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The Effectiveness of Serum pNF-H Level Interpreting Brain Damage in Rats with Traumatic Brain Injury Model

Yıl 2021, Cilt: 47 Sayı: 2, 195 - 199, 01.08.2021

Halil İbrahim Çıkrıklar Vahide Aslıhan Durak Tülin Alkan Birnur Aydin Deniz Sığırlı Hakan Salcı Erol Armagan

https://doi.org/10.32708/uutfd.938519

Öz

The aim of our study is to investigate whether pNF-H level is effective in demonstrating traumatic brain injury in serum samples taken from rats with experimental traumatic brain injury. In our experimental study where the Marmarou model was modified and used, it was aimed to create trauma with the intensity of 0.05, 0.1, 0.2 and 0.4 Newton respectively by using balls of different weights from different heights with free fall method. The pNF-H level was investigated in the blood taken from the heart of rats 2 hours after the induction of trauma. As a result, the changes in pNF-H levels in the blood taken at the 2nd hour from rats with experimental traumatic brain injury were not found to be statistically significant. These results show that pNF-H, which is studied in the blood in the second hour after traumatic brain injury, is not diagnostically effective.

Anahtar Kelimeler

emergency department pNF-H traumatic brain injury

Kaynakça

  • Taylor CA, Bell JM, Breiding MJ, Xu L. Traumatic brain injury-related emergency department visits, hospitalizations, and deaths - United States, 2007 and 2013. MMWRSurveill. Summ 2017; 66:1–16.
  • Rabinowitz AR, Levin HS. Cognitive sequelae of traumatic brain injury. Psychiatr. Clin. N. Am. 2014; 37:1–11.
  • Pearson WS, Sugerman DE, McGuire LC, Coronado VG. Emergency department visits for traumatic brain injury in older adults in the United States: 2006–08. West J Emerg Med 2012;13(3), 289–293.
  • Papa L, Edwards D, Ramia M. Exploring serum biomarkers for mild traumatic brain injury. In Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects; Kobeissy, F.H., Ed.; CRC Press/Taylor & Francis: Boca Raton, FL, USA, 2015; ISBN 9781466565982.
  • Azar S, Hasan A, Younes R, Najdi F, Baki L, Ghazale H, Kobeissy FH, Zibara K, Mondello S. Biofluid Proteomics and Biomarkers in Traumatic Brain Injury. Methods Mol. Biol 2017;1598:45–63.
  • Yuh EL, Mukherjee P, Lingsma HF, Yue JK, Ferguson AR, GordonWA, Valadka AB, Schnyer DM, Okonkwo DO, Maas AIR et al. Magnetic resonance imaging improves 3-month outcome prediction in mild traumatic brain injury. Ann. Neurol 2013;73:224–235.
  • Wang KK, Yang Z, Zhu T, Shi Y, Rubenstein RJ, Tyndall A and Manley GT. An update on diagnostic and prognostic biomarkers for traumatic brain injury. Expert Rev Mol Diagn 2018;18(2): 165–180.
  • Nadel J, McNally JS, DiGiorgio A & Grandhi R. Emerging Utility of Applied Magnetic Resonance Imaging in the Management of Traumatic Brain Injury. Med Sci (Basel) 2021;9(1).
  • Smith LGF, Milliron E, Ho ML, Hu HH, Rusin J, Leonard J ve ark. Advanced neuroimaging in traumatic brain injury: an overview. Neurosurg Focus 2019;47(6): 17.
  • Yue JK, Upadhyayula PS, Avalos LN, Deng H and Wang KKW. Review: The Role of Blood Biomarkers for Magnetic Resonance Imaging Diagnosis of Traumatic Brain Injury. Medicina 2020;56:87
  • Mac Donald CL, Barber J, Jordan M, Johnson AM, Dikmen S, Fann JR et al. Early clinical predictors of 5-year outcome after concussive blast traumatic brain injury. JAMA Neurol 2017;74, 821–829.
  • Gardner RC and Yaffe K. Epidemiology of mild traumatic brain injury and neurodegenerative disease. Mol. Cell. Neurosci, 2015;66:75–80.
  • Jagoda AS, Bazarian JJ, Bruns JJ, Cantrill SV, Gean AD, Howard PK, Ghajar J, Riggio S, Wright DW, Wears RL et al. Clinical policy: Neuroimaging and decisionmaking in adult mild traumatic brain injury in the acute setting. Ann. Emerg. Med. 2008; 52:714–748.
  • Tomar GS, Singha GP, Lahkarb D, Sengarc K, Nigamd R, Mohand M, Anindyad R. Review: New biomarkers in brain trauma. Clinica Chimica Acta, 2018;487:325–329.
  • Li Y, Zhang L, Kallakuri S, Cohen A, Cavanaugh JM. Correlation of mechanical impact responses and biomarker levels: A new model for biomarker evaluation in TBI. J. Neurol. Sci 2015;359(1–2): 280–286.
  • Anderson KJ, Scheff SW, Miller KM, et al. The phosphorylated axonal form of the neurofilament subunit NF-H (pNF-H) as a blood biomarker of traumatic brain injury. J. Neurotrauma 2008;25(9):1079–1085.
  • Julien JP, Mushynski WE. Neurofilaments in health and disease, Prog. Nucleic Acid Res. Mol. Biol 1998;61:1–23.
  • Posmantur RM, Zhao X, Kampfl A, Clifton GL, Hayes RL. Immunoblot analyses of the relative contributions of cysteine and aspartic proteases to neurofilament breakdown products following experimental brain injury in rats. Neurochemical research 1998;23(10):1265–1276.
  • Siman R, Toraskar N, Dang A, McNeil E, M. McGarvey M, J. Plaum J, E. Maloney E, M.S. Grady MS. A panel of neuron-enriched proteins as markers for traumatic brain injury in humans, J. Neurotrauma, 2009;26 (11):1867–1877.
  • Neselius S, Zetterberg H, Blennow K, Marcusson J, Brisby H. Increased CSF levels of phosphorylated neurofilament heavy protein following bout in amateur boxers. PLoS ONE, 2013;8(11):81249.
  • Zurek J, Bartlova L, Fedora M. Hyperphosphorylated neurofilament NF-H as a predictor of mortality after brain injury in children. Brain Inj 2011;25 (2):221–226.
  • Marmarou A, Foda MA, van den Brink W, Campbell J, Kita H, Demetriadou K: A new model of diffuse brain injury in rats. Part I: Pathophysiology and biomechanics. J Neurosurg 1994;80(2):291-300.
  • Benady A, Freidin D, Pick CG, Rubovitch V. GM1 ganglioside prevents axonal regeneration inhibition and cognitive defcits in a mouse model of traumatic brain injury. Scientific Reports, 2018;8:13340
  • Buki, A. and Povlishock, J.T. All roads lead to disconnection?– Traumatic axonal injury revisited. Acta Neurochir (Wien) 2006;148:181–193.
  • Shaw G, Yang C, Ellis R, Anderson K, Mickle J, Scheff S, Pike B, Anderson D and Howland, D. Hyperphosphorylated neurofilament NF-H is a serum biomarker of axonal injury. Biochem. Biophys. Res. Commun. 2005;336:1268–1277.
  • Gordon BA. Neurofilaments in disease: what do we know? Curr Opin Neurobiol 2020;61:105-115.
  • Yang Z, Zhu T, Mondello S, Akel M, Wong AT, Kothari IM, Lin F, Shear DA, Gilsdorf JS, Leung LY, Bramlett HM, Dixon CE, Dietrich WD, Hayes RL, Povlishock TJ, Tortella FC, Kochanek PM, Wang KK. Serum-based phosphoneurofilament-heavy protein as theranostic biomarker in three models of traumatic brain injury: an operation brain trauma therapy study, J Neurotrauma 2019;36(2):348-359.
  • Park HO, Kim JW, Kim SH, Moon SH, Byun JH, Kim KN ve ark. Usability verification of the Emergency Trauma Score (EMTRAS) and Rapid Emergency Medicine Score (REMS) in patients with trauma: A retrospective cohort study. Medicine (Baltimore) 2017;96(44):8449.
  • Capizzi A, Woo J & Verduzco-Gutierrez M. Traumatic Brain Injury: An Overview of Epidemiology, Pathophysiology, and Medical Management. Med Clin North Am 2020;104(2), 213-238.
  • Shackelford SA, Del Junco DJ, Reade MC, Bell R, Becker T, Gurney J ve ark. Association of time to craniectomy with survival in patients with severe combat-related brain injury. Neurosurg Focus 2018;45(6):2.
  • Karasu A, Sabancı PA, Cansever T, et al. Kafa travmalı hastalarda epidemiyolojik çalışma. Ulus Travma Acil Cerrahi Derg. 2009;15(2):159-63.
  • Çıkrıklar H, Ekici MA, Coşan D, Ekici A, Üstündağ Y, Karaali M, Kaynak M, Uz K, Baydemir C, Yürümez Y. Serum GFAP Düzeyi, Minor Kafa Travmalı Çocuklarda Beyin Tomografisine Alternatif Olabilir Mi? Bozok Tıp Derg 2014; 4(1):6-12.
  • Czeiter E, Amrein K, Gravesteijn BY, Lecky F, Menon DK, Mondello S ve ark. Blood biomarkers on admission in acute traumatic brain injury: Relations to severity, CT findings and care path in the CENTER-TBI study. EBioMedicine 2020;56, 102785.
  • Shibahashi K, Doi T, Tanaka S, Hoda H, Chikuda H, Sawada Y, Takasu Y, Chiba K, Nozaki T, Hamabe Y, Ogata T. The Serum Phosphorylated Neurofilament Heavy Subunit as a Predictive Marker for Outcome in Adult Patients after Traumatic Brain Injury. J Neurotrauma, 2016;15;33(20):1826-1833
  • Cikriklar HI, Uysal O, Ekici MA, Ozbek Z, Cosan DT, Yucel M, et al. Effectiveness of GFAP in determining neuronal damage in rats with induced head trauma. Turk Neurosurg 2016;26(6):878–89.

Deneysel Olarak Travmatik Beyin Hasarı Oluşturulan Ratlarda Serum pNF-H Düzeyinin Beyin Hasarını Göstermede Etkinliği

Yıl 2021, Cilt: 47 Sayı: 2, 195 - 199, 01.08.2021

Halil İbrahim Çıkrıklar Vahide Aslıhan Durak Tülin Alkan Birnur Aydin Deniz Sığırlı Hakan Salcı Erol Armagan

https://doi.org/10.32708/uutfd.938519

Öz

Çalışmamızın amacı deneysel olarak hafif travmatik beyin hasarı oluşturulan sıçanlardan alınan serum örneklerinde pNF-H düzeyinin hasarı göstermede etkin olup olmadığını araştırmaktır. Marmarou modelinin modifiye edilerek kullanıldığı deneysel çalışmamızda farklı yüksekliklerden farklı ağırlıklarda bilyeler serbest düşme yöntemiyle bırakılarak sırayla 0.05, 0.1, 0.2 ve 0.4 Newton şiddetinde travma oluşturulması hedeflendi. Travmanın indüksiyonundan 2 saat sonra sıçanların kalbinden alınan kanlarda pNF-H düzeyi araştırıldı. Sonuç olarak deneysel olarak hafif travmatik beyin hasarı oluşturduğumuz ratlarda 2.saatte alınan kanlarda pNF-H düzeylerindeki değişiklikler istatistiksel olarak anlamlı bulunmamıştır. Bu sonuçlar hafif travmatik beyin hasarından sonraki 2.saatte kanda çalışılan pNF-H’ın tanısal olarak etkin olmadığını göstermektedir.

Anahtar Kelimeler

Acil Servis pNF-H travmatik beyin hasarı

Kaynakça

  • Taylor CA, Bell JM, Breiding MJ, Xu L. Traumatic brain injury-related emergency department visits, hospitalizations, and deaths - United States, 2007 and 2013. MMWRSurveill. Summ 2017; 66:1–16.
  • Rabinowitz AR, Levin HS. Cognitive sequelae of traumatic brain injury. Psychiatr. Clin. N. Am. 2014; 37:1–11.
  • Pearson WS, Sugerman DE, McGuire LC, Coronado VG. Emergency department visits for traumatic brain injury in older adults in the United States: 2006–08. West J Emerg Med 2012;13(3), 289–293.
  • Papa L, Edwards D, Ramia M. Exploring serum biomarkers for mild traumatic brain injury. In Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects; Kobeissy, F.H., Ed.; CRC Press/Taylor & Francis: Boca Raton, FL, USA, 2015; ISBN 9781466565982.
  • Azar S, Hasan A, Younes R, Najdi F, Baki L, Ghazale H, Kobeissy FH, Zibara K, Mondello S. Biofluid Proteomics and Biomarkers in Traumatic Brain Injury. Methods Mol. Biol 2017;1598:45–63.
  • Yuh EL, Mukherjee P, Lingsma HF, Yue JK, Ferguson AR, GordonWA, Valadka AB, Schnyer DM, Okonkwo DO, Maas AIR et al. Magnetic resonance imaging improves 3-month outcome prediction in mild traumatic brain injury. Ann. Neurol 2013;73:224–235.
  • Wang KK, Yang Z, Zhu T, Shi Y, Rubenstein RJ, Tyndall A and Manley GT. An update on diagnostic and prognostic biomarkers for traumatic brain injury. Expert Rev Mol Diagn 2018;18(2): 165–180.
  • Nadel J, McNally JS, DiGiorgio A & Grandhi R. Emerging Utility of Applied Magnetic Resonance Imaging in the Management of Traumatic Brain Injury. Med Sci (Basel) 2021;9(1).
  • Smith LGF, Milliron E, Ho ML, Hu HH, Rusin J, Leonard J ve ark. Advanced neuroimaging in traumatic brain injury: an overview. Neurosurg Focus 2019;47(6): 17.
  • Yue JK, Upadhyayula PS, Avalos LN, Deng H and Wang KKW. Review: The Role of Blood Biomarkers for Magnetic Resonance Imaging Diagnosis of Traumatic Brain Injury. Medicina 2020;56:87
  • Mac Donald CL, Barber J, Jordan M, Johnson AM, Dikmen S, Fann JR et al. Early clinical predictors of 5-year outcome after concussive blast traumatic brain injury. JAMA Neurol 2017;74, 821–829.
  • Gardner RC and Yaffe K. Epidemiology of mild traumatic brain injury and neurodegenerative disease. Mol. Cell. Neurosci, 2015;66:75–80.
  • Jagoda AS, Bazarian JJ, Bruns JJ, Cantrill SV, Gean AD, Howard PK, Ghajar J, Riggio S, Wright DW, Wears RL et al. Clinical policy: Neuroimaging and decisionmaking in adult mild traumatic brain injury in the acute setting. Ann. Emerg. Med. 2008; 52:714–748.
  • Tomar GS, Singha GP, Lahkarb D, Sengarc K, Nigamd R, Mohand M, Anindyad R. Review: New biomarkers in brain trauma. Clinica Chimica Acta, 2018;487:325–329.
  • Li Y, Zhang L, Kallakuri S, Cohen A, Cavanaugh JM. Correlation of mechanical impact responses and biomarker levels: A new model for biomarker evaluation in TBI. J. Neurol. Sci 2015;359(1–2): 280–286.
  • Anderson KJ, Scheff SW, Miller KM, et al. The phosphorylated axonal form of the neurofilament subunit NF-H (pNF-H) as a blood biomarker of traumatic brain injury. J. Neurotrauma 2008;25(9):1079–1085.
  • Julien JP, Mushynski WE. Neurofilaments in health and disease, Prog. Nucleic Acid Res. Mol. Biol 1998;61:1–23.
  • Posmantur RM, Zhao X, Kampfl A, Clifton GL, Hayes RL. Immunoblot analyses of the relative contributions of cysteine and aspartic proteases to neurofilament breakdown products following experimental brain injury in rats. Neurochemical research 1998;23(10):1265–1276.
  • Siman R, Toraskar N, Dang A, McNeil E, M. McGarvey M, J. Plaum J, E. Maloney E, M.S. Grady MS. A panel of neuron-enriched proteins as markers for traumatic brain injury in humans, J. Neurotrauma, 2009;26 (11):1867–1877.
  • Neselius S, Zetterberg H, Blennow K, Marcusson J, Brisby H. Increased CSF levels of phosphorylated neurofilament heavy protein following bout in amateur boxers. PLoS ONE, 2013;8(11):81249.
  • Zurek J, Bartlova L, Fedora M. Hyperphosphorylated neurofilament NF-H as a predictor of mortality after brain injury in children. Brain Inj 2011;25 (2):221–226.
  • Marmarou A, Foda MA, van den Brink W, Campbell J, Kita H, Demetriadou K: A new model of diffuse brain injury in rats. Part I: Pathophysiology and biomechanics. J Neurosurg 1994;80(2):291-300.
  • Benady A, Freidin D, Pick CG, Rubovitch V. GM1 ganglioside prevents axonal regeneration inhibition and cognitive defcits in a mouse model of traumatic brain injury. Scientific Reports, 2018;8:13340
  • Buki, A. and Povlishock, J.T. All roads lead to disconnection?– Traumatic axonal injury revisited. Acta Neurochir (Wien) 2006;148:181–193.
  • Shaw G, Yang C, Ellis R, Anderson K, Mickle J, Scheff S, Pike B, Anderson D and Howland, D. Hyperphosphorylated neurofilament NF-H is a serum biomarker of axonal injury. Biochem. Biophys. Res. Commun. 2005;336:1268–1277.
  • Gordon BA. Neurofilaments in disease: what do we know? Curr Opin Neurobiol 2020;61:105-115.
  • Yang Z, Zhu T, Mondello S, Akel M, Wong AT, Kothari IM, Lin F, Shear DA, Gilsdorf JS, Leung LY, Bramlett HM, Dixon CE, Dietrich WD, Hayes RL, Povlishock TJ, Tortella FC, Kochanek PM, Wang KK. Serum-based phosphoneurofilament-heavy protein as theranostic biomarker in three models of traumatic brain injury: an operation brain trauma therapy study, J Neurotrauma 2019;36(2):348-359.
  • Park HO, Kim JW, Kim SH, Moon SH, Byun JH, Kim KN ve ark. Usability verification of the Emergency Trauma Score (EMTRAS) and Rapid Emergency Medicine Score (REMS) in patients with trauma: A retrospective cohort study. Medicine (Baltimore) 2017;96(44):8449.
  • Capizzi A, Woo J & Verduzco-Gutierrez M. Traumatic Brain Injury: An Overview of Epidemiology, Pathophysiology, and Medical Management. Med Clin North Am 2020;104(2), 213-238.
  • Shackelford SA, Del Junco DJ, Reade MC, Bell R, Becker T, Gurney J ve ark. Association of time to craniectomy with survival in patients with severe combat-related brain injury. Neurosurg Focus 2018;45(6):2.
  • Karasu A, Sabancı PA, Cansever T, et al. Kafa travmalı hastalarda epidemiyolojik çalışma. Ulus Travma Acil Cerrahi Derg. 2009;15(2):159-63.
  • Çıkrıklar H, Ekici MA, Coşan D, Ekici A, Üstündağ Y, Karaali M, Kaynak M, Uz K, Baydemir C, Yürümez Y. Serum GFAP Düzeyi, Minor Kafa Travmalı Çocuklarda Beyin Tomografisine Alternatif Olabilir Mi? Bozok Tıp Derg 2014; 4(1):6-12.
  • Czeiter E, Amrein K, Gravesteijn BY, Lecky F, Menon DK, Mondello S ve ark. Blood biomarkers on admission in acute traumatic brain injury: Relations to severity, CT findings and care path in the CENTER-TBI study. EBioMedicine 2020;56, 102785.
  • Shibahashi K, Doi T, Tanaka S, Hoda H, Chikuda H, Sawada Y, Takasu Y, Chiba K, Nozaki T, Hamabe Y, Ogata T. The Serum Phosphorylated Neurofilament Heavy Subunit as a Predictive Marker for Outcome in Adult Patients after Traumatic Brain Injury. J Neurotrauma, 2016;15;33(20):1826-1833
  • Cikriklar HI, Uysal O, Ekici MA, Ozbek Z, Cosan DT, Yucel M, et al. Effectiveness of GFAP in determining neuronal damage in rats with induced head trauma. Turk Neurosurg 2016;26(6):878–89.
Toplam 35 adet kaynakça vardır.

Ayrıntılar

Birincil Dil Türkçe
Konular Acil Tıp
Bölüm Özgün Araştırma Makaleleri
Yazarlar

Halil İbrahim Çıkrıklar 0000-0002-8073-6207

Vahide Aslıhan Durak 0000-0003-0836-7862

Tülin Alkan Bu kişi benim 0000-0001-6466-5042

Birnur Aydin 0000-0002-8193-474X

Deniz Sığırlı 0000-0002-4006-3263

Hakan Salcı 0000-0001-6548-8754

Erol Armagan 0000-0002-4641-9873

Yayımlanma Tarihi 1 Ağustos 2021
Kabul Tarihi 15 Haziran 2021
Yayımlandığı Sayı Yıl 2021 Cilt: 47 Sayı: 2

Kaynak Göster

APA Çıkrıklar, H. İ., Durak, V. A., Alkan, T., Aydin, B., vd. (2021). Deneysel Olarak Travmatik Beyin Hasarı Oluşturulan Ratlarda Serum pNF-H Düzeyinin Beyin Hasarını Göstermede Etkinliği. Uludağ Üniversitesi Tıp Fakültesi Dergisi, 47(2), 195-199. https://doi.org/10.32708/uutfd.938519
AMA Çıkrıklar Hİ, Durak VA, Alkan T, Aydin B, Sığırlı D, Salcı H, Armagan E. Deneysel Olarak Travmatik Beyin Hasarı Oluşturulan Ratlarda Serum pNF-H Düzeyinin Beyin Hasarını Göstermede Etkinliği. Uludağ Tıp Derg. Ağustos 2021;47(2):195-199. doi:10.32708/uutfd.938519
Chicago Çıkrıklar, Halil İbrahim, Vahide Aslıhan Durak, Tülin Alkan, Birnur Aydin, Deniz Sığırlı, Hakan Salcı, ve Erol Armagan. “Deneysel Olarak Travmatik Beyin Hasarı Oluşturulan Ratlarda Serum PNF-H Düzeyinin Beyin Hasarını Göstermede Etkinliği”. Uludağ Üniversitesi Tıp Fakültesi Dergisi 47, sy. 2 (Ağustos 2021): 195-99. https://doi.org/10.32708/uutfd.938519.
EndNote Çıkrıklar Hİ, Durak VA, Alkan T, Aydin B, Sığırlı D, Salcı H, Armagan E (01 Ağustos 2021) Deneysel Olarak Travmatik Beyin Hasarı Oluşturulan Ratlarda Serum pNF-H Düzeyinin Beyin Hasarını Göstermede Etkinliği. Uludağ Üniversitesi Tıp Fakültesi Dergisi 47 2 195–199.
IEEE H. İ. Çıkrıklar, “Deneysel Olarak Travmatik Beyin Hasarı Oluşturulan Ratlarda Serum pNF-H Düzeyinin Beyin Hasarını Göstermede Etkinliği”, Uludağ Tıp Derg, c. 47, sy. 2, ss. 195–199, 2021, doi: 10.32708/uutfd.938519.
ISNAD Çıkrıklar, Halil İbrahim vd. “Deneysel Olarak Travmatik Beyin Hasarı Oluşturulan Ratlarda Serum PNF-H Düzeyinin Beyin Hasarını Göstermede Etkinliği”. Uludağ Üniversitesi Tıp Fakültesi Dergisi 47/2 (Ağustos 2021), 195-199. https://doi.org/10.32708/uutfd.938519.
JAMA Çıkrıklar Hİ, Durak VA, Alkan T, Aydin B, Sığırlı D, Salcı H, Armagan E. Deneysel Olarak Travmatik Beyin Hasarı Oluşturulan Ratlarda Serum pNF-H Düzeyinin Beyin Hasarını Göstermede Etkinliği. Uludağ Tıp Derg. 2021;47:195–199.
MLA Çıkrıklar, Halil İbrahim vd. “Deneysel Olarak Travmatik Beyin Hasarı Oluşturulan Ratlarda Serum PNF-H Düzeyinin Beyin Hasarını Göstermede Etkinliği”. Uludağ Üniversitesi Tıp Fakültesi Dergisi, c. 47, sy. 2, 2021, ss. 195-9, doi:10.32708/uutfd.938519.
Vancouver Çıkrıklar Hİ, Durak VA, Alkan T, Aydin B, Sığırlı D, Salcı H, Armagan E. Deneysel Olarak Travmatik Beyin Hasarı Oluşturulan Ratlarda Serum pNF-H Düzeyinin Beyin Hasarını Göstermede Etkinliği. Uludağ Tıp Derg. 2021;47(2):195-9.
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ISSN: 1300-414X, e-ISSN: 2645-9027

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