A possible biomarker for methadone related deaths

Alessandro Pitruzzella, Paolo Procaccianti, Antonina Argo, Maria Laura Uzzo, Stefania Zerbo, Cettina Sortino, Giovanni Francesco Spatola, Stefania Zerbo, Steven B. Karch, Cettina Sortino, Antonietta Lanzarone, Antonina Argo, Paolo Procaccianti, Gabriella Roda, Veniero Gambaro, Fiorenza Farè, Antonietta Lanzarone

Risultato della ricerca: Article

1 Citazione (Scopus)

Abstract

Methadone (MTH) concentrations in those dying of MTH toxicity totally overlap concentrations where the presence of MTH is only an incidental finding, making it very difficult to make distinctions in actual cases. A biomarker, be it anatomical or biochemical for MTH toxicity is badly needed, particularly if that markers were known to disrupt effective ventilation. Because the brainstem houses the regulatory centers for cardiorespiratory-control enters, it would seem to be the most likely anatomical site to seek abnormalities in cardiorespiratory control. Objective To locate and describe the cells of nucleus of the solitary tract (TS)(NTS) in human brainstem and determine if neuronal cell death, either necrotic or apoptotic, within the TS of humans is more common in deaths due directly to MTH toxicity than with in the solitary tract itself. Design, setting, participants This was a single cohort study of MTH related decedents autopsied at a large university hospital. Each decedent had a recent history of non medical/illicit MTH use and had been pronounced dead in the field, prior to ever reaching the hospital. Complete autopsy and complete toxicology testing were performed on the formalin fixed brains of each individual. Multiple blocks were prepared of the area of interest, namely the tissue lying immediately between the inferior and the super colliculi. This volume, by definition, would have included the area of the Rostral Ventrolateral Medulla (RVLM), the location of the TS. Immunohistochemistry studies utilizing caspase-9 reaction (a protease enzyme involved in the process of preprogrammed death) were performed in order to estimate the degree and proportion of neuronal apoptosis, and also access the degree of classical necrosis within the NTS. Main outcomes and measures The primary outcome measure was the presence or absence of neuronal apoptosis and/or necrosis within the NTS. Results Cells displaying evidence of early apoptosis and advanced apoptosis, consisting primarily of nuclear fragmentation, admixed with other neurons displaying the features of classic necrosis were found. Evidence of classic necrosis was identifiable in most of the controls, though minor degrees of apoptosis were identifiable with Caspase staining and quantitative image analysis of immunohistochemical stains. Conclusions and Relevance: Our study shows that neurons, primarily along the TS, but occasionally in other cell nuclei (even controls) are vulnerable, both to direct MTH toxicity (via apoptosis) and indirectly (via hypoxia leading to classical cell necrosis). When MTH is found to be present in significant concentrations, but apoptotic lesions are absent, it would be reasonable to assume that MTH was not primarily the cause of cardiorespiratory arrest.
Lingua originaleEnglish
pagine (da-a)8-14
Numero di pagine7
RivistaJournal of Forensic and Legal Medicine
Volume49
Stato di pubblicazionePublished - 2017

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Methadone
Biomarkers
death
Apoptosis
Necrosis
dying
fragmentation
evidence
brain
Cell Nucleus
Brain Stem
cause
Outcome Assessment (Health Care)
university
Neurons
history
Inferior Colliculi
Solitary Nucleus
Incidental Findings
Caspase 9

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Law

Cita questo

A possible biomarker for methadone related deaths. / Pitruzzella, Alessandro; Procaccianti, Paolo; Argo, Antonina; Uzzo, Maria Laura; Zerbo, Stefania; Sortino, Cettina; Spatola, Giovanni Francesco; Zerbo, Stefania; Karch, Steven B.; Sortino, Cettina; Lanzarone, Antonietta; Argo, Antonina; Procaccianti, Paolo; Roda, Gabriella; Gambaro, Veniero; Farè, Fiorenza; Lanzarone, Antonietta.

In: Journal of Forensic and Legal Medicine, Vol. 49, 2017, pag. 8-14.

Risultato della ricerca: Article

Pitruzzella, A, Procaccianti, P, Argo, A, Uzzo, ML, Zerbo, S, Sortino, C, Spatola, GF, Zerbo, S, Karch, SB, Sortino, C, Lanzarone, A, Argo, A, Procaccianti, P, Roda, G, Gambaro, V, Farè, F & Lanzarone, A 2017, 'A possible biomarker for methadone related deaths', Journal of Forensic and Legal Medicine, vol. 49, pagg. 8-14.
Pitruzzella, Alessandro ; Procaccianti, Paolo ; Argo, Antonina ; Uzzo, Maria Laura ; Zerbo, Stefania ; Sortino, Cettina ; Spatola, Giovanni Francesco ; Zerbo, Stefania ; Karch, Steven B. ; Sortino, Cettina ; Lanzarone, Antonietta ; Argo, Antonina ; Procaccianti, Paolo ; Roda, Gabriella ; Gambaro, Veniero ; Farè, Fiorenza ; Lanzarone, Antonietta. / A possible biomarker for methadone related deaths. In: Journal of Forensic and Legal Medicine. 2017 ; Vol. 49. pagg. 8-14.
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abstract = "Methadone (MTH) concentrations in those dying of MTH toxicity totally overlap concentrations where the presence of MTH is only an incidental finding, making it very difficult to make distinctions in actual cases. A biomarker, be it anatomical or biochemical for MTH toxicity is badly needed, particularly if that markers were known to disrupt effective ventilation. Because the brainstem houses the regulatory centers for cardiorespiratory-control enters, it would seem to be the most likely anatomical site to seek abnormalities in cardiorespiratory control. Objective To locate and describe the cells of nucleus of the solitary tract (TS)(NTS) in human brainstem and determine if neuronal cell death, either necrotic or apoptotic, within the TS of humans is more common in deaths due directly to MTH toxicity than with in the solitary tract itself. Design, setting, participants This was a single cohort study of MTH related decedents autopsied at a large university hospital. Each decedent had a recent history of non medical/illicit MTH use and had been pronounced dead in the field, prior to ever reaching the hospital. Complete autopsy and complete toxicology testing were performed on the formalin fixed brains of each individual. Multiple blocks were prepared of the area of interest, namely the tissue lying immediately between the inferior and the super colliculi. This volume, by definition, would have included the area of the Rostral Ventrolateral Medulla (RVLM), the location of the TS. Immunohistochemistry studies utilizing caspase-9 reaction (a protease enzyme involved in the process of preprogrammed death) were performed in order to estimate the degree and proportion of neuronal apoptosis, and also access the degree of classical necrosis within the NTS. Main outcomes and measures The primary outcome measure was the presence or absence of neuronal apoptosis and/or necrosis within the NTS. Results Cells displaying evidence of early apoptosis and advanced apoptosis, consisting primarily of nuclear fragmentation, admixed with other neurons displaying the features of classic necrosis were found. Evidence of classic necrosis was identifiable in most of the controls, though minor degrees of apoptosis were identifiable with Caspase staining and quantitative image analysis of immunohistochemical stains. Conclusions and Relevance: Our study shows that neurons, primarily along the TS, but occasionally in other cell nuclei (even controls) are vulnerable, both to direct MTH toxicity (via apoptosis) and indirectly (via hypoxia leading to classical cell necrosis). When MTH is found to be present in significant concentrations, but apoptotic lesions are absent, it would be reasonable to assume that MTH was not primarily the cause of cardiorespiratory arrest.",
author = "Alessandro Pitruzzella and Paolo Procaccianti and Antonina Argo and Uzzo, {Maria Laura} and Stefania Zerbo and Cettina Sortino and Spatola, {Giovanni Francesco} and Stefania Zerbo and Karch, {Steven B.} and Cettina Sortino and Antonietta Lanzarone and Antonina Argo and Paolo Procaccianti and Gabriella Roda and Veniero Gambaro and Fiorenza Far{\`e} and Antonietta Lanzarone",
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TY - JOUR

T1 - A possible biomarker for methadone related deaths

AU - Pitruzzella, Alessandro

AU - Procaccianti, Paolo

AU - Argo, Antonina

AU - Uzzo, Maria Laura

AU - Zerbo, Stefania

AU - Sortino, Cettina

AU - Spatola, Giovanni Francesco

AU - Zerbo, Stefania

AU - Karch, Steven B.

AU - Sortino, Cettina

AU - Lanzarone, Antonietta

AU - Argo, Antonina

AU - Procaccianti, Paolo

AU - Roda, Gabriella

AU - Gambaro, Veniero

AU - Farè, Fiorenza

AU - Lanzarone, Antonietta

PY - 2017

Y1 - 2017

N2 - Methadone (MTH) concentrations in those dying of MTH toxicity totally overlap concentrations where the presence of MTH is only an incidental finding, making it very difficult to make distinctions in actual cases. A biomarker, be it anatomical or biochemical for MTH toxicity is badly needed, particularly if that markers were known to disrupt effective ventilation. Because the brainstem houses the regulatory centers for cardiorespiratory-control enters, it would seem to be the most likely anatomical site to seek abnormalities in cardiorespiratory control. Objective To locate and describe the cells of nucleus of the solitary tract (TS)(NTS) in human brainstem and determine if neuronal cell death, either necrotic or apoptotic, within the TS of humans is more common in deaths due directly to MTH toxicity than with in the solitary tract itself. Design, setting, participants This was a single cohort study of MTH related decedents autopsied at a large university hospital. Each decedent had a recent history of non medical/illicit MTH use and had been pronounced dead in the field, prior to ever reaching the hospital. Complete autopsy and complete toxicology testing were performed on the formalin fixed brains of each individual. Multiple blocks were prepared of the area of interest, namely the tissue lying immediately between the inferior and the super colliculi. This volume, by definition, would have included the area of the Rostral Ventrolateral Medulla (RVLM), the location of the TS. Immunohistochemistry studies utilizing caspase-9 reaction (a protease enzyme involved in the process of preprogrammed death) were performed in order to estimate the degree and proportion of neuronal apoptosis, and also access the degree of classical necrosis within the NTS. Main outcomes and measures The primary outcome measure was the presence or absence of neuronal apoptosis and/or necrosis within the NTS. Results Cells displaying evidence of early apoptosis and advanced apoptosis, consisting primarily of nuclear fragmentation, admixed with other neurons displaying the features of classic necrosis were found. Evidence of classic necrosis was identifiable in most of the controls, though minor degrees of apoptosis were identifiable with Caspase staining and quantitative image analysis of immunohistochemical stains. Conclusions and Relevance: Our study shows that neurons, primarily along the TS, but occasionally in other cell nuclei (even controls) are vulnerable, both to direct MTH toxicity (via apoptosis) and indirectly (via hypoxia leading to classical cell necrosis). When MTH is found to be present in significant concentrations, but apoptotic lesions are absent, it would be reasonable to assume that MTH was not primarily the cause of cardiorespiratory arrest.

AB - Methadone (MTH) concentrations in those dying of MTH toxicity totally overlap concentrations where the presence of MTH is only an incidental finding, making it very difficult to make distinctions in actual cases. A biomarker, be it anatomical or biochemical for MTH toxicity is badly needed, particularly if that markers were known to disrupt effective ventilation. Because the brainstem houses the regulatory centers for cardiorespiratory-control enters, it would seem to be the most likely anatomical site to seek abnormalities in cardiorespiratory control. Objective To locate and describe the cells of nucleus of the solitary tract (TS)(NTS) in human brainstem and determine if neuronal cell death, either necrotic or apoptotic, within the TS of humans is more common in deaths due directly to MTH toxicity than with in the solitary tract itself. Design, setting, participants This was a single cohort study of MTH related decedents autopsied at a large university hospital. Each decedent had a recent history of non medical/illicit MTH use and had been pronounced dead in the field, prior to ever reaching the hospital. Complete autopsy and complete toxicology testing were performed on the formalin fixed brains of each individual. Multiple blocks were prepared of the area of interest, namely the tissue lying immediately between the inferior and the super colliculi. This volume, by definition, would have included the area of the Rostral Ventrolateral Medulla (RVLM), the location of the TS. Immunohistochemistry studies utilizing caspase-9 reaction (a protease enzyme involved in the process of preprogrammed death) were performed in order to estimate the degree and proportion of neuronal apoptosis, and also access the degree of classical necrosis within the NTS. Main outcomes and measures The primary outcome measure was the presence or absence of neuronal apoptosis and/or necrosis within the NTS. Results Cells displaying evidence of early apoptosis and advanced apoptosis, consisting primarily of nuclear fragmentation, admixed with other neurons displaying the features of classic necrosis were found. Evidence of classic necrosis was identifiable in most of the controls, though minor degrees of apoptosis were identifiable with Caspase staining and quantitative image analysis of immunohistochemical stains. Conclusions and Relevance: Our study shows that neurons, primarily along the TS, but occasionally in other cell nuclei (even controls) are vulnerable, both to direct MTH toxicity (via apoptosis) and indirectly (via hypoxia leading to classical cell necrosis). When MTH is found to be present in significant concentrations, but apoptotic lesions are absent, it would be reasonable to assume that MTH was not primarily the cause of cardiorespiratory arrest.

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M3 - Article

VL - 49

SP - 8

EP - 14

JO - Journal of Forensic and Legal Medicine

JF - Journal of Forensic and Legal Medicine

SN - 1752-928X

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