected minimal hemostatic changes by fibrinogen treatment. TEG and ROTEM showed various degrees of correlations with CCTs. TEG MA and ROTEM MCF provided better predictions for plasma and RBC transfusions than CCTs, but poor accuracy for cryoprecipitate transfusion. Both TEG and ROTEM well predicted hypofibrinogenemia (fibrinogen concentration < 1 g/L), but poorly detected coagulopathy (INR ≥ 1.2).

Conclusions

TEG and ROTEM detected increases in clot strength following early use of fibrinogen. ROTEM also detected changes in coagulation time and clot lysis. Both were better than CCTs for monitoring coagulation profiles and predicting transfusion requirements.


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Quality control optimization part II: A method to optimize the accuracy of laboratory quality control

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Robert L. Schmidt, Lauren N. Pearson

Abstract
Background

Quality control (QC) can be viewed as a diagnostic test that is used to determine whether an assay is in statistical control. Using this framework, QC performance can be evaluated using familiar metrics associated with diagnostic tests. QC plan parameters can be adjusted to optimize performance metrics.

Methods

We developed a simple dichotomous model based on classification of assay errors. Errors are classified as important or unimportant based on a critical shift size, defined as Sc. Using this scheme, we show how QC policies can be analyzed using common accuracy metrics such as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). We conducted computer experiments to determine the QC plan that optimizes QC accuracy under a wide range of scenarios.

Results

In general, traditional QC plans (based on2 or 3 standard deviation limits) are approximately 90% as accurate as optimized QC limits in the scenarios that were tested. There are special circumstances when traditional QC plans do not perform well.

Conclusion

QC performance can be optimized for specific contexts.


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Serum soluble TWEAK levels in severe traumatic brain injury and its prognostic significance

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Bei Tang, Ze Zhong, Zheng Qiu, Hui-Ping Wu, Jia-Yuan Hu, Jian-Ping Ma, Jin-Ping Wu

Abstract
Background

Severe traumatic brain injury (sTBI) is characterized by a high mortality. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) participates in inflammation. We determined serum soluble TWEAK (sTWEAK) levels with respect to its prognostic ability.

Methods

This was a single-center prospective, observational study that was performed from December 2014 to December 2017. A total of 114 sTBI patients who met the inclusion criteria and 114 randomly selected healthy controls were included in the study. Serum sTWEAK levels were gauged. Patients were followed-up until death or completion of 6 months. Poor outcome was referred to as Glasgow outcome scale score of 1–3.

Results

In comparison with controls, patients displayed predominantly higher serum sTWEAK levels. Serum sTWEAK levels were strongly correlated with Glasgow coma scale scores and serum C-reactive protein levels. 32 patients (28.1%) died and 60 patients (52.6%) suffered from a poor outcome. Receiver operating characteristic curve analysis clearly showed that serum sTWEAK levels had substantially high predictive performance for 6-month mortality and poor outcome. Serum sTWEAK emerged as an independent predictor for 6-month mortality, overall survival and poor outcome.

Conclusions

Raised serum sTWEAK levels are closely related to increasing inflammatory response, elevated trauma severity and worse clinical outcome after sTBI.


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Characteristics of apparently healthy individuals with a very low C-reactive protein

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Tomer Ziv-Baran, Asaf Wasserman, Ilana Goldiner, Moshe Stark, Shani Shenhar-Tsarfaty, Itzhak Shapira, David Zeltser, Inna Mailis, Shlomo Berliner, Ori Rogowski

Abstract
Background

The importance of the inflammatory processes and C-reactive protein (CRP) evaluation was observed. Only few studies used cut-off value <1 mg/L.

We sought to evaluate the association between very low CRP (vlCRP) and health status, to describe the repetition of vlCRP and to identify predictors for repetition.

Methods

A historical cohort study of all participants who underwent a routine annual check-up between January 2002 and July 2018 at the Tel Aviv Sourasky medical center. CRP test was evaluated in all participants. Individuals who use statins or with CRP >10 mg/L were excluded. CRP ≤0.12 mg/L was considered as vlCRP.

Results

The final study cohort included 14,161 individuals. Of them, 5065 were females and mean age was 43.4 years (SD 10.6). vlCRP at first check-up was observed in 1299 (9.2%) of the participants. In multivariable analysis, older age, hyperlipidemia, hypertension and smoking were significantly associated with lower probability of vlCRP. At the second check-up, 50.1% vlCRP repetition was observed with no significant predictor from previous visit.

Conclusion

vlCRP is associated with younger age, non-smoking, and absence of hyperlipidemia and of hypertension. However, it may also be part of the individual physiology.


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Cardiac biomarkers but not measures of vascular atherosclerosis predict mortality in patients with peripheral artery disease

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Robert K. Clemens, Wijtske Annema, Frederic Baumann, Stephanie Roth-Zetzsche, Burkhardt Seifert, Arnold von Eckardstein, Beatrice R. Amann-Vesti

Abstract
Background

Peripheral artery disease (PAD) becomes more prevalent with advancing age and is associated with elevated risk of cardiovascular events and shortened life expectancy. We investigated the prognostic performance of cardiac and vascular biomarkers in a cohort of PAD patients.

Methods

A total of 95 PAD patients were enrolled (mean age 68 years, range 47 to 86 years, 73 males). Carotid intima-media thickness (cIMT), ankle brachial index (ABI), high sensitive cardiac troponin T, and N-terminal pro-B-type Natriuretic Peptide (NT-proBNP) were measured.

Results

During a median follow-up time of 9.5 years, 44 patients died and 51 patients survived. Upon Kaplan-Meier survival analysis hs-TnT (P < .001) or NT-proBNP levels (P < .001) above the median but not cIMT above the median (P = .488) or ABI below the median (P < .436)were associated with reduced survival rate. Upon univariate cox regression and after adjustment for age, gender, prior cerebral artery disease, and diabetes mellitus only the association between hs-cTnT and mortality remained significant (HR 1.93, 95% CI 1.33–2.79, P < .001). In receiver operating curve analysis hs-cTnT (area under the curve [AUC]: 0.77, 95% CI: 0.67–0.87, P < .001) NT-proBNP (AUC: 0.74, 95% CI: 0.64–0.84, P < .001) as well as hs-cTnT, and NT-proBNP combined (AUC: 0.79, 95% CI: 0.69–0.88, P < .001) were superior to cIMT (AUC: 0.64, 95%, CI: 0.53–0.76, P = .022) and ABI (AUC: 0.57, 95% CI: 0.44–0.68, P = .313) in discriminating risk for mortality.

Conclusion

hs-cTnT and NT-proBNP should be taken into account for prognosis of patients with PAD.


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Clinical performance of non-criteria antibodies to phospholipids in Chinese patients with antiphospholipid syndrome

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Shulan Zhang, Ziyan Wu, Wen Zhang, Fengchun Zhang, Yongzhe Li, Yudong Liu

Abstract
Background

Increasing evidence suggests the role of non-criteria aPLs as important supplements to the current criteria aPLs in APS. In this study, we evaluated the clinical performance of a panel of non-criteria antibodies to phospholipid antigens, including, phosphatidylserine (aPS), phosphatidylinositol (aPI), sphingomyelin (aSM), phosphatidylcholine (aPC) and phosphatidylethanolamine (aPE) in a well-defined Chinese APS cohort.

Methods

A total of 229 subjects were tested, including 86 patients with APS, 104 disease controls (DCs) and 39 healthy controls (HCs). Serum IgG/IgM aCL, IgG/IgM aβ2GP1, IgG/IgM aPS, IgG/IgM aPI, IgG/IgM aSM, IgG/IgM aPC, and IgG/IgM aPE were tested by ELISA.

Results

The presence of aPE, aPS, aPI, aPC, and aSM in patients with APS and Disease Controls were 8.1% (7/86) and 1.0% (1/104), 37.2% (32/86) and 9.6% (10/104), 50.0% (43/86) and 8.7% (9/104), 23.3% (20/86) and 1.0% (1/104), and 18.6% (16/86) and 1.9% (2/104), respectively. In criteria aPLs, aCL IgG demonstrated the highest positive likelihood ratio (LR+) of 35.75, followed by LA (LR+ of 13.51) and aCL IgM (LR+ of 11.64). In non-criteria aPLs, aPC IgG demonstrated the highest LR+ of 24.94 followed by aSM IgM (LR+ of 14.97). Importantly, the non-criteria aPLs were detected in 18.8% (3/16) of seronegative APS patients. The criteria aPLs, including LA, IgG aCL and IgG aβ2GPI, were significantly correlated with both arterial thrombosis and venous thrombosis, while the non-criteria aPLs, including IgG aPS, IgM aPS, IgG aPI and IgG aPC were significantly associated with arterial thrombosis but not venous thrombosis.

Conclusions

In summary, our findings indicate that those non-criteria aPLs may be particularly helpful for patients in whom APS is highly suspected, but conventional aPLs are repeatedly negative as well as for predicting APS patients with arterial thrombosis.


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Estradiol reference intervals in women during the menstrual cycle, postmenopausal women and men using an LC-MS/MS method

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Sara J.E. Verdonk, Hubert W. Vesper, Frans Martens, Patrick M. Sluss, Jacquelien J. Hillebrand, Annemieke C. Heijboer

Abstract
Background

For optimal medical decision-making, harmonized reference intervals for estradiol for different ages and both sexes are needed. Our aim was to establish reference intervals using a highly accurate and traceable LC-MS/MS method and to compare these with reference intervals in literature.

Methods

Estradiol was measured in serum obtained daily during the menstrual cycle of 30 healthy premenopausal women and in serum of 64 men and 33 postmenopausal women. The accuracy of our LC-MS/MS method was demonstrated by a method comparison with the CDC reference method.

Results

Our LC-MS/MS method was traceable to the reference method. Estradiol reference interval during the early follicular phase (days −15 to −6) was 31–771 pmol/L; during the late follicular phase (days −5 to −1) 104–1742 pmol/L; during the LH peak (day 0) 275–2864 pmol/L; during the early luteal phase (days +1 to +4) 95–1188 pmol/L; during mid luteal phase (days +5 to +9) 151–1941 pmol/L; during late luteal phase (days +10 to +14) 39–1769 pmol/L. The reference interval for men was 12–136 pmol/L and for postmenopausal women <26 pmol/L.

Conclusions

The established estradiol reference intervals can be used for all traceable LC-MS/MS methods for medical-decision making.


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Platelet activation status in the diagnosis and postoperative prognosis of hepatocellular carcinoma

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Beili Wang, Jie Zhu, Xiaolu Ma, Hao Wang, Shuangjian Qiu, Baishen Pan, Jian Zhou, Jia Fan, Xinrong Yang, Wei Guo, Yunfeng Cheng

Abstract
Background

The venous thromboembolism, which may be caused by increased platelet activation, is a risk factor for tumor prognosis. We determined the platelet activation status for diagnosis and predicting postoperative prognosis of hepatocellular carcinoma.

Methods

We conducted a prospective study of 191 patients diagnosed with HCC at Zhongshan Hospital from April 2016 to July 2016 as well as 99 healthy people. The platelet activation status was assessed by 2 platelet markers, PAC-1 and CD62p, using flow cytometry. The patients were treated with TACE or resection and monitored for ≥6 months. The diagnostic value of marker-positive platelets was determined by the receiver operating characteristic curve and the postoperative value were analyzed using the Kaplan-Meier method and COX regression model.

Results

All the 3 groups with high levels of marker-positive platelets were likely to be diagnosed with HCC and the PAC-1+ percentage had the best efficacy. The univariate analysis showed that the levels of PAC-1+ and CD62p+ platelets was risker factors for poor postoperative prognosis after both TACE and resection. Moreover, the multivariate analysis revealed that the level of PAC-1+ platelets was an independent risk factor for poor prognosis.

Conclusions

The PAC-1+ percentage of platelets is a new indicator for diagnosis and predicting postoperative prognosis.


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Rapid liquid chromatography-tandem mass spectrometry to determine very-long-chain fatty acids in human and to establish reference intervals for the Chinese population

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Danchen Wang, Songlin Yu, Yuanyuan Zhang, Yicong Yin, Qian Cheng, Shaowei Xie, Jialei Yu, Honglei Li, Xinqi Cheng, Ling Qiu

Abstract

Very-long-chain fatty acids (VLCFAs), including hexacosanoic, tetracosanoic, and docosanoic acids, are peroxisomal disease markers, whose abnormal accumulation warrants prompt detection for timely, effective treatment. This study aimed to establish and validate a robust liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based method to simultaneously quantify VLCFAs and provide reference intervals among Chinese individuals, quantify VLCFAs in pregnancy, and explore potential associations between plasma and amniotic fluid. Analytes were extracted via water-bath incubation with HCl and liquid-liquid extraction. Method linearity, limit of detection/quantitation, precision, carryover, and recovery were evaluated according to Clinical and Laboratory Standard Institute (CLSI) guidelines. VLCFAs showed good reproducibility based on low within-run coefficient variations (CVs) and total CVs, and correlation coefficients of linearity were > 0.99. The reference interval of C22:0, C24:0, and C26:0 were 32.0–73.4 μmol/L, 30.3–72.0 μmol/L, and 0.20–0.71 μmol/L, respectively; C24:0/C22:0 and C26:0/C22:0 ratios were 0.75–1.28 and 0.005–0.0139, respectively. Plasma and amniotic fluid of the same pregnant women displayed no significant correlation in the second trimester. This study presents the simple, efficient, accurate, and robust LC-MS/MS method to simultaneously detect C22:0, C24:0, and C26:0 without derivatization; it can be used to establish reference intervals among Chinese individuals and has diagnostic and other clinical applications.


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High serum adipocyte fatty acid binding protein concentration linked with increased aortic arterial stiffness in patients with type 2 diabetes

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Pei-Wei Tseng, Jia-Sian Hou, Du-An Wu, Bang-Gee Hsu

Abstract
Background

Adipocyte fatty acid binding protein (A-FABP) is a novel adipokine that contributes to the development of metabolic disorder, type 2 diabetes mellitus (T2DM) and atherosclerosis. We determined the correlation between serum A-FABP and aortic stiffness in T2DM patients.

Methods

Fasting blood samples were obtained from 156 patients with T2DM. Serum A-FABP concentration were determined using a commercial enzyme immunoassay. Carotid-femoral pulse wave velocity (cfPWV) was measured using SphygmoCor System, and cfPWV values of >10 m/s were defined as high aortic stiffness.

Results

Sixty participants (38.4%) fell under the high aortic stiffness group. This group, compared to the control group, showed older age (P = .004), higher systolic blood pressure (P < .001), diastolic blood pressure (P = .027), urine albumin-to-creatinine ratio (P = .003), serum A-FABP (P < .001) and lower estimated glomerular filtration rate (P = .001). After adjusting for factors significantly associated with aortic stiffness using multivariable logistic regression analysis, serum A-FABP [OR = 1.029 (1.002–1.058), P = .039] was found to be an independent predictor of aortic stiffness in T2DM patients.

Conclusions

Serum A-FABP is positively correlated with aortic arterial stiffness in patients with T2DM.


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DGCR8 expression is altered in children with congenital heart defects

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Zhikuan Guo, Baoping Li, Peng Tian, Dan Li, Yuwei Zhang, Qun Li, Taibing Fan, Junming Yue, Yuqi Guo

Abstract
Aim

To explore the correlation of DGCR8 expression in children with congenital heart defects (CHD) and its clinical significance.

Methods

Full blood samples were collected from children with congenital heart disease(n = 40) and healthy children(n = 40), respectively.Real-time PCR was used to detect the expression of DGCR8 in the blood of healthy children and CHD. Myocardial tissues were collected from children with ventricular septal defect (VSD)(n = 25), and tetralogy of Fallot (TOF)(n = 16),. Real-time PCR and Western blotting were used to detect the expression of DGCR8 in myocardial tissues. Analyze the correlation between DGCR8 expression and congenital heart disease.

Results

The expression levels of DGCR8 was significantly lower in CHD than healthy children (P = 0.037), and lower in TOF tissues compared with VSD tissues (P = 0.046). There was no significant correlation between the expression of DGCR8 and the size of VSD(r = −0.022, P = 0.917).

Conclusions

The low expression of DGCR8 was significantly correlated with the occurrence of CHD, which may affect the development of heart and the formation of blood vessels. The lower expression of DGCR8 was correlated with severe CHD. However, DGCR8 expression did not associate with the size of VSD.


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Flow injection ionization-tandem mass spectrometry-based estimation of a panel of lysophosphatidylcholines in dried blood spots for screening of X-linked adrenoleukodystrophy

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Archana Natarajan, Rita Christopher, Manjunath Netravathi, Maya D. Bhat, Sadanandavalli Retnaswami Chandra

Abstract
Background

Elevated blood C26:0 lysophosphatidylcholine (LPC) is a diagnostic marker for X-linked adrenoleukodystrophy (X-ALD). Our aim was to develop a flow injection ionization-tandem mass spectrometry (FIA-MS/MS) method for estimating a panel of LPCs (C20:0-C26:0-LPCs) in dried blood spots (DBS) and to determine the sensitivity and specificity of this method for high-throughput screening for X-ALD.

Methods

LPCs (C20:0-C26:0) were extracted from 3.2 mm DBS in a 96-well plate, spiked with isotopically-labelled internal standard (C26:0-d4-LPC) and measured by FIA-MS/MS in electrospray ionization (ESI)-positive, multiple reaction monitoring (MRM) mode using a triple quadrupole, tandem mass spectrometer. The sensitivity and specificity of the FIA-MS/MS method for screening of X-ALD was determined. The FIA-MS/MS method was compared with the LC-MS/MS method for estimating LPC concentrations.

Results

Elevated C26:0 and C24:0-LPCs were 100% sensitive for identification of X-ALD. However, specificity was only 78.33% for C26:0 and 98.33% for C24:0-LPCs. Sensitivity for C22:0 and C20:0 LPCs were 89.29%, 78.33% and specificity, 67.86% and 73.33%, respectively. The FIA-MS/MS method showed good concordance with the LC-MS/MS method.

Conclusion

The FIA-MS/MS method for estimating C26:0 and C24:0-LPCs in DBS is suitable for first-tier screening of newborns for X-ALD. Second-tier confirmatory testing is required to screen positive cases.


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The development and validation of a combined kinetic fluorometric activity assay for fibroblast activation protein alpha and prolyl oligopeptidase in plasma

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): An Bracke, Roos Van Elzen, Pieter Van Der Veken, Koen Augustyns, Ingrid De Meester, Anne-Marie Lambeir

Abstract
Background

Fibroblast activiation protein alpha (FAP) is considered a diagnostic and prognostic biomarker for various types of cancer. FAP shares substrate specificity with prolyl oligopeptidase (PREP), studied in (neuro)inflammation and neurodegeneration as well as cancer. Current assays inadequately discriminate between FAP and PREP and there is need for an assay that reliably quantitates the FAP/PREP activity ratio in plasma.

Methods

FAP and PREP activities were measured in human EDTA-plasma in presence of well characterized PREP and FAP inhibitors.

Results

A combined kinetic assay was developed in conditions to optimally measure FAP as well as PREP activity with Z-Gly-Pro-AMC as substrate. Limit of detection was 0.009 U/L and limit of quantitation was 0.027 U/L for the combined FAP-PREP assay. Within-run coefficient of variation was 3% and 4% and between-run precision was 7% and 12% for PREP and FAP, respectively. Accuracy was demonstrated by comparison with established end-point assays. Hemolysis interferes with the assay with 1.5 g/L hemoglobin as cut-off value. PREP (but not FAP) activity can increase upon lysis of platelets and red blood cells during sample preparation.

Conclusion

With this new assay, on average 67% of the Z-Gly-Pro-AMC converting activity in plasma can be attributed to FAP.

Graphical abstract

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Multifactorial impact on the outcome of interval debulking surgery in patients with advanced epithelial ovarian or peritoneal cancers

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Qing-xiu Jiang, Yu-xia Jiang, Xuan Wang, Shu-juan Luo, Rong Zhou, Hua Linghu

Abstract
Objective

To evaluate the impact of multiple clinical features upon the outcome of interval cytoreductive surgery and thus upon the survival in patients with advanced ovarian cancer and primary peritoneal carcinoma.

Methods

A retrospective analysis of patients receiving NACT followed by IDS between 2009 and 2017. Patients were analyzed according to the pre-NACT CA125, pre-IDS CA125, pre-IDS CA125 decline, patients' pre-IDS BMI, multisite bowel involvement and different working years of surgeons, for their influence upon the IDS outcome (e.g. optimal vs suboptimal) and the survival.

Results

After interval debulking surgery following 1–6 cycles of NACT, all patients analyzed were identified as optimal (n = 113) and suboptimal (n = 47) based on patients' record. The PFS/OS were 21/68 months and 9/26 months in optimal and suboptimal groups, respectively (p = .000, p = .000). Although differential levels of pre-IDS CA125, pre-IDS CA125 decline, bowel involvement and surgeons' working years were found to be significantly different between the two groups, surgeons' working years and multisite bowel invasion were the independent factors for IDS outcome, and the latter one was also highly related to survival.

Conclusions

Following NACT, the rate of optimal IDS might be improved for patients without multisite bowel involvement. For those with bowel involvement, management strategy made by well-experienced surgeons might be a key factor for the outcome of IDS.


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Increasing waist circumference is associated with decreased levels of glycated albumin

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Yiting Xu, Xiaojing Ma, Yun Shen, Yufei Wang, Jian Zhou, Yuqian Bao

Abstract
Background

Glycated albumin (GA) levels are affected by body fat and its distribution. We explored the association of waist circumference (WC) with GA and to assess the extent to which WC influences GA.

Methods

We recruited 1799 subjects (age 26–82 y) from communities. GA was determined using the enzyme method, and glycated hemoglobin A1c (HbA1c) was detected using high-performance liquid chromatography.

Results

Subjects with central obesity had lower GA and GA/HbA1c than those without (both P < .01). GA and GA/HbA1c were negatively correlated with central obesity (both P < .01), whereas HbA1c was not correlated (P = .833). In the euglycemic and hyperglycemic subpopulations, GA and GA/HbA1c showed decreasing trends as WC levels increased (both P for trends <0.01). WC was a significant negative determinant of GA (P < .05). In the hyperglycemic subpopulation, the GA value decreased by approximately 0.15% for each 5 cm increment in WC regardless of the presence of central obesity.

Conclusions

The GA value was reduced by approximately 0.15% for each 5 cm increment in WC, suggesting that more attention should be paid to actual blood glucose underestimated by GA in obese people.


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Relationships between alcohol intake and cardiovascular risk factors in middle-aged men with hypo-HDL cholesterolemia

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Ichiro Wakabayashi

Abstract
Background

Light-to-moderate alcohol drinking reduces the risk of ischemic heart disease, and this effect of alcohol is mainly explained by alcohol-induced elevation of HDL cholesterol. Hypo-HDL cholesterolemia is a potent risk factor for cardiovascular disease. The aim of this study was to clarify how alcohol relates to cardiovascular risk factors in men with hypo-HDL-cholesterolemia.

Methods

The subjects were middle-aged men with hypo-HDL cholesterolemia (< 40 mg/dl), and they were divided into four groups by daily alcohol consumption (non-; light, < 22 g ethanol/day; moderate, ≥22 g ethanol and <44 g ethanol/day; heavy drinkers, ≥44 g ethanol/day). Each risk factor was compared among the groups after adjustment for age and histories of smoking and regular exercise.

Results

Systolic and diastolic blood pressure levels, log-transformed lipid accumulation product and log-transformed cardio-metabolic index were significantly higher in moderate and heavy drinkers than in nondrinkers. Log-transformed triglycerides and triglycerides-to-HDL cholesterol ratio were significantly higher in light, moderate and heavy drinkers than in nondrinkers and tended to be higher with an increase of alcohol intake. LDL cholesterol and LDL cholesterol-to-HDL cholesterol ratio were significantly lower in light, moderate and heavy drinkers than in nondrinkers and tended to be lower with an increase of alcohol intake. The above trends for the relationships of alcohol drinking with the cardiovascular risk factors were also found in multivariate logistic regression analysis.

Conclusions

In men with hypo-HDL cholesterolemia, alcohol drinking shows positive associations with blood pressure and triglycerides and an inverse association with LDL cholesterol.


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Reliability of the point-of care analyzer “StatStrip® Xpress™” for measurement of fetal blood lactate

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Linda Iorizzo, Kristina E.M. Persson, Karl H. Kristensen, Nana Wiberg

Abstract
Objectives

Measurement of lactate in fetal blood is used to assess the degree of anaerobic metabolism. The technical difficulties in obtaining enough scalp blood for analysis by a bloodgas-analyzer advocates for the use of a point-of-care device. StatStrip®Xpress™ (SSX) has shown promising properties but needs further evaluation before implementation into fetal surveillance.

Methods

Arterial/venous umbilical cord blood from 112 newborns were analyzed simultaneously with SSX and the reference method ABL800™. From 321 fetuses with abnormal heart rate scalp blood was sampled and analyzed repeatedly with SSX.

Results

ABL800™ -lactate ranged from 1.9–13.3 mmol/L in arterial to 1.5–10.2 mmol/L in venous cord blood with excellent correlation to SSX (R2 = 0.95). SSX-values were lower compared to the reference method ranging from −0.79 mmol/L for low values to −1.68 mmol/L for high values. The mean CV for SSX-values in cord respectively scalp blood was: lactate ≤3 mmol/L 7.1% respectively 8.4%; lactate >3 mmol/L 3.8% respectively 6.8%. Repeated measurements of the same sample with SSX where without significant difference in cord/scalp blood (p = 0.11).

Conclusion

SSX-lactate values were constantly lower but correlated excellent to the reference method. The reproducibility was good for cord and scalp blood. We suggest SSX as an attractive device for measurement of fetal lactate.


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Establishment of a quantitative detection method for magnetic microparticle chemiluminescence of anti-SSA-60 antibody

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): YuPing Li, Qiang Wang, XiaoLan Lu, Qin Du, Jia Xu, WenYi Luo, ShuQi Wang, GuoYuan Zhang, JianPing Liu, DongSheng Wang

Abstract
Objective

To produce 60-kDa recombinant Sjőren's syndrome antigen A (SSA-60) by gene engineering and establish and evaluate the performance of a magnetic microparticle chemiluminescence quantitative method for detecting anti-SSA-60 antibody in sera.

Methods

Recombinant antigen was prepared by gene recombination technology and purified by high affinity Ni2+ resin. The immunogenicity of the recombinant antigen was verified in immunized BALB/c female mice, and the immune reactivity of our recombinant antigen was assessed using the enzyme-linked immunosorbent assay (ELISA) method. With this recombinant antigen, a specific magnetic microparticles chemiluminescence assay (MMC assay) was developed and performed using various parameters.

Results

The inner-group difference among high, medium and low density sera mixtures was 7.65%, 2.24%, and 2.47%, respectively, and the inter-group precision rate was 8.25%, 6.26%, and 4.87%, respectively, using the MMC assay. The low detection limit was 1.36 relative unit per milliliter (Ru/mL), and the quantitative limit was 4.48 Ru/mL. The linear range of this method was 2–400 Ru/mL, which is wider than that of ELISA. The standard error (SE) of the differences was 31.3 between the two methods. Good correlation (y = 1.04x − 7.86, R2 = 0.979, P < 0.05) and high agreement (Kappa = 0.95) were noted between the two methods.

Conclusions

These data show that the MMC assay provides high sensitivity and specificity and a wider linear range in anti-SSA-60 aab detection and fairly good agreement and correlation between the MMC assay and ELISA. The MMC assay has potential in rapid, high-throughput, quantitative and automated autoimmune antibody testing.


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Tandem mass spectrometry analysis of urinary podocalyxin and podocin in the investigation of podocyturia in women with preeclampsia and Fabry disease patients

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Tristan Martineau, Michel Boutin, Anne-Marie Côté, Bruno Maranda, Daniel G. Bichet, Christiane Auray-Blais

Abstract
Background

Podocytes are highly differentiated visceral cells, and several related specific proteins, such as podocalyxin and podocin are potential tools for the evaluation of podocyturia. However, precise quantitation of podocyturia-related proteins is complex and often unreliable.

Method

A reversed-phase ultra-performance liquid chromatography coupled to tandem mass spectrometry method was developed and validated to quantify podocalyxin and podocin levels in urine supernatant by using specific cleavable peptides and standards. Urine samples from women with normotensive or hypertensive pregnancies, gestational diabetes and preeclampsia, as well as treated and untreated Fabry patients, and gender-matched controls were investigated.

Results

The multiplex analysis shows that podocalyxin levels were higher than podocin levels in patients, the former being particularly higher in pregnant women. Women with preeclampsia had abnormal urine levels of both proteins with a higher sensitivity for podocalyxin. Slightly increased levels of podocin were also observed in Fabry males, while both proteins were increased in untreated Fabry females. Correlations were established between podocalyxin and podocin levels and clinical parameters associated with Fabry disease and preeclampsia.

Conclusions

This methodology makes possible the precise, simultaneous and reliable analysis of podocalyxin and podocin levels, and offers a valuable tool for the evaluation of podocyturia.

Graphical abstract

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Estimating the cost of quality of errors in the analytical phase

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Robert L. Schmidt, Lauren N. Pearson

Abstract
Background

Cost of quality (COQ) can be defined as the difference between the current cost of providing laboratory services and the cost that would be incurred if there were no errors in the measurement process. Errors due to analytical imprecision and bias are not traditionally included in COQ. The objective of this study was to develop methods to estimate the COQ due to errors in the analytical phase.

Methods

We consider 2 types of error events: errors in patient results and run failures due to violation of a quality control (QC) rule. We provide a general and a simplified model for estimating the cost of analytical errors in patient results and a separate model for estimating costs due to QC failures.

Results

An example calculation is provided. The COQ for 12 mass spectrometry assays using the simplified cost model for estimating analytical errors and the cost model for run failures is presented.

Conclusions

The models provide a way to estimate COQ associated with analytical error, which have not been previously incorporated into clinical laboratory standards or published literature. Estimating COQ and using those data to prioritize improvement efforts can be challenging for laboratories but are important for value-driven patient care.


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Independent effect of alanine transaminase on the incidence of type 2 diabetes mellitus, stratified by age and gender: A secondary analysis based on a large cohort study in China

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Feng Gao, Xie-lin Huang, Xue-Pei Jiang, Min Xue, Ya-Ling Li, Xin-Ran Lin, Yi-Han Chen, Zhi-Ming Huang

Abstract
Background

Previous studies have revealed that alanine aminotransferase (ALT) may be one of the risk factors of developing diabetes. We aimed to demonstrate the independent effect of ALT on incident diabetes and to investigate whether the association between ALT and incident diabetes is modified by age and gender in the general Chinese population.

Methods

The present study was a retrospective cohort study, including 210,051 Chinese adult participants. The primary outcome was developing diabetes. The serum ALT activities were stratified by quintiles. We obtained data from ‘DATADRYAD’ website and used the data for secondary analysis.

Results

At a median follow-up of 3.0 y, 4144 of 210,051 (1.97%) participants developed diabetes. After adjustment for potential confounders, a significantly higher risk of the incident diabetes (HR: 1.43, 95% CI: 1.25–1.63) was found in participants in the fifth quintile (Q5, ≥31 U/L) compared to those in the first to fourth quintiles (Q1–4) for ALT activities. Among males aged 30 to 40 and 40 to 50 y with the fifth quintile of ALT activity had 2.4- and 1.5-fold increased odds of developing diabetes, respectively, in comparison with those in the lower ALT activities. Among females with age 30 to 40 and ≥ 70 y, the fifth quintile of ALT activity had 4.9- and 2.2-fold increased odds for incident diabetes.

Conclusion

Our result indicated that the ALT activity was positively associated with the incident diabetes among Chinese persons. Moreover, 30–40 y individuals, whether male or female, with elevated ALT activities had the greatest increased risk for diabetes compared with persons with lower ALT activities in the same age group.


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Patients with down syndrome have increased prevalence of rheumatoid factor but not autoantibodies to anti-cyclic citrullinated peptide

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Erik Orro, Kristi Alnek, Tiia Reimand, Koit Reimand, Oivi Uibo, Tiina Talvik, Kadri Haller-Kikkatalo, Kalle Kisand, Raivo Uibo

Abstract

The association between Down syndrome (DS), a genetic disorder resulting from trisomy of the 21st chromosome, and the autoantibodies of rheumatoid arthritis (RA) has been proposed but not unequivocally proven. The aim of this study was to determine whether adult patients with DS present higher levels of anti-cyclic citrullinated peptide (anti-CCP) antibodies and/or rheumatoid factor (RF) than the general population. Our results showed that none of the 68 patients with DS had anti-CCP antibodies, whereas among 204 age- and sex-matched controls these autoantibodies were present in one person. However, DS patients presented a higher number of RF positive cases than controls (11.7% to 3.2% respectively; Fisher's exact test, p = .027). The higher number of RF positive cases in the DS group without increase of anti-CCP antibodies may be indicative of immune disturbances in general rather than RA in these patients. Our study supports the view that RA does not occur with higher frequency in patients with DS than in the general population.


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Applying a multiplexed primer extension method on dried blood spots increased the detection of carriers at risk of glucose-6-phosphate dehydrogenase deficiency in newborn screening program

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Yen-Hui Chiu, Hsiao-Jan Chen, Ying-Chen Chang, Yu-Ning Liu, Shu-Min Kao, Mei-Ying Liu, Ying-Yen Weng, Kwang-Jen Hsiao, Tze-Tze Liu

Abstract
Background

Patients with glucose-6-phosphate dehydrogenase deficiency might develop acute hemolytic anemia, chronic hemolytic anemia, and neonatal hyperbilirubinemia when exposed to high levels of oxidative stress. Severe hemolysis may occur in not only patients but also female carriers under certain conditions. However, 80%–85% of female carriers were undetected in an existing newborn screening program because of their wide-ranging levels of enzyme activity.

Methods

We developed a cost- and time-efficient multiplex SNaPshot assay using dried blood spots.

Results

By detecting 21 common mutations in Taiwan and Southeast Asia, the assay could determine 98.2% of the mutant alleles in our cohort of Taiwanese newborns. The 9 undetermined mutant alleles were consequently detected by Sanger sequencing, of which 5 unpublished variations—c.187G > A (Pingtung), c.585G > C (Tainan), c.586A > T (Changhua), c.743G > A (Chiayi), and c.1330G > A (Tainan-2)—were detected. Furthermore, 13% of mild mutations were missed in male infants whose enzyme levels at 6.1–7.0 U/gHb in the newborn screening program when set the cutoff value at 6.0 U/gHb. We therefore suggest increasing the cutoff value and applying the multiplex SNaPshot assay as the second tier for neonatal screening.

Conclusions

Our approach could significantly increase the detection rate of male patients and female carriers with a reasonable cost and a reasonable number of clinic referrals.


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The potentiality of salivary peptide biomarkers for screening patients with periodontal diseases by mass spectrometry

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Han Tang, Chao Yuan, Zhangke Ma, Ce Zhu, Peiyuan Tong, Jennifer Elizabeth Gallagher, Xiangyu Sun, Shuguo Zheng

Abstract
Background

Certain candidate biomarkers for periodontal diseases in saliva, gingival crevicular fluid (GCF), and serum were reported by some previous studies, but little evidence was obtained in their potentiality for screening patients with periodontal diseases.

Methods

Unstimulated whole saliva, GCF, and serum samples, which were collected from 17 patients with chronic periodontitis, 17 with gingivitis, and 16 periodontally healthy persons as control, were analysed by MALDI-TOF MS. Cluster analysis and receiver operating characteristic (ROC) curve analysis were carried out to evaluate the ability of candidate peptides to distinguish patients with periodontal diseases from healthy subjects. Nano-LC/ESI-MS/MS was performed to identify possible proteins that these peptides might derive from.

Results

Most of the differentially expressed peptides exhibited an increase in participants with chronic periodontitis and gingivitis compared with healthy controls. Cluster analysis showed a good clustering capacity between chronic periodontitis and healthy controls. Most AUCs for differentially expressed peptides were >0.7, whereas some peptides from GCF and serum even exhibited AUCs of 0.9–1.0.

Conclusions

Some peptides in saliva, GCF, and serum act as biomarkers for chronic periodontitis and gingivitis, which have certain potentiality for screening patients with periodontal diseases and distinguishing them from healthy individuals in a comparatively large population by mass spectrometry.


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Inherited monogenic defects of ceramide metabolism: Molecular bases and diagnoses

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Patricia Dubot, Frédérique Sabourdy, Jitka Rybova, Jeffrey A. Medin, Thierry Levade

Abstract

Ceramides are membrane lipids implicated in the regulation of numerous biological functions. Recent evidence suggests that specific subsets of molecular species of ceramide may play distinct physiological roles. The importance of this family of molecules in vertebrates is witnessed by the deleterious consequences of genetic alterations in ceramide metabolism. This brief review summarizes the clinical presentation of human disorders due to the deficiency of enzymes involved either in the biosynthesis or the degradation of ceramides. Information on the possible underlying pathophysiological mechanisms is also provided, based on knowledge gathered from animal models of these inherited rare conditions. When appropriate, tools for chemical and molecular diagnosis of these disorders and therapeutic options are also presented.


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A gradual change of chromosome mosaicism from placenta to fetus leading to T18 false negative result by NIPS

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Zhiwei Wang, Xinxin Tang, Shuting Yang, Ting Yin, Yali Zhao, Anshun Zheng, Rong Zhang, Ying Gu, Leilei Wang

Abstract
Background

Noninvasive prenatal screening (NIPS) has higher sensitivity and specificity compared to traditional prenatal screening. Nevertheless, the discordant results between the NIPS and prenatal diagnosis were occasionally reported. In current study, we investigated the genetic basis of a T18 fetus with a discordant trisomy 5 (T5) positive and trisomy 18 (T18) negative NIPS result.

Methods

NIPS was used to detect fetal DNA in maternal circulating plasma based on semiconductor sequencing platform. The aneuploidies of the fetus and different part of placental tissues were investigated by copy number variation sequencing (CNV-seq) and chromosome microarray analysis (CMA).

Results

The positive result of T5 was detected for the pregnant woman in NIPS, while T18 was found in the fetal karyotyping analysis after amniocentesis. Furthermore, placental mosaicism of T5 and T18 was found by CNV-seq and CMA, which revealed the mosaic ratio of T5 was gradually increased from umbilical cord to the placenta center, while that of T18 was gradually decreased.

Conclusion

For the reason of cell-free fetal DNA (cff DNA) in the maternal circulation originates from trophoblast cells of placenta, the level of placental mosaicism could cause false negative NIPS result in multiple aneuploidies. The present study proved that a discordant T5 positive and T18 negative NIPS result was caused by placental mosaicism. This study highlights placental mosaicism as a significant risk factor for discordant NIPS results. The result will be helpful for genetic counseling and clinical management of such pregnant woman.


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Development of an algorithm for ruling-out non-ST elevation myocardial infarction in the emergency department using high sensitivity troponin T assay

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Fabrizio Cappellini, Rosanna Falbo, Donata Saltafossi, Fausto Avanzini, Stefano Signorini, Chiara Fania, Jari Intra, Giuseppe Limonta, Marina Pitto, Paolo Brambilla

Abstract
Introduction

Chest pain and its clinical manifestations are the most common reasons for presentation to the emergency department (ED). Given that the prevalence of chest pain due to acute myocardial infarction (AMI) in the ED is modest, clinicians should use cardiac troponins to safely and rapidly rule out AMI, avoiding the delayed release of low risk patients.

The study aims to develop and validate an algorithm to early rule-out of non-ST elevation myocardial infarction (NSTEMI) in subjects admitted to the ED with symptoms of myocardial infarction.

Methods

High sensitivity cardiac Troponin T (hs-cTnT) serial measurements (baseline, T0; after 1 h, T1; after 3 h, T3) were used to develop and validate the algorithm, respectively, in 6403 and 773 consecutive admissions suggestive of AMI.

Results

Patients were classified as having or not having NSTEMI according to clinical assessment, diagnostic imaging, and serial measurements ofhs-cTnT; ROC curve analysis allowed to find changes in consecutive hs-cTnT associated with diagnostic sensitivity close to 100%.

Only patients with hs-cTnTat T0 lower than 14 ng/L resultedto be eligible for the safe rule-out of NSTEMI.

Conclusions

Although some points remain to be improved, the results obtained indicate that algorithms for fast NSTEMI rule-out are feasible and safe.


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Recommendations for laboratory informatics specifications needed for the application of patient-based real time quality control

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Tze Ping Loh, Mark A. Cervinski, Alex Katayev, Andreas Bietenbeck, Huub van Rossum, Tony Badrick, on behalf of the International Federation of Clinical Chemistry and Laboratory Medicine Committee on Analytical Quality

Abstract

Patient based real time Quality Control (PBRTQC) algorithms provide many advantages over conventional QC approaches including lower cost, absence of commutability problems, continuous real-time monitoring of performance, and sensitivity to pre-analytical error. However, PBRTQC is not as simple to implement as conventional QC because of the requirement to access patient data as well as setting up appropriate rules, action protocols, and choosing best statistical algorithms. These requirements need capable and flexible laboratory informatics (middleware). In this document, the necessary features of software packages needed to support PBRTQC are discussed as well as recommendations for optimal integration of this technique into laboratory practice.


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Oncoproteomics: Current status and future opportunities

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Yujia He, Abidali Mohamedali, Canhua Huang, Mark S. Baker, Edouard C. Nice

Abstract

Oncoproteomics is the systematic study of cancer samples using omics technologies to detect changes implicated in tumorigenesis. Recent progress in oncoproteomics is already opening new avenues for the identification of novel biomarkers for early clinical stage cancer detection, targeted molecular therapies, disease monitoring, and drug development. Such information will lead to new understandings of cancer biology and impact dramatically on the future care of cancer patients.

In this review, we will summarize the advantages and limitations of the key technologies used in (onco)proteogenomics, (the Omics Pipeline), explain how they can assist us in understanding the biology behind the overarching “Hallmarks of Cancer”, discuss how they can advance the development of precision/personalised medicine and the future directions in the field.


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CXC chemokine ligand 12 (CXCL12) in atherosclerosis: An underlying therapeutic target

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Jia-Hui Gao, Xiao-Hua Yu, Chao-Ke Tang

Abstract

CXC chemokine ligand 12 (CXCL12) is a specific chemokine ligand and plays a significant role in cell chemotaxis. Upon binding to CXC chemokine receptor 4 (CXCR4) or CXCR7, CXCL12 can activate different signaling cascades to regulate cell proliferation, migration, and metabolism. CXCL12 exerts a pro-atherogenic action by aggravating multiple pathogenesis of atherogenesis, including dyslipidemia, inflammation, neointima hyperplasia, angiogenesis, and insulin resistance. Serum CXCL12 levels are also markedly increased in patients with atherosclerosis-associated disease. The present review focuses on recent advances in CXCL12 research in the pathogenesis of atherosclerosis together with its clinical values. This may provide insight into potential novel therapies for atherosclerosis.


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Liquid chromatography tandem mass spectrometry for plasma metadrenalines

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): S.L. Davies, A.S. Davison

Abstract

Evidence is accumulating which may result in plasma free metadrenalines (PMets) becoming the preferred test for diagnosing phaeochromocytoma and paraganglioma. Moreover, increased availability and benefits over other analytical methods like liquid chromatography with electrochemical detection and immunoassay are causing liquid chromatography tandem mass spectrometry (LC-MS/MS) to become the method of choice for PMet measurement. This review explores the evidence-base supporting this, and summarises published LC-MS/MS analytical methods for PMet analysis. Key aspects of methods (including SPE extraction, HILIC chromatography, MRM MS-detection and standardisation) are discussed. Common causes of analytical interference (e.g. ion suppression/enhancement, ionic cross talk, in source transformation and isobaric interferences) are outlined to illustrate the importance of sample purification and chromatographic resolution. The importance of supine, fasting sampling and Bayesian interpretation against supine, fasting reference intervals are explained, as well as the importance of age-specific reference intervals for normetadrenaline. Confounding factors like diet, drugs, renal function and acute illness are explored, along with potential strategies to address these (e.g. CKD-specific reference intervals).


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Substance P in cardiovascular diseases – A bioanalytical review

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Martin Feickert, Bjoern B. Burckhardt

Abstract

Substance P has recently received much attention as a mediator of adverse heart remodelling and cardiac inflammation by releasing proinflammatory cytokines and matrix metalloproteases from immune and cardiac mast cells. Based on animal models, Substance P is highly associated with the development of cardiomyopathies, subsequently leading to heart failure. After a brief overview of the pathological role of Substance P in cardiac remodelling and cardiac inflammation, this review summarizes the limited, existing data of Substance P blood levels in adults with cardiovascular diseases, demonstrating a high variability of blood concentrations. The investigation of blood levels led to the conclusion that variability is mainly caused by differences in blood sampling and determination. Furthermore, this review illustrates alternate strategies to investigate human Substance P levels as deeper knowledge of them enables further insights into the potential role of Substance P in cardiovascular diseases.


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ST2 and the ST2/IL-33 signalling pathway–biochemistry and pathophysiology in animal models and humans

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Irene Pusceddu, Benjamin Dieplinger, Thomas Mueller

Abstract

ST2 is an interleukin (IL)-1 receptor family member with transmembrane (ST2L) and soluble (sST2) isoforms. Structurally, the ST2 gene products are very similar in mice and humans. In humans and in mice, alternative promoter activation and splicing produce ST2L and sST2. ST2L represents the longest transcript, whereas sST2 is the truncated, soluble isoform. ST2L is the biological receptor for IL-33, a member of the IL-1 family. IL-33 is the functional ligand of ST2L and signals the presence of tissue damage to local immune cells. IL-33/ST2L signalling leads to the production of inflammatory cytokines/chemokines and to the induction of the immune response. Conversely, sST2 functions as a decoy receptor for IL-33, inhibiting the effects of IL-33/ST2L signalling. Animal studies have allowed the investigation of ST2 and the IL-33/ST2L signalling pathway at multiple levels. However, clinical studies have mainly focused on the determination of sST2 in the circulation. In humans, plasma concentrations of sST2 increase in several diseases, such as heart disease, pulmonary disease, burn injury and graft-versus-host disease. Consequently, increased plasma concentrations of sST2 are not specific for a single disorder in humans and are thus of limited value for diagnostic purposes. However, increased plasma concentrations of sST2 have been linked to a worse prognosis in numerous diseases. Nevertheless, the major source of circulating sST2 in healthy and diseased humans is currently not fully established. In addition, whether the downregulation of sST2 can improve the outcome of patients in the clinical setting has not been elucidated. The aim of the present review was to provide an update on the findings regarding the biochemistry and pathophysiology of ST2 and the sST2 signalling pathway in humans and experimental models.


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Plasma <em>EGFR</em> mutation testing in non-small cell lung cancer: A value proposition

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Michael Oellerich, Robert H. Christenson, Julia Beck, Philip D. Walson

Abstract

Genomics-driven precision medicine using targeted therapies requires advanced molecular diagnostic tests. Decisions about the use and reimbursement for such tests are increasingly being made on the basis of more outcome-based and value-based approaches. The value proposition concept is a tool to assess the benefits of laboratory testing to each stakeholder of the care pathway with respect to outcomes. This concept was applied to the use of noninvasive plasma epidermal growth factor receptor (EGFR) mutation testing in patients with advanced or metastatic non-small cell lung cancer (NSCLC) to guide treatment with EGFR tyrosine kinase inhibitors (TKIs). Using the value proposition framework, we evaluated published key evidence regarding clinical validity, economic implications, and limitations of this approach. It has been shown that plasma EGFR mutation testing is essential for guiding clinical decisions regarding prediction of eligibility of individual patients for TKI treatment, real-time monitoring, or adjustment of treatment regimens and tracking resistance. The appropriate use of plasma EGFR mutation testing has been shown to deliver both clinical and economic benefits to stakeholders across the entire care pathway; especially in clinical situations where biopsy material is inadequate or unavailable and where it leads to fewer tissue biopsies.


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Biological variation data for lipid cardiovascular risk assessment biomarkers. A systematic review applying the biological variation data critical appraisal checklist (BIVAC)

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Jorge Díaz-Garzón, Pilar Fernández–Calle, Joana Minchinela, Aasne K. Aarsand, William A. Bartlett, Berna Aslan, Beatriz Boned, Federica Braga, Anna Carobene, Abdurrahman Coskun, Elisabet Gonzalez-Lao, Niels Jonker, Fernando Marques-Garcia, Carmen Perich, Carmen Ricos, Margarita Simón, Sverre Sandberg

Abstract
Background

Biological variation (BV) data can be used to set analytical performance specifications (APS) for lipid assays. Poor performance will impact upon the efficacy of international guidelines for cardiovascular risk assessment (CVR) and relevant clinical decision limits. This systematic review applies the Biological Variation Data Critical Appraisal Checklist (BIVAC) to published studies of BV of CVR biomarkers enabling metanalysis of the data.

Methods

Studies of BV of total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and apolipoproteins A1 and B, retrieved using a systematic literature search, were evaluated and graded using the BIVAC. Meta-analysis of CVI and CVG estimates were performed utilizing weightings based upon BIVAC grades and the width of the data confidence intervals.

Results

Applying the BIVAC, ten publications were graded as D, 43 as C, 5 as B and 1 as A (fully compliant). A total of 196 CVI and 87 CVG estimates were available for the different lipid measurands. The meta-analysis-derived BV data estimates were generally concordant with those in the online 2014 BV database.

Conclusions

Application of BIVAC identifies BV data suitable for many important applications including setting APS. Additionally, this review identifies a need for new BIVAC compliant studies to deliver BV reference data in different subpopulations.


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Data mining: Biological and temporal factors associated with blood cardiac troponin I concentration in a Chinese population

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Dandan Li, Danying Wang, Danchen Wang, Chaochao Ma, Jie Wu, Pengchang Li, Xiuzhi Guo, Ling Qiu

Abstract
Background

Cardiac troponin is the cornerstone biomarker for the diagnosis of acute myocardial infarction. The aims of this study were to evaluate the association of biological and temporal factors with plasma cardiac troponin I (cTnI) concentration in a large group of Chinese outpatients and to explore which factor (sex, age, time of blood sampling, and season of the year) had the largest influence on plasma cTnI levels.

Methods

Analytical data with outpatient cTnI results were downloaded from the laboratory information system from January 1, 2012 to September 20, 2018. All cTnI measurements were performed with a Siemens Dimension EXL automatic chemiluminescence immunoassay analyzer. A statistical method was used to strictly exclude outliers. A total of 86,381 outpatients were enrolled in the study.

Results

In individuals over 60 years old, cTnI levels gradually increased with age in both males and females. cTnI reached its highest levels in individuals over 80 years old (0.030 μg/L in males and 0.027 μg/L in females). In individuals over 70 years old, cTnI levels were significantly higher in males than in females (P < .05). cTnI concentration varied between individuals with different times of blood sampling. In both men and women, cTnI concentrations reached a maximum at 05:00 (0.030 μg/L and 0.026 μg/L, respectively) and peaked again at 20:00 (0.029 μg/L and 0.023 μg/L, respectively). Additionally, there were significant differences in cTnI levels between the four seasons of the year (P < .05). In winter, cTnI levels were usually higher than in spring. Linear regression analysis showed that the factor “age ≥ 80” had the greatest impact on cTnI levels.

Conclusion

Plasma cTnI levels were significantly influenced by sex, age, time of blood sampling, and season of the year. Thus, in order to avoid incorrect identification of cTnI values as abnormal, a cTnI reference interval should be established, taking into consideration the sex and age of the individual, the time of day of blood sampling, and the season of the year.


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Advances in the relationship between glycosyltransferases and multidrug resistance in cancer

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Yinshuang Wu, Xixi Chen, Shidan Wang, Shujing Wang

Abstract

Despite great progress in clinical treatment, cancer remains a serious health problem contributing to significant morbidity and mortality worldwide. Although chemotherapy is a common therapeutic measure, multidrug resistance (MDR) presents a major challenge that often leads to poor prognosis. The abnormal expression of glycosyltransferases (GTs) leading to aberrant glycosylation patterns are considered a marker of cancer. Furthermore, the biosynthesis of these glycoconjugates has been associated with tumor proliferation, invasion and metastasis. Recently, studies have found that GTs are involved in mediating MDR in cancer cells through complex mechanisms and can influence therapeutic effect. In this review, we focus on several types of cancers and summarize previous studies on the correlation between GTs and MDR.


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Metabolomics workflow for lung cancer: Discovery of biomarkers

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Yuqing Tang, Zhou Li, Lissy Lazar, Zhiling Fang, Chunlan Tang, Jinshun Zhao

Abstract

Lung cancer is one of the most common cancers in the world. Due to the limitations of current diagnostic techniques and methods, most lung cancers are diagnosed at the advanced stage, which is not conducive to early treatment. The rise of metabolomics has provided new ideas for the early diagnosis of lung cancer. As a method for the comprehensive analysis of endogenous metabolites of the biological system, metabolomics has shown significant application potential for the early diagnosis and individualized treatment of various cancers including lung cancers. Via advanced analytical techniques and bioinformatics tools, the metabolome was excavated to find biomarkers related to cancer and its prognosis. In this review, the research methods and workflow of metabolomics are summarized, with an emphasis on the recent discovery of biomarkers and major metabolic pathways for lung cancers.


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PCSK9: A new participant in lipophagy in regulating atherosclerosis?

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Jun Xiao, Yi-Min Deng, Xiang-Rui Liu, Jian-Ping Cao, Min Zhou, Ya-Ling Tang, Wen-Hao Xiong, Zhi-Sheng Jiang, Zhi-Han Tang, Lu-Shan Liu

Abstract

Proprotein convertase subtilisin kexin 9 (PCSK9) regulates lipid metabolism by degrading low-density lipoprotein receptor on the surface of hepatocytes. PCSK9-mediated lipid degradation is associated with lipophagy. Lipophagy is a process by which autophagosomes selectively sequester lipid-droplet-stored lipids and are delivered to lysosomes for degradation. Lipophagy was first discovered in hepatocytes, and its occurrence provides important fundamental insights into how lipid metabolism regulates cellular physiology and pathophysiology. Furthermore, PCSK9 may regulate lipid levels by affecting lipophagy. This review will discuss recent advances by which PCSK9 mediates lipid degradation via the lipophagy pathway and present lipophagy as a potential therapeutic target for atherosclerosis.


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Liquid biopsy: Circulating exosomal long noncoding RNAs in cancer

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Nan Jiang, Jinchang Pan, Shuai Fang, Chengwei Zhou, Ying Han, Jun Chen, Xiaodan Meng, Xiaofeng Jin, Zhaohui Gong

Abstract

Despite many advances in diagnostics and multimodal treatment (surgery, radiotherapy, chemotherapy), cancer still remains one of the most important public health challenges worldwide because of the associated morbidity and mortality. Liquid biopsy has been developed to detect cancer at an early stage based on minimally invasive and serial body fluid tests with the advantage of following tumor evolution in real time. Circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), circulating cell-free noncoding RNAs (cfRNAs) and circulating exosomes represent the major components of liquid biopsy analysis. Liquid biopsy already has been implemented in cancer management, and most studies thus far are mainly focused on CTCs and ctDNA. In fact, the circulating long noncoding RNAs (lncRNAs) in exosomes have been discovered and confirmed to be closely related to tumorigenesis, metastasis and therapy. Thus this review is mainly focused on the clinical potential of circulating exosomal lncRNAs as a source of liquid biopsy biomarkers in cancer diagnosis, prognosis, and response to treatment, offering novel insights into the precision medicine of oncology.


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BCL10 in cell survival after DNA damage

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Yichen Luo, Jing Wu, Juan Zou, Yijing Cao, Yan He, Hui Ling, Tiebing Zeng

Abstract

The complex defense mechanism of the DNA damage response (DDR) developed by cells during long-term evolution is an important mechanism for maintaining the stability of the genome. Defects in the DDR pathway can lead to the occurrence of various diseases, including tumor development. Most cancer treatments cause DNA damage and apoptosis. However, cancer cells have the natural ability to repair this damage and inhibit apoptosis, ultimately leading to the development of drug resistance. Therefore, investigating the mechanism of DNA damage may contribute markedly to the future treatment of cancer. The CARMA-BCL10-MALT1 (CBM) complex formed by B cell lymphoma/leukemia 10 (BCL10) regulates apoptosis by activating NF-κB signaling. BCL10 is involved in the formation of complexes that antagonize apoptosis and contribute to cell survival after DNA damage, with cytoplasmic BCL10 entering the nucleus to promote DNA damage repair, including histone ubiquitination and the recruitment of homologous recombination (HR) repair factors. This article reviews the role of BCL10 in cell survival following DNA damage.


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Blood and urine biomarkers in chronic kidney disease: An update

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Mohammad Zulkarnain Bidin, Anim Md Shah, J. Stanslas, Christopher Lim Thiam Seong

Abstract
Introduction

Chronic kidney disease (CKD) is a silent disease. Most CKD patients are unaware of their condition during the early stages of the disease which poses a challenge for healthcare professionals to institute treatment or start prevention. The trouble with the diagnosis of CKD is that in most parts of the world, it is still diagnosed based on measurements of serum creatinine and corresponding calculations of eGFR. There are controversies with the current staging system, especially in the methodology to diagnose and prognosticate CKD.

Objective

The aim of this review is to examine studies that focused on the different types of samples which may serve as a good and promising biomarker for early diagnosis of CKD or to detect rapidly declining renal function among CKD patient.

Method

The review of international literature was made on paper and electronic databases Nature, PubMed, Springer Link and Science Direct. The Scopus index was used to verify the scientific relevance of the papers. Publications were selected based on the inclusion and exclusion criteria.

Result

63 publications were found to be compatible with the study objectives. Several biomarkers of interest with different sample types were taken for comparison.

Conclusion

Biomarkers from urine samples yield more significant outcome as compare to biomarkers from blood samples. But, validation and confirmation with a different type of study designed on a larger population is needed. More comparison studies on different types of samples are needed to further illuminate which biomarker is the better tool for the diagnosis and prognosis of CKD.


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Exosomes: A new approach to asthma pathology

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): José A. Cañas, Beatriz Sastre, José M. Rodrigo-Muñoz, Victoria del Pozo

Abstract

Asthma is a chronic inflammatory disease of the airways with a complex pathophysiology, making the development of diagnostic and therapeutic tools a challenge. Exosomes are extracellular membranous nanovesicles implicated in intercellular communication. Exosome composition and cargo are highly heterogeneous depending on their cellular origin and physiological state. They contain proteins (tetraspanins, heat-shock proteins), nucleic acids (RNA, microRNA), and lipids (ceramides, cholesterol, sphingolipids). Current scientific advances show that exosomes play a pivotal role in the pathology of asthma as well as other inflammatory diseases, and all types of inflammatory cells (neutrophils, dendritic cells, lymphocytes, eosinophils) release exosomes. Also, structural lung cells such as airway epithelial cells and airway smooth muscle cells produce and secrete these nanovesicles. Exosomes influence and modify the functionality of these inflammatory and structural cells, triggering the characteristic processes of asthma disease. Additionally, exosomes are used as biomarkers in several disorders because they are easier to collect from different biofluids, making them a non-invasive method for screening human pathologies. Also, due to their special molecular characteristics, they can be loaded with different molecules and employed as a drug-delivery vehicle. This review focuses on recent advances related to the role of exosomes in asthma disease.


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Bias in analytical chemistry: A review of selected procedures for incorporating uncorrected bias into the expanded uncertainty of analytical measurements and a graphical method for evaluating the concordance of reference and test procedures

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Robert Frenkel, Ian Farrance, Tony Badrick

Abstract

The Evaluation of measurement data - Guide to the Expression of Uncertainty in Measurement (GUM) provides the framework for evaluating measurement uncertainty. The preferred GUM approach for addressing bias assumes that all systematic errors are identified and corrected at an early stage in the measurement process. We review some procedures for treating uncorrected bias and its inclusion into an overall uncertainty statement. When bias and its uncertainty are recognised as metrological states independent of scatter in the test results, the uncertainty of the reference and uncertainty of the bias can be equated. The net standard uncertainty of a test result is the root-sum-square of the standard uncertainty of the bias and the standard uncertainty of measurements on the test. Since an incomplete and therefore potentially erroneous formula is often used for estimating bias standard uncertainty, we propose an alternative calculation. We next propose a graphical method using a simple algorithm that quantifies the discrepancy between the results of a test measurement and the corresponding reference value, in terms of the percentage overlap of two probability density functions. We propose that bias should be corrected wherever possible and we illustrate this approach using the graphical method. Even though this review is focused principally on analytical chemistry and medical laboratory applications, much of the discussion is applicable to all areas of metrology.


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Titin in muscular dystrophy and cardiomyopathy: Urinary titin as a novel marker

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Tomofumi Misaka, Akiomi Yoshihisa, Yasuchika Takeishi

Abstract

Titin, encoded by the gene TTN, is the largest human protein, and plays central roles in sarcomeric structures and functions in skeletal and cardiac muscles. Mutations of TTN are causally related to specific types of muscular dystrophies and cardiomyopathies. A developed methodology of next generation sequencing has recently led to the identification of novel TTN mutations in such diseases. The clinical significance of titin is now emerging as a target for genetic strategies. Titin-related muscular dystrophies include tibial muscular dystrophy, limb-girdle muscular dystrophy, Emery-Dreifuss muscular dystrophy, hereditary myopathy with early respiratory failure, central core myopathy, centronuclear myopathies, and Salih myopathy. Truncation mutations of TTN have been identified as the most frequent genetic cause of dilated cardiomyopathy. In this review article, we highlight the role of titin and impact of TTN mutations in the pathogenesis of muscular dystrophies and cardiomyopathies. Recently, a novel sensitive sandwich enzyme-linked immunosorbent assay (ELISA) for the detection of the urinary titin N-terminal fragments (U-TN) has been established. We discuss the clinical significance of U-TN in the diagnosis of muscular dystrophies and differential diagnosis of cardiomyopathies, as well as risk stratification in dilated cardiomyopathy.


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Extracellular vesicles in atherosclerosis

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): WenYi Deng, TingTing Tang, YangFeng Hou, Qian Zeng, YuFei Wang, WenJing Fan, ShunLin Qu

Abstract

Extracellular vesicles (EVs), which exist in human blood, are increased in some inflammation-related cardiovascular diseases. EVs are involved in inflammation, immunity, signal transduction, cell survival and apoptosis, angiogenesis, thrombosis, and autophagy, all of which are highly significant for maintaining homeostasis and disease progression. Therefore, EVs are also associated with key steps in atherosclerosis, including cellular lipid metabolism, endothelial dysfunction and vascular wall inflammation, ultimately resulting in vascular remodelling. In this review, we summarize recent studies on EV contents and biological function, focusing on their potential effect in atherosclerosis, including cholesterol metabolism, vascular inflammation, angiogenesis, coagulation and the development of atherosclerotic lesions. EVs may represent potential biomarkers and pharmacological targets for atherosclerotic diseases.


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The absent in melanoma 2 (AIM2) inflammasome in microbial infection

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Wenbo Zhu, Xuyu Zu, Shuangquan Liu, Hongbo Zhang

Abstract

Inflammasomes play a very important role in the host defense against multiple pathogenic microbes, including bacteria and viruses. Inflammasomes are multiprotein complex platforms that mediate the processing of the two most important inflammatory cytokines, pro-IL-1β and pro-IL-18, to their active forms. The inflammasome is formed by the apoptosis-associated speck-like protein containing a CARD (ASC), procaspase-1 and a sensor protein, either a NOD-like receptor (NLR) or an absent in melanoma 2 (AIM2)-like receptor. The sensor molecule determines inflammasome specificity by detecting specific and conserved microbial products or cell stress signals. Compared with the other inflammasomes, there is much more unknown about the activation or regulation mechanisms of the AIM2 inflammasome. In this review, we will discuss these mechanisms and the specific roles of the AIM2 inflammasome in response to diverse pathogens.


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Recent AHA/ACC guidelines on cholesterol management expands the role of the clinical laboratory

Publication date: August 2019

Source: Clinica Chimica Acta, Volume 495

Author(s): Jing Cao, Sridevi Devaraj

Abstract

The American Heart Association (AHA) and American College of Cardiology (ACC) recently published new guidelines for managing blood cholesterol. Five years from the publication of Pooled Cohort Equation to estimate 10-year risk of atherosclerotic cardiovascular disease (ASCVD), the newest guidelines put more focus on individualized risk assessment which necessitates increased participation of laboratory medicine in the prevention and management of ASCVD.

This mini-review summarizes key ideas from the new guideline that influence laboratory practice, including the renewed low-density lipoprotein cholesterol (LDL-C) treatment targets in primary and secondary prevention, the use of non-fasting lipids, new calculations of LDL cholesterol, and recommendations on assessing risk-enhancing factors in certain populations to aid the decision on statin and non-statin therapy. The shift in strategies for monitoring and lowering LDL-C has created opportunities for clinical laboratorians to more actively contribute to better identification of individuals at risk for ASCVD and partner with physicians taking care of the patient.


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Category: Current Chemistry Research

Last update: 28.03.2018.






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