Total skin electron beam (TSEB) therapy in pediatric patients: A review of the literature

Aim

A literature review was undertaken to identify current TSEB therapy in pediatric patients.

Background

Total skin electron beam (TSEB) therapy is a method of irradiation with low energy electron beam dedicated to patients who have superficial skin lesions all over their body. Such skin malignancies are sparse among adults and even more uncommon with pediatric population.

Materials and methods

In this study, all reported case reports were summed up with a special emphasis on techniques used, doses prescribed and special shielding of critical organs. Moreover, potential problems that were encountered during TSEB irradiation of very young patients were depicted.

Results

The literature has described only seven case reports of children undergoing TSEB therapy. Most of them were infants; however, two adolescents were also treated. For all infants, general anesthesia was provided to allow safe and accurate TSEB irradiation. The prescribed dose varied from 16 Gy to 28 Gy depending on the irradiation schedule and patient condition. Usually, boost fields were applied to the scalp and perineum. Typical shields for fingernails, toenails and lenses were usually used.

Conclusion

This paper revealed that TSEB therapy may be considered as a palliative treatment for pediatric patients with leukemia cutis. However, its role is still unclear and should be further investigated.     

TLR9 agonist protects mice from radiation-induced gastrointestinal syndrome

Purpose

Radiation-induced gastrointestinal syndrome (RIGS) is due to the clonogenic loss of crypt cells and villi depopulation, resulting in disruption of mucosal barrier, bacterial invasion, inflammation and sepsis. Intestinal macrophages could recognize invading bacterial DNA via TLR9 receptors and transmit regenerative signals to the neighboring crypt. We therefore investigated whether systemic administration of designer TLR9 agonist could ameliorate RIGS by activating TLR9.

Methods and Materials

Male C57Bl6 mice were distributed in four experimental cohorts, whole body irradiation (WBI) (8.4–10.4 Gy), TLR9 agonist (1 mg/kg s.c.), 1 h pre- or post-WBI and TLR9 agonist+WBI+iMyd88 (pretreatment with inhibitory peptide against Myd88). Animals were observed for survival and intestine was harvested for histological analysis. BALB/c mice with CT26 colon tumors in abdominal wall were irradiated with 14 Gy single dose of whole abdominal irradiation (AIR) for tumor growth study.

Results

Mice receiving pre-WBI TLR9 agonist demonstrated improvement of survival after 10.4 Gy (p<0.03), 9.4 Gy (p<0.008) and 8.4 Gy (p<0.002) of WBI, compared to untreated or iMyd88-treated controls. Post-WBI TLR9 agonist mitigates up to 8.4 Gy WBI (p<0.01). Histological analysis and xylose absorption test demonstrated significant structural and functional restitution of the intestine in WBI+TLR9 agonist cohorts. Although, AIR reduced tumor growth, all animals died within 12 days from RIGS. TLR9 agonist improved the survival of mice beyond 28 days post-AIR (p<0.008) with significant reduction of tumor growth (p<0.0001).

Conclusions

TLR9 agonist treatment could serve both as a prophylactic or mitigating agent against acute radiation syndrome and also as an adjuvant therapy to increase the therapeutic ratio of abdominal Radiation Therapy for Gastro Intestinal malignancies.     

Progesterone Treatment Shows Benefit in a Pediatric Model of Moderate to Severe Bilateral Brain Injury

Purpose

Controlled cortical impact (CCI) models in adult and aged Sprague-Dawley (SD) rats have been used extensively to study medial prefrontal cortex (mPFC) injury and the effects of post-injury progesterone treatment, but the hormone''s effects after traumatic brain injury (TBI) in juvenile animals have not been determined. In the present proof-of-concept study we investigated whether progesterone had neuroprotective effects in a pediatric model of moderate to severe bilateral brain injury.

Methods

Twenty-eight-day old (PND 28) male Sprague Dawley rats received sham (n = 24) or CCI (n = 47) injury and were given progesterone (4, 8, or 16 mg/kg per 100 g body weight) or vehicle injections on post-injury days (PID) 1–7, subjected to behavioral testing from PID 9–27, and analyzed for lesion size at PID 28.

Results

The 8 and 16 mg/kg doses of progesterone were observed to be most beneficial in reducing the effect of CCI on lesion size and behavior in PND 28 male SD rats.

Conclusion

Our findings suggest that a midline CCI injury to the frontal cortex will reliably produce a moderate TBI comparable to what is seen in the adult male rat and that progesterone can ameliorate the injury-induced deficits.     

Correlation of Plasma FL Expression with Bone Marrow Irradiation Dose

Purpose

Ablative bone marrow irradiation is an integral part of hematopoietic stem cell transplantation. These treatment regimens are based on classically held models of radiation dose and the bone marrow response. Flt-3 ligand (FL) has been suggested as a marker of hematopoiesis and bone marrow status but the kinetics of its response to bone marrow irradiation has yet to be fully characterized. In the current study, we examine plasma FL response to total body and partial body irradiation in mice and its relationship with irradiation dose, time of collection and pattern of bone marrow exposure.

Materials/Methods

C57BL6 mice received a single whole body or partial body irradiation dose of 1–8 Gy. Plasma was collected by mandibular or cardiac puncture at 24, 48 and 72 hr post-irradiation as well as 1–3 weeks post-irradiation. FL levels were determined via ELISA assay and used to generate two models: a linear regression model and a gated values model correlating plasma FL levels with radiation dose.

Results

At all doses between 1–8 Gy, plasma FL levels were greater than control and the level of FL increased proportionally to the total body irradiation dose. Differences in FL levels were statistically significant at each dose and at all time points. Partial body irradiation of the trunk areas, encompassing the bulk of the hematopoietically active bone marrow, resulted in significantly increased FL levels over control but irradiation of only the head or extremities did not. FL levels were used to generate a dose prediction model for total body irradiation. In a blinded study, the model differentiated mice into dose received cohorts of 1, 4 or 8 Gy based on plasma FL levels at 24 or 72 hrs post-irradiation.

Conclusion

Our findings indicate that plasma FL levels might be used as a marker of hematopoietically active bone marrow and radiation exposure in mice.     

Lactate and the Lactate-to-Pyruvate Molar Ratio Cannot Be Used as Independent Biomarkers for Monitoring Brain Energetic Metabolism: A Microdialysis Study in Patients with Traumatic Brain Injuries

Background

For decades, lactate has been considered an excellent biomarker for oxygen limitation and therefore of organ ischemia. The aim of the present study was to evaluate the frequency of increased brain lactate levels and the LP ratio (LPR) in a cohort of patients with severe or moderate traumatic brain injury (TBI) subjected to brain microdialysis monitoring to analyze the agreement between these two biomarkers and to indicate brain energy metabolism dysfunction.

Methods

Forty-six patients with an admission Glasgow coma scale score of ≤13 after resuscitation admitted to a dedicated 10-bed Neurotraumatology Intensive Care Unit were included, and 5305 verified samples of good microdialysis data were analyzed.

Results

Lactate levels were above 2.5 mmol/L in 56.9% of the samples. The relationships between lactate and the LPR could not be adequately modeled by any linear or non-linear model. Neither Cohen’s kappa nor Gwet’s statistic showed an acceptable agreement between both biomarkers to classify the samples in regard to normal or abnormal metabolism. The dataset was divided into four patterns defined by the lactate concentrations and the LPR. A potential interpretation for these patterns is suggested and discussed. Pattern 4 (low pyruvate levels) was found in 10.7% of the samples and was characterized by a significantly low concentration of brain glucose compared with the other groups.

Conclusions

Our study shows that metabolic abnormalities are frequent in the macroscopically normal brain in patients with traumatic brain injuries and a very poor agreement between lactate and the LPR when classifying metabolism. The concentration of lactate in the dialysates must be interpreted while taking into consideration the LPR to distinguish between anaerobic metabolism and aerobic hyperglycolysis.     

Amantadine Ameliorates Dopamine-Releasing Deficits and Behavioral Deficits in Rats after Fluid Percussion Injury

Aims

To investigate the role of dopamine in cognitive and motor learning skill deficits after a traumatic brain injury (TBI), we investigated dopamine release and behavioral changes at a series of time points after fluid percussion injury, and explored the potential of amantadine hydrochloride as a chronic treatment to provide behavioral recovery.

Materials and Methods

In this study, we sequentially investigated dopamine release at the striatum and behavioral changes at 1, 2, 4, 6, and 8 weeks after fluid percussion injury. Rats subjected to 6-Pa cerebral cortical fluid percussion injury were treated by using subcutaneous infusion pumps filled with either saline (sham group) or amantadine hydrochloride, with a releasing rate of 3.6mg/kg/hour for 8 weeks. The dopamine-releasing conditions and metabolism were analyzed sequentially by fast scan cyclic voltammetry (FSCV) and high-pressure liquid chromatography (HPLC). Novel object recognition (NOR) and fixed-speed rotarod (FSRR) behavioral tests were used to determine treatment effects on cognitive and motor deficits after injury.

Results

Sequential dopamine-release deficits were revealed in 6-Pa-fluid-percussion cerebral cortical injured animals. The reuptake rate (tau value) of dopamine in injured animals was prolonged, but the tau value became close to the value for the control group after amantadine therapy. Cognitive and motor learning impairments were shown evidenced by the NOR and FSRR behavioral tests after injury. Chronic amantadine therapy reversed dopamine-release deficits, and behavioral impairment after fluid percussion injuries were ameliorated in the rats treated by using amantadine-pumping infusion.

Conclusion

Chronic treatment with amantadine hydrochloride can ameliorate dopamine-release deficits as well as cognitive and motor deficits caused by cerebral fluid-percussion injury.     

Traumatic Brain Injury in the Netherlands: Incidence,Costs and Disability-Adjusted Life Years

Objective

Traumatic brain injury (TBI) is a major cause of death and disability, leading to great personal suffering and huge costs to society. Integrated knowledge on epidemiology, economic consequences and disease burden of TBI is scarce but essential for optimizing healthcare policy and preventing TBI. This study aimed to estimate incidence, cost-of-illness and disability-adjusted life years (DALYs) of TBI in the Netherlands.

Methods

This study included data on all TBI patients who were treated at an Emergency Department (ED - National Injury Surveillance System), hospitalized (National Medical Registration), or died due to their injuries in the Netherlands between 2010–2012. Direct healthcare costs and indirect costs were determined using the incidence-based Dutch Burden of Injury Model. Disease burden was assessed by calculating years of life lost (YLL) owing to premature death, years lived with disability (YLD) and DALYs. Incidence, costs and disease burden were stratified by age and gender.

Results

TBI incidence was 213.6 per 100,000 person years. Total costs were €314.6 (USD $433.8) million per year and disease burden resulted in 171,200 DALYs (on average 7.1 DALYs per case). Men had highest mean costs per case (€19,540 versus €14,940), driven by indirect costs. 0–24-year-olds had high incidence and disease burden but low economic costs, whereas 25–64-year-olds had relatively low incidence but high economic costs. Patients aged 65+ had highest incidence, leading to considerable direct healthcare costs. 0–24-year-olds, men aged 25–64 years, traffic injury victims (especially bicyclists) and home and leisure injury victims (especially 0–5-year-old and elderly fallers) are identified as risk groups in TBI.

Conclusions

The economic and health consequences of TBI are substantial. The integrated approach of assessing incidence, costs and disease burden enables detection of important risk groups in TBI, development of prevention programs that target these risk groups and assessment of the benefits of these programs.     

Diffuse Brain Injury Induces Acute Post-Traumatic Sleep

Objective

Clinical observations report excessive sleepiness immediately following traumatic brain injury (TBI); however, there is a lack of experimental evidence to support or refute the benefit of sleep following a brain injury. The aim of this study is to investigate acute post-traumatic sleep.

Methods

Sham, mild or moderate diffuse TBI was induced by midline fluid percussion injury (mFPI) in male C57BL/6J mice at 9:00 or 21:00 to evaluate injury-induced sleep behavior at sleep and wake onset, respectively. Sleep profiles were measured post-injury using a non-invasive, piezoelectric cage system. In separate cohorts of mice, inflammatory cytokines in the neocortex were quantified by immunoassay, and microglial activation was visualized by immunohistochemistry.

Results

Immediately after diffuse TBI, quantitative measures of sleep were characterized by a significant increase in sleep (>50%) for the first 6 hours post-injury, resulting from increases in sleep bout length, compared to sham. Acute post-traumatic sleep increased significantly independent of injury severity and time of injury (9:00 vs 21:00). The pro-inflammatory cytokine IL-1β increased in brain-injured mice compared to sham over the first 9 hours post-injury. Iba-1 positive microglia were evident in brain-injured cortex at 6 hours post-injury.

Conclusion

Post-traumatic sleep occurs for up to 6 hours after diffuse brain injury in the mouse regardless of injury severity or time of day. The temporal profile of secondary injury cascades may be driving the significant increase in post-traumatic sleep and contribute to the natural course of recovery through cellular repair.     

Risk Factors Associated with Sleep Disturbance following Traumatic Brain Injury: Clinical Findings and Questionnaire Based Study

Background

Sleep disturbance is very common following traumatic brain injury (TBI), which may initiate or exacerbate a variety of co-morbidities and negatively impact rehabilitative treatments. To date, there are paradoxical reports regarding the associations between inherent characteristics of TBI and sleep disturbance in TBI population. The current study was designed to explore the relationship between the presence of sleep disturbance and characteristics of TBI and identify the factors which are closely related to the presence of sleep disturbance in TBI population.

Methods

98 TBI patients (72 males, mean age ± SD, 47 ± 13 years, range 18-70) were recruited. Severity of TBI was evaluated based on Glasgow Coma Scale (GCS). All participants performed cranial computed tomography and were examined on self-reported sleep quality, anxiety, and depression.

Results

TBI was mild in 69 (70%), moderate in 15 (15%) and severe in 14 (15%) patients. 37 of 98 patients (38%) reported sleep disturbance following TBI. Insomnia was diagnosed in 28 patients (29%) and post-traumatic hypersomnia in 9 patients (9%). In TBI with insomnia group, 5 patients (18%) complained of difficulty falling asleep only, 8 patients (29%) had difficulty maintaining sleep without difficulty in initial sleep and 15 patients (53%) presented both difficulty falling asleep and difficulty maintaining sleep. Risk factors associated with insomnia were headache and/or dizziness and more symptoms of anxiety and depression rather than GCS. In contrast, GCS was independently associated with the presence of hypersomnia following TBI. Furthermore, there was no evidence of an association between locations of brain injury and the presence of sleep disturbance after TBI.

Conclusion

Our data support and contribute to a growing body of evidence which indicates that TBI patients with insomnia are prone to suffer from concomitant headache and/or dizziness, report more symptoms of anxiety and depression and severe TBI patients are likely to experience hypersomnia.     

Single Intraperitoneal Injection of Monocrotaline as a Novel Large Animal Model of Chronic Pulmonary Hypertension in Tibet Minipigs

Objective

The purpose of this study was to establish an animal model of chronic pulmonary hypertension with a single-dose intraperitoneal injection of monocrotaline (MCT) in young Tibet minipigs, so as to enable both invasive and noninvasive measurements and hence facilitate future studies.

Methods

Twenty-four minipigs (8-week-old) were randomized to receive single-dose injection of 12.0 mg/kg MCT (MCT group, n = 12) or placebo (control group, n = 12 each). On day 42, all animals were evaluated for pulmonary hypertension with conventional transthoracic echocardiography, right heart catheterization (RHC), and pathological changes. Findings of these studies were compared between the two groups.

Results

At echocardiography, the MCT group showed significantly higher pulmonary arterial mean pressure (PAMP) compared with the controls (P<0.001). The pulmonary valve curve showed v-shaped signals with reduction of a-waves in minipigs treated with MCT. In addition, the MCT group had longer pulmonary artery pre-ejection phases, and shorter acceleration time and ejection time. RHC revealed higher mean pulmonary arterial pressure (mPAP) in the MCT group than in the control group (P<0.01). A significant and positive correlation between the mPAP values and the PAMP values (R = 0.974, P<0.0001), and a negative correlation between the mPAP and ejection time (R = 0.680, P<0.0001) was noted. Pathology demonstrated evidence of pulmonary vascular remodeling and higer index of right ventricular hypertrophy in MCT-treated minipigs.

Conclusion

A chronic pulmonary hypertension model can be successfully established in young minipigs at six weeks after MCT injection. These minipig models exhibited features of pulmonary arterial hypertension that can be evaluated by both invasive (RHC) and noninvasive (echocardiography) measurements, and may be used as an easy and stable tool for future studies on pulmonary hypertension.     

Minocycline Synergizes with N-Acetylcysteine and Improves Cognition and Memory Following Traumatic Brain Injury in Rats

Background

There are no drugs presently available to treat traumatic brain injury (TBI). A variety of single drugs have failed clinical trials suggesting a role for drug combinations. Drug combinations acting synergistically often provide the greatest combination of potency and safety. The drugs examined (minocycline (MINO), N-acetylcysteine (NAC), simvastatin, cyclosporine A, and progesterone) had FDA-approval for uses other than TBI and limited brain injury in experimental TBI models.

Methodology/Principal Findings

Drugs were dosed one hour after injury using the controlled cortical impact (CCI) TBI model in adult rats. One week later, drugs were tested for efficacy and drug combinations tested for synergy on a hierarchy of behavioral tests that included active place avoidance testing. As monotherapy, only MINO improved acquisition of the massed version of active place avoidance that required memory lasting less than two hours. MINO-treated animals, however, were impaired during the spaced version of the same avoidance task that required 24-hour memory retention. Co-administration of NAC with MINO synergistically improved spaced learning. Examination of brain histology 2 weeks after injury suggested that MINO plus NAC preserved white, but not grey matter, since lesion volume was unaffected, yet myelin loss was attenuated. When dosed 3 hours before injury, MINO plus NAC as single drugs had no effect on interleukin-1 formation; together they synergistically lowered interleukin-1 levels. This effect on interleukin-1 was not observed when the drugs were dosed one hour after injury.

Conclusions/Significance

These observations suggest a potentially valuable role for MINO plus NAC to treat TBI.     

Inhibition of Phosphatase and Tensin Homolog Deleted on Chromosome 10 Decreases Rat Cortical Neuron Injury and Blood-Brain Barrier Permeability,and Improves Neurological Functional Recovery in Traumatic Brain Injury Model

Background and Purpose

Recent evidence has supported the neuroprotective effect of bpV (pic), an inhibitor of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), in models of ischemic stroke. However, whether PTEN inhibitors improve long-term functional recovery after traumatic brain injury (TBI) and whether PTEN affects blood brain barrier (BBB) permeability need further elucidation. The present study was performed to address these issues.

Methods

Adult Sprague-Dawley rats were subjected to fluid percussion injury (FPI) after treatment with a well-established PTEN inhibitor bpV (pic) or saline starting 24 h before FPI. Western blotting, real-time quantitative PCR, or immunostaining was used to measure PTEN, p-Akt, or MMP-9 expression. We determined the presence of neuron apoptosis by TUNEL assay. Evans Blue dye extravasation was measured to evaluate the extent of BBB disruption. Functional recovery was assessed by the neurological severity score (NSS), and Kaplan-Meier analysis was used for survival analysis.

Results

PTEN expression was up-regulated after TBI. After bpV (pic) treatment, p-Akt was also up-regulated. We found that bpV (pic) significantly decreased BBB permeability and reduced the number of TUNEL-positive cells. We further demonstrated that PTEN inhibition improved neurological function recovery in the early stage after TBI.

Conclusion

These data suggest that treatment with the PTEN inhibitor bpV (pic) has a neuroprotective effect in TBI rats.     

Comparison of therapeutic effects between pulsed and continuous wave 810-nm wavelength laser irradiation for traumatic brain injury in mice

Background and Objective

Transcranial low-level laser therapy (LLLT) using near-infrared light can efficiently penetrate through the scalp and skull and could allow non-invasive treatment for traumatic brain injury (TBI). In the present study, we compared the therapeutic effect using 810-nm wavelength laser light in continuous and pulsed wave modes in a mouse model of TBI.

Study Design/Materials and Methods

TBI was induced by a controlled cortical-impact device and 4-hours post-TBI 1-group received a sham treatment and 3-groups received a single exposure to transcranial LLLT, either continuous wave or pulsed at 10-Hz or 100-Hz with a 50% duty cycle. An 810-nm Ga-Al-As diode laser delivered a spot with diameter of 1-cm onto the injured head with a power density of 50-mW/cm² for 12-minutes giving a fluence of 36-J/cm². Neurological severity score (NSS) and body weight were measured up to 4 weeks. Mice were sacrificed at 2, 15 and 28 days post-TBI and the lesion size was histologically analyzed. The quantity of ATP production in the brain tissue was determined immediately after laser irradiation. We examined the role of LLLT on the psychological state of the mice at 1 day and 4 weeks after TBI using tail suspension test and forced swim test.

Results

The 810-nm laser pulsed at 10-Hz was the most effective judged by improvement in NSS and body weight although the other laser regimens were also effective. The brain lesion volume of mice treated with 10-Hz pulsed-laser irradiation was significantly lower than control group at 15-days and 4-weeks post-TBI. Moreover, we found an antidepressant effect of LLLT at 4-weeks as shown by forced swim and tail suspension tests.

Conclusion

The therapeutic effect of LLLT for TBI with an 810-nm laser was more effective at 10-Hz pulse frequency than at CW and 100-Hz. This finding may provide a new insight into biological mechanisms of LLLT.     

Energy dependence of radiochromic dosimetry films for use in radiotherapy verification

Aim

The purpose of the study was to examine the energy dependence of Gafchromic EBT radiochromic dosimetry films, in order to assess their potential use in intensity-modulated radiotherapy (IMRT) verifications.

Materials and methods

The film samples were irradiated with doses from 0.1 to 12 Gy using photon beams from the energy range 1.25 MeV to 25 MV and the film response was measured using a flat-bed scanner. The samples were scanned and the film responses for different beam energies were compared.

Results

A high uncertainty in readout of the film response was observed for samples irradiated with doses lower than 1 Gy. The relative difference exceeds 20% for doses lower than 1 Gy while for doses over 1 Gy the measured film response differs by less than 5% for the whole examined energy range. The achieved uncertainty of the experimental procedure does not reveal any energy dependence of Gafchromic EBT film response in the investigated energy range.

Conclusions

Gafchromic EBT film does not show any energy dependence in the conditions typical for IMRT but the doses measured for pre-treatment plan verifications should exceed 1 Gy.     

Tau Reduction Diminishes Spatial Learning and Memory Deficits after Mild Repetitive Traumatic Brain Injury in Mice

Objective

Because reduction of the microtubule-associated protein Tau has beneficial effects in mouse models of Alzheimer''s disease and epilepsy, we wanted to determine whether this strategy can also improve the outcome of mild traumatic brain injury (TBI).

Methods

We adapted a mild frontal impact model of TBI for wildtype C57Bl/6J mice and characterized the behavioral deficits it causes in these animals. The Barnes maze, Y maze, contextual and cued fear conditioning, elevated plus maze, open field, balance beam, and forced swim test were used to assess different behavioral functions. Magnetic resonance imaging (MRI, 7 Tesla) and histological analysis of brain sections were used to look for neuropathological alterations. We also compared the functional effects of this TBI model and of controlled cortical impact in mice with two, one or no Tau alleles.

Results

Repeated (2-hit), but not single (1-hit), mild frontal impact impaired spatial learning and memory in wildtype mice as determined by testing of mice in the Barnes maze one month after the injury. Locomotor activity, anxiety, depression and fear related behaviors did not differ between injured and sham-injured mice. MRI imaging did not reveal focal injury or mass lesions shortly after the injury. Complete ablation or partial reduction of tau prevented deficits in spatial learning and memory after repeated mild frontal impact. Complete tau ablation also showed a trend towards protection after a single controlled cortical impact. Complete or partial reduction of tau also reduced the level of axonopathy in the corpus callosum after repeated mild frontal impact.

Interpretation

Tau promotes or enables the development of learning and memory deficits and of axonopathy after mild TBI, and tau reduction counteracts these adverse effects.     

Bone marrow stromal cell transplantation mitigates radiation-induced gastrointestinal syndrome in mice

Background

Nuclear accidents and terrorism presents a serious threat for mass casualty. While bone-marrow transplantation might mitigate hematopoietic syndrome, currently there are no approved medical countermeasures to alleviate radiation-induced gastrointestinal syndrome (RIGS), resulting from direct cytocidal effects on intestinal stem cells (ISC) and crypt stromal cells. We examined whether bone marrow-derived adherent stromal cell transplantation (BMSCT) could restitute irradiated intestinal stem cells niche and mitigate radiation-induced gastrointestinal syndrome.

Methodology/Principal Findings

Autologous bone marrow was cultured in mesenchymal basal medium and adherent cells were harvested for transplantation to C57Bl6 mice, 24 and 72 hours after lethal whole body irradiation (10.4 Gy) or abdominal irradiation (16–20 Gy) in a single fraction. Mesenchymal, endothelial and myeloid population were characterized by flow cytometry. Intestinal crypt regeneration and absorptive function was assessed by histopathology and xylose absorption assay, respectively. In contrast to 100% mortality in irradiated controls, BMSCT mitigated RIGS and rescued mice from radiation lethality after 18 Gy of abdominal irradiation or 10.4 Gy whole body irradiation with 100% survival (p<0.0007 and p<0.0009 respectively) beyond 25 days. Transplantation of enriched myeloid and non-myeloid fractions failed to improve survival. BMASCT induced ISC regeneration, restitution of the ISC niche and xylose absorption. Serum levels of intestinal radioprotective factors, such as, R-Spondin1, KGF, PDGF and FGF2, and anti-inflammatory cytokines were elevated, while inflammatory cytokines were down regulated.

Conclusion/Significance

Mitigation of lethal intestinal injury, following high doses of irradiation, can be achieved by intravenous transplantation of marrow-derived stromal cells, including mesenchymal, endothelial and macrophage cell population. BMASCT increases blood levels of intestinal growth factors and induces regeneration of the irradiated host ISC niche, thus providing a platform to discover potential radiation mitigators and protectors for acute radiation syndromes and chemo-radiation therapy of abdominal malignancies.     

Characterizing Brain Structures and Remodeling after TBI Based on Information Content,Diffusion Entropy

Background

To overcome the limitations of conventional diffusion tensor magnetic resonance imaging resulting from the assumption of a Gaussian diffusion model for characterizing voxels containing multiple axonal orientations, Shannon''s entropy was employed to evaluate white matter structure in human brain and in brain remodeling after traumatic brain injury (TBI) in a rat.

Methods

Thirteen healthy subjects were investigated using a Q-ball based DTI data sampling scheme. FA and entropy values were measured in white matter bundles, white matter fiber crossing areas, different gray matter (GM) regions and cerebrospinal fluid (CSF). Axonal densities'' from the same regions of interest (ROIs) were evaluated in Bielschowsky and Luxol fast blue stained autopsy (n = 30) brain sections by light microscopy. As a case demonstration, a Wistar rat subjected to TBI and treated with bone marrow stromal cells (MSC) 1 week after TBI was employed to illustrate the superior ability of entropy over FA in detecting reorganized crossing axonal bundles as confirmed by histological analysis with Bielschowsky and Luxol fast blue staining.

Results

Unlike FA, entropy was less affected by axonal orientation and more affected by axonal density. A significant agreement (r = 0.91) was detected between entropy values from in vivo human brain and histologically measured axonal density from post mortum from the same brain structures. The MSC treated TBI rat demonstrated that the entropy approach is superior to FA in detecting axonal remodeling after injury. Compared with FA, entropy detected new axonal remodeling regions with crossing axons, confirmed with immunohistological staining.

Conclusions

Entropy measurement is more effective in distinguishing axonal remodeling after injury, when compared with FA. Entropy is also more sensitive to axonal density than axonal orientation, and thus may provide a more accurate reflection of axonal changes that occur in neurological injury and disease.     

Access to reliable information about long-term prognosis influences clinical opinion on use of lifesaving intervention

Background

Decompressive craniectomy has been traditionally used as a lifesaving rescue treatment in severe traumatic brain injury (TBI). This study assessed whether objective information on long-term prognosis would influence healthcare workers'' opinion about using decompressive craniectomy as a lifesaving procedure for patients with severe TBI.

Method

A two-part structured interview was used to assess the participants'' opinion to perform decompressive craniectomy for three patients who had very severe TBI. Their opinion was assessed before and after knowing the predicted and observed risks of an unfavourable long-term neurological outcome in various scenarios.

Results

Five hundred healthcare workers with a wide variety of clinical backgrounds participated. The participants were significantly more likely to recommend decompressive craniectomy for their patients than for themselves (mean difference in visual analogue scale [VAS] −1.5, 95% confidence interval −1.3 to −1.6), especially when the next of kin of the patients requested intervention. Patients'' preferences were more similar to patients who had advance directives. The participants'' preferences to perform the procedure for themselves and their patients both significantly reduced after knowing the predicted risks of unfavourable outcomes, and the changes in attitude were consistent across different specialties, amount of experience in caring for similar patients, religious backgrounds, and positions in the specialty of the participants.

Conclusions

Access to objective information on risk of an unfavourable long-term outcome influenced healthcare workers'' decision to recommend decompressive craniectomy, considered as a lifesaving procedure, for patients with very severe TBI.