Browsing by Author "Unsal, Ibrahim"

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A Simple Method for Quantification of Five Urinary Porphyrins, Porphobilinogen and 5-Aminolevulinic Acid, Using Liquid Chromatography Tandem Mass Spectrometry
(SPRINGER INDIA, 2019-01-01) Dogan, Ozlem; Serdar, Muhittin A.; Murat, Koza; Sonmez, Cigdem; Ispir, Emre; Serteser, Mustafa; Unsal, Ibrahim
Analysis of porphyrins and 5-aminolevulinic acid (ALA), porphobilinogen (PBG) in physiological liquids is required for diagnosis and follow-up of porphyrias. High performance liquid chromatography (HPLC) and liquid chromatography tandem mass spectrometry (LC-MS) methods with higher specificity and sensitivity have been developed. The major disadvantage of those methods is that they require longer extraction times due to their matrix effects. The present study suggests a simple, fast, sensitive, and specific assay for determination of Coproporphyrin, 5-carboxylporphyrin, 6-carboxylporphyrin, 7-carboxylporphyrin, Uroporphyrin I and ALA, PBG in urine sample by direct injection without sample pre-treatment using LC-MS. For the purposes of the present study LC-MS device was set to multiple reaction monitoring (MRM) and positive ion mode. Porphyrins and ALA, porphobilinogen were characterized by their MS/MS product ion, spectra. ALA, PBG and 5 porphyrins were detected simultaneously. Limit of detection for Coproporphyrin, 5-carboxylporphyrin, 6-carboxylporphyrin, 7-carboxylporphyrin, Uroporphyrin I were 2nmol/L, where it was 5mol/L for ALA and 2mol/L for porphobilinogen. The present study suggests that the present method is very effective compared to many other available methods for it does not require pre-treatment, provides simultaneous results of ALA, PBG and 5 porphyrins quantitatively in a shorter span of time, and has suitable sensitivity and selectivity. LC-MS technique was used clinically for the determination of urine porphyrin levels.
ANALYSIS OF CHANGES IN PARATHYROID HORMONE AND 25 (OH) VITAMIN D LEVELS WITH RESPECT TO AGE, GENDER AND SEASON: A DATA MINING STUDY
(SCIENDO, 2017-01-01) Serdar, Muhittin A.; Can, Basar Batu; Kilercik, Meltem; Durer, Zeynep A.; Aksungar, Fehime Benli; Serteser, Mustafa; Coskun, Abdurrahman; Ozpinar, Aysel; Unsal, Ibrahim
Background: 25 (OH) vitamin D3 (25(OH) D) and parathyroid hormone (PTH) are important regulators of calcium homeostasis. The aim of this study was to retrospectively determine the cut-off for sufficient 25(OH) D in a four-season region and the influence of age, seasons, and gender on serum 25(OH) D and PTH levels. Methods: Laboratory results of 9890 female and 2723 male individuals aged 38.8 +/- 22.1 years who had simultaneous measurements of 25(OH) D and PTH were retrospectively analyzed by statistical softwares. Serum 25(OH) D and PTH levels were measured by a mass spectrometry method and by an electrochemiluminescence immunoassay, respectively. Results: Mean serum 25(OH) D levels showed a sinusoidal fluctuation throughout the year and were significantly (p < 0.01) higher in summer and autumn. On the other hand, PTH levels were significantly higher (p < 0.01) in women and showed an opposite response to seasonal effects relative to 25(OH) D. Lowest levels of 25(OH) D were detected in people aged between 20 and 40 years whereas PTH hormone levels were gradually increasing in response to aging. The significant exponential inverse relationship that was found between PTH and 25(OH) D (PTH = (exp)(4.12-0.064{*}(sqrt)(25(OH) D)) (r=-0.325, R-squared=0.105, p < 0.001)) suggested that the cut-off for sufficient 25(OH) D should be 75 nmol/L. Conclusions: Our retrospective study based on large data set supports the suitability of the currently accepted clinical cut-off of 75 nmol/L for sufficient 25(OH) D. However, the issue of assessing Vitamin D deficiency remains difficult due to seasonal variations in serum 25(OH) D. Therefore, PTH measurements should complement 25(OH) D results for diagnosing Vitamin D deficiency. It is imperative that seasonally different criteria should be considered in future.
Association Between Serum Pregnancy-Associated Plasma Protein-A and Bicarbonate in Hemodialysis Patients
(JOHN WILEY \& SONS INC, 2014-01-01) Bicik, Zerrin; Coskun, Abdurrahman; Serteser, Mustafa; Bulur, Atilla; Mese, Meral; Unsal, Ibrahim
Background Acidosis is associated with protein-energy malnutrition, inflammation, and bone disease, and low bicarbonate levels have been implicated in higher mortality rates in chronic kidney disease. Recently, the concentration of serum pregnancy-associated plasma protein-A (PAPP-A) has become accepted as a prognostic marker in hemodialysis patients. This study determined the relationship between PAPP-A and bicarbonate levels in these patients. Methods The study enrolled 65 hemodialysis patients (41 males, 24 females) and 26 control subjects (11 males, 15 females). Serum PAPP-A, intact parathormone (iPTH), calcium, phosphorus (P), and bicarbonate levels were measured. Correlations between PAPP-A and bicarbonate, iPTH, calcium, and phosphorus were evaluated. Results Median PAPP-A levels were significantly higher in hemodialysis patients {[}15.1 (<0.03-158.8) ng/ml] than in control subjects {[}6.6 (<0.03-16.4) ng/ml] (P < 0.05). There were statistically significant correlations between serum PAPP-A and bicarbonate, iPTH, and P in hemodialysis patients but not in control subjects. Conclusion Elevation of serum PAPP-A has been found in hemodialysis patients and its significant correlation with bicarbonate suggests that it may be a prognostic factor.
Biological Variation Estimates Obtained from 91 Healthy Study Participants for 9 Enzymes in Serum
(AMER ASSOC CLINICAL CHEMISTRY, 2017-01-01) Carobene, Anna; Roraas, Thomas; Solvik, Una Orvim; Sylte, Marit Sverresdotter; Sandberg, Sverre; Guerra, Elena; Marino, Irene; Jonker, Niels; Barla, Gerhard; Bartlett, William A.; Fernandez-Calle, Pilar; Diaz-Garzon, Jorge; Tosato, Francesca; Plebani, Mario; Coskun, Abdurrahman; Serteser, Mustafa; Unsal, Ibrahim; Ceriottil, Ferruccio; Biological, E.F.L.M. Working Grp
BACKGROUND: We sought to develop estimates of biological variation (BV) for 9 enzymes in blood serum as part of the European Biological Variation Study. METHODS: Ninety-one healthy study participants (38 male and 53 female, 21-69 years old) were phlebotomized in each of 10 consecutive weeks at 6 European laboratories. The same preanalytical sample-handling protocol was followed at each center before transport to San Raffaele Hospital, Milan, Italy, for analysis. Sera were stored at -80 degrees C before analysis in duplicate within a single run on an ADVIA 2400 Clinical Chemistry System (Siemens Healthcare) following a protocol designed to minimize analytical imprecision. Assay traceability was established using frozen sera with target values assigned by reference methods. The results were subjected to outlier analysis before CV-ANOVA to deliver valid BV estimates. Results for 9 enzymes were subsequently partitioned for graphical display allowing visual assessment of the effects of country of origin, sex, and age on BV estimates. RESULTS: We found no effect of country upon the observed variation, but overall sex-related differences were evident for alanine amino transferase (ALT), gamma-glutamyl transferase (GGT), and creatine kinase (CK). The following estimates for within-subject BV (CVI) and between-subject BV (CVG), respectively, were obtained: ALT: 9.3\%, 28.2\%
Biological variations of ADAMTS13 and von Willebrand factor in human adults
(CROATIAN SOC MEDICAL BIOCHEMISTS, 2014-01-01) Kilercik, Meltem; Coskun, Abdurrahman; Serteser, Mustafa; Inan, Deniz; Unsal, Ibrahim
Background: The ultra-large von Willebrand factor (vWF) multimers are very active and must be degraded by ADAMTS13 for optimal activity. A severe functional deficiency of ADAMTS13 has been associated with thrombotic thrombocytopenic purpura. The correct interpretation of patient vWF and ADAMTS13 plasma levels requires an understanding of the biological variation associated with these analytes. In the present paper, we aimed to determine the biological variation of ADAMTS13 and vWF in human adults. Materials and methods: Blood samples were collected weekly from 19 healthy subjects for 5 consecutive weeks. vWF activity and antigenicity were determined using aggregometric and immunoturbidimetric methods. ADAMTS13 antigenicity and activity were determined by ELISA. Results: The within-subject biological variations for vWF activity and antigenicity were 8.06\% and 14.37\%, respectively, while the between-subject biological variations were 18.5\% and 22.59\%, respectively. The index of individuality for vWF activity was 0.44, while vWF antigenicity was 0.64. Similarly, ADAMTS13 activity and antigenicity within-subject biological variations were 12.73\% and 9.75\%, respectively, while between-subject biological variations were 9.63\% and 6.28\%, respectively. The ADAMTS13 indexes of individuality were 1.32 and 1.55, respectively. Conclusion: We report high biological variation and individuality in vWF antigenicity and activity levels. However, ADAMTS13 antigenicity and activity displayed high biological variation, but low individuality. Thus, population-based reference intervals may be useful for monitoring ADAMTS13 antigenicity and activity, but not for vWF, which displays high individuality. These findings should be considered when determining the reference interval and other clinical variables associated with ADAMTS13 and vWF levels.
CHALLENGES IN VITAMIN D ANALYSIS
(SCIENDO, 2012-01-01) Serteser, Mustafa; Coskun, Abdurrahman; Inal, Tamer C.; Unsal, Ibrahim
Vitamin D is an important determinant for the regulation of calcium and phosphorus levels and mineralization of the bone. The most reliable indicator of vitamin D status is the measurement of plasma or serum 25OH-D concentration. Several studies reported discrepancies between the results of assays. These high variabilities in 25OH-D measurements are due to used assay technologies and lack of standardization against the reference materials. Different assays have been employed for the measurement of 25OH-D levels: Competitive Protein Binding Assays, immunoassays, direct detection methods. Choosing an assay platform is important both for clinical laboratory professionals and researchers, and several factors affect this process. Recently, liquid chromatography and tandem mass spectrometry is an alternative method to traditional assays and provides higher specificity and sensitivity than many assays
Cofilin-1 as a potential biomarker to evaluate acute kidney injury
(WALTER DE GRUYTER GMBH, 2019-01-01) Coskun, Abdurrahman; Ucal, Yasemin; Berber, Ibrahim; Cakir, Ulkem; Serteser, Mustafa; Moldur, Derya Emel; Derelioglu, Ecenur Izzete; Yozgatli, Tahir Koray; Ozpinar, Aysel; Unsal, Ibrahim
Acute kidney injury (AKI) is a worldwide health problem and defined by rapid loss of excretory function of the kidney with the accumulation of metabolic end products. For effective treatment and prevent complications the early diagnosis of AKI is crucial. The current analytes used to diagnose AKI are not adequately sensitive and specific and therefore clinicians need new biomarkers. One of the new promising biomarker candidates of renal injury is cofilin-1. Previously, in our laboratory we isolated cofilin-1 in kidney preservation solution prior to transplantation and attempted to measure serum cofilin-1 in renal transplanted patients. However, cofilin-1 was not accurately measured in serum samples due to the methodological issues. In this mini-review, we summarized the current knowledge and concepts both in the literature and our experiences with cofilin-1 as a potential biomarker for the diagnosis and management of AKI.
Easy method for newborn screening of six lysosomal storage disorders using online solid-phase extraction with mass spectrometry
(WALTER DE GRUYTER GMBH, 2016-01-01) Serdar, Muhittin; Lay, Incilay; Coskun, Julide; Aslan, Berna; Aslan, Huseyin; Coskun, Abdurrahman; Serteser, Mustafa; Unsal, Ibrahim; Ozpinar, Aysel
Objective: A modified method for screening of six lysosomal storage disorders (LSDs) by tandem mass spectrometry was presented. Methods: The enzyme activities for six LSDs (Gaucher, Pompe, Krabbe, Fabry, Niemann-Pick A/B and Mucopolysaccharidosis Type I) was measured by using ultra-HPLC and mass spectrometry. After overnight incubation of dried blood spots with three distinct reaction cocktails containing substrates and internal standards, reactions were stopped and online trapping was performed with ultra-HPLC preceding to mass spectrometry. Ultra-HPLC was equipped with online solid phase extraction and Hypersil Gold C8 analytical columns and coupled with TSQ Quantum Access Max mass spectrometry. Results: Activities of acid-ss-glucocerebrosidase (ABG), acid glucosidase (GAA), galactocerebroside-ss-galactosidase (GALC), acid-galactosidase A (GLA), acid sphingomyelinase (ASM), and alpha-L-iduronidase (IDU) were obtained from DBSs of patients and healthy individuals. The intra- and inter-assay precisions were <20\% (CV). Conclusion: Our modified method, needing less DBS punches and only three reaction coctails, with the online trapping methodology, accurately differentiates newborns with LSDs from healthy newborns.
Exposure to Perchlorate in Lactating Women and Its Associations With Newborn Thyroid Stimulating Hormone
(FRONTIERS MEDIA SA, 2018-01-01) Ucal, Yasemin; Sahin, Ozlem N.; Serdar, Muhittin; Blount, Ben; Kumru, Pinar; Muhcu, Murat; Eroglu, Mustafa; Akin-Levi, Cansu; Keles, Z. Zeynep Yildirim; Turam, Cem; Valentin-Blasini, Liza; Morel-Espinosa, Maria; Serteser, Mustafa; Unsal, Ibrahim; Ozpinar, Aysel
Background: Perchlorate, thiocyanate, and nitrate can block iodide transport at the sodium iodide symporter (NIS) and this can subsequently lead to decreased thyroid hormone production and hypothyroidism. NIS inhibitor exposure has been shown to reduce iodide uptake and thyroid hormone levels
Hepatitis C virus positive patient diagnosed after detection of atypical cryoglobulin
(BAISHIDENG PUBLISHING GROUP INC, 2016-01-01) Ongen, Belkiz; Aksungar, Fehime Benli; Cicek, Bahattin; Akyar, Isin; Coskun, Abdurrahman; Serteser, Mustafa; Unsal, Ibrahim
A 60-year-old male patient presented with jaundice and dark urine for three days, icteric sclerae and skin rash on his legs for six months. Laboratory inves-tigations revealed an atypical cryoglobulinemia with high hepatitis C virus (HCV)-RNA levels. Imaging studies showed cholestasis was accompanying HCV. Capillary zone electrophoresis using immunosubtraction method revealed a polyclonal immunoglobulin G and immunoglobulin A (IgA) monoclonal cryoglobulin and that IgA lambda was absent in immu-nofixation electrophoresis. After a liver biopsy, chronic hepatitis C, HCV related mixed cryoglobulinemia and cryoglobulinemic vasculitis were diagnosed and antiviral therapy was initiated. Our HCV patient presented with cryoglobulinemic symptoms with an atypical cryoglobulinemia that was detected by an alternative method: Immunosubtraction by capillary electrophoresis. Different types of cryoglobulins may therefore have a correlation with clinical symptoms and prognosis. Therefore, the accurate immunotyping of cryoglobulins with alternative methods may provide more information about cryoglobulin-generated pathology.
HOW ISO-15189 LABORATORY ACCREDITATION ASSURES PATIENT SAFETY?
(SOC MEDICAL BIOCHEMISTS SERBIA, 2012-01-01) Serteser, Mustafa; Coskun, Abdurrahman; Inal, Tamer C.; Unsal, Ibrahim
Healthcare is a complex profession involving the state-of-art technology and sometimes leading to unintentional harm. Many factors contribute to the occurrence of medical errors. Patient safety is one of the most serious global health issues and defined as the absence of preventable harm to a patient during any process of medical care. The frequency of medical errors is higher than expected. It has been concluded that the majority of medical errors are not because of the individual attitudes but mainly caused by faulty systems or processes leading the staff to make mistakes or fail to prevent them. Patient safety is a shared responsibility comprised of many stakeholders such as society, patients, nurses, educators, administrators, researchers, physicians, government and legislative bodies, professional associations and accrediting agencies. Medical laboratory services are essential to patient care and need to be available to meet the needs of both patients and caregivers. ISO-15189:2007 Medical Laboratories-Particular requirements for quality and competence, an internationally recognized standard containing requirements necessary for diagnostic laboratories to demonstrate their competence to deliver reliable laboratory services. It applies quality system requirements to the clinical laboratories with a strong focus on responsiveness to the needs of patients and clinicians. Applying the performance improvement strategies focusing on different phases in total testing process will significantly reduce the errors and therefore will improve the patient safety. In this way, laboratory professionals contribute to improvement of safety and outcomes of care by working in interdisciplinary approach manner.
Human papillomavirus prevalence and type in liquid-based cervical samples from Turkish women in a selected risk group
(TUBITAK SCIENTIFIC \& TECHNICAL RESEARCH COUNCIL TURKEY, 2013-01-01) Akyar, Ism; Aydin, Ozlem; Yakicier, Mustafa Cengiz; Kocagoz, Zuhtu Taml; Ince, Umit; Unsal, Ibrahim
Aim: To detect the prevalence and type distribution of human papillomavirus (HPV) in different cytological diagnostic categories. Materials and methods: Between 2007 and 2010, a total of 1014 liquid-based thin preparations of cervical smears were selected and classified according to cytology results. HPV DNA polymerase chain reaction (PCR) was also performed using these samples. HPV DNA-positive samples were genotyped by DNA sequencing. Results: Of those enrolled in the study, 45.3\% were negative cytologically, 36.4\% had atypical squamous cells of undetermined significance, 0.3\% had atypical squamous cells preventing the exclusion of a high-grade squamous intraepithelial lesion, 16.8\% showed a low-grade squamous intraepithelial lesion, and 1.3\% had an high-grade squamous intraepithelial lesion. Conclusion: PCR assays showed HPV positivity in 63.0\% of cytologically negative and 90.8\% of cytologically positive samples. The most common types of HPV detected were 16, 6, 18, 31, 66, 56, 53, 81, 45, and 62. Of HPV DNA-positive samples, 47.7\% were high, 4.7\% were intermediate, and 17.9\% were low risk. The high-risk types of HPV detected were 16, 18, 31, 56, 53, 45, 62, 58, 59, 67, 51, 35, 73, 52, 33, 39, 68, and 82.
Indirect Reference Intervals Estimated from Hospitalized Population for Thyrotropin and Free Thyroxine
(MEDICINSKA NAKLADA, 2010-01-01) Inal, Tamer C.; Serteser, Mustafa; Coskun, Abdurrahman; Ozpinar, Aysel; Unsal, Ibrahim
Aim To establish indirect reference intervals from patient results obtained during routine laboratory work as an alternative to laborious and expensive producing of their own reference range values according to international instructions. Methods All results for thyrotropin (TSH) and free thyroxine (T4) that were stored in our laboratory information system between 2004 and 2008 were included in this study. After a logarithmic transformation of the raw data, outliers were excluded. Non-parametric reference intervals were estimated statistically after visual observation of the distribution using stem-and-leaf plots and histograms. A standard normal deviation test was performed to test the significance of differences between sub-groups. Results There was no significant difference in serum TSH or free T4 concentrations between male and female participants. Because no differences were found within the time span of the study, combined reference intervals were calculated. Indirect reference values were 0.43- 3.93 mU/L for TSH and 11.98-21.33 pmol/L for free T4. Conclusion Using patient laboratory data values is a relatively easy and cheap method of establishing laboratory specific reference values if skewness and kurtosis of the distribution are not too large.
INHIBITION OF CHOLESTEROL BIOSYNTHESIS IN HYPERCHOLESTEROLEMIA - IS IT THE RIGHT CHOICE?
(DE GRUYTER POLAND SP ZOO, 2013-01-01) Coskun, Abdurrahman; Serteser, Mustafa; Unsal, Ibrahim
Cholesterol biosynthesis is a complex pathway comprising more than 20 biochemical reactions. Although the final product created in the pathway is cholesterol, the intermediate products, such as ubiquinone and dolichol, also provide vital metabolic functions. Statins are HGM-CoA reductase inhibitors that stop the production of cholesterol by directly inhibiting the mevalonate production. Mevalonate is a precursor of two additional vital molecules, squalene and ubiquinone (coenzyme Q10). We hypothesized that inhibiting the cholesterol biosynthesis with statins for an extended duration may potentiate the oxidative stress, neurodegenerative disease and cancer. Our recommendation was to measure muscle enzymes, antioxidant capacity, and ubiquinone to monitor patients receiving the statins for prolonged periods of time.
Iodine Status in Turkish Populations and Exposure to Iodide Uptake Inhibitors
(PUBLIC LIBRARY SCIENCE, 2014-01-01) Ozpinar, Aysel; Kelestimur, Fahrettin; Songur, Yildiran; Can, Ozge; Valentin, Liza; Caldwell, Kathleen; Arikan, Ender; Unsal, Ibrahim; Serteser, Mustafa; Inal, Tamer; Erdemgil, Yigit; Coskun, Abdurrahman; Bakirci, Nadi; Sezgin, Ozlem; Blount, Ben
Perchlorate, nitrate, and thiocyanate are competitive inhibitors of the sodium iodide symporter of the thyroid membrane. These inhibitors can decrease iodine uptake by the symporter into the thyroid gland and may disrupt thyroid function. This study assesses iodine status and exposure to iodide uptake inhibitors of non-pregnant and non-lactating adult women living in three different cities in Turkey (Istanbul, Isparta and Kayseri). We measured iodine and iodide uptake inhibitors in 24-hr urines collected from study participants (N = 255). All three study populations were mildly iodine deficient, with median urinary iodine (UI) levels of 77.5 mu g/L in Istanbul, 58.8 mu g/L in Isparta, and 69.8 mu g/L in Kayseri. Perchlorate doses were higher in the study population (median 0.13 mu g/kg/day), compared with a reference population (median 0.059 mu g/kg/day), but lower than the U. S. EPA reference dose (0.7 mu g/kg/day). Urinary thiocyanate levels increased with increasing exposure to tobacco smoke, with non-smokers (268 mu g/L) significantly lower than light smokers (1110 mu g/L), who were significantly lower than heavy smokers (2410 mu g/L). This pilot study provides novel data indicating that study participants were moderately iodine deficient and had higher intakes of the iodide uptake inhibitor perchlorate compared with a reference population. Further investigation is needed to characterize the thyroid impact resulting from iodine deficiency coupled with exposure to iodide uptake inhibitors such as perchlorate, thiocyanate and nitrate.
Melatonin in preservation solutions prevents ischemic injury in rat kidneys
(PUBLIC LIBRARY SCIENCE, 2022-01-01) Coskun, Abdurrahman; Yegen, Cumhur; Arbak, Serap; Attaallah, Wafi; Gunal, Omer; Elmas, Merve Acikel; Ucal, Yasemin; Can, Ozge; Bas, Banu; Yildirim, Zeynep; Seckin, Ismail; Demirci, Sibel; Serteser, Mustafa; Ozpinar, Aysel; Belce, Ahmet; Basdemir, Gulcin; Moldur, Derya Emel; Derelioglu, Ecenur Izzete; Yozgatli, Tahir Koray; Erdemgil, Yigit; Unsal, Ibrahim
Transplantation is lifesaving and the most effective treatment for end-stage organ failure. The transplantation success depends on the functional preservation of organs prior to transplantation. Currently, the University of Wisconsin (UW) and histidine-tryptophan-ketoglutarate (HTK) are the most commonly used preservation solutions. Despite intensive efforts, the functional preservation of solid organs prior to transplantation is limited to hours. In this study, we modified the UW solution containing components from both the UW and HTK solutions and analyzed their tissue-protective effect against ischemic injury. The composition of the UW solution was changed by reducing hydroxyethyl starch concentration and adding Histidine/Histidine-HCI which is the main component of HTK solution. Additionally, the preservation solutions were supplemented with melatonin and glucosamine. The protective effects of the preservation solutions were assessed by biochemical and microscopical analysis at 2, 10, 24, and 72 h after preserving the rat kidneys with static cold storage. Lactate dehydrogenase (LDH) activity in preservation solutions was measured at 2, 10, 24, and 72. It was not detectable at 2 h of preservation in all groups and 10 h of preservation in modified UW+melatonin (mUW-m) and modified UW+glucosamine (mUW-g) groups. At the 72nd hour, the lowest LDH activity (0.91 IU/g (0.63-1.17)) was measured in the mUW-m group. In comparison to the UW group, histopathological damage score was low in modified UW (mUW), mUW-m, and mUW-g groups at 10, 24, and 72 hours. The mUW-m solution at low temperature was an effective and suitable solution to protect renal tissue for up to 72 h.
Personalized reference intervals - statistical approaches and considerations
(WALTER DE GRUYTER GMBH, 2022-01-01) Coskun, Abdurrahman; Sandberg, Sverre; Unsal, Ibrahim; Yavuz, Fulya G.; Cavusoglu, Coskun; Serteser, Mustafa; Kilercik, Meltem; Aarsand, Aasne K.
For many measurands, physicians depend on population-based reference intervals (popRI), when assessing laboratory test results. The availability of personalized reference intervals (prRI) may provide a means to improve the interpretation of laboratory test results for an individual. prRI can be calculated using estimates of biological and analytical variation and previous test results obtained in a steady-state situation. In this study, we aim to outline statistical approaches and considerations required when establishing and implementing prRI in clinical practice. Data quality assessment, including analysis for outliers and trends, is required prior to using previous test results to estimate the homeostatic set point. To calculate the prRI limits, two different statistical models based on `prediction intervals' can be applied. The first model utilizes estimates of `within-person biological variation' which are based on an individual's own data. This model requires a minimum of five previous test results to generate the prRI. The second model is based on estimates of `within-subject biological variation', which represents an average estimate for a population and can be found, for most measurands, in the EFLM Biological Variation Database. This model can be applied also when there are lower numbers of previous test results available. The prRI offers physicians the opportunity to improve interpretation of individuals' test results, though studies are required to demonstrate if using prRI leads to better clinical outcomes. We recommend that both popRIs and prRIs are included in laboratory reports to aid in evaluating laboratory test results in the follow-up of patients.
Personalized Reference Intervals in Laboratory Medicine: A New Model Based on Within-Subject Biological Variation
(OXFORD UNIV PRESS INC, 2021-01-01) Coskun, Abdurrahman; Sandberg, Sverre; Unsal, Ibrahim; Cavusoglu, Coskun; Serteser, Mustafa; Kilercik, Meltem; Aarsand, Aasne K.
BACKGROUND: The concept of personalized medicine has received widespread attention in the last decade. However, personalized medicine depends on correct diagnosis and monitoring of patients, for which personalized reference intervals for laboratory tests may be beneficial. In this study, we propose a simple model to generate personalized reference intervals based on historical, previously analyzed results, and data on analytical and within-subject biological variation. METHODS: A model using estimates of analytical and within-subject biological variation and previous test results was developed. We modeled the effect of adding an increasing number of measurement results on the estimation of the personal reference interval. We then used laboratory test results from 784 adult patients (>18 years) considered to be in a steady-state condition to calculate personalized reference intervals for 27 commonly requested clinical chemistry and hematology measurands. RESULTS: Increasing the number of measurements had little impact on the total variation around the true homeostatic set point and using >= 3 previous measurement results delivered robust personalized reference intervals. The personalized reference intervals of the study participants were different from one another and, as expected, located within the common reference interval. However, in general they made up only a small proportion of the population-based reference interval. CONCLUSIONS: Our study shows that, if using results from patients in steady state, only a few previous test results and reliable estimates of within-subject biological variation are required to calculate personalized reference intervals. This may be highly valuable for diagnosing patients as well as for follow-up and treatment.
Post-translational modifications of transthyretin affect the triiodonine-binding potential
(WILEY, 2015-01-01) Henze, Andrea; Homann, Thomas; Serteser, Mustafa; Can, Ozge; Sezgin, Ozlem; Coskun, Abdurrahman; Unsal, Ibrahim; Schweigert, Florian J.; Ozpinar, Aysel
Transthyretin (TTR) is a visceral protein, which facilitates the transport of thyroid hormones in blood and cerebrospinal fluid. The homotetrameric structure of TTR enables the simultaneous binding of two thyroid hormones per molecule. Each TTR subunit provides a single cysteine residue (Cys(10)), which is frequently affected by oxidative post-translational modifications. As Cys(10) is part of the thyroid hormone-binding channel within the TTR molecule, PTM of Cys(10) may influence the binding of thyroid hormones. Therefore, we analysed the effects of Cys(10) modification with sulphonic acid, cysteine, cysteinylglycine and glutathione on binding of triiodothyronine (T3) by molecular modelling. Furthermore, we determined the PTM pattern of TTR in serum of patients with thyroid disease by immunoprecipitation and mass spectrometry to evaluate this association in vivo. The in silico assays demonstrated that oxidative PTM of TTR resulted in substantial reorganization of the intramolecular interactions and also affected the binding of T3 in a chemotype- and site-specific manner with S-glutathionylation as the most potent modulator of T3 binding. These findings were supported by the in vivo results, which indicated thyroid function-specific patterns of TTR with a substantial decrease in S-sulphonated, S-cysteinylglycinated and S-glutathionylated TTR in hypothyroid patients. In conclusion, this study provides evidence that oxidative modifications of Cys(10) seem to affect binding of T3 to TTR probably because of the introduction of a sterical hindrance and induction of conformational changes. As oxidative modifications can be dynamically regulated, this may represent a sensitive mechanism to adjust thyroid hormone availability.
Proteins associated with neutrophil degranulation are upregulated in nasopharyngeal swabs from SARS-CoV-2 patients
(PUBLIC LIBRARY SCIENCE, 2020-01-01) Akgun, Emel; Tuzuner, Mete Bora; Sahin, Betul; Kilercik, Meltem; Kulah, Canan; Cakiroglu, Hacer Nur; Serteser, Mustafa; Unsal, Ibrahim; Baykal, Ahmet Tarik
COVID-19 or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appeared throughout the World and currently affected more than 9 million people and caused the death of around 470,000 patients. The novel strain of the coronavirus disease is transmittable at a devastating rate with a high rate of severe hospitalization even more so for the elderly population. Naso-oro-pharyngeal swab samples as the first step towards detecting suspected infection of SARS-CoV-2 provides a non-invasive method for PCR testing at a high confidence rate. Furthermore, proteomics analysis of PCR positive and negative naso-oropharyngeal samples provides information on the molecular level which highlights disease pathology. Samples from 15 PCR positive cases and 15 PCR negative cases were analyzed with nanoLC-MS/MS to identify the differentially expressed proteins. Proteomic analyses identified 207 proteins across the sample set and 17 of them were statistically significant. Protein-protein interaction analyses emphasized pathways like Neutrophil degranulation, Innate Immune System, Antimicrobial Peptides. Neutrophil Elastase (ELANE), Azurocidin (AZU1), Myeloperoxidase (MPO), Myeloblastin (PRTN3), Cathepsin G (CTSG) and Transcobalamine-1 (TCN1) were found to be significantly altered in naso-oropharyngeal samples of SARS-CoV-2 patients. The identified proteins are linked to alteration in the innate immune system specifically via neutrophil degranulation and NETosis.