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Article ; Online: Blast-Induced Neurotrauma Results in Spatially Distinct Gray Matter Alteration Alongside Hormonal Alteration: A Preliminary Investigation.

Hellewell, Sarah C / Granger, Douglas A / Cernak, Ibolja

International journal of molecular sciences

2023 Volume 24, Issue 7

Abstract: Blast-induced neurotrauma (BINT) frequently occurs during military training and deployment and has been linked to long-term neuropsychological and neurocognitive changes, and changes in brain structure. As military personnel experience frequent exposures ...

Abstract	Blast-induced neurotrauma (BINT) frequently occurs during military training and deployment and has been linked to long-term neuropsychological and neurocognitive changes, and changes in brain structure. As military personnel experience frequent exposures to stress, BINT may negatively influence stress coping abilities. This study aimed to determine the effects of BINT on gray matter volume and hormonal alteration. Participants were Canadian Armed Forces personnel and veterans with a history of BINT (
MeSH term(s)	Humans ; Blast Injuries ; Hydrocortisone ; Gray Matter ; Canada ; Brain ; Magnetic Resonance Imaging
Chemical Substances	Hydrocortisone (WI4X0X7BPJ)
Language	English
Publishing date	2023-04-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24076797
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Article ; Online: Blast-Induced Neurotrauma Results in Spatially Distinct Gray Matter Alteration Alongside Hormonal Alteration

Sarah C. Hellewell / Douglas A. Granger / Ibolja Cernak

International Journal of Molecular Sciences, Vol 24, Iss 6797, p

A Preliminary Investigation

2023 Volume 6797

Abstract	Blast-induced neurotrauma (BINT) frequently occurs during military training and deployment and has been linked to long-term neuropsychological and neurocognitive changes, and changes in brain structure. As military personnel experience frequent exposures to stress, BINT may negatively influence stress coping abilities. This study aimed to determine the effects of BINT on gray matter volume and hormonal alteration. Participants were Canadian Armed Forces personnel and veterans with a history of BINT ( n = 12), and first responder controls ( n = 8), recruited due to their characteristic occupational stress professions. Whole saliva was collected via passive drool on the morning of testing and analyzed for testosterone (pg/mL), cortisol (μg/dL), and testosterone/cortisol (T/C) ratio. Voxel-based morphometry was performed to compare gray matter (GM) volume, alongside measurement of cortical thickness and subcortical volumes. Saliva analyses revealed distinct alterations following BINT, with significantly elevated testosterone and T/C ratio. Widespread and largely symmetric loci of reduced GM were found specific to BINT, particularly in the temporal gyrus, precuneus, and thalamus. These findings suggest that BINT affects hypothalamic–pituitary–adrenal and –gonadal axis function, and causes anatomically-specific GM loss, which were not observed in a comparator group with similar occupational stressors. These findings support BINT as a unique injury with distinct structural and endocrine consequences.
Keywords	blast (explosion) wave-induced neurotrauma ; traumatic brain injury (craniocerebral trauma) ; brain volume changes ; occupational stress ; testosterone ; military ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	150
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Understanding blast-induced neurotrauma: how far have we come?

Cernak, Ibolja

Concussion (London, England)

2017 Volume 2, Issue 3, Page(s) CNC42

Abstract: Blast injuries, including blast-induced neurotrauma (BINT), are caused by blast waves generated during an explosion. Accordingly, their history coincides with that of explosives. Hence, it is intriguing that, after more than 1000 years of using ... ...

Abstract	Blast injuries, including blast-induced neurotrauma (BINT), are caused by blast waves generated during an explosion. Accordingly, their history coincides with that of explosives. Hence, it is intriguing that, after more than 1000 years of using explosives, our understanding of the pathological consequences of blast and body/brain interactions is extremely limited. Postconflict recovery mechanisms seemingly include the suppression of painful experiences, such as explosive injuries. Unfortunately, ignoring the knowledge generated by previous generations of scientists retards research progress, leading to superfluous and repetitive studies. This article summarizes clinical and experimental findings published about blast injuries and BINT following the wars of the 20th and 21th centuries. Moreover, it offers a personal view on potential factors interfering with the progress of BINT research working toward providing better diagnosis, treatment and rehabilitation for military personnel affected by blast exposure.
Language	English
Publishing date	2017-06-08
Publishing country	England
Document type	Journal Article ; Review
ISSN	2056-3299
ISSN (online)	2056-3299
DOI	10.2217/cnc-2017-0006
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Article: Blast-induced neurotrauma models and their requirements.

Cernak, Ibolja

Frontiers in neurology

2014 Volume 5, Page(s) 128

Language	English
Publishing date	2014-07-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564214-5
ISSN	1664-2295
ISSN	1664-2295
DOI	10.3389/fneur.2014.00128
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Article ; Online: Measuring Resilience to Operational Stress in Canadian Armed Forces Personnel.

Hellewell, Sarah C / Cernak, Ibolja

Journal of traumatic stress

2018 Volume 31, Issue 1, Page(s) 89–101

Abstract: Adaptability to stress is governed by innate resilience, comprised of complex neuroendocrine and immune mechanisms alongside inherited or learned behavioral traits. Based on their capacity to adapt, some people thrive in stressful situations, whereas ... ...

Abstract	Adaptability to stress is governed by innate resilience, comprised of complex neuroendocrine and immune mechanisms alongside inherited or learned behavioral traits. Based on their capacity to adapt, some people thrive in stressful situations, whereas others experience maladaptation. In our study, we used state-of-the-art tools to assess the resilience level in individuals, as well as their susceptibility to developing military stress-induced behavioral and cognitive deficits. To address this complex question, we tested Canadian Armed Forces (CAF) personnel in three distinct stress environments (baselines): during predeployment training, deployment in Afghanistan, and readjustment upon return to Canada. Our comprehensive outcome measures included psychometric tests, saliva biomarkers, and computerized cognitive tests that used the Cambridge Neuropsychological Automated Test Battery. Participants were categorized based on initial biomarker measurements as being at low-, moderate-, or high stress-maladaptation risk. Biomarkers showed significant changes (ds = 0.56 to 2.44) between baselines, calculated as "delta" changes. Participants at low stress-maladaptation risk demonstrated minimal changes, whereas those at high stress-maladaptation risk showed significant biomarker variations. The psychometric patterns and cognitive functions were likewise affected across baselines, suggesting that the panel of saliva stress biomarkers could be a useful tool for determining the risk of stress maladaptation that can cause psychological and cognitive decline.
MeSH term(s)	Adaptation, Psychological/physiology ; Adult ; Afghan Campaign 2001- ; Biomarkers/metabolism ; C-Reactive Protein/metabolism ; Canada ; Chromogranin A/metabolism ; Cognition Disorders/etiology ; Disease Susceptibility/psychology ; Female ; Humans ; Hydrocortisone/metabolism ; Male ; Mental Disorders/etiology ; Military Personnel/psychology ; Neuropsychological Tests ; Occupational Stress/metabolism ; Occupational Stress/psychology ; Psychiatric Status Rating Scales ; Resilience, Psychological ; Saliva/metabolism ; Testosterone/metabolism ; alpha-Amylases/metabolism
Chemical Substances	Biomarkers ; Chromogranin A ; Testosterone (3XMK78S47O) ; C-Reactive Protein (9007-41-4) ; alpha-Amylases (EC 3.2.1.1) ; Hydrocortisone (WI4X0X7BPJ)
Language	English
Publishing date	2018-02-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639478-4
ISSN	1573-6598 ; 0894-9867
ISSN (online)	1573-6598
ISSN	0894-9867
DOI	10.1002/jts.22261
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Article ; Online: In vivo imaging of nitric oxide in the male rat brain exposed to a shock wave.

Kawauchi, Satoko / Inaba, Masaki / Muramatsu, Yuriko / Kono, Akemi / Nishidate, Izumi / Adachi, Takeshi / Cernak, Ibolja / Sato, Shunichi

Journal of neuroscience research

2023 Volume 101, Issue 6, Page(s) 976–989

Abstract: While numerous studies have suggested the involvement of cerebrovascular dysfunction in the pathobiology of blast-induced traumatic brain injury (bTBI), its exact mechanisms and how they affect the outcome of bTBI are not fully understood. Our previous ... ...

Abstract	While numerous studies have suggested the involvement of cerebrovascular dysfunction in the pathobiology of blast-induced traumatic brain injury (bTBI), its exact mechanisms and how they affect the outcome of bTBI are not fully understood. Our previous study showed the occurrence of cortical spreading depolarization (CSD) and subsequent long-lasting oligemia/hypoxemia in the rat brain exposed to a laser-induced shock wave (LISW). We hypothesized that this hemodynamic abnormality is associated with shock wave-induced generation of nitric oxide (NO). In this study, to verify this hypothesis, we used an NO-sensitive fluorescence probe, diaminofluorescein-2 diacetate (DAF-2 DA), for real-time in vivo imaging of male Sprague-Dawley rats' brain exposed to a mild-impulse LISW. We observed the most intense fluorescence, indicative of NO production, along the pial arteriolar walls during the period of 10-30 min post-exposure, parallel with CSD occurrence. This post-exposure period also coincided with the early phase of hemodynamic abnormalities. While the changes in arteriolar wall fluorescence measured in rats receiving pharmacological NO synthase inhibition by nitro-L-arginine methyl ester (L-NAME) 24 h before exposure showed a temporal profile similar to that of changes observed in LISW-exposed rats with CSD, their intensity level was considerably lower; this suggests partial involvement of NOS in shock wave-induced NO production. To the best of our knowledge, this is the first real-time in vivo imaging of NO in rat brain, confirming the involvement of NO in shock-wave-induced hemodynamic impairments. Finally, we have outlined the limitations of this study and our future research directions.
MeSH term(s)	Rats ; Male ; Animals ; Nitric Oxide/pharmacology ; Rats, Sprague-Dawley ; Cortical Spreading Depression/physiology ; Brain ; Nitric Oxide Synthase ; Enzyme Inhibitors/pharmacology
Chemical Substances	Nitric Oxide (31C4KY9ESH) ; Nitric Oxide Synthase (EC 1.14.13.39) ; Enzyme Inhibitors
Language	English
Publishing date	2023-02-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	195324-2
ISSN	1097-4547 ; 0360-4012
ISSN (online)	1097-4547
ISSN	0360-4012
DOI	10.1002/jnr.25172
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Article ; Online: The importance of systemic response in the pathobiology of blast-induced neurotrauma.

Cernak, Ibolja

Frontiers in neurology

2010 Volume 1, Page(s) 151

Abstract: Due to complex injurious environment where multiple blast effects interact with the body parallel, blast-induced neurotrauma is a unique clinical entity induced by systemic, local, and cerebral responses. Activation of autonomous nervous system; sudden ... ...

Abstract	Due to complex injurious environment where multiple blast effects interact with the body parallel, blast-induced neurotrauma is a unique clinical entity induced by systemic, local, and cerebral responses. Activation of autonomous nervous system; sudden pressure increase in vital organs such as lungs and liver; and activation of neuroendocrine-immune system are among the most important mechanisms that contribute significantly to molecular changes and cascading injury mechanisms in the brain. It has been hypothesized that vagally mediated cerebral effects play a vital role in the early response to blast: this assumption has been supported by experiments where bilateral vagotomy mitigated bradycardia, hypotension, and apnea, and also prevented excessive metabolic alterations in the brain of animals exposed to blast. Clinical experience suggests specific blast-body-nervous system interactions such as (1) direct interaction with the head either through direct passage of the blast wave through the skull or by causing acceleration and/or rotation of the head; and (2) via hydraulic interaction, when the blast overpressure compresses the abdomen and chest, and transfers its kinetic energy to the body's fluid phase, initiating oscillating waves that traverse the body and reach the brain. Accumulating evidence suggests that inflammation plays important role in the pathogenesis of long-term neurological deficits due to blast. These include memory decline, motor function and balance impairments, and behavioral alterations, among others. Experiments using rigid body- or head protection in animals subjected to blast showed that head protection failed to prevent inflammation in the brain or reduce neurological deficits, whereas body protection was successful in alleviating the blast-induced functional and morphological impairments in the brain.
Language	English
Publishing date	2010-12-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564214-5
ISSN	1664-2295 ; 1664-2295
ISSN (online)	1664-2295
ISSN	1664-2295
DOI	10.3389/fneur.2010.00151
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Article: Perspectives on Primary Blast Injury of the Brain: Translational Insights Into Non-inertial Low-Intensity Blast Injury.

Siedhoff, Heather R / Chen, Shanyan / Song, Hailong / Cui, Jiankun / Cernak, Ibolja / Cifu, David X / DePalma, Ralph G / Gu, Zezong

Frontiers in neurology

2022 Volume 12, Page(s) 818169

Abstract: Most traumatic brain injuries (TBIs) during military deployment or training are clinically "mild" and frequently caused by non-impact blast exposures. Experimental models were developed to reproduce the biological consequences of high-intensity blasts ... ...

Abstract	Most traumatic brain injuries (TBIs) during military deployment or training are clinically "mild" and frequently caused by non-impact blast exposures. Experimental models were developed to reproduce the biological consequences of high-intensity blasts causing moderate to severe brain injuries. However, the pathophysiological mechanisms of low-intensity blast (LIB)-induced neurological deficits have been understudied. This review provides perspectives on primary blast-induced mild TBI models and discusses translational aspects of LIB exposures as defined by standardized physical parameters including overpressure, impulse, and shock wave velocity. Our mouse LIB-exposure model, which reproduces deployment-related scenarios of open-field blast (OFB), caused neurobehavioral changes, including reduced exploratory activities, elevated anxiety-like levels, impaired nesting behavior, and compromised spatial reference learning and memory. These functional impairments associate with subcellular and ultrastructural neuropathological changes, such as myelinated axonal damage, synaptic alterations, and mitochondrial abnormalities occurring in the absence of gross- or cellular damage. Biochemically, we observed dysfunctional mitochondrial pathways that led to elevated oxidative stress, impaired fission-fusion dynamics, diminished mitophagy, decreased oxidative phosphorylation, and compensated cell respiration-relevant enzyme activity. LIB also induced increased levels of total tau, phosphorylated tau, and amyloid β peptide, suggesting initiation of signaling cascades leading to neurodegeneration. We also compare translational aspects of OFB findings to alternative blast injury models. By scoping relevant recent research findings, we provide recommendations for future preclinical studies to better reflect military-operational and clinical realities. Overall, better alignment of preclinical models with clinical observations and experience related to military injuries will facilitate development of more precise diagnosis, clinical evaluation, treatment, and rehabilitation.
Language	English
Publishing date	2022-01-13
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2564214-5
ISSN	1664-2295
ISSN	1664-2295
DOI	10.3389/fneur.2021.818169
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Article ; Online: Creating a Distinct Medication-Use System for Children at the Point of Care: The Time is Now.

Ii, Richard Parrish / Cernak, Ibolja

Pharmacy (Basel, Switzerland)

2015 Volume 3, Issue 3, Page(s) 72–78

Abstract: Children need a distinct medicines-use system designed explicitly for them since their continued inclusion in a system of prescription processing developed for adults generates insoluble risk points and workarounds. The American Academy of Pediatrics ( ... ...

Abstract	Children need a distinct medicines-use system designed explicitly for them since their continued inclusion in a system of prescription processing developed for adults generates insoluble risk points and workarounds. The American Academy of Pediatrics (AAP), in its policy statement released by the AAP Committee on Drugs in early 2014 about off-label use in children, posits that federal legislation on increased drug testing in children has been effective, as "there have been over 500 pediatric-specific labeling changes." However, the AAP's position has not changed materially since the original 2002 policy statement. Indeed, other health professionals, their organizations, or affiliated practice-based research network (PBRNs) mechanisms continue to be excluded from consideration, collaboration, or even honorable mention. It is noteworthy that most of the 500 labeling changes made since 1997 have addressed the scientific validity of indications for medication use in pediatric population without regard to pharmacotherapy formulation or monitoring. Medication use in children continues to be associated with an unacceptably high rate of adverse events, morbidity, and death. Children should no longer be "shoehorned" into the adult medication-use system, which faces challenges in addressing even the adult population's needs. The time is now to design a multi-phasic, systematic approach to the pharmacotherapy of children. This paper will argue for the establishment of a distinct medication use system for children, a trans-disciplinary system designed thoughtfully and intentionally, not by convention, consensus, or imitation.
Language	English
Publishing date	2015-06-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2737194-3
ISSN	2226-4787 ; 2226-4787
ISSN (online)	2226-4787
ISSN	2226-4787
DOI	10.3390/pharmacy3030072
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Article ; Online: Creating a Distinct Medication-Use System for Children at the Point of Care

Richard Parrish II / Ibolja Cernak

Pharmacy, Vol 3, Iss 3, Pp 72-

The Time is Now

2015 Volume 78

Abstract	Children need a distinct medicines-use system designed explicitly for them since their continued inclusion in a system of prescription processing developed for adults generates insoluble risk points and workarounds. The American Academy of Pediatrics (AAP), in its policy statement released by the AAP Committee on Drugs in early 2014 about off-label use in children, posits that federal legislation on increased drug testing in children has been effective, as “there have been over 500 pediatric-specific labeling changes.” However, the AAP’s position has not changed materially since the original 2002 policy statement. Indeed, other health professionals, their organizations, or affiliated practice-based research network (PBRNs) mechanisms continue to be excluded from consideration, collaboration, or even honorable mention. It is noteworthy that most of the 500 labeling changes made since 1997 have addressed the scientific validity of indications for medication use in pediatric population without regard to pharmacotherapy formulation or monitoring. Medication use in children continues to be associated with an unacceptably high rate of adverse events, morbidity, and death. Children should no longer be “shoehorned” into the adult medication-use system, which faces challenges in addressing even the adult population’s needs. The time is now to design a multi-phasic, systematic approach to the pharmacotherapy of children. This paper will argue for the establishment of a distinct medication use system for children, a trans-disciplinary system designed thoughtfully and intentionally, not by convention, consensus, or imitation.
Keywords	AAP Committee on Drugs ; medication-use system ; off-label ; pediatrics ; pharmacotherapy ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
Subject code	360
Publishing date	2015-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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