Attentional dysfunction and recovery in concussion: effects on the P300m and contingent magnetic variation.

PRIMARY OBJECTIVE: To examine the effect of concussion on indices of attention using magnetoencephalography. METHODS AND PROCEDURES: Thirteen patients were recruited from the emergency department and scanned within 3-6 days of injury. Five returned for follow-up scans one and three months post-injury. Thirteen healthy controls also completed testing. During MEG acquisition, participants performed the Attention Network Test (ANT). Cognitive evoked responses to this task include a cue-evoked P300m, a contingent magnetic variation (CMV) and a target-evoked P300m. The Rivermead Postconcussion Symptom Questionnaire and Sport Concussion Assessment Tool (SCAT3) were administered in all sessions. RESULTS: Patients suffering from concussion had slower response times and benefitted more from spatial cues than did controls. Global activation for all three evoked responses was lower for patients than controls. In a small sample of patients who returned for follow-up, the CMV and target P300m improved with recovery. CONCLUSIONS: MEG-evoked responses to the ANT reveal neurophysiological evidence of attentional dysfunction within days of injury. A pattern of improvement was also observed over the course of three months for the P300m, while behavioural performance did not change significantly. Further development of this method may yield a useful adjunct to neurological examination for concussion diagnosis and monitoring.

Fat-suppressed alternating-SSFP for whole-brain fMRI using breath-hold and visual stimulus paradigms.

PURPOSE: To achieve artifact-suppressed whole-brain pass-band-balanced steady-state free precession functional MRI from a single functional magnetic resonance imaging (fMRI) scan. METHODS: A complete and practical data acquisition sequence for alt-SSFP fMRI was developed. First, multishot flyback-echo-planar imaging (EPI) and echo-time shifting were used to achieve data acquisition that was robust against eddy currents, gradient delays, and ghosting artifacts. Second, a steady-state catalyzation scheme was implemented to reduce oscillations in the transient signal when catalyzing in and out of alternate steady states. Next, a short spatial-spectral radiofrequency (RF) pulse was designed to achieve excellent fat-suppression while maintaining a repetition time <15 ms to sensitize functional activation toward smaller vessels and capillaries. Lastly, parallel imaging was used to achieve whole-brain coverage and sufficiently high temporal resolution. RESULTS: Breath-hold experiments showed excellent fat-suppression and alt-SSFP's capability to recover functional sensitivity from signal dropout regions of conventional gradient-echo and banding artifacts from conventional pass-band-balanced steady-state free precession. Applying fat-suppression resulted in improved activation maps and increased temporal SNR. Visual stimulus functional studies verify the proposed method's excellent functional sensitivity to neuronal activation. CONCLUSION: Artifact-suppressed images are demonstrated, showing a practical pass-band-balanced steady-state free precession fMRI method that permits whole-brain imaging with excellent blood oxygen level-dependent sensitivity and fat suppression.

Equity in children's dental caries before and after cessation of community water fluoridation: differential impact by dental insurance status and geographic material deprivation.

BACKGROUND: One of the main arguments made in favor of community water fluoridation is that it is equitable in its impact on dental caries (i.e., helps to offset inequities in dental caries). Although an equitable effect of fluoridation has been demonstrated in cross-sectional studies, it has not been studied in the context of cessation of community water fluoridation (CWF). The objective of this study was to compare the socio-economic patterns of children's dental caries (tooth decay) in Calgary, Canada, in 2009/10 when CWF was in place, and in 2013/14, after it had been discontinued. METHODS: We analyzed data from population-based samples of schoolchildren (grade 2) in 2009/10 and 2013/14. Data on dental caries (decayed, missing, and filled primary and permanent teeth) were gathered via open mouth exams conducted in schools by registered dental hygienists. We examined the association between dental caries and 1) presence/absence of dental insurance and 2) small area index of material deprivation, using Poisson (zero-inflated) and logistic regression, for both time points separately. For small-area material deprivation at each time point, we also computed the concentration index of inequality for each outcome variable. RESULTS: Statistically significant inequities by dental insurance status and by small area material deprivation were more apparent in 2013/14 than in 2009/10. CONCLUSIONS: Results are consistent with increasing inequities in dental caries following cessation of CWF. However, further research is needed to 1) confirm the effects in a study that includes a comparison community, and 2) explore possible alternative reasons for the findings, including changes in treatment and preventive programming.

Intramuscular cobinamide sulfite in a rabbit model of sublethal cyanide toxicity.

STUDY OBJECTIVE: Exposure to cyanide in fires and industrial exposures and intentional cyanide poisoning by terrorists leading to mass casualties is an ongoing threat. Current treatments for cyanide poisoning must be administered intravenously, and no rapid treatment methods are available for mass casualty cyanide exposures. Cobinamide is a cobalamin (vitamin B(12)) analog with an extraordinarily high affinity for cyanide that is more water-soluble than cobalamin. We investigate the use of intramuscular cobinamide sulfite to reverse cyanide toxicity-induced physiologic changes in a sublethal cyanide exposure animal model and determine the ability of an intramuscular cobinamide sulfite injection to rapidly reverse the physiologic effects of cyanide toxicity. METHODS: New Zealand white rabbits were given 10 mg sodium cyanide intravenously over 60 minutes. Quantitative diffuse optical spectroscopy and continuous-wave near-infrared spectroscopy monitoring of tissue oxyhemoglobin and deoxyhemoglobin concentrations were performed concurrently with blood cyanide level measurements and cobinamide levels. Immediately after completion of the cyanide infusion, the rabbits were injected intramuscularly with cobinamide sulfite (n=6) or inactive vehicle (controls, n=5). RESULTS: Intramuscular administration led to rapid mobilization of cobinamide and was extremely effective at reversing the physiologic effects of cyanide on oxyhemoglobin and within deoxyhemoglobin extraction. Recovery time to 63% of their baseline values in the central nervous system occurred within a mean of 1,032 minutes in the control group and 9 minutes in the cobinamide group, with a difference of 1,023 minutes (95% confidence interval 116 to 1,874 minutes). In muscle tissue, recovery times were 76 and 24 minutes, with a difference of 52 minutes (95% confidence interval 7 to 98 minutes). RBC cyanide levels returned toward normal significantly faster in cobinamide sulfite-treated animals than in control animals. CONCLUSION: Intramuscular cobinamide sulfite rapidly and effectively reverses the physiologic effects of cyanide poisoning, suggesting that a compact cyanide antidote kit can be developed for mass casualty cyanide exposures.

Glass transitions in one-, two-, three-, and four-dimensional binary Lennard-Jones systems.

We investigate the calorimetric liquid-glass transition by performing simulations of a binary Lennard-Jones mixture in one through four dimensions. Starting at a high temperature, the systems are cooled to T = 0 and heated back to the ergodic liquid state at constant rates. Glass transitions are observed in two, three and four dimensions as a hysteresis between the cooling and heating curves. This hysteresis appears in the energy and pressure diagrams, and the scanning rate dependence of the area and height of the hysteresis can be described using power laws. The one-dimensional system does not experience a glass transition but its specific heat curve resembles the shape of the D≥2 results in the supercooled liquid regime above the glass transition. As D increases, the radial distribution functions reflect reduced geometric constraints. Nearest neighbor distances become smaller with increasing D due to interactions between nearest and next-nearest neighbors. Simulation data for the glasses are compared with crystal and melting data obtained with a Lennard-Jones system with only one type of particle and we find that with increasing D crystallization becomes increasingly more difficult.

Efficient liver-directed gene transfer by in situ generation of retroviral vector from adenoviral templates.

UNLABELLED: To improve liver-directed retroviral-mediated gene transfer, we injected C57/BL10 mice intravenously with three adenoviral vectors encoding retroviral vector genome and structural components: AdGagPol expressing the respective structural genes of Moloney murine leukaemia virus, Ad10A1Env expressing the 10A1 envelope protein of 10A1-MuLV, and AdLEIN, encoding the LEIN retrovirus genome, expressing green fluorescence protein (eGFP) and the neomycin resistance gene. MATERIALS AND METHODS: The extent of eGFP expression was determined after 1 and 15 weeks by fluorescence microscopy and FACS analysis. Proviral integration was determined by a novel PCR-based technique. RESULTS: Hepatocytes infected with all three Ad vectors generated LEIN retrovirus after one week and in situ transduction of neighbouring cells resulted in stable proviral integration associated with eGFP expression ranging from 4.3% to 20.5% in different liver cell populations 15 weeks post-infection. CONCLUSION: Hybrid adeno-retroviral vectors can be efficiently used to improve the efficiency of retroviral-mediated gene transfer to the liver.

Model-free prostate cancer segmentation from dynamic contrast-enhanced MRI with recurrent convolutional networks: A feasibility study.

Dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI) is a method of temporal imaging that is commonly used to aid in prostate cancer (PCa) diagnosis and staging. Typically, machine learning models designed for the segmentation and detection of PCa will use an engineered scalar image called Ktrans to summarize the information in the DCE time-series images. This work proposes a new model that amalgamates the U-net and the convGRU neural network architectures for the purpose of interpreting DCE time-series in a temporal and spatial basis for segmenting PCa in MR images. Ultimately, experiments show that the proposed model using the DCE time-series images can outperform a baseline U-net segmentation model using Ktrans. However, when other types of scalar MR images are considered by the models, no significant advantage is observed for the proposed model.

Polyvalent dendrimer glucosamine conjugates prevent scar tissue formation.

Dendrimers are hyperbranched macromolecules that can be chemically synthesized to have precise structural characteristics. We used anionic, polyamidoamine, generation 3.5 dendrimers to make novel water-soluble conjugates of D(+)-glucosamine and D(+)-glucosamine 6-sulfate with immuno-modulatory and antiangiogenic properties respectively. Dendrimer glucosamine inhibited Toll-like receptor 4-mediated lipopolysaccharide induced synthesis of pro-inflammatory chemokines (MIP-1 alpha, MIP-1 beta, IL-8) and cytokines (TNF-alpha, IL-1 beta, IL-6) from human dendritic cells and macrophages but allowed upregulation of the costimulatory molecules CD25, CD80, CD83 and CD86. Dendrimer glucosamine 6-sulfate blocked fibroblast growth factor-2 mediated endothelial cell proliferation and neoangiogenesis in human Matrigel and placental angiogenesis assays. When dendrimer glucosamine and dendrimer glucosamine 6-sulfate were used together in a validated and clinically relevant rabbit model of scar tissue formation after glaucoma filtration surgery, they increased the long-term success of the surgery from 30% to 80% (P = 0.029). We conclude that synthetically engineered macromolecules such as the dendrimers described here can be tailored to have defined immuno-modulatory and antiangiogenic properties, and they can be used synergistically to prevent scar tissue formation.

Redirecting public oral health fluoride varnish intervention to low socio-economic status children in Alberta.

SETTING: Dental decay is most prevalent among low socio-economic status (SES) groups where cost limits access to dental care. To address inequities in oral health outcomes, Alberta Health Services (AHS) Oral Health Action Plan encompasses a population health approach that redirects fluoride varnish (FV) applications to low SES children. Using low SES measures to establish the eligibility criteria is fundamental to the delivery of FV applications to the target population. INTERVENTION: A series of four FV applications over two years is directed to children age 12-35 months and two applications per year to children in Kindergarten and grades 1 and 2, using low SES measures for eligibility criteria. The provincial objective for children receiving the first FV application is 10%-20% of the population age. Additional objectives are set for rates of subsequent FV applications for each population group. OUTCOMES: From 2015 to 2016, the rate of first FV applications for eligible target populations is below the provincial objective for children age 12-35 months (5%) and within the objective for children in Kindergarten and grades 1 and 2 (16%). Rates of subsequent FV applications in the school setting are being met. IMPLICATIONS: Encompassing a population health approach to deliver standardized fluoride varnish applications to low SES children better targets inequities in oral health outcomes in Alberta. Challenges of redirecting the FV intervention include creating the eligibility criteria and engaging the target population, particularly for the preschool population. Achieving population objectives are challenged by unequal distribution of resources across the province.

Expression of the common heat-shock protein receptor CD91 is increased on monocytes of exposed yet HIV-1-seronegative subjects.

The significantly higher surface expression of the surface heat-shock protein receptor CD91 on monocytes of human immunodeficiency virus type-1 (HIV-1)-infected, long-term nonprogressors suggests that HIV-1 antigen uptake and cross-presentation mediated by CD91 may contribute to host anti-HIV-1 defenses and play a role in protection against HIV-1 infection. To investigate this further, we performed phenotypic analysis to compare CD91 surface expression on CD14(+) monocytes derived from a cohort of HIV-1-exposed seronegative (ESN) subjects, their seropositive (SP) partners, and healthy HIV-1-unexposed seronegative (USN) subjects. The median fluorescent intensity (MFI) of CD91 on CD14(+) monocytes was significantly higher in ESN compared with SP (P = 0.028) or USN (P = 0.007), as well as in SP compared with USN subjects (P = 0.018). CD91 MFI was not normalized in SP subjects on highly active antiretroviral therapy (HAART) despite sustainable, undetectable plasma viraemia. Data in three SP subjects experiencing viral rebounds following interruption of HAART showed low CD91 MFI comparable with levels in USN subjects. There was a significant positive correlation between CD91 MFI and CD8(+) T cell counts in HAART-naïve SP subjects (r = 0.7, P = 0.015). Increased surface expression of CD91 on CD14(+) monocytes is associated with the apparent HIV-1 resistance that is observed in ESN subjects.

Fully automated quality assurance and localization of volumetric MEG for single-subject mapping.

BACKGROUND: Robust and reproducible source mapping with magnetoencephalography is particularly challenging at the individual level. We evaluated a receiver-operating characteristic reliability (ROC-r) method for automated production of volumetric MEG maps in single-subjects. ROC-r provides quality assurance comparable to that offered by goodness-of-fit (GoF) and confidence volume (CV) for equivalent current dipole (ECD) modeling. NEW METHOD: ROC-r utilizes within-session reproducibility for quality assurance, latency identification, and thresholding of volumetric source maps. We tested ROC-r on simulated and real MEG with a strongly focal source, using somatosensory evoked fields (SEFs) elicited by bilateral median nerve stimulation (MNS). For quality assurance, the ROC-r reliable fraction (FR) was compared to the ECD GoF and CV. Peak beamformer locations and latencies identified by ROC-r were compared to the ECD for co-localization accuracy. RESULTS: The predominant component of the SEF response occurred around 35ms, contralateral to the MNS. COMPARISON WITH EXISTING METHODS: FR and 1/CV were more strongly correlated (mean Pearson's correlation: 0.76; 95% CI 0.60-0.87) than FR and GoF (0.65; 95% CI 0.32-0.85). There was no difference in the latency of the peak GoF (35.0+/-0.6ms), CV (34.8+/-0.7ms) and FR (35.5+/-0.8ms). The ECD fits and ROC-r peaks co-localized to within a mean (median) distance of 8.3+/-5.9mm (6.2mm). CONCLUSION: ROC-r volumetric mapping co-localized closely with the standard ECD approach. This analysis can be added to any whole-brain MEG source imaging protocol, and is especially useful for single-subject mapping. Additionally, the development of FR as an analogue to GoF or CV for volumetric mapping is a critical improvement for clinical applications.

Natural killer cells are not infected by Kaposi's sarcoma-associated herpesvirus in vivo, and natural killer cell counts do not correlate with the risk of developing Kaposi's sarcoma.

Although the innate immune system is implicated in the control of Kaposi's sarcoma (KS), the risk of developing KS is not associated with the nadir natural killer (NK) cell count, and NK cell counts do not significantly increase or decrease during KS resolution. KS-associated herpesvirus replication was not demonstrated in vivo or in vitro within NK cells, suggesting that NK cells do not contribute to the resolution of KS. Their role appears limited to events occurring during early infection.

New insights into the immunology and evolution of HIV.

Fewer than one million HIV infected individuals are currently receiving anti-retroviral therapy. The limitations of such treatment have underscored the need to develop more effective strategies to control the spread and pathogenesis of HIV. Typically, naturally occurring protective immune responses provide the for such development. It is now clear however that HIV can utilise the milieu of an activated immune system to its own replicative advantage. Mobilisation of the immune response, intended to thwart the virus, may instead fuel its dissemination, 'immune escape' and spread. The immense genetic variation of HIV contributes to lack of immune control and the development of progressive disease in the majority of infected, untreated individuals. Further delineation of the intimate interactions between the HIV and the immune system will be critical and recent advances in this direction are discussed.

Studies on the allostimulatory function of dendritic cells from HCV-HIV-1 co-infected patients.

There is increasing recognition of the potential morbidity and mortality associated with HIV-1 and hepatitis C (HCV) co-infection. HIV appears to adversely affect HCV disease while the reciprocal effect of HCV on HIV remains controversial. We therefore studied the effect of co-infection on dendritic cell function versus HIV infection alone, as previous work has shown that HCV impairs dendritic cell (DC) function. HIV-1 positive individuals with HCV were matched for CD4 count, HIV-1 RNA viral load and therapy, to HIV-1 positive patients without HCV. Monocyte-derived DC were generated and mixed leukocyte reactions were performed. We assessed allostimulatory capacity with and without administration of exogenous Th1 cytokines, using thymidine uptake and cell division analyses with the vital dye CFSE. We found that monocyte-derived DC from co-infected individuals showed no significant differences in allostimulatory capacity to ex vivo generated DC from HIV-1 infected individuals without HCV. Unlike the situation with HCV infection alone, this impairment was not reversed by increasing concentrations of either interleukin-2 or -12. Monocyte-derived DC from HIV-1 and HCV co-infected individuals have a similar allostimulatory capacity to DC from matched patients with HIV-1 alone. These findings are compatible with results of prior clinical studies that found no evidence that HCV co-infection altered HIV disease progression and has implications for immunotherapeutic approaches in co-infected individuals.

Conservative treatment of an acute traumatic extensor carpi ulnaris tendon subluxation in a collegiate basketball player: a case report.

OBJECTIVE: To present the case of an acute traumatic extensor carpi ulnaris (ECU) subluxation in a National Collegiate Athletic Association Division II female basketball player. BACKGROUND: The ECU tendon is stabilized in the ulnar groove by a subsheath located inferior to the extensor retinaculum. The subsheath can be injured with forced supination, ulnar deviation, and wrist flexion, resulting in the ECU tendon subluxing in the palmar and ulnar directions during wrist circumduction. Several methods of intervention exist, but controversy remains on how to best treat this condition. DIFFERENTIAL DIAGNOSIS: Distal ulnar fracture, ulnar collateral ligament sprain, triangular fibrocartilage complex lesion, lunotriquetral instability, distal radioulnar joint injury, pisotriquetral joint injury, ECU tendinopathy or subluxation. TREATMENT: The wrist was placed in a short-arm cast in slight extension and radial deviation for 4 weeks. At that time, the patient was still able to actively sublux the ECU tendon, so a long-arm cast was applied with the wrist in slight extension, radial deviation, and pronation for an additional 4 weeks. The ECU tendon was then found to be stable. She wore a rigid wrist brace for 3 more weeks while she pursued rehabilitation. At the final follow-up appointment, the ECU tendon remained stable, and the wrist was asymptomatic. UNIQUENESS: Subluxations of the ECU are rare. If the patient does not improve with conservative measures, surgical intervention is warranted to repair the sixth dorsal compartment. CONCLUSIONS: A long-arm cast with the elbow flexed to 90° and the wrist in approximately 30° of extension, radial deviation, and pronation was appropriate treatment for this type of injury.

All for CD91 and CD91 for all.

Heat shock proteins interact with antigen-presenting cells through their receptor, CD91, eliciting a cascade of events including maturation, activation and representation of chaperoned foreign peptides with class I molecules on their surface. In turn, this facilitates recognition of non-self leading to induction of a cytotoxic T cell response. The abundance of heat shock proteins in tumours and their presence in virion coats makes them attractive propositions for use in antitumour and antiviral strategies.

Ex vivo analysis of HIV-1 co-receptors at the endocervical mucosa of women using oral contraceptives.

Combined oral contraceptives may alter the microenvironment of the female genital tract and, thus, influence susceptibility of endocervical cells to HIV-1 transmission. The mechanism for this effect is unknown but might involve combined oral contraceptive up-regulation of chemokine receptors on CD4+ endocervical cells. We measured chemokine co-receptor (CCR5 and CXCR4) expression on cervical intraepithelial CD4+ T lymphocytes, macrophages and dendritic cells using flow cytometry in 32 healthy women, 16 of whom were combined oral contraceptive users and 16 non-users. All women tested negative for sexually transmitted infections. Combined oral contraceptive users showed a higher proportion of CCR5+ CD4+ T lymphocytes compared with combined oral contraceptive non-users (P < 0.05). However, expression of both co-receptors on cervical intraepithelial macrophages and dendritic cells was no different between the two groups. Up-regulation of CCR5 on cervical intraepithelial CD4+ T lymphocytes offers a potential explanation by which women receiving combined oral contraceptives may be at increased risk of HIV transmission.

Chemokine receptor expression on mucosal dendritic cells from the endocervix of healthy women.

Dendritic cells (DCs) may be an initial target of human immunodeficiency virus (HIV) during heterosexual transmission. An analysis of DCs in the intraepithelial layer of the endocervix of the female genital tract from healthy women showed that ~20% expressed CD1a, and 30% expressed cutaneous leukocyte antigen (CLA). Langerin, a molecule associated with Langerhans DCs, was on CD1a-positive and -negative DCs and on CLA-positive cells. CCR5 and CXCR4 were detected on CD1a-positive and -negative cervical DCs. These findings suggest that DCs in the genital tract are potential targets for macrophage-tropic and lymphotropic strains of HIV.