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.     

Diffusion Tensor and Volumetric Magnetic Resonance Measures as Biomarkers of Brain Damage in a Small Animal Model of HIV

Background

There are currently no widely accepted neuro-HIV small animal models. We wanted to validate the HIV-1 Transgenic rat (Tg) as an appropriate neuro-HIV model and then establish in vivo imaging biomarkers of neuropathology, within this model, using MR structural and diffusion tensor imaging (DTI).

Methods

Young and middle-aged Tg and control rats were imaged using MRI. A subset of middle-aged animals underwent longitudinal repeat imaging six months later. Total brain volume (TBV), ventricular volume (VV) and parenchymal volume (PV = TBV–VV) were measured. Fractional anisotropy (FA) and mean diffusivity (MD) values of the corpus callosum (CC) were calculated from DTI data.

Results

TBV and PV were smaller in Tg compared to control rats in young and middle-aged cohorts (p<0.0001). VV increased significantly (p = 0.005) over time in the longitudinal Tg cohort. There were lower FA (p<0.002) and higher MD (p<0.003) values in the CC of middle-aged Tg rats compared to age-matched controls. Longitudinally, MD significantly decreased over time in Tg rats (p<0.03) while it did not change significantly in the control cohort over the same period of time (p>0.05).

Conclusions

We detected brain volume loss in the Tg rat, probably due to astrocytic dysfunction/loss, loss of structural/axonal matrix and striatal neuronal loss as suggested by immunofluorescence. Increased MD and decreased FA in the CC probably reflect microstructural differences between the Tg and Control rats which could include increased extracellular space between white matter tracts, demyelination and axonal degeneration, among other pathologies. We believe that the Tg rat is an adequate model of neuropathology in HIV and that volumetric MR and DTI measures can be potentially used as biomarkers of disease progression.     

Differences in Prefrontal,Limbic, and White Matter Lesion Volumes According to Cognitive Status in Elderly Patients with First-Onset Subsyndromal Depression

The purpose of this preliminary study was to test the hypothesis that subsyndromal depression is associated with the volume of medial prefrontal regional gray matter and that of white matter lesions (WMLs) in the brains of cognitively normal older people. We also explored the relationships between subsyndromal depression and medial prefrontal regional gray matter volume, limbic regional gray matter volume, and lobar WMLs in the brains of patients with mild cognitive impairment (MCI) and Alzheimer''s disease (AD). We performed a cross-sectional study comparing patients with subsyndromal depression and nondepressed controls with normal cognition (n = 59), MCI (n = 27), and AD (n = 27), adjusting for sex, age, years of education, and results of the Mini-Mental State Examination. Frontal WML volume was greater, and right medial orbitofrontal cortical volume was smaller in cognitively normal participants with subsyndromal depression than in those without subsyndromal depression. No volume differences were observed in medial prefrontal, limbic, or WML volumes according to the presence of subsyndromal depression in cognitively impaired patients. The absence of these changes in patients with MCI and AD suggests that brain changes associated with AD pathology may override the changes associated with subsyndromal depression.     

MRI of Neuronal Recovery after Low-Dose Methamphetamine Treatment of Traumatic Brain Injury in Rats

We assessed the effects of low dose methamphetamine treatment of traumatic brain injury (TBI) in rats by employing MRI, immunohistology, and neurological functional tests. Young male Wistar rats were subjected to TBI using the controlled cortical impact model. The treated rats (n = 10) received an intravenous (iv) bolus dose of 0.42 mg/kg of methamphetamine at eight hours after the TBI followed by continuous iv infusion for 24 hrs. The control rats (n = 10) received the same volume of saline using the same protocol. MRI scans, including T2-weighted imaging (T2WI) and diffusion tensor imaging (DTI), were performed one day prior to TBI, and at 1 and 3 days post TBI, and then weekly for 6 weeks. The lesion volumes of TBI damaged cerebral tissue were demarcated by elevated values in T₂ maps and were histologically identified by hematoxylin and eosin (H&E) staining. The fractional anisotropy (FA) values within regions-of-interest (ROI) were measured in FA maps deduced from DTI, and were directly compared with Bielschowsky’s silver and Luxol fast blue (BLFB) immunohistological staining. No therapeutic effect on lesion volumes was detected during 6 weeks after TBI. However, treatment significantly increased FA values in the recovery ROI compared with the control group at 5 and 6 weeks after TBI. Myelinated axons histologically measured using BLFB were significantly increased (p<0.001) in the treated group (25.84±1.41%) compared with the control group (17.05±2.95%). Significant correlations were detected between FA and BLFB measures in the recovery ROI (R = 0.54, p<0.02). Methamphetamine treatment significantly reduced modified neurological severity scores from 2 to 6 weeks (p<0.05) and foot-fault errors from 3 days to 6 weeks (p<0.05) after TBI. Thus, the FA data suggest that methamphetamine treatment improves white matter reorganization from 5 to 6 weeks after TBI in rats compared with saline treatment, which may contribute to the observed functional recovery.     

Increased CSF Levels of Phosphorylated Neurofilament Heavy Protein following Bout in Amateur Boxers

Introduction

Diagnosis of mild TBI is hampered by the lack of imaging or biochemical measurements for identifying or quantifying mild TBI in a clinical setting. We have previously shown increased biomarker levels of protein reflecting axonal (neurofilament light protein and tau) and glial (GFAP and S-100B) damage in cerebrospinal fluid (CSF) after a boxing bout. The aims of this study were to find other biomarkers of mild TBI, which may help clinicians diagnose and monitor mild TBI, and to calculate the role of APOE ε4 allele genotype which has been associated with poor outcome after TBI.

Materials and Methods

Thirty amateur boxers with a minimum of 45 bouts and 25 non-boxing matched controls were included in a prospective cohort study. CSF and blood were collected at one occasion between 1 and 6 days after a bout, and after a rest period for at least 14 days (follow up). The controls were tested once. CSF levels of neurofilament heavy (pNFH), amyloid precursor proteins (sAPPα and sAPPβ), ApoE and ApoA1 were analyzed. In blood, plasma levels of Aβ42 and ApoE genotype were analyzed.

Results

CSF levels of pNFH were significantly increased between 1 and 6 days after boxing as compared with controls (p<0.001). The concentrations decreased at follow up but were still significantly increased compared to controls (p = 0.018). CSF pNFH concentrations correlated with NFL (r =  0.57 after bout and 0.64 at follow up, p<0.001). No significant change was found in the other biomarkers, as compared to controls. Boxers carrying the APOE ε4 allele had similar biomarker concentrations as non-carriers.

Conclusions

Subconcussive repetitive trauma in amateur boxing causes a mild TBI that may be diagnosed by CSF analysis of pNFH, even without unconsciousness or concussion symptoms. Possession of the APOE ε4 allele was not found to influence biomarker levels after acute TBI.     

Depression and Health Related Quality of Life in Adolescent Survivors of a Traumatic Brain Injury: A Pilot Study

Traumatic brain injury is (TBI) a leading cause of morbidity and mortality in youth. Adult survivors of a severe pediatric TBI are vulnerable to global impairments, including greater employment difficulties, poor quality of life (HRQoL) and increased risk of mental health problems. When estimating the health related quality of life in adolescents, the presence of anxiety and depression and the quality of social relationships are important considerations, because adolescents are entrenched in social development during this phase of maturation. The influence of anxiety, depression and loneliness on health related quality of life in adolescent survivors of TBI has not been documented. This pilot study aimed to identify and measure the relationship between anxiety, depression and loneliness and perceived health related quality of life in adolescent survivors of a TBI. Method: mixed method/cohort pilot study (11 adolescents, mild to severe TBI; 9 parents), using self-report and proxy-report measures of anxiety, depression, health related quality of life, loneliness and clinical psychiatric interviews (adolescent only). Results: Self-reported depression was significantly correlated with self-reported HRQoL (rs [11] = −0.88, p<0.001). Age at injury was significantly correlated with self-reported HRQoL (rs [11] = −0.68, p = 0.02). Self-reported depression predicted self-reported HRQoL (R² = 0.79, F [1, 10] = 33.48, p<0.001), but age at injury did not (R² = 0.19, F [1, 10] = 2.09, p = 0.18). Conclusions: Our results suggest that depression is a predictor of health related quality of life in youth post-TBI. The possibility of using targeted assessment and therapy for depression post-TBI to improve health related quality of life should be explored.     

Diffusion Tensor Imaging of Brain Abnormalities Induced by Prenatal Exposure to Radiation in Rodents

We assessed brain abnormalities in rats exposed prenatally to radiation (X-rays) using magnetic resonance imaging (MRI) and histological experiments. Pregnant rats were divided into 4 groups: the control group (n = 3) and 3 groups that were exposed to different radiation doses (0.5, 1.0, or 1.5 Gy; n = 3 each). Brain abnormalities were assessed in 32 neonatal male rats (8 per group). Ex vivo T₂-weighted imaging and diffusion tensor imaging (DTI) were performed using 11.7-T MRI. The expression of markers of myelin production (Kluver–Barrera staining, KB), nonpyramidal cells (calbindin-D28k staining, CaBP), and pyramidal cells (staining of the nonphosphorylated heavy-chain neurofilament SMI-32) were histologically evaluated. Decreased brain volume, increased ventricle volume, and thinner cortices were observed by MRI in irradiated rats. However, no abnormalities in the cortical 6-layered structure were observed via KB staining in radiation-exposed rats. The DTI color-coded map revealed a dose-dependent reduction in the anisotropic signal (vertical direction), which did not represent reduced numbers of pyramidal cells; rather, it indicated a signal reduction relative to the vertical direction because of low nerve cell density in the entire cortex. We conclude that DTI and histological experiments are useful tools for assessing cortical and hippocampal abnormalities after prenatal exposure to radiation in rats.     

Axon Diameter and Intra-Axonal Volume Fraction of the Corticospinal Tract in Idiopathic Normal Pressure Hydrocephalus Measured by Q-Space Imaging

Purpose

Previous studies suggest that compression and stretching of the corticospinal tract (CST) potentially cause treatable gait disturbance in patients with idiopathic normal pressure hydrocephalus (iNPH). Measurement of axon diameter with diffusion MRI has recently been used to investigate microstructural alterations in neurological diseases. In this study, we investigated alterations in the axon diameter and intra-axonal fraction of the CST in iNPH by q-space imaging (QSI) analysis.

Methods

Nineteen patients with iNPH and 10 age-matched controls were recruited. QSI data were obtained with a 3-T system by using a single-shot echo planar imaging sequence with the diffusion gradient applied parallel to the antero-posterior axis. By using a two-component low-q fit model, the root mean square displacements of intra-axonal space ( =  axon diameter) and intra-axonal volume fraction of the CST were calculated at the levels of the internal capsule and body of the lateral ventricle, respectively.

Results

Wilcoxon''s rank-sum test revealed a significant increase in CST intra-axonal volume fraction at the paraventricular level in patients (p<0.001), whereas no significant difference was observed in the axon diameter. At the level of the internal capsule, neither axon diameter nor intra-axonal volume fraction differed significantly between the two groups.

Conclusion

Our results suggest that in patients with iNPH, the CST does not undergo irreversible axonal damage but is rather compressed and/or stretched owing to pressure from the enlarged ventricle. These analyses of axon diameter and intra-axonal fraction yield insights into microstructural alterations of the CST in iNPH.     

Association between Serum Tissue Inhibitor of Matrix Metalloproteinase-1 Levels and Mortality in Patients with Severe Brain Trauma Injury

Objective

Matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) play a role in neuroinflammation after brain trauma injury (TBI). Previous studies with small sample size have reported higher circulating MMP-2 and MMP-9 levels in patients with TBI, but no association between those levels and mortality. Thus, the aim of this study was to determine whether serum TIMP-1 and MMP-9 levels are associated with mortality in patients with severe TBI.

Methods

This was a multicenter, observational and prospective study carried out in six Spanish Intensive Care Units. Patients with severe TBI defined as Glasgow Coma Scale (GCS) lower than 9 were included, while those with Injury Severity Score (ISS) in non-cranial aspects higher than 9 were excluded. Serum levels of TIMP-1, MMP-9 and tumor necrosis factor (TNF)-alpha, and plasma levels of tissue factor (TF) and plasminogen activator inhibitor (PAI)-1 plasma were measured in 100 patients with severe TBI at admission. Endpoint was 30-day mortality.

Results

Non-surviving TBI patients (n = 27) showed higher serum TIMP-1 levels than survivor ones (n = 73). We did not find differences in MMP-9 serum levels. Logistic regression analysis showed that serum TIMP-1 levels were associated 30-day mortality (OR = 1.01; 95% CI = 1.001–1.013; P = 0.03). Survival analysis showed that patients with serum TIMP-1 higher than 220 ng/mL presented increased 30-day mortality than patients with lower levels (Chi-square = 5.50; P = 0.02). The area under the curve (AUC) for TIMP-1 as predictor of 30-day mortality was 0.73 (95% CI = 0.624–0.844; P<0.001). An association between TIMP-1 levels and APACHE-II score, TNF- alpha and TF was found.

Conclusions

The most relevant and new findings of our study, the largest series reporting data on TIMP-1 and MMP-9 levels in patients with severe TBI, were that serum TIMP-1 levels were associated with TBI mortality and could be used as a prognostic biomarker of mortality in TBI patients.     

Study of 320-Slice Dynamic Volume CT Perfusion in Different Pathologic Types of Kidney Tumor: Preliminary Results

Objective

To investigate microcirculatory differences between pathologic types of kidney tumor using 320-slice dynamic volume CT perfusion.

Methods

Perfusion imaging with 320-slice dynamic volume CT was prospectively performed in 85 patients with pathologically proven clear cell renal cell carcinoma (RCC) (n = 66), papillary RCC (n = 7), chromophobe RCC (n = 5), angiomyolipoma (AML) with minimal fat (n = 7), or RCC (n = 78). Equivalent blood volume (Equiv BV), permeability surface-area product (PS; clearance/unit volume = permeability), and blood flow (BF) of tumor and normal renal cortex were measured and analyzed. Effective radiation dose was calculated.

Results

There was a significant difference in all three parameters between tumor and normal renal cortex (P<0.001). Equiv BV was significantly different between RCC and AML with minimal fat (P = 0.038) and between clear cell RCC and AML with minimal fat (P<0.001). Mean Equiv BV and BF were significantly higher in clear cell RCC than in papillary RCC (P<0.001 for both) and mean Equiv BV was higher in clear cell RCC than in chromophobe RCC (P<0.001). The effective radiation dose of the CT perfusion protocol was 18.5 mSv.

Conclusion

Perfusion imaging using 320-slice dynamic volume CT can be used to evaluate hemodynamic features of the whole kidney and kidney tumors, which may be useful in the differential diagnosis of these four pathologic types of kidney tumor.     

Association between Irrigation Fluids,Washout Volumes and Risk of Local Recurrence of Anterior Resection for Rectal Cancer: A Meta-Analysis of 427 Cases and 492 Controls

Background

Rectal washout can prevent local recurrence after anterior resection of rectal cancer. Few studies have focused particularly on the association between irrigation fluids volume or agents and the risk of local recurrence after anterior resection of rectal cancer.

Objective

To estimate the association between irrigation fluids types, volumes of rectal washout and risk of local recurrence after anterior resection for cancer.

Data Sources

Relevant studies were identified by a search of Medline, Embase, Wiley Online Library, China National Knowledge Infrastructure, Cochrane Oral Health Group Specialized Register, Wanfang databases and Google Website from their inception until October 18,2013.

Study Selection

Studies reporting the association between rectal washout types and volumes and risk of local recurrence after anterior resection for cancer were included.

Interventions

Eligible studies used rectal washout. Control groups were defined as no washout.

Study Appraisal and Synthesis Methods

Random-effects model were used to obtain summary estimates of RR and 95% CI, with Stata version 11 and RevMan 5.2.5 softwares used. The quality of report was appraised in reference to the MINORS item.

Results

Of the 919 rectal cancer patients in 8 included studies, a total of 61(6.64%) cases of local recurrence were reported, with a pooled RR 0.51 (95%CI = 0.28–0.92, P = 0.03). The RRs 0.37 and 0.39 in normal saline and washout volume (≥1500 ml normal saline) subgroup, respectively, indicated that rectal washout with normal saline, or ≥1500 ml in volume could significantly reduce local recurrence (LR) rate (95% CI = 0.17–0.79, P = 0.01; 95% CI = 0.18–0.87, P = 0.02) after anterior resection for cancer.

Limitation

The included studies were non-randomized observational studies, with diversity of study designs.

Conclusion

Rectal washout with normal saline alone can reduce the risk of local recurrence in patients with resectable rectal cancer, and 1.5 liters rectal washout in volume is recommended.     

Decreases in Molecular Diffusion,Perfusion Fraction and Perfusion-Related Diffusion in Fibrotic Livers: A Prospective Clinical Intravoxel Incoherent Motion MR Imaging Study

Purpose

This study was aimed to determine whether pure molecular-based diffusion coefficient (D) and perfusion-related diffusion parameters (perfusion fraction f, perfusion-related diffusion coefficient D*) differ in healthy livers and fibrotic livers through intra-voxel incoherent motion (IVIM) MR imaging.

Material and Methods

17 healthy volunteers and 34 patients with histopathologically confirmed liver fibrosis patients (stage 1 = 14, stage 2 = 8, stage 3& 4 = 12, METAVIR grading) were included. Liver MR imaging was performed at 1.5-T. IVIM diffusion weighted imaging sequence was based on standard single-shot DW spin echo-planar imaging, with ten b values of 10, 20, 40, 60, 80, 100, 150, 200, 400, 800 sec/mm² respectively. Pixel-wise realization and regions-of-interest based quantification of IVIM parameters were performed.

Results

D, f, and D* in healthy volunteer livers and patient livers were 1.096±0.155 vs 0.917±0.152 (10⁻³ mm²/s, p = 0.0015), 0.164±0.021 vs 0.123±0.029 (p<0.0001), and 13.085±2.943 vs 9.423±1.737 (10⁻³ mm²/s, p<0.0001) respectively, all significantly lower in fibrotic livers. As the fibrosis severity progressed, D, f, and D* values decreased, with a trend significant for f and D*.

Conclusion

Fibrotic liver is associated with lower pure molecular diffusion, lower perfusion volume fraction, and lower perfusion-related diffusion. The decrease of f and D* in the liver is significantly associated liver fibrosis severity.     

Dissecting the Gene Dose-Effects of the APOE ε4 and ε2 Alleles on Hippocampal Volumes in Aging and Alzheimer’s Disease

Objective

To investigate whether there is a specific dose-dependent effect of the Apolipoprotein E (APOE) ε4 and ε2 alleles on hippocampal volume, across the cognitive spectrum, from normal aging to Alzheimer’s Disease (AD).

Materials and Methods

We analyzed MR and genetic data on 662 patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database–198 cognitively normal controls (CN), 321 mild-cognitive impairment (MCI) subjects, and 143 AD subjects–looking for dose-dependent effects of the ε4 and ε2 alleles on hippocampal volumes. Volumes were measured using a fully-automated algorithm applied to high resolution T1-weighted MR images. Statistical analysis consisted of a multivariate regression with repeated-measures model.

Results

There was a dose-dependent effect of the ε4 allele on hippocampal volume in AD (p = 0.04) and MCI (p = 0.02)–in both cases, each allele accounted for loss of >150 mm³ (approximately 4%) of hippocampal volume below the mean volume for AD and MCI subjects with no such alleles (Cohen’s d = −0.16 and −0.19 for AD and MCI, respectively). There was also a dose-dependent, main effect of the ε2 allele (p<0.0001), suggestive of a moderate protective effect on hippocampal volume–an approximately 20% per allele volume increase as compared to CN with no ε2 alleles (Cohen’s d = 0.23).

Conclusion

Though no effect of ε4 was seen in CN subjects, our findings confirm and extend prior data on the opposing effects of the APOE ε4 and ε2 alleles on hippocampal morphology across the spectrum of cognitive aging.     

Complication Probability Models for Radiation-Induced Heart Valvular Dysfunction: Do Heart-Lung Interactions Play a Role?

Purpose

The purpose of this study is to compare different normal tissue complication probability (NTCP) models for predicting heart valve dysfunction (RVD) following thoracic irradiation.

Methods

All patients from our institutional Hodgkin lymphoma survivors database with analyzable datasets were included (n = 90). All patients were treated with three-dimensional conformal radiotherapy with a median total dose of 32 Gy. The cardiac toxicity profile was available for each patient. Heart and lung dose-volume histograms (DVHs) were extracted and both organs were considered for Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) NTCP model fitting using maximum likelihood estimation. Bootstrap refitting was used to test the robustness of the model fit. Model performance was estimated using the area under the receiver operating characteristic curve (AUC).

Results

Using only heart-DVHs, parameter estimates were, for the LKB model: D₅₀ = 32.8 Gy, n = 0.16 and m = 0.67; and for the RS model: D₅₀ = 32.4 Gy, s = 0.99 and γ = 0.42. AUC values were 0.67 for LKB and 0.66 for RS, respectively. Similar performance was obtained for models using only lung-DVHs (LKB: D₅₀ = 33.2 Gy, n = 0.01, m = 0.19, AUC = 0.68; RS: D₅₀ = 24.4 Gy, s = 0.99, γ = 2.12, AUC = 0.66). Bootstrap result showed that the parameter fits for lung-LKB were extremely robust. A combined heart-lung LKB model was also tested and showed a minor improvement (AUC = 0.70). However, the best performance was obtained using the previously determined multivariate regression model including maximum heart dose with increasing risk for larger heart and smaller lung volumes (AUC = 0.82).

Conclusions

The risk of radiation induced valvular disease cannot be modeled using NTCP models only based on heart dose-volume distribution. A predictive model with an improved performance can be obtained but requires the inclusion of heart and lung volume terms, indicating that heart-lung interactions are apparently important for this endpoint.     

Comparison of Drug Release and Pharmacokinetics after Transarterial Chemoembolization Using Diverse Lipiodol Emulsions and Drug-Eluting Beads

In many studies for chemoembolization of hepatocellular carcinoma, the Lipiodol emulsion preparation protocols, especially the mixing steps, were unclear or even unrevealed at all. However, doxorubicin (DOX) release may depend on the composition and volume ratio (Lipiodol to DOX solution) of a Lipiodol emulsion. Therefore, we conducted a preclinical study to compare in-vitro drug release and in-vivo pharmacokinetics of DOX from diverse Lipiodol emulsions and drug-eluting beads (DEBs) and to compare the tumor response in a rabbit VX2 carcinoma model. DOX release profiles of four types of Lipiodol emulsions with different media (normal saline or Pamiray as an iodinated contrast medium), volume ratio (Lipiodol to DOX solution), and DEBs were investigated in-vitro. For the in-vivo study, 15 rabbits bearing VX2 carcinoma in the liver were treated with 4∶1 volume ratio Lipiodol emulsion (group A), 1∶1 volume ratio Lipiodol emulsion (group B), and DEBs (group C) chemoembolization. Blood and tissue sampling was conducted to evaluate DOX concentration in plasma and tissues, histological changes, and liver toxicity. The most stable emulsion was formed with Pamiray (including DOX) at a 4∶1 volume ratio. The AUC value of group A was significantly lower than that of group B (p = 0.003) but comparable to that of group C (p = 0.071). The C_max value of group A was significantly different compared with those of group B (p = 0.004) and C (p = 0.015). The tissue drug concentration in group A was comparable to that in group C (p = 0.251). No viable tumor was detected in rabbits of group A and B. In group C, viable tumor less than 10% was seen in two of the five rabbits. There were no significant differences in liver enzyme levels after the procedure. In conclusion, DOX release and pharmacokinetics of presented emulsion systems depend substantially on their composition. Therefore, Lipiodol emulsion type should be considered when interpreting data and designing new studies dealing with chemoembolization.     

Chronic Alcoholism-Mediated Impairment in the Medulla Oblongata: A Mechanism of Alcohol-Related Mortality in Traumatic Brain Injury?

Alcohol-related traumatic brain injury (TBI) is a common condition in medical and forensic practice, and results in high prehospital mortality. We investigated the mechanism of chronic alcoholism-related mortality by examining the effects of alcohol on the synapses of the medulla oblongata in a rat model of TBI. Seventy adult male Sprague–Dawley rats were randomly assigned to either ethanol (EtOH) group, EtOH-TBI group, or control groups (water group, water-TBI group). To establish chronic alcoholism model, rats in the EtOH group were given EtOH twice daily (4 g/kg for 2 weeks and 6 g/kg for another 2 weeks). The rats also received a minor strike on the occipital tuberosity with an iron pendulum. Histopathologic and ultrastructure changes and the numerical density of the synapses in the medulla oblongata were examined. Expression of postsynaptic density-95 (PSD-95) in the medulla oblongata was measured by ELISA. Compared with rats in the control group, rats in the chronic alcoholism group showed: (1) minor axonal degeneration; (2) a significant decrease in the numerical density of synapses (p < 0.01); and (3) compensatory increase in PSD-95 expression (p < 0.01). Rats in the EtOH-TBI group showed: (1) high mortality (50 %, p < 0.01); (2) inhibited respiration before death; (3) severe axonal injury; and (4) decrease in PSD-95 expression (p < 0.05). Chronic alcoholism induces significant synapse loss and axonal impairment in the medulla oblongata and renders the brain more susceptible to TBI. The combined effects of chronic alcoholism and TBI induce significant synapse and axon impairment and result in high mortality.     

Factors Predicting Reversion from Mild Cognitive Impairment to Normal Cognitive Functioning: A Population-Based Study

Introduction

Mild cognitive impairment (MCI) is associated with an increased risk of developing dementia. However, many individuals diagnosed with MCI are found to have reverted to normal cognition on follow-up. This study investigated factors predicting or associated with reversion from MCI to normal cognition.

Methods

Our analyses considered 223 participants (48.9% male) aged 71–89 years, drawn from the prospective, population-based Sydney Memory and Ageing Study. All were diagnosed with MCI at baseline and subsequently classified with either normal cognition or repeat diagnosis of MCI after two years (a further 11 participants who progressed from MCI to dementia were excluded). Associations with reversion were investigated for (1) baseline factors that included diagnostic features, personality, neuroimaging, sociodemographics, lifestyle, and physical and mental health; (2) longitudinal change in potentially modifiable factors.

Results

There were 66 reverters to normal cognition and 157 non-reverters (stable MCI). Regression analyses identified diagnostic features as most predictive of prognosis, with reversion less likely in participants with multiple-domain MCI (p = 0.011), a moderately or severely impaired cognitive domain (p = 0.002 and p = 0.006), or an informant-based memory complaint (p = 0.031). Reversion was also less likely for participants with arthritis (p = 0.037), but more likely for participants with higher complex mental activity (p = 0.003), greater openness to experience (p = 0.041), better vision (p = 0.014), better smelling ability (p = 0.040), or larger combined volume of the left hippocampus and left amygdala (p<0.040). Reversion was also associated with a larger drop in diastolic blood pressure between baseline and follow-up (p = 0.026).

Discussion

Numerous factors are associated with reversion from MCI to normal cognition. Assessing these factors could facilitate more accurate prognosis of individuals with MCI. Participation in cognitively enriching activities and efforts to lower blood pressure might promote reversion.     

Ecology of Leptospira interrogans in Norway Rats (Rattus norvegicus) in an Inner-City Neighborhood of Vancouver,Canada

Background

Leptospira interrogans is a bacterial zoonosis with a worldwide distribution for which rats (Rattus spp.) are the primary reservoir in urban settings. In order to assess, monitor, and mitigate the risk to humans, it is important to understand the ecology of this pathogen in rats. The objective of this study was to characterize the ecology of L. interrogans in Norway rats (Rattus norvegicus) in an impoverished inner-city neighborhood of Vancouver, Canada.

Methodology/Principal Findings

Trapping was performed in 43 city blocks, and one location within the adjacent port, over a 12 month period. Kidney samples were tested for the presence of L. interrogans using PCR and sequencing. A multivariable model was built to predict L. interrogans infection status in individual rats using season and morphometric data (e.g., weight, sex, maturity, condition, etc.) as independent variables. Spatial analysis was undertaken to identify clusters of high and low L. interrogans prevalence. The prevalence of L. interrogans varied remarkably among blocks (0–66.7%), and spatial clusters of both high and low L. interrogans prevalence were identified. In the final cluster-controlled model, characteristics associated with L. interrogans-infection in rats included weight (OR = 1.14, 95% CI = 1.07–1.20), increased internal fat (OR = 2.12, 95% CI = 1.06–4.25), and number of bite wounds (OR = 1.20, 95% CI = 0.96–1.49).

Conclusions/Significance

Because L. interrogans prevalence varied with weight, body fat, and bite wounds, this study suggests that social structure and interactions among rats may influence transmission. The prevalence and distribution of L. interrogans in rats was also highly variable even over a short geographic distance. These factors should be considered in future risk management efforts.     

A New Improved Method for Assessing Brain Deformation after Decompressive Craniectomy

Background

Decompressive craniectomy (DC) is a surgical intervention used following traumatic brain injury to prevent or alleviate raised intracranial pressure. However the clinical effectiveness of the intervention remains in doubt. The location of the craniectomy (unilateral or bifrontal) might be expected to change the brain deformation associated with the operation and hence the clinical outcome. As existing methods for assessing brain deformation have several limitations, we sought to develop and validate a new improved method.

Methods

Computed tomography (CT) scans were taken from 27 patients who underwent DC (17 bifrontal patients and 10 unilateral patients). Pre-operative and post-operative images were processed and registered to determine the change in brain position associated with the operation. The maximum deformation in the herniated brain, the change in volume and estimates of the craniectomy area were determined from the images. Statistical comparison was made using the Pearson’s correlation coefficient r and a Welch’s two-tailed T-test, with statistical significance reported at the 5% level.

Results

There was a reasonable correlation between the volume increase and the maximum brain displacement (r = 0.64), a low correlation between the volume increase and the craniectomy area (r = 0.30) and no correlation between the maximum displacement and the craniectomy area (r = −0.01). The maximum deformation was significantly lower (P  = 0.023) in the bifrontal patients (mean = 22.5 mm) compared with the unilateral patients (mean = 29.8 mm). Herniation volume was significantly lower (P = 0.023) in bifrontal (mean = 50.0 ml) than unilateral patients (mean = 107.3 ml). Craniectomy area was not significantly different for the two craniectomy locations (P = 0.29).

Conclusions

A method has been developed to quantify changes in brain deformation due to decompressive craniectomy from CT images and allow comparison between different craniectomy locations. Measured displacement is a reasonable way to characterise volume changes.