Potentiating Hemorrhage in a Periadolescent Rat Model of Closed-Head Traumatic Brain Injury Worsens Hyperexcitability but Not Behavioral Deficits

Post-traumatic epilepsy (PTE) and neurocognitive deficits are devastating sequelae of head injuries that are common in adolescents. Investigating desperately needed treatments is hindered by the difficulties in inducing PTE in rodents and the lack of established immature rat models of pediatric PTE. Hemorrhage is a significant risk factor for PTE, but compared to humans, rats are less prone to bleeding because of their rapid blood coagulation system. In this study, we promoted bleeding in the controlled cortical impact (CCI) closed-head injury model with a 20 min pre-impact 600 IU/kg intraperitoneal heparin injection in postnatal day 35 (P35) periadolescent rats, given the preponderance of such injuries in this age group. Temporo-parietal CCI was performed post-heparin (HTBI group) or post-saline (TBI group). Controls were subjected to sham procedures following heparin or saline administration. Continuous long-term EEG monitoring was performed for 3 months post-CCI. Sensorimotor testing, the Morris water maze, and a modified active avoidance test were conducted between P80 and P100. Glial fibrillary acidic protein (GFAP) levels and neuronal damage were also assessed. Compared to TBI rats, HTBI rats had persistently higher EEG spiking and increased hippocampal GFAP levels (p < 0.05). No sensorimotor deficits were detected in any group. Compared to controls, both HTBI and TBI groups had a long-term hippocampal neuronal loss (p < 0.05), as well as contextual and visuospatial learning deficits (p < 0.05). The hippocampal astrogliosis and EEG spiking detected in all rats subjected to our hemorrhage-promoting procedure suggest the emergence of hyperexcitable networks and pave the way to a periadolescent PTE rat model.

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Repeated Mild Closed Head Injuries Induce Long-Term White Matter Pathology and Neuronal Loss That Are Correlated With Behavioral Deficits

ASN NEURO ◽

10.1177/1759091418781921 ◽

2018 ◽

Vol 10 ◽

pp. 175909141878192 ◽

Cited By ~ 20

Author(s):

Eric M. Gold ◽

Vitaly Vasilevko ◽

Jonathan Hasselmann ◽

Casey Tiefenthaler ◽

Danny Hoa ◽

...

Keyword(s):

Cortical Neurons ◽

Chronic Traumatic Encephalopathy ◽

Head Injuries ◽

Closed Head Injury ◽

Neuronal Loss ◽

Significant Loss ◽

Behavioral Deficits ◽

Closed Head ◽

Behavioral Impairments

An estimated 5.3 million Americans are living with a disability from a traumatic brain injury (TBI). There is emerging evidence of the detrimental effects from repeated mild TBIs (rmTBIs). rmTBI manifests its own unique set of behavioral and neuropathological changes. A subset of individuals exposed to rmTBI develop permanent behavioral and pathological consequences, defined postmortem as chronic traumatic encephalopathy. We have combined components of two classic rodent models of TBI, the controlled cortical impact model and the weight drop model, to develop a repeated mild closed head injury (rmCHI) that produces long-term deficits in several behaviors that correlate with neuropathological changes. Mice receiving rmCHI performed differently from 1-hit or sham controls on the elevated plus maze; these deficits persist up to 6 months postinjury (MPI). rmCHI mice performed worse than 1-hit and control sham mice at 2 MPI and 6 MPI on the Morris water maze. Mice receiving rmCHI exhibited significant atrophy of the corpus callosum at both 2 MPI and 6 MPI, as assessed by stereological volume analysis. Stereological analysis also revealed significant loss of cortical neurons in comparison with 1-hit and controls. Moreover, both of these pathological changes correlated with behavioral impairments. In human tau transgenic mice, rmCHI induced increases in hyperphosphorylated paired helical filament 1 tau in the hippocampus. This suggests that strategies to restore myelination or reduce neuronal loss may ameliorate the behavioral deficits observed following rmCHI and that rmCHI may model chronic traumatic encephalopathy in human tau mice.

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Long-term hematologic toxicity of 177Lu-octreotate-capecitabine-temozolomide therapy of GEPNET

Endocrine Related Cancer ◽

10.1530/erc-21-0082 ◽

2021 ◽

Author(s):

Murali Kesavan ◽

Piyush Grover ◽

Wei-Sen Lam ◽

Phillip G Claringbold ◽

J. Harvey Turner

Keyword(s):

Cumulative Incidence ◽

Significant Risk ◽

Significant Risk Factor ◽

Baseline Risk ◽

Hematologic Toxicity ◽

Gastroenteropancreatic Neuroendocrine Tumors ◽

Prospective Phase ◽

Grade 3

Thirty-seven patients with advanced gastroenteropancreatic neuroendocrine tumors (GEPNETs) were treated on a prospective phase II single-center study with 4 cycles of 7.8 GBq 177Lu-octreotate combined with capecitabine and temozolomide chemotherapy (CAPTEM). Each 8-week cycle combined radiopeptide therapy with 14 days of capecitabine (1500 mg/m2) and 5 days of temozolomide (200 mg/m2). The incidence of grade ≥3 hematologic toxicity was analysed. We found that at a median follow-up of 7-years (range 1-10), 6 (16%) patients developed persistent hematologic toxicity (PHT, defined as sustained grade ≥3 hematologic toxicity beyond 36-months follow up) and 3 (8%) developed MDS/AL with a median time-to-event of 46 and 34-months respectively. Estimated cumulative incidence of MDS/AL was 11% (95% CI: 3.45 to 24.01). Development of PHT was the only significant risk factor for secondary (RR, 16; 95% CI: 2.53 to 99.55; p<0.001). The median PFS was 48 months (95% CI: 40.80-55.20) and median OS was 86 months (95% CI: 56.90-115.13). 21 deaths were recorded, including 13 (62%) due to progressive disease and all 3 (14%) patients with MDS/AL. We conclude that 177Lu-octreotate CAPTEM therapy for GEPNETs is associated with a risk of long-term hematologic toxicity. The rising cumulative incidence of MDS/AL >10% mandates for the long-term monitoring of treated patients. However, time to onset is unpredictable and incidence does not correlate with conventional baseline risk factors. Novel methods are required for stratification of prospective patients based on genetic risk.

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Abstract 2605: Hypoglycemia Does Not Increase Long-term Mortality Or Morbidity In Diabetic Patients With Myocardial Infarction. A Report From The Digami 2 Trial.

Circulation ◽

10.1161/circ.116.suppl_16.ii_577 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Linda G Mellbin ◽

Klas Malmberg ◽

Anders Waldenstrom ◽

Hans Wedel ◽

Lars Ryden

Keyword(s):

Myocardial Infarction ◽

Blood Glucose ◽

Negative Impact ◽

Significant Risk ◽

Significant Risk Factor ◽

Diabetic Patients ◽

Type 2 Dm ◽

Hazard Ratios

Aims Tight, insulin-based glucose control is recommended to diabetic patients (DM pat) with acute myocardial infarction (AMI). A potential draw-back would be if insulin induced hypoglycaemia (HG) had a negative impact of future prognosis. Methods 1253 pat (mean age 68 years; 67% males) with type 2 DM and suspect AMI were followed for a median of 2.1 years. 947 were randomised to insulin infusion during at least 24 hours while 306 were treated routinely. HG (blood glucose<3.0 mmol/L with or without symptoms) was recorded during hospitalisation. Unadjusted and adjusted (age, sex, smoking, previous MI and heart failure, renal function, duration of DM, coronary interventions, blood glucose at randomisation) Hazard Ratios (HR) and 95% Confidence Intervals (CI) for cardiovascular events (CVE = death, MI or stroke) during follow up were calculated. Results 153 pat (12.2%) experienced HG. During the first 24 hours 111 (11.7%) insulin-treated pat experienced HG (symptomatic 23.4%) compared with 3 (1.0%) pat on routine treatment (symptomatic 33.3%). As outlined in the figure HG was not an independent predictor of subsequent CVE. Conclusion Insulin induced HG was not a significant risk factor for subsequent CVE in AMI-pat with type 2 DM. Hypoglycaemic seem to identify patients at high risk for other reasons.

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Long-term outcome of learning and memory in children following severe closed head injury

Pediatric Rehabilitation ◽

10.1080/1363849021000007088 ◽

2002 ◽

Vol 5 (1) ◽

pp. 37-41 ◽

Cited By ~ 11

Author(s):

J. E. Nelson ◽

T. P. Kelly

Keyword(s):

Head Injury ◽

Learning And Memory ◽

Closed Head Injury ◽

Term Outcome ◽

Long Term Outcome ◽

Closed Head

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New-onset Atrial Fibrillation after Cardiac Surgery is a Significant Risk Factor for Long-term Stroke: An 8-Year Prospective Cohort Study

Journal of Cardiothoracic and Vascular Anesthesia ◽

10.1053/j.jvca.2021.07.003 ◽

2021 ◽

Author(s):

Kevin K.P. Wang ◽

Weiling Liu ◽

Sophia T.H. Chew ◽

Lian Kah Ti ◽

Liang Shen

Keyword(s):

Atrial Fibrillation ◽

Cardiac Surgery ◽

Risk Factor ◽

Cohort Study ◽

Prospective Cohort ◽

Significant Risk ◽

Significant Risk Factor ◽

Onset Atrial Fibrillation ◽

New Onset

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Long-term neuropsychological outcome of closed head injury

Journal of Neurosurgery ◽

10.3171/jns.1979.50.4.0412 ◽

1979 ◽

Vol 50 (4) ◽

pp. 412-422 ◽

Cited By ~ 245

Author(s):

Harvey S. Levin ◽

Robert G. Grossman ◽

James E. Rose ◽

Graham Teasdale

Keyword(s):

Head Injury ◽

Social Adjustment ◽

Prognostic Significance ◽

Closed Head Injury ◽

Memory Storage ◽

Acute Injury ◽

Closed Head ◽

Disabled Patients

✓ Long-term recovery from severe closed head injury was investigated in predominantly young adults whose Glasgow Coma score was 8 or less at the time of admission. Of the 27 patients studied (median follow-up interval of 1 year), 10 attained a good recovery, 12 were moderately disabled, and five were severely disabled. In contrast to previous studies suggesting that intellectual ability after severe closed head injury eventually recovers to a normal level, our findings showed that residual intellectual level, memory storage and retrieval, linguistic deficit, and personal social adjustment corresponded to overall outcome. All severely disabled patients and several moderately disabled patients exhibited unequivocal cognitive and emotional sequelae after long follow-up intervals. Analysis of persistent neuropsychological deficit in relation to neurological indices of acute injury severity demonstrated the prognostic significance of oculovestibular deficit.

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