Relative Deficiency of Plasma A Disintegrin and Metalloprotease with Thrombospondin Type 1 Repeats 13 Activity and Elevation of Human Neutrophil Peptides in Patients with Traumatic Brain Injury

Background: In hospital-based studies, hypotension (HT, SBP <90) is more likely to occur in multisystem traumatic brain injury (MTBI) than isolated (ITBI). However, there are few EMS studies on this issue. Hypothesis: Prehospital HT is associated with differential effects in MTBI and ITBI and these effects are influenced by the severity of primary brain injury. Methods: Inclusion: TBI cases in the EPIC Study (NIH 1R01NS071049) before TBI guideline implementation (1/07-3/14). ITBI: Major TBI cases (CDC Barell Matrix Type 1) that had no injury with ICD9-based Regional Severity Score [RSS (AIS equivalent)] ≥3 in any other body region. MTBI: Type 1 TBI plus at least one non-head region injury with RSS ≥3. Results: Included were 13,435 cases [Excl: age <10 (5.9%), missing data (6.2%)]. 10,374 (77.2%) were ITBI, 3061 (22.8%) MTBI. Mortality: ITBI: 7.7% (797/10,374), MTBI: 19.2% (587/3061, p<0.0001). Prehospital HT occurred 3.5 times more often in MTBI (14.8%, 453/3061 vs 4.2%, 437/10,374; p<0.0001). Among HT cases, 40.8% (185/453) with MTBI died vs 30.9% with ITBI (135/437; p<0.0001). In the hypotensive moderate/severe TBI cohort (RSS-Head 3/4), MTBI mortality was 2.4 times higher (17.2%, 40/232) than ITBI (7.1%, 17/240, p = 0.001). However, in the hypotensive very/extremely severe TBI group (RSS-Head 5/6), mortality was almost identical in MTBI (73.4%, 141/192) and ITBI (72.1%, 116/161, p = 0.864). Conclusion: Among major TBI patients with prehospital HT, those with MTBI were much more likely to die than those with ITBI. However, this association varied dramatically with TBI severity. In mod/severe TBI cases with HT, MTBI mortality was 2.4 times higher than in ITBI. In contrast, in very/extremely severe TBI with HT, there was no identifiable mortality difference. Thus, in cases with substantial potential to survive the primary brain injury (mod/severe), outcome is markedly worse in patients with multisystem injuries. However, in very/extremely severe TBI, non-head region injuries have no apparent association with mortality. This may be because the TBI is the primary factor leading to death in these cases. The main EPIC study is evaluating whether this severity-based difference in “effect” has implications for TBI guideline treatment effectiveness.

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Astrocytic ceruloplasmin expression, which is induced by IL-1? and by traumatic brain injury, increases in the absence of the IL-1 type 1 receptor

Glia ◽

10.1002/glia.10273 ◽

2003 ◽

Vol 44 (1) ◽

pp. 76-84 ◽

Cited By ~ 30

Author(s):

Christopher J. Kuhlow ◽

J. Kyle Krady ◽

Anirban Basu ◽

Steven W. Levison

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury

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Traumatic brain injury associated with dementia risk among people with type 1 diabetes

Neurology ◽

10.1212/wnl.0000000000006391 ◽

2018 ◽

Vol 91 (17) ◽

pp. e1611-e1618 ◽

Cited By ~ 3

Author(s):

Paola Gilsanz ◽

Kathleen Albers ◽

Michal Schnaider Beeri ◽

Andrew J. Karter ◽

Charles P. Quesenberry ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Type 1 Diabetes ◽

Brain Injury ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Competing Risk ◽

Middle Aged ◽

Risk Of Death ◽

Dementia Risk

ObjectiveTo examine the association between traumatic brain injury (TBI) and dementia risk among a cohort of middle-aged and elderly individuals with type 1 diabetes (T1D).MethodsWe evaluated 4,049 members of an integrated health care system with T1D ≥50 years old between January 1, 1996, and September 30, 2015. Dementia and TBI diagnoses throughout the study period were abstracted from medical records. Cox proportional hazards models estimated associations between time-dependent TBI and dementia adjusting for demographics, HbA1c, nephropathy, neuropathy, stroke, peripheral artery disease, depression, and dysglycemic events. Fine and Gray regression models evaluated the association between baseline TBI and dementia risk accounting for competing risk of death.ResultsA total of 178 individuals (4.4%) experienced a TBI and 212 (5.2%) developed dementia. In fully adjusted models, TBI was associated with 3.6 times the dementia risk (hazard ratio [HR] 3.64; 95% confidence interval [CI] 2.34, 5.68). When accounting for the competing risk of death, TBI was associated with almost 3 times the risk of dementia (HR 2.91; 95% CI 1.29, 5.68).ConclusionThis study demonstrates a marked increase in risk of dementia associated with TBI among middle-aged and elderly people with T1D. Given the complexity of self-care for individuals with T1D, and the comorbidities that predispose them to trauma and falls, future work is needed on interventions protecting brain health in this vulnerable population, which is now living to old age.

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Abstract TP445: Angiotensin Receptor Type 1 Deficiency Attenuates Brain Damage and Improves Outcome After Experimental Traumatic Brain Injury

Stroke ◽

10.1161/str.47.suppl_1.tp445 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Jong Youl Kim ◽

Nuri Kim ◽

Meshell Johnson ◽

Midoir A. Yenari

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Lesion Size ◽

Receptor Type ◽

Neurological Deficits ◽

Brain Hemorrhage ◽

Angiotensin Ii Receptor ◽

Improved Outcomes ◽

Adhesive Removal

Inflammation which accompanies traumatic brain injury (TBI) can exacerbate neurological deficits. Thus, anti-inflammatory treatments have the potential to improve outcome. Angiotensin II receptor type 1 (ART1) mediates vasoconstriction, and its inhibition has been widely used to treat hypertension. However, recent work has suggested that it may also modulate apoptosis, and neuroinflammation. Thus, treatment with already available ART1 blockers may have additional neuroprotective value. We explore the contribution of ART1 to neuroprotection and brain hemorrhage in a model of TBI. Male, wildtype (Wt) and ART1 knockout (Ko) mice were subjected to TBI using controlled cortical impact (CCI). This model leads to reproducible traumatic brain injury with disruption of motor function and hemorrhage into the area of injury. Sensorimotor function (adhesive removal & elevated body swing tests), brain hemorrhage and lesion size were assessed at 3, 7 and 14 days. To explore the clinical relevance of ART1 in brain injury, we also gave Wt mice an ATR1 inhibitor (candesartan, 0.1mg/kg IP). We found that ATR1 deficient mice were protected from CCI as evidenced by decreased lesion and hemorrhage volumes (decreases of ∼40% in lesion size amongst Ko mice, n=6/group, p<0.05), improved neurobehavioral outcomes (n=6/group, p<0.05) and fewer activated microglia in Ko mice (p<0.05). This was also associated with decreased cytokine expression relative to Wt. Candesartan similarly protected against brain injury and improved neurological outcome out to 14 days post CCI (n=6/group, p<0.05). These data are consistent with the notion that ART1 contributes negatively to traumatic brain injury, and its inhibition or deficiency leads to improved outcomes and decreased immune responses. Considering the clinical availability of ART1 inhibitors, this approach may be a promising novel therapeutic target against TBI and related conditions including stroke.

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Abstract 4: The Effect of Prehospital Hypoxia and Hypotension on Outcome in Major Traumatic Brain Injury: A Deadly Combination

Circulation ◽

10.1161/circ.130.suppl_2.4 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Daniel W Spaite ◽

Uwe Stolz ◽

Bentley J Bobrow ◽

Vatsal Chikani ◽

Duane Sherrill ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Trauma Center ◽

Treatment Guidelines ◽

Controlled Study ◽

Negative Effect ◽

Severe Tbi ◽

The Impact ◽

The Relationship

BACKGROUND: Hypoxia (HOx) or hypotension (HT) occurring during the EMS management of major traumatic brain injury-TBI reduces survival. However, little is known about the impact of both HOx and HT, occurring together, on outcome. Only a handful of reports have studied the combination of prehospital HOx/HT in TBI and the largest of these only had 14 cases with both. Objectives: To evaluate the associations between mortality and prehospital HOx and HT, both separately and in combination. METHODS: All moderate/severe TBI cases (CDC Barell Matrix Type-1) in the Excellence in Prehospital Injury Care (EPIC) TBI Study (a statewide, before/after controlled study of the impact of implementing the EMS TBI Treatment Guidelines-NIH/NINDS: 1R01NS071049) from 1/1/08-6/30/12 were evaluated [exclusions: age<10; death before ED arrival; EMS O2 saturation-“sat”<11%; EMS SBP less than 40 or greater than 200; missing sat (5.4% of cases) or SBP (3.1% of cases)]. The relationship between mortality and HOx (sat <90) and/or HT (SBP<90) was assessed with crude and adjusted odds ratios (cOR, aOR) using multivariable logistic regression, controlling for important confounders (see Figure) and accounting for clustering by Trauma Center. RESULTS: 9194 cases were included [Median age: 46 (IQR: 26-65); Male: 68.1%]. 8109 (88.2%) had no HOx/HT, 535 (5.8%) had HOx only, 419 (4.6%) had HT only, and 131 (1.4%) had both HOx/HT. The Figure shows the cORs and aORs for death. CONCLUSION: In this large analysis of major TBI, prehospital HOx and HT were associated with significantly increased mortality. However, the combination of HT and HOx together had a profoundly-negative effect on survival even after controlling for significant confounders. In fact, the aOR for death in patients with both HOx/HT was more than 3 times greater than for those with HOx or HT alone. Since the TBI Guidelines emphasize the prevention and treatment of HOx and HT, their implementation has the potential to significantly impact outcome.

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Plasminogen Activator Inhibitor Type 1: A Possible Novel Biomarker of Late Pituitary Dysfunction after Mild Traumatic Brain Injury

Journal of Neurotrauma ◽

10.1089/neu.2017.5198 ◽

2017 ◽

Vol 34 (23) ◽

pp. 3238-3244 ◽

Cited By ~ 2

Author(s):

Istvan Frendl ◽

Monika Katko ◽

Erika Galgoczi ◽

Judit Boda ◽

Noemi Zsiros ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Plasminogen Activator ◽

Mild Traumatic Brain Injury ◽

Plasminogen Activator Inhibitor ◽

Pituitary Dysfunction ◽

Inhibitor Type ◽

Activator Inhibitor Type ◽

Activator Inhibitor

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Angiotensin Receptor Type 1 Inhibition in Lymphopenia and in Neutropenia After Traumatic Brain Injury In Mice: a Randomized Controlled Study (ATLANTIS)

10.21203/rs.3.rs-999453/v1 ◽

2021 ◽

Author(s):

Ralph Timaru-Kast ◽

Shila P. Coronel-Castello ◽

Tobias Krämer ◽

André V. Hugonnet ◽

Michael K.E. Schäfer ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Brain Damage ◽

Receptor Type ◽

Wild Type ◽

Secondary Brain Damage ◽

Neutrophil Depletion ◽

Cerebral Inflammation

Abstract Background: Cerebral inflammation with invasion of neutrophils and lymphocytes is an important factor in the process of secondary brain damage expansion after traumatic brain injury (TBI). Depletion of neutrophils in mice has been shown to reduce neurologic impairment after TBI. The intrinsic cerebral renin-angiotensin system is an important mediator of cerebral inflammation, as inhibition of the angiotensin II receptor type 1 (AT1) with candesartan improves neurologic recovery, and reduces secondary brain damage and cerebral neutrophil invasion after TBI. The present study was therefore designed to determine the role of immune cells in AT1 inhibition-mediated neuroprotection after TBI. Methods: In study A we assessed the effect of neutrophil depletion in mice after TBI. In study B we investigated the impact of RAG1 deficiency (RAG1-/-; mice without mature B- and T-lymphocytes) after TBI. In study C we investigated the role of neutrophils in candesartan mediated protection after TBI in wild-type mice with and without neutrophil depletion. In study D we examined the role of lymphocytes in AT1 inhibition mediated neuroprotection after TBI in RAG1-/-.Results: Neutropenic and RAG1-/- mice showed reduced brain damage compared to control groups. In control antibody treated wild type mice AT1 inhibition reduced lesion volumes and inflammation compared to vehicle, while in neutropenic mice, candesartan had no effect. In RAG1-/- mice AT1 inhibition resulted in reduction of brain damage and neuroinflammation compared to vehicle group. Conclusion: The present results demonstrate, that reduction of neutrophils and of lymphocytes as well as AT1 inhibition in wild type and RAG1-/- mice reduce brain damage and inflammation after TBI. However, AT1 inhibition was neuroprotective in RAG1-/- mice, but not in neutropenic mice. Therefore, the results indicate that AT1 inhibition mediated neuroprotection may be exerted by anti-inflammatory effects on neutrophils, with a subsequent reduction of neutrophil invasion.

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