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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition that primarily affects the motor system and shares many features with frontotemporal dementia (FTD). Evidence suggests that ALS is a 'dying-back' disease, with peripheral denervation and axonal degeneration occurring before loss of motor neuron cell bodies. Distal to a nerve injury, a similar pattern of axonal degeneration can be seen, which is mediated by an active axon destruction mechanism called Wallerian degeneration. Sterile alpha and TIR motif-containing 1 (Sarm1) is a key gene in the Wallerian pathway and its deletion provides long-term protection against both Wallerian degeneration and Wallerian-like, non-injury induced axonopathy, a retrograde degenerative process that occurs in many neurodegenerative diseases where axonal transport is impaired. Here, we explored whether Sarm1 signalling could be a therapeutic target for ALS by deleting Sarm1 from a mouse model of ALS-FTD, a TDP-43 Q331K , YFP-H double transgenic mouse. Sarm1 deletion attenuated motor axon degeneration and neuromuscular junction denervation. Motor neuron cell bodies were also significantly protected. Deletion of Sarm1 also attenuated loss of layer V pyramidal neuronal dendritic spines in the primary motor cortex. Structural MRI identified the entorhinal cortex as the most significantly atrophic region, and histological studies confirmed a greater loss of neurons in the entorhinal cortex than in the motor cortex, suggesting a prominent FTD-like pattern of neurodegeneration in this transgenic mouse model. Despite the reduction in neuronal degeneration, Sarm1 deletion did not attenuate age-related behavioural deficits caused by TDP-43 Q331K . However, Sarm1 deletion was associated with a significant increase in the viability of male TDP-43 Q331K mice, suggesting a detrimental role of Wallerian-like pathways in the earliest stages of TDP-43 Q331K -mediated neurodegeneration. Collectively, these results indicate that anti-SARM1 strategies have therapeutic potential in ALS-FTD.

Neuroinflammation and microglial activation are significant processes in Alzheimer's disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes in association with Alzheimer's disease, and experimental data have demonstrated microglial proliferation as a significant component of the neuropathology. In this study, we tested the efficacy of the selective CSF1R inhibitor JNJ-40346527 (JNJ-527) in the P301S mouse tauopathy model. We first demonstrated the anti-proliferative effects of JNJ-527 on microglia in the ME7 prion model, and its impact on the inflammatory profile, and provided potential CNS biomarkers for clinical investigation with the compound, including pharmacokinetic/pharmacodynamics and efficacy assessment by TSPO autoradiography and CSF proteomics. Then, we showed for the first time that blockade of microglial proliferation and modification of microglial phenotype leads to an attenuation of tau-induced neurodegeneration and results in functional improvement in P301S mice. Overall, this work strongly supports the potential for inhibition of CSF1R as a target for the treatment of Alzheimer's disease and other tau-mediated neurodegenerative diseases., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Pyoderma gangrenosum (PG) is an uncommon inflammatory skin disorder characterized by neutrophil dysfunction. There are currently no FDA-approved drugs for the treatment of this disease, and treatment has typically relied on traditional immunosuppressive medications such as prednisone or cyclosporine. The efficacy of biologics in the treatment of other pro-inflammatory conditions such as psoriasis, rheumatoid arthritis, and inflammatory bowel disease is well-documented in the literature. Therefore, the use of biologic medications for the treatment of rarer inflammatory skin conditions, such as PG, is a compelling topic for investigation. Biologic and small-molecule therapies allow physicians to target specific pro-inflammatory mediators that underlie PG pathogenesis. This review provides an update on the use of biologic and small-molecule medications for the treatment of PG and summarizes the latest data on the clinical efficacy and pharmacology of these treatments.

Objective: Neurotrophin-3 (NT3) plays a key role in the development and function of locomotor circuits including descending serotonergic and corticospinal tract axons and afferents from muscle and skin. We have previously shown that gene therapy delivery of human NT3 into affected forelimb muscles improves sensorimotor recovery after stroke in adult and elderly rats. Here, to move toward the clinic, we tested the hypothesis that intramuscular infusion of NT3 protein could improve sensorimotor recovery after stroke., Methods: Rats received unilateral ischemic stroke in sensorimotor cortex. To simulate a clinically feasible time to treatment, 24 hours later rats were randomized to receive NT3 or vehicle by infusion into affected triceps brachii for 4 weeks using implanted catheters and minipumps., Results: Radiolabeled NT3 crossed from the bloodstream into the brain and spinal cord in rodents with or without strokes. NT3 increased the accuracy of forelimb placement during walking on a horizontal ladder and increased use of the affected arm for lateral support during rearing. NT3 also reversed sensory impairment of the affected wrist. Functional magnetic resonance imaging during stimulation of the affected wrist showed spontaneous recovery of peri-infarct blood oxygenation level-dependent signal that NT3 did not further enhance. Rather, NT3 induced neuroplasticity of the spared corticospinal and serotonergic pathways., Interpretation: Our results show that delayed, peripheral infusion of NT3 can improve sensorimotor function after ischemic stroke. Phase I and II clinical trials of NT3 (for constipation and neuropathy) have shown that peripheral high doses are safe and well tolerated, which paves the way for NT3 as a therapy for stroke. ANN NEUROL 2019;85:32-46., (© 2018 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Introduction: The development of clinically useful tracers for PET imaging is enormously challenging and expensive. The intranasal (IN) route of administration is purported to be a viable route for delivering drugs to the brain but has, as yet, not been investigated for the delivery of PET tracers. If the intranasal (IN) pathway presents a viable option, it extends the PET imaging field by increasing the number of tracers available for human use. Here we report the results of a rodent study testing the feasibility of the IN route to administer radiotracers for brain PET imaging., Methods: We used two different, well characterised, brain penetrant radiotracers, [ 18 F]fluorodeoxyglucose ([ 18 F]FDG) and [ 18 F]fallypride, and aimed to evaluate the pharmacokinetics after administration of the tracers via the intranasal route, and contrast this to intravenous administration. Image acquisition was carried out after tracer administration and arterial blood samples were collected at different time intervals, centrifuged to extract plasma and gamma counted. We hypothesised that [brain region]:[plasma] ratios would be higher via the intranasal route as there are two inputs, one directly from the nose to the brain, and another from the peripheral circulation. To assess the feasibility of using this approach clinically, we used these data to estimate radiation dosimetry in humans., Results: Contrary to our hypothesis, in case of both radiotracers, we did not see a higher ratio in the expected brain regions, except in the olfactory bulb, that is closest to the nose. It appears that the radiotracers move into the olfactory bulb region, but then do not progress further into other brain regions. Moreover, as the nasal cavity has a small surface area, the extrapolated dosimetry estimations for intranasal human imaging showed an unacceptably high level (15 mSv/MBq) of cumulative skin radiation exposure., Conclusions: Therefore, although an attractive route for brain permeation, we conclude that the intranasal route would present difficulties due to non-specific signal and radiation dosimetry considerations for brain PET imaging., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Preliminary studies have suggested that γ-aminobutyric acid type A (GABA A ) receptors, and potentially the GABA A α5 subtype, are deficient in autism spectrum disorder (ASD). However, prior studies have been confounded by the effects of medications, and these studies did not compare findings across different species. We measured both total GABA A and GABA A α5 receptor availability in two positron emission tomography imaging studies. We used the tracer [ 11 C]flumazenil in 15 adults with ASD and in 15 control individuals without ASD and the tracer [ 11 C]Ro15-4513 in 12 adults with ASD and in 16 control individuals without ASD. All participants were free of medications. We also performed autoradiography, using the same tracers, in three mouse models of ASD: the Cntnap2 knockout mouse, the Shank3 knockout mouse, and mice carrying a 16p11.2 deletion. We found no differences in GABA A receptor or GABA A α5 subunit availability in any brain region of adults with ASD compared to those without ASD. There were no differences in GABA A receptor or GABA A α5 subunit availability in any of the three mouse models. However, adults with ASD did display altered performance on a GABA-sensitive perceptual task. Our data suggest that GABA A receptor availability may be normal in adults with ASD, although GABA signaling may be functionally impaired., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Exposure to early adversity is implicated in the development of aggressive behaviour later in life in some but not all individuals. The reasons for the variability in response to such experiences are not clear but may relate to pre-existing individual differences that influence their downstream effects. Applying structural magnetic resonance imaging (MRI) to a rat model of abnormal aggression induced by peripubertal stress, we examined whether individual differences in the development of an aggressive phenotype following stress exposure were underpinned by variation in the structure of aggression-associated, corticolimbic brain regions. We also assessed whether responsiveness of the hypothalamic-pituitary-adrenal axis to stress was associated with neurobehavioural outcome following adversity. A subset of the rats exposed to peripubertal stress developed an aggressive phenotype, while the remaining rats were affected in other behavioural domains, such as increased anxiety-like behaviours and reduced sociability. Peripubertal stress led to changes in tissue microstructure within prefrontal cortex, amygdala and hippocampal formation only in those individuals displaying an aggressive phenotype. Attenuated glucocorticoid response to stress during juvenility predicted the subsequent development of an aggressive phenotype in peripubertal stress-exposed rats. Our study establishes a link between peripubertal stress exposure in rats and structural deviations in brain regions linked to abnormal aggression and points towards low glucocorticoid responsiveness to stress as a potential underlying mechanism. We additionally highlight the importance of considering individual differences in behavioural response to stress when determining neurobiological correlates., (© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Genetic frontotemporal dementia is most commonly caused by mutations in the progranulin (GRN) , microtubule-associated protein tau ( MAPT) and chromosome 9 open reading frame 72 (C9orf72 ) genes. Previous small studies have reported the presence of cerebral white matter hyperintensities (WMH) in genetic FTD but this has not been systematically studied across the different mutations. In this study WMH were assessed in 180 participants from the Genetic FTD Initiative (GENFI) with 3D T1- and T2-weighed magnetic resonance images: 43 symptomatic (7 GRN , 13 MAPT and 23 C9orf72 ), 61 presymptomatic mutation carriers (25 GRN , 8 MAPT and 28 C9orf72 ) and 76 mutation negative non-carrier family members. An automatic detection and quantification algorithm was developed for determining load, location and appearance of WMH. Significant differences were seen only in the symptomatic GRN group compared with the other groups with no differences in the MAPT or C9orf72 groups: increased global load of WMH was seen, with WMH located in the frontal and occipital lobes more so than the parietal lobes, and nearer to the ventricles rather than juxtacortical. Although no differences were seen in the presymptomatic group as a whole, in the GRN cohort only there was an association of increased WMH volume with expected years from symptom onset. The appearance of the WMH was also different in the GRN group compared with the other groups, with the lesions in the GRN group being more similar to each other. The presence of WMH in those with progranulin deficiency may be related to the known role of progranulin in neuroinflammation, although other roles are also proposed including an effect on blood-brain barrier permeability and the cerebral vasculature. Future studies will be useful to investigate the longitudinal evolution of WMH and their potential use as a biomarker as well as post-mortem studies investigating the histopathological nature of the lesions.

Resting-state functional MRI (rsfMRI) is an imaging technology that has recently gained attention for its ability to detect disruptions in functional brain networks in humans, including in patients with Parkinson's disease (PD), revealing early and widespread brain network abnormalities. This methodology is now readily applicable to experimental animals offering new possibilities for cross-species translational imaging. In this context, we herein describe the application of rsfMRI to the unilaterally-lesioned 6-hydroxydopamine (6-OHDA) rat, a robust experimental model of the dopamine depletion implicated in PD. Using graph theory to analyse the rsfMRI data, we were able to provide meaningful and translatable measures of integrity, influence and segregation of the underlying functional brain architecture. Specifically, we confirm that rats share a similar functional brain network topology as observed in humans, characterised by small-worldness and modularity. Interestingly, we observed significantly reduced functional connectivity in the 6-OHDA rats, primarily in the ipsilateral (lesioned) hemisphere as evidenced by significantly lower node degree, local efficiency and clustering coefficient in the motor, orbital and sensorimotor cortices. In contrast, we found significantly, and bilaterally, increased thalamic functional connectivity in the lesioned rats. The unilateral deficits in the cortex are consistent with the unilateral nature of this model and further support the validity of the rsfMRI technique in rodents. We thereby provide a methodological framework for the investigation of brain networks in other rodent experimental models of PD, as well as of animal models in general, for cross-comparison with human data.

TAK-063 is a selective phosphodiesterase 10A (PDE10A) inhibitor that produces potent antipsychotic-like and pro-cognitive effects at 0.3mg/kg (26% PDE10A occupancy in rats) or higher in rodents through the balanced activation of the direct and indirect pathways of striatal medium spiny neurons (MSNs). In this study, we evaluated the specific binding of TAK-063 using in vitro autoradiography (ARG) and the modulation of brain activity using pharmacological magnetic resonance imaging (phMRI) and electroencephalography (EEG). [ 3 H]TAK-063 significantly accumulated in the caudate-putamen (CPu), ventral pallidum (VP), substantia nigra (SN), hippocampus (Hipp), and amygdala (Amy), but not in the frontal cortex (Fcx), brainstem (Bs), or cerebellum (Cb) in an ARG study using rat brain sections. [ 3 H]TAK-063 accumulation in the CPu was more than eighteen-fold higher than that in the Hipp and Amy. TAK-063 at 0.3mg/kg increased the blood oxygenation level-dependent (BOLD) signal in the striatum and Amy, and decreased it in the Fcx in a phMRI study with anesthetized rats. TAK-063 at 0.3mg/kg significantly reduced the ketamine-induced increase in EEG gamma power both in awake and anesthetized rats. TAK-063 at 0.2mg/kg (35% PDE10A occupancy in monkeys) also reduced the ketamine-induced increase in EEG gamma power in awake monkeys. In line with the EEG data, TAK-063 at 0.3mg/kg reversed the ketamine-induced BOLD signal changes in the cortex, Bs, and Cb in a phMRI study with anesthetized rats. These data suggest that TAK-063 at about 30% PDE10A occupancy modulates activities of multiple brain regions through activation of neuronal circuits in rats and monkeys., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

Myelin is a critical component of the nervous system and a major contributor to contrast in Magnetic Resonance (MR) images. However, the precise contribution of myelination to multiple MR modalities is still under debate. The cuprizone mouse is a well-established model of demyelination that has been used in several MR studies, but these have often imaged only a single slice and analysed a small region of interest in the corpus callosum. We imaged and analyzed the whole brain of the cuprizone mouse ex-vivo using high-resolution quantitative MR methods (multi-component relaxometry, Diffusion Tensor Imaging (DTI) and morphometry) and found changes in multiple regions, including the corpus callosum, cerebellum, thalamus and hippocampus. The presence of inflammation, confirmed with histology, presents difficulties in isolating the sensitivity and specificity of these MR methods to demyelination using this model., Competing Interests: The authors declare that they have no competing interests. Samuel A. Hurley is an employee of Synaptive Medical, Toronto, ON, Canada.

Background: The unilaterally-lesioned 6-hydroxydopamine (6-OHDA) rat is one of the most commonly used experimental models of Parkinson's disease (PD). Here we investigated whether magnetic resonance imaging (MRI) that is widely used in human PD research, has the potential to non-invasively detect macroscopic structural brain changes in the 6-OHDA rat in ways translatable to humans., Methods: We measured the gray matter (GM) composition in the unilateral 6-OHDA rat in comparison to sham animals using whole-brain voxel-based morphometry (VBM) - an unbiased MR image analysis technique. The number of nigral dopamine (DA) neurons and the density of their cortical projections were examined post-mortem using immunohistochemistry., Results: VBM revealed widespread bilateral changes in gray matter volume (GMV) on a topographic scale in the brains of 6-OHDA rats, compared to sham-operated rats. The greatest changes were in the lesioned hemisphere, which displayed reductions of GMV in motor, cingulate and somatosensory cortex. Histopathological results revealed dopaminergic cell loss in the substantia nigra (SN) and a denervation in the striatum, as well as in the frontal, somatosensory and cingulate cortices., Conclusion: Unilateral nigrostriatal 6-OHDA lesioning leads to widespread GMV changes, which extend beyond the nigrostriatal system and resemble advanced Parkinsonism. This study highlights the potential of structural MRI, and VBM in particular, for the system-level phenotyping of rodent models of Parkinsonism and provides a methodological framework for future studies in novel rodent models as they become available to the research community., (Copyright © 2016 IBRO. All rights reserved.)

Objective: This study assesses perceptions of overall harm, short-term health and social risks, long-term health risks, and benefits associated with various tobacco products including conventional cigarettes, e-cigarettes, cigars, chew, and hookah. This study also assesses whether and how perceptions differ by age, gender, race/ethnicity, and previous experience with tobacco., Methods: A total of 722 high school students completed an online survey, answering questions about their use and perceptions of a variety of tobacco products. Differences in perceptions across products were assessed using a generalized estimation equation with an exchangeable correlation structure., Results: Adolescents rated the various tobacco products as conferring significantly different levels of risks and benefits. Generally, adolescents rated cigarettes as most risky, followed by cigars and chew, with hookah and e-cigarettes rated as least risky. Adolescents rated hookah followed by cigarettes and e-cigarettes as most likely to make them look cool or fit in and cigars and chew as least likely to confer these benefits. There were interaction effects by age and use, with older adolescents and those with tobacco experience holding lower perceptions of risk. There were no significant interaction effects by race/ethnicity or gender., Conclusion: Given the significant differences in adolescents' perceptions of risks and benefits of using different tobacco products and research showing the predictive relationship between perceptions and behavior, there is a need for comprehensive messaging that discusses risks of all tobacco products, particularly hookah and e-cigarettes. There is also a need to address perceived benefits of tobacco products, especially hookah and e-cigarettes., Competing Interests: The authors have no potential conflicts of interest., (Copyright © 2016 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

This paper discusses the evolution of scientific and social understanding that has led to the development of knowledge systems supporting the application of El Niño-Southern Oscillation (ENSO) forecasts, including the development of successful efforts to connect climate predictions with sectoral applications and actions "on the ground". The evolution of "boundary-spanning" activities to connect science and decisionmaking is then discussed, setting the stage for a report of outcomes from an international workshop comprised of producers, translators, and users of climate predictions. The workshop, which focused on identifying critical boundary-spanning features of successful boundary organizations, included participants from Australia, Hawaii, and the Pacific Islands, the US Pacific Northwest, and the state of Ceará in northwestern Brazil. Workshop participants agreed that boundary organizations have multiple roles including those of information broker, convenor of forums for engagement, translator of scientific information, arbiter of access to knowledge, and exemplar of adaptive behavior. Through these roles, boundary organizations will ensure the stability of the knowledge system in a changing political, economic, and climatic context. The international examples reviewed in this workshop demonstrated an interesting case of convergent evolution, where organizations that were very different in origin evolved toward similar structures and individuals engaged in them had similar experiences to share. These examples provide evidence that boundary organizations and boundary-spanners fill some social/institutional roles that are independent of culture.

Stroke typically occurs in elderly people with a range of comorbidities including carotid (or other arterial) atherosclerosis, high blood pressure, obesity and diabetes. Accordingly, when evaluating therapies for stroke in animals, it is important to select a model with excellent face validity. Ischemic stroke accounts for 80% of all strokes, and the majority of these occur in the territory of the middle cerebral artery (MCA), often inducing infarcts that affect the sensorimotor cortex, causing persistent plegia or paresis on the contralateral side of the body. We demonstrate in this video a method for producing ischemic stroke in elderly rats, which causes sustained sensorimotor disability and substantial cortical infarcts. Specifically, we induce permanent distal middle cerebral artery occlusion (MCAO) in elderly female rats by using diathermy forceps to occlude a short segment of this artery. The carotid artery on the ipsilateral side to the lesion was then permanently occluded and the contralateral carotid artery was transiently occluded for 60 min. We measure the infarct size using structural T2-weighted magnetic resonance imaging (MRI) at 24 hr and 8 weeks after stroke. In this study, the mean infarct volume was 4.5% ± 2.0% (standard deviation) of the ipsilateral hemisphere at 24 hr (corrected for brain swelling using Gerriet's equation, n = 5). This model is feasible and clinically relevant as it permits the induction of sustained sensorimotor deficits, which is important for the elucidation of pathophysiological mechanisms and novel treatments.

Myelin-associated glycoprotein (MAG) is an inhibitor of axon growth. MAG levels increase after stroke. GSK249320 is a monoclonal antibody that neutralizes MAG-mediated inhibition and so may promote axon outgrowth and improve post-stroke outcomes. The current study tested the hypothesis that GSK249320 initiated 24 hours or 7 days after experimental stroke improves behavioural outcomes. Rats with right middle cerebral artery occlusion for 90 minutes were randomized to receive 6 weeks of intravenous (a) GSK249320 starting 24 hours post-stroke, (b) GSK249320 starting 7 days post-stroke, or (c) vehicle. Behavioral testing was performed over 7 weeks. Serial MRI demonstrated no differences in infarct volume across groups. Animals treated with GSK249320 24 hours post-stroke showed larger increases in Neuroscore (time X group, p = 0.0008) and staircase test (main effect of group, p = 0.0214) as compared to controls, but animals treated 7 days post-stroke showed no significant behavioral benefit. No significant results were found for the sticky tape or cylinder tests. A separate set of animals with experimental stroke received a single intravenous dose of GSK249320 or vehicle at 1 hour, 24 hours, 48 hours or 1 week post-stroke, and immunohistochemistry methods were used to measure GSK249320 distribution; GSK249320 was found in the ipsilesional hemisphere only, the extent of which increased with later times of injection. These data suggest that intravenous GSK249320 penetrates the lesion site and is associated with a small effect on functional outcomes when initiated 24 hours post-stroke and so support the translational potential of this monoclonal antibody as a restorative therapy for patients with stroke.

This paper introduces a novel method for inferring spatially varying regularisation in non-linear registration. This is achieved through full Bayesian inference on a probabilistic registration model, where the prior on the transformation parameters is parameterised as a weighted mixture of spatially localised components. Such an approach has the advantage of allowing the registration to be more flexibly driven by the data than a traditional globally defined regularisation penalty, such as bending energy. The proposed method adaptively determines the influence of the prior in a local region. The strength of the prior may be reduced in areas where the data better support deformations, or can enforce a stronger constraint in less informative areas. Consequently, the use of such a spatially adaptive prior may reduce unwanted impacts of regularisation on the inferred transformation. This is especially important for applications where the deformation field itself is of interest, such as tensor based morphometry. The proposed approach is demonstrated using synthetic images, and with application to tensor based morphometry analysis of subjects with Alzheimer's disease and healthy controls. The results indicate that using the proposed spatially adaptive prior leads to sparser deformations, which provide better localisation of regional volume change. Additionally, the proposed regularisation model leads to more data driven and localised maps of registration uncertainty. This paper also demonstrates for the first time the use of Bayesian model comparison for selecting different types of regularisation., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

Clinical annotations, such as voxel-wise binary or probabilistic tissue segmentations, structural parcellations, pathological regions-of-interest and anatomical landmarks are key to many clinical studies. However, due to the time consuming nature of manually generating these annotations, they tend to be scarce and limited to small subsets of data. This work explores a novel framework to propagate voxel-wise annotations between morphologically dissimilar images by diffusing and mapping the available examples through intermediate steps. A spatially-variant graph structure connecting morphologically similar subjects is introduced over a database of images, enabling the gradual diffusion of information to all the subjects, even in the presence of large-scale morphological variability. We illustrate the utility of the proposed framework on two example applications: brain parcellation using categorical labels and tissue segmentation using probabilistic features. The application of the proposed method to categorical label fusion showed highly statistically significant improvements when compared to state-of-the-art methodologies. Significant improvements were also observed when applying the proposed framework to probabilistic tissue segmentation of both synthetic and real data, mainly in the presence of large morphological variability.

Crowding is a breakdown in the ability to identify objects in clutter, and is a major constraint on object recognition. Crowding particularly impairs object perception in peripheral, amblyopic and possibly developing vision. Here we argue that crowding is also a critical factor limiting object perception in central vision of individuals with neurodegeneration of the occipital cortices. In the current study, individuals with posterior cortical atrophy (n=26), typical Alzheimer's disease (n=17) and healthy control subjects (n=14) completed centrally-presented tests of letter identification under six different flanking conditions (unflanked, and with letter, shape, number, same polarity and reverse polarity flankers) with two different target-flanker spacings (condensed, spaced). Patients with posterior cortical atrophy were significantly less accurate and slower to identify targets in the condensed than spaced condition even when the target letters were surrounded by flankers of a different category. Importantly, this spacing effect was observed for same, but not reverse, polarity flankers. The difference in accuracy between spaced and condensed stimuli was significantly associated with lower grey matter volume in the right collateral sulcus, in a region lying between the fusiform and lingual gyri. Detailed error analysis also revealed that similarity between the error response and the averaged target and flanker stimuli (but not individual target or flanker stimuli) was a significant predictor of error rate, more consistent with averaging than substitution accounts of crowding. Our findings suggest that crowding in posterior cortical atrophy can be regarded as a pre-attentive process that uses averaging to regularize the pathologically noisy representation of letter feature position in central vision. These results also help to clarify the cortical localization of feature integration components of crowding. More broadly, we suggest that posterior cortical atrophy provides a neurodegenerative disease model for exploring the basis of crowding. These data have significant implications for patients with, or who will go on to develop, dementia-related visual impairment, in whom acquired excessive crowding likely contributes to deficits in word, object, face and scene perception., (© The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Automated analysis of structural magnetic resonance images is a promising way to improve early detection of neurodegenerative brain diseases. Clinical applications of such methods involve multiple scanners with potentially different hardware and/or acquisition sequences and demographically heterogeneous groups. To improve classification performance, we propose to correct effects of subject-specific covariates (such as age, total intracranial volume, and sex) as well as effects of scanner by using a non-linear Gaussian process model. To test the efficacy of the correction, we performed classification of carriers of the genetic mutation leading to Huntington's disease (HD) versus healthy controls. Half of the HD carriers were free of typical HD symptoms and had an estimated 5 to 20years before onset of clinical symptoms, thus providing a model for preclinical diagnosis of a neurodegenerative disease. Structural magnetic resonance brain images were acquired at four sites with pairs of sites which had the identical scanner type, equipment, and acquisition parameters. For automatic classification, we used spatially normalized probabilistic maps of gray matter, then removed confounding effects by Gaussian process regression, and then performed classification with a support vector machine. Voxel-based morphometry of gray matter maps showed disease effects that were spatially wider spread than effects of scanner, but no significant interactions between scanner and disease were found. A model trained with data from a single scanner generalized well to data from a different scanner. When confounding diagnostics groups and scanner during training, e.g. by using controls from one scanner and gene carriers from another, classification accuracy dropped significantly in many cases. By regressing out confounds with Gaussian process regression, the performance levels were comparable to those obtained in scenarios without confound. We conclude that models trained on data acquired with a single scanner generalized well to data acquired with a different same-generation scanner even when the vendor differed. When confounding grouping and scanner during training is unavoidable to gather training data, regressing out inter-scanner and between-subject variability can reduce the loss in accuracy due to the confound., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Reading deficits are a common early feature of the degenerative syndrome posterior cortical atrophy (PCA) but are poorly understood even at the single word level. The current study evaluated the reading accuracy and speed of 26 PCA patients, 17 typical Alzheimer's disease (tAD) patients and 14 healthy controls on a corpus of 192 single words in which the following perceptual properties were manipulated systematically: inter-letter spacing, font size, length, font type, case and confusability. PCA reading was significantly less accurate and slower than tAD patients and controls, with performance significantly adversely affected by increased letter spacing, size, length and font (cursive < non-cursive), and characterised by visual errors (69% of all error responses). By contrast, tAD and control accuracy rates were at or near ceiling, letter spacing was the only perceptual factor to influence reading speed in the same direction as controls, and, in contrast to PCA patients, control reading was faster for larger font sizes. The inverse size effect in PCA (less accurate reading of large than small font size print) was associated with lower grey matter volume in the right superior parietal lobule. Reading accuracy was associated with impairments of early visual (especially crowding), visuoperceptual and visuospatial processes. However, these deficits were not causally related to a universal impairment of reading as some patients showed preserved reading for small, unspaced words despite grave visual deficits. Rather, the impact of specific types of visual dysfunction on reading was found to be (con)text specific, being particularly evident for large, spaced, lengthy words. These findings improve the characterisation of dyslexia in PCA, shed light on the causative and associative factors, and provide clear direction for the development of reading aids and strategies to maximise and sustain reading ability in the early stages of disease., (Copyright © 2014. Published by Elsevier Ltd.)

Severe scorpion envenoming (SSE) is more frequent in children and is characterized by systemic dysfunctions with a mortality rate of up to 9%. Recent evidence shows that the central nervous system (CNS) plays a key role in triggering the cascade of symptoms present in SSE. The age-dependent role of the CNS in SSE lethality may be summarized in 3 hypotheses: (1) the shown increased blood brain barrier permeability of infants to the toxins would especially and primarily compromise neurovegetative control areas, (2) the neurons within these areas have high affinity to the toxins, and (3) the neurovascular interaction is such that SSE metabolically compromises proper function of toxin-targeted areas. A pharmacological magnetic resonance imaging paradigm was used to evaluate localized hemodynamic changes in relative cerebral blood volume (rCBV) for 30 min after the injection of TsTX, the most lethal toxin from the venom of the Tityus serrulatus scorpion. The brainstem showed significant rCBV reduction 1 min after TsTX administration, whereas rostral brain areas had delayed increase in rCBV (confirmed by laser Doppler measurements of cortical cerebral blood flow). Moreover, metabolic activity by 14C-2-deoxyglucose autoradiography showed the highest relative increase at the brainstem. To test whether TsTX has high affinity to brainstem neurons, the lateral ventricle was injected with Alexa Fluor 568 TsTX. Although some neurons showed intense fluorescence, the labeling pattern suggests that specific neurons were targeted. Altogether, these results suggest that brainstem areas involved in neurovegetative control are most likely within the primary structures triggering the cascade of symptoms present in SSE.

Disruption of the blood-brain barrier (BBB) and cerebral edema are the major pathogenic mechanisms leading to neurological dysfunction and death after ischemic stroke. The brain protects itself against infarction via activation of endogenous antioxidant defense mechanisms, and we here report the first evidence that sulforaphane-mediated preactivation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target heme oxygenase-1 (HO-1) in the cerebral vasculature protects the brain against stroke. To induce ischemic stroke, Sprague-Dawley rats were subjected to 70 min middle cerebral artery occlusion (MCAo) followed by 4, 24, or 72 h reperfusion. Nrf2 and HO-1 protein expression was upregulated in cerebral microvessels of peri-infarct regions after 4-72 h, with HO-1 preferentially associated with perivascular astrocytes rather than the cerebrovascular endothelium. In naïve rats, treatment with sulforaphane increased Nrf2 expression in cerebral microvessels after 24h. Upregulation of Nrf2 by sulforaphane treatment prior to transient MCAo (1h) was associated with increased HO-1 expression in perivascular astrocytes in peri-infarct regions and cerebral endothelium in the infarct core. BBB disruption, lesion progression, as analyzed by MRI, and neurological deficits were reduced by sulforaphane pretreatment. As sulforaphane pretreatment led to a moderate increase in peroxynitrite generation, we suggest that hormetic preconditioning underlies sulforaphane-mediated protection against stroke. In conclusion, we propose that pharmacological or dietary interventions aimed to precondition the brain via activation of the Nrf2 defense pathway in the cerebral microvasculature provide a novel therapeutic approach for preventing BBB breakdown and neurological dysfunction in stroke., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

Background and Aim: The management of femoral periprosthetic fractures following hip replacement surgery is a complex and challenging situation. Whilst the early complications for both primary hip arthroplasty and proximal femoral fracture surgery have been widely documented, there is a paucity of published data regarding early outcomes following periprosthetic fracture surgery. Delay to surgery for native proximal femoral fractures has been clearly documented as a predictor towards adverse outcome. This study therefore aims to correlate the timing of operative intervention with the complication rate following periprosthetic fracture surgery. In addition, the study aims to identify further factors in the perioperative period that positively predict a poor postoperative outcome., Methods: Sixty patients who were operatively managed for a femoral implant periprosthetic fracture were identified and each case assessed retrospectively., Results and Conclusion: There was an overall complication rate of 45% including a 30-day mortality of 10%. An abbreviated mental test score of 8 out of 10 or less and a delay to surgery of >72h were found to be significant risk factors for adverse outcome. Both the patient cohort in this study and the predictors for poor postoperative outcome were comparable to those for native proximal femoral fractures., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Anatomical segmentation of structures of interest is critical to quantitative analysis in medical imaging. Several automated multi-atlas based segmentation propagation methods that utilise manual delineations from multiple templates appear promising. However, high levels of accuracy and reliability are needed for use in diagnosis or in clinical trials. We propose a new local ranking strategy for template selection based on the locally normalised cross correlation (LNCC) and an extension to the classical STAPLE algorithm by Warfield et al. (2004), which we refer to as STEPS for Similarity and Truth Estimation for Propagated Segmentations. It addresses the well-known problems of local vs. global image matching and the bias introduced in the performance estimation due to structure size. We assessed the method on hippocampal segmentation using a leave-one-out cross validation with optimised model parameters; STEPS achieved a mean Dice score of 0.925 when compared with manual segmentation. This was significantly better in terms of segmentation accuracy when compared to other state-of-the-art fusion techniques. Furthermore, due to the finer anatomical scale, STEPS also obtains more accurate segmentations even when using only a third of the templates, reducing the dependence on large template databases. Using a subset of Alzheimer's Disease Neuroimaging Initiative (ADNI) scans from different MRI imaging systems and protocols, STEPS yielded similarly accurate segmentations (Dice=0.903). A cross-sectional and longitudinal hippocampal volumetric study was performed on the ADNI database. Mean±SD hippocampal volume (mm(3)) was 5195 ± 656 for controls; 4786 ± 781 for MCI; and 4427 ± 903 for Alzheimer's disease patients and hippocampal atrophy rates (%/year) of 1.09 ± 3.0, 2.74 ± 3.5 and 4.04 ± 3.6 respectively. Statistically significant (p<10(-3)) differences were found between disease groups for both hippocampal volume and volume change rates. Finally, STEPS was also applied in a multi-label segmentation propagation scenario using a leave-one-out cross validation, in order to parcellate 83 separate structures of the brain. Comparisons of STEPS with state-of-the-art multi-label fusion algorithms showed statistically significant segmentation accuracy improvements (p<10(-4)) in several key structures., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Accurately identifying the patients that have mild cognitive impairment (MCI) who will go on to develop Alzheimer's disease (AD) will become essential as new treatments will require identification of AD patients at earlier stages in the disease process. Most previous work in this area has centred around the same automated techniques used to diagnose AD patients from healthy controls, by coupling high dimensional brain image data or other relevant biomarker data to modern machine learning techniques. Such studies can now distinguish between AD patients and controls as accurately as an experienced clinician. Models trained on patients with AD and control subjects can also distinguish between MCI patients that will convert to AD within a given timeframe (MCI-c) and those that remain stable (MCI-s), although differences between these groups are smaller and thus, the corresponding accuracy is lower. The most common type of classifier used in these studies is the support vector machine, which gives categorical class decisions. In this paper, we introduce Gaussian process (GP) classification to the problem. This fully Bayesian method produces naturally probabilistic predictions, which we show correlate well with the actual chances of converting to AD within 3 years in a population of 96 MCI-s and 47 MCI-c subjects. Furthermore, we show that GPs can integrate multimodal data (in this study volumetric MRI, FDG-PET, cerebrospinal fluid, and APOE genotype with the classification process through the use of a mixed kernel). The GP approach aids combination of different data sources by learning parameters automatically from training data via type-II maximum likelihood, which we compare to a more conventional method based on cross validation and an SVM classifier. When the resulting probabilities from the GP are dichotomised to produce a binary classification, the results for predicting MCI conversion based on the combination of all three types of data show a balanced accuracy of 74%. This is a substantially higher accuracy than could be obtained using any individual modality or using a multikernel SVM, and is competitive with the highest accuracy yet achieved for predicting conversion within three years on the widely used ADNI dataset.

The Minimal Interval Resonance Imaging in Alzheimer's Disease (MIRIAD) dataset is a series of longitudinal volumetric T1 MRI scans of 46 mild-moderate Alzheimer's subjects and 23 controls. It consists of 708 scans conducted by the same radiographer with the same scanner and sequences at intervals of 2, 6, 14, 26, 38 and 52 weeks, 18 and 24 months from baseline, with accompanying information on gender, age and Mini Mental State Examination (MMSE) scores. Details of the cohort and imaging results have been described in peer-reviewed publications, and the data are here made publicly available as a common resource for researchers to develop, validate and compare techniques, particularly for measurement of longitudinal volume change in serially acquired MR., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Propionibacterium acnes is a common pathogen in infections after shoulder surgery. Recent reports found positive P acnes cultures in a high percentage of patients who had revision shoulder arthroplasty for "aseptic loosening" without any overt signs of infection. Isolation of P acnes is difficult, and by use of conventional microbiological protocols of 48-hour incubation, a considerable proportion of patients with possible P acnes infection may remain unidentified. We recently noted P acnes in shoulder joint cultures in patients undergoing primary shoulder replacement for glenohumeral arthropathy without any signs of infection., Methods: We collected aspirates and biopsy specimens from 55 consecutive patients with arthritic shoulders undergoing primary joint replacement and examined them for the presence of P acnes. Special measures were taken to ensure that the specimens were carefully taken from within the joint to reduce the risk of contamination to minimal., Results: In 23 of 55 consecutive patients (41.8%) undergoing primary shoulder joint replacement, P acnes was found in the joint fluid and tissues taken before the insertion of the implants. All these patients were treated early postoperatively with pathogen-directed specific dual oral antibiotic treatment for 4 weeks. In none have any signs of infection developed., Discussion and Conclusion: This finding of a high incidence of P acnes in joints before arthroplasty may suggest a role of P acnes in the pathogenesis of glenohumeral arthropathy. In addition, it raises the question of whether development of painful joint replacement later on and presumed aseptic loosening do, in fact, comprise an unrecognized low-grade infection that has been present since before the index operation., (Copyright © 2013 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Mosby, Inc. All rights reserved.)

Tract-based spatial statistics (TBSS) is a popular method for the analysis of diffusion tensor imaging data. TBSS focuses on differences in white matter voxels with high fractional anisotropy (FA), representing the major fibre tracts, through registering all subjects to a common reference and the creation of a FA skeleton. This work considers the effect of choice of reference in the TBSS pipeline, which can be a standard template, an individual subject from the study, a study-specific template or a group-wise average. While TBSS attempts to overcome registration error by searching the neighbourhood perpendicular to the FA skeleton for the voxel with maximum FA, this projection step may not compensate for large registration errors that might occur in the presence of pathology such as atrophy in neurodegenerative diseases. This makes registration performance and choice of reference an important issue. Substantial work in the field of computational anatomy has shown the use of group-wise averages to reduce biases while avoiding the arbitrary selection of a single individual. Here, we demonstrate the impact of the choice of reference on: (a) specificity (b) sensitivity in a simulation study and (c) a real-world comparison of Alzheimer's disease patients to controls. In (a) and (b), simulated deformations and decreases in FA were applied to control subjects to simulate changes of shape and WM integrity similar to what would be seen in AD patients, in order to provide a "ground truth" for evaluating the various methods of TBSS reference. Using a group-wise average atlas as the reference outperformed other references in the TBSS pipeline in all evaluations.

Aim: This study aimed to identify plasma protein changes in a rat model of ischemic stroke using a proteomic approach., Materials & Methods: Four male Sprague-Dawley rats (3-6 months old) were subjected to 90 min of left middle cerebral artery occlusion under anesthesia with 1.5% isoflurane in O(2)/air followed by 24-h reperfusion. Blood samples (~100 µl) were collected at baseline, at the end of 90-min middle cerebral artery occlusion and at 24-h postreperfusion. Brain injuries were assessed by MRI at 24-h postreperfusion. Quantitative comparison of global plasma protein expression was performed using 2D differential in-gel electrophoresis. Differentially expressed protein spots were identified using peptide sequencing tandem mass spectrometry., Results: These rats had clear brain infarction in the left hemisphere detected by MRI. Thirty-three protein spots of plasma samples were differentially expressed following focal cerebral ischemia/reperfusion. These protein spots belonged to eight proteins. Six of them (α2-macroglobulin, complement C3, inter-α- trypsin inhibitor heavy chain H3, serum albumin, haptoglobin and transthyretin), which are a class of acute-phase proteins, changed significantly., Conclusion: This study describes the responses of young rats to focal cerebral ischemia and suggests that future studies should use aged animals to better mimic the clinical ischemic stroke setting.

SUMMARYStaphylococcus aureus is a leading cause of infections in deployed service members. Based on a molecular epidemiological study of 182 MRSA isolates from patients in three U.S. Army combat support hospitals in separate regions in Iraq, USA300 clone was the most predominant (80%) pulsotype. This finding suggested that strain carriage from the home country by military personnel is epidemiologically more important than local acquisition.

This paper describes the presence of tenodesis effects in normal physiology and explores the uses of operative tenodesis in surgery of the upper limb.

A practical method to assemble rodlike tobacco mosaic virus and bateriophage M13 with polymers was developed, which afforded a 3D core-shell composite with morphological control.

Complementary and alternative medicine (CAM) has been gaining interest among individuals with serious mental illnesses. Yet, very little is known about how CAM may be beneficial to mental health. This study explored the specific benefits attributed to CAM by a national sample of 255 individuals with a serious mental illness who experienced CAM as having a positive impact on their mental health. Data about the CAM benefits were gathered through open-ended questions embedded in a mail survey that examined the patterns of CAM use in this population. Qualitative analysis revealed a wide spectrum of benefits that encompassed all major areas of human functioning, including physical, emotional, cognitive, self, social, spiritual, and overall functioning, and addressed both the improvement of psychiatric symptomatology and the promotion of functional recovery. Study findings provide useful information that can guide both everyday clinical practice and future research on the efficacy of CAM for psychiatric populations.

This paper examines the various meanings persons with serious mental illnesses attribute to the concepts of religion and spirituality. In-depth semi-structured interviews were conducted with forty individuals with serious mental illnesses who have incorporated alternative healing practices into their recovery process. The qualitative data analysis revealed that study participants differentially defined religion and spirituality using two sets of descriptors: (a) core characteristics describing the nature of each concept, and (b) functional characteristics describing the impact of religion and spirituality on the individual. Implications for clinical practice and future research on the role of religion and spirituality in recovery are discussed.

The loss of dopamine in idiopathic or animal models of Parkinson's disease induces synchronized low-frequency oscillatory burst-firing in subthalamic nucleus neurones. We sought to establish whether these firing patterns observed in vivo were preserved in slices taken from dopamine-depleted animals, thus establishing a role for the isolated subthalamic-globus pallidus complex in generating the pathological activity. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) showed significant reductions of over 90% in levels of dopamine as measured in striatum by high pressure liquid chromatography. Likewise, significant reductions in tyrosine hydroxylase immunostaining within the striatum (>90%) and tyrosine hydroxylase positive cell numbers (65%) in substantia nigra were observed. Compared with slices from intact mice, neurones in slices from MPTP-lesioned mice fired significantly more slowly (mean rate of 4.2 Hz, cf. 7.2 Hz in control) and more irregularly (mean coefficient of variation of inter-spike interval of 94.4%, cf. 37.9% in control). Application of ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2-amino-5-phosphonopentanoic acid (AP5) and the GABA(A) receptor antagonist picrotoxin caused no change in firing pattern. Bath application of dopamine significantly increased cell firing rate and regularized the pattern of activity in cells from slices from both MPTP-treated and control animals. Although the absolute change was more modest in control slices, the maximum dopamine effect in the two groups was comparable. Indeed, when taking into account the basal firing rate, no differences in the sensitivity to dopamine were observed between these two cohorts. Furthermore, pairs of subthalamic nucleus cells showed no correlated activity in slices from either control (21 pairs) or MPTP-treated animals (20 pairs). These results indicate that the isolated but interconnected subthalamic-globus pallidus network is not itself sufficient to generate the aberrant firing patterns in dopamine-depleted animals. More likely, inputs from other regions, such as the cortex, are needed to generate pathological oscillatory activity.

Background: Heightened activity of the AKT signaling pathway is prominent in malignant gliomas and has been suggested to play a role in treatment resistance. Selective targeting of AKT, therefore, may increase chemosensitivity. Recently, a novel class of AKT-selective inhibitors has been described, including SH-6, a phosphatidylinositol analogue., Methods: The effects of SH-6 on AKT signaling were tested in glioma cells, and the putative role of AKT signaling in chemoresistance was tested by attenuating AKT signaling pharmacologically and genetically. The initial characterization of SH-6 included treatment of glioma cells with increasing doses of SH-6 (0.30-30 microM) and examining the effects on AKT signaling proteins by Western blot analyses and in kinase assays with immunoprecipitated AKT1. Dose-response studies with SH-6 administered to glioma cell lines were performed using a luminescent cell-viability assay (0.1-30 microM). Studies examining the effect of carmustine, either alone or in combination with either the phosphatidylinositol 3-kinase inhibitor LY294002 or SH-6, were performed by cell viability assays and clonogenic survival assays. The effect of carmustine on AKT activity as a response to treatment also was examined. Caspase assays were used to examine the potential role of apoptosis in SH-6/ carmustine -elicited cell death. Finally, the induction of a dominant-negative AKT1 transgene was used in combination with carmustine to demonstrate the role of AKT1 in carmustine chemoresistance., Results: Serum-stimulated phosphorylation of AKT1 was inhibited by SH-6 at doses > or =10 microM (>70% decrease in Threonine 308 and Serine 473 phosphorylation of AKT1). In adenosine triphosphate assays, 72 hours of treatment with SH-6 led to 50% lethal doses near 10 microM for 2 cell lines tested. SH-6 enhancement of carmustine-mediated cell death led to synergistic increases in Caspase 3/Capsase 7 activity, implicating apoptosis as the cell death mechanism. In clonogenic assays, SH-6 cotreatment with carmustine significantly decreased the number of colonies at 10 microM (P < .05) compared with carmustine alone. No decrease was observed in cells that were treated with SH-6 alone (10 microM). LY294002 (10 microM) was also able to enhance the effects of carmustine significantly in both cell lines., Conclusions: In the current study, the authors characterized the efficacy of a new class of adjuvant chemotherapeutics that show promise in enhancing the efficacy of standard chemotherapy regimens in gliomas.

Rationale: Ketamine is a chiral molecule that is reported to model aspects of schizophrenia., Objectives: To investigate the stereospecificity of the isomers of ketamine using pharmacological magnetic resonance imaging (phMRI) in order to further understand ketamine's pharmacodynamic actions., Method: Responses to 25 mg kg-1S(+) isomer, R(-) isomer and racemic ketamine in independent groups of Sprague-Dawley rats were investigated using a prepulse inhibition paradigm, locomotor observations, MRI and 2-deoxyglucose techniques., Results: Racemic ketamine and the S(+) isomer were both capable of disrupting sensorimotor gating as measured using prepulse inhibition and produced a longer period of hyperlocomotion comparative to the R(-) isomer. In contrast, large alterations in the BOLD MR signal were observed with R(-) isomer, whereas S(+) isomer and racemate precipitated more localized BOLD signal changes predominantly in cortical, hippocampal and hindbrain regions. Glucose utilization rates in conscious animals are in agreement with previously published data and verify the BOLD responses in the racemic group. However, no significant changes in glucose utilization were observed in the anesthetized cohort., Conclusions: Ketamine and its isomers have stereospecific effects on sensorimotor gating and locomotion that correlate with the enantiomer's affinity for the NMDA receptor. It would appear that anesthesia, as required for preclinical MRI procedures, may interact with and potentially attenuate the drug's response. Although analysis of the main effect of isomers in comparison to each other or the racemate offers an alternative analysis method that should be less susceptible to anesthetic interactions, only the R(-) isomer comparative to the racemate offers significant differences of interest.

Background: The incorporation of chemotherapy and radiation, either sequentially or concurrently, has been increasingly used for organ preservation in patients with advanced laryngeal cancer. Traditional outcome measures of clinical response such as locoregional control and survival have been similar for patients treated with chemoradiotherapy and those treated with total laryngectomy (TL). The impact of concurrent chemoradiotherapy for laryngeal preservation on the overall quality of life (QOL) of patients has not been clearly evaluated, particularly in direct comparison with TL., Objective: To compare the QOL of patients treated with concurrent chemoradiotherapy with those treated with TL., Design: Nonrandomized, retrospective, cross-sectional study., Setting: Academic tertiary care referral center., Methods: The study included 42 patients with advanced stage III or IV cancer of the larynx, who were treated with either concurrent chemoradiotherapy or TL with postoperative radiation therapy. Patients had to be without evidence of recurrence and to have completed therapy at least 3 months prior to inclusion in the study. Quality of life was measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) in tandem with the head and neck module (EORTC QLQ-H&N35)., Results: On the core questionnaire (QLQ-C30), there were no statistically significant differences in the overall QOL score between the 2 groups. Functional subscale analysis revealed a trend for patients in the surgery and radiotherapy group to experience greater difficulties with social functioning (P =.18) relative to the chemoradiation group. On the QLQ-H&N35, surgery patients reported significantly greater difficulties with sensory disturbances (smell and taste, P =.001), use of painkillers (P =.049), and coughing (P =.004). On the other hand, chemoradiation patients reported significantly greater problems with dry mouth (P =.02)., Conclusions: Both chemoradiation and TL affect, albeit differently, the QOL of patients treated for advanced cancer of the larynx. Although these differences can be detected by functional and subscale analysis, the overall QOL scores of both groups seem similar.

Preferential migration of stem cells toward the site of a lesion is a highly desirable property of stem cells that allows flexibility in the site of graft implantation in the damaged brain. In rats with unilateral stroke damage, neural stem cells transplanted into the contralateral hemisphere migrate across to the lesioned hemisphere and populate the area around the ischaemic infarct. To date, the migration of neural stem cells in the damaged brain has been mainly inferred from snapshot histological images. In this study, we demonstrate that by pre-labelling neural stem cells with the bimodal contrast agent Gadolinium-RhodamIne Dextran [GRID, detectable by both magnetic resonance imaging (MRI) and fluorescent microscopy], the transhemispheric migration of transplanted neural stem cells contralateral to a stroke lesion can be followed in vivo by serial MRI and corroborated by subsequent histological analyses. Our results indicate that neural stem cells migrated from the injection tract mainly along the corpus callosum within 7 days of transplantation and extensively re-populated the peri-lesion area by 14 days following implantation. In contrast, neural stem cells transplanted into sham controls did not show any substantial migration outside of the injection tract, suggesting that the transcallosal migration observed in the stroke-lesioned animals is due to neural stem cells being attracted by the lesion site. In vivo tracking of the migration of neural stem cells responding to damage will greatly enhance our understanding of optimal transplantation strategies as well as how neural stem cells promote functional and anatomical recovery in neurological disorders.

There is currently great interest in combining data from different imaging modalities, either by image registration methods that are performed after the data has been acquired or using new devices that can acquire data from two modalities simultaneously, or near simultaneously. In this paper a small prototype NMR-compatible PET scanner capable of acquiring PET images simultaneously with either NMR images or NMR spectra is described. In an associated paper [1], Pamela Garlick describes some investigations of cardiac metabolism that have been made using this system. One of the main challenges in constructing an NMR-compatible PET scanner is that photomultiplier tubes, which are an essential element of nearly all current PET systems, will not function in a high magnetic field. In collaboration with Simon Cherry and the Crump Institute of Biomedical Imaging at UCLA Medical School, a small (5.4 cm diameter) NMR-compatible PET scanner that will operate within the bore of an NMR magnet has been developed. Long optical fibres are used to transport light from the scintillation crystals that form the detector head to photomultiplier tubes situated in a low magnetic field region several metres from the magnet. This system has been used to perform simultaneous PET and NMR spectroscopy measurements with a 9.4T spectroscopy system, and has also been used to obtain simultaneous PET and MR images in several MRI scanners including a 4.7T small bore animal imaging system. Current efforts in the development of this technology are directed at experimental studies on small animals, both because this is less demanding technically and because it is in this area that applications are likely to appear first. However, there is no reason in principle why human PET-MR would not be feasible. Below, work with the prototype system and the next stage in its development are described, and some of the future possibilities and challenges are discussed.

The ability to track stem cell transplants in the brain by in vivo neuroimaging will undoubtedly aid our understanding of how these cells mediate functional recovery after neural transplantation. One major challenge for the development and refinement of stem cell transplantation is to map the spatial distribution and rate of migration in situ. Here we report a method for tracking transplanted stem cells in the ischemia-damaged rat hippocampus by magnetic resonance imaging (MRI). Before transplantation, stem cells were labeled in vitro either with a novel bifunctional contrast agent, gadolinium rhodamine dextran (GRID), identifiable by both MRI and fluorescence microscopy, or with PKH26, visible exclusively under fluorescence microscopy. At different time points following engraftment, the brains were evaluated by both histology and ex vivo MR imaging. Transplanted stem cells were identified by MRI only if prelabeled with GRID, whereas fluorescence microscopy detected transplanted cells using either label. The distribution of GRID-labeled stem cells identified by MRI corresponded to those detected using fluorescence microscopy. These results demonstrate that GRID-enhanced MRI can reliably identify transplanted stem cells and their migration in the brain.

Using serial magnetic resonance imaging we have evaluated the effectiveness of aminoguanidine (AG) as a neuroprotective agent in a rat model of transient middle cerebral artery occlusion (MCAO). Because aminoguanidine's neuroprotective properties have primarily been ascribed to its action as iNOS inhibitor, we also performed a biochemical analysis of nitric oxide metabolites and NOS isoforms in our model of ischaemia. Daily injections of AG (100 mg/kg) or saline, were started at 6 h after the occlusion and the effects of this treatment on lesion progression monitored by T(2)-weighted MRI at 6 (pre-treatment scan), 24 and 72 h. Measurements of lesion volumes showed that between 6 and 72 h post-MCAO, lesion growth was slower in AG-treated rats than in control rats. This difference was most pronounced between 24 and 72 h post-MCAO when AG halted the lesion volume expansion observed in control rats. Measurements of plasma NOx (nitrite plus nitrate) at 0, 24, 48 and 72 h after MCAO, showed that NO levels did not differ significantly between the AG- and saline-treated groups at any time-point. Moreover, NOS activity assays revealed that no iNOS activity was present in any of the brains tested and that constitutive neuronal NOS activity was similar across the two hemispheres between both groups. The absence of iNOS protein in the ischaemic and contralateral hemispheres at 48 and 72 h after MCAO (control group only) was confirmed by Western blot analysis. These results suggest that AG treatment reduces the rate of growth of ischaemic lesions, perhaps preserving the functioning of perifocal neurons. Our observations contradict suggestions that high levels of NO generated by iNOS are partially responsible for exacerbating the neuronal damage in the postischaemic phase of MCAO. Although this does not rule out a role for AG as a neuroprotective agent via its ability to inhibit iNOS, these findings indicate that neuroprotective actions of AG may also be mediated via other cellular targets.

Forest fertilization with granular urea is a well-established management practice in many forested regions of the world. We hypothesize that chemical forest fertilizers may be affecting forest-dwelling wildlife. In the laboratory, we studied the effects of fertilization doses of granular urea on three species of forest-dwelling amphibians (Plethodon vehiculum, Rhyacotriton variegatus, and Taricha granulosa). In avoidance experiments, the three species avoided a substrate treated with a dose of 225 kg N/ha urea. In toxicity experiments, we exposed amphibians to urea at doses of 225 kg N/ha and 450 kg N/ha for 4 days. The observed effects increased with time and dose, and there were significant differences in sensitivity among the species. Both treatment levels had an acute effect on survival of P. vehiculum and R. variegatus. At 24 h, mortality at the highest dose was 67% for P. vehiculum, and 47% for R. variegatus. In contrast, there was no mortality for T. granulosa at these concentrations. We suggest that environmental levels of urea could be affecting behavior and survival of some amphibians species in fertilized forests.

We describe a new Cognitive Analytic Therapy (CAT)-based intervention for those who repeatedly self-harm. It is specifically designed to be deliverable by staff with no training in psychotherapy. The intervention is simply manualized into sequential tasks that are mediated by new CAT-style standardized tools. A particular feature of this intervention is the deliberate use of feelings elicited in the therapist ('counter-transference') as (a) a guide to how professional poise is being threatened or lost and (b) an indicator of the appropriate focus for this very brief therapy. The psychiatrists' reflection on their elicited feelings is mediated by a new CAT tool, the 'Assessor's Response File' developed in this project. Audiotape analysis suggested that following a very brief learning period, trainee psychiatrists were able to adhere to the structure of the model and arrive at an appropriate reformulation in the first session but tended to be collusive in reciprocating the patients' dysfunctional coping styles.

In order to analyse target genes regulated by retinoic acid in urodele limb regeneration, we have used pseudotyped retroviruses to obtain stably transfected newt limb blastemal (progenitor) cells in culture which express chimeric retinoic acid/thyroid hormone receptors delta1 or delta2. After treatment with thyroid hormone to activate the chimeric receptors, we used a polymerase chain reaction (PCR)-based subtraction method to identify target genes which are retinoid regulated. Newt connective tissue growth factor, a secreted protein recognised in several vertebrates, has been identified in this way and found to be expressed in the limb blastema and regulated by retinoic acid. This approach should permit a systematic analysis of retinoid target genes in limb regeneration.