The TLR2/6 ligand PAM2CSK4 is a Th2 polarizing adjuvant in Leishmania major and Brugia malayi murine vaccine models.

Toll-like receptors (TLRs) play an important role in the innate and adaptive immune responses to pathogens, and are the target of new vaccine adjuvants. TLR2 plays a role in parasite recognition and activation of immune responses during cutaneous leishmaniasis infection, suggesting that TLR2 could be targeted by adjuvants for use in Leishmania vaccines. We therefore explored using Pam2CSK4 (Pam2) and Pam3CSK4 (Pam3) lipopeptide adjuvants, which activate TLR2/6 and TLR2/1 heterodimers respectively, in vaccine models for parasitic infections.The use of lipopeptide adjuvants was explored using two vaccine models. For cutaneous leishmaniasis, the lipopeptide adjuvants Pam2 and Pam3 were compared to that of the Th1-driving double-stranded DNA TLR9 agonist CpG for their ability to improve the efficacy of the autoclaved Leishmania major (ALM) vaccine to protect against L. major infection. The ability of Pam2 to enhance the efficacy of a soluble Brugia malayi microfilariae extract (BmMfE) vaccine to protect against filarial infection was also assessed in a peritoneal infection model of B. malayi filariasis. Parasite antigen-specific cellular and humoral immune responses were assessed post-challenge.The use of lipopeptides in ALM-containing vaccines did not provide any protection upon infection with L. major, and Pam2 exacerbated the disease severity in vaccinated mice post-challenge. Pam2, and to a lesser extent Pam3, were able to elevate antigen-specific immune responses post-challenge in this model, but these responses displayed a skewed Th2 phenotype as characterised by elevated levels of IgG1. In the B. malayi vaccine model, the use of Pam2 as an adjuvant with BmMfE induced significant protective immunity to the same level as inclusion of an Alum adjuvant. Here, both Pam2 and Alum were found to enhance antigen-specific antibody production post-challenge, and Pam2 significantly elevated levels of antigen-specific IL-4, IL-5 and IL-13 produced by splenocytes.These data indicate that TLR2/6-targeting ligands could be considered as adjuvants for vaccines that require robust Th2 and/or antibody-dependent immunity

Reconstructing the eclectic psychiatry of Thomas Ferguson Rodger

This article provides an introduction to the approach of the Scottish psychiatrist Thomas Ferguson Rodger (1907–78), as reconstructed from his archive. Rodger’s contribution has been largely neglected within the history of Scottish psychiatry. This paper amends this neglect through situating Rodger’s eclecticism in relation to both the biopsychosocial approach of his mentors, Adolf Meyer and David Henderson, and psychiatry’s de-institutionalization in the 1950s and 1960s. It is posited that Rodger’s eclecticism was a considered response to the pressures of this transitional phase to balance physical, psychological and social approaches, and a critical acknowledgement of the instability of contemporary psychiatric therapeutics. More psychodynamic than his predecessors, the importance of social relations for Rodger led him to acknowledge psychiatry’s limitations

Neuronal network disintegration: common pathways linking neurodegenerative diseases

Neurodegeneration refers to a heterogeneous group of brain disorders that progressively evolve. It has been increasingly appreciated that many neurodegenerative conditions overlap at multiple levels and therefore traditional clinicopathological correlation approaches to better classify a disease have met with limited success. Neuronal network disintegration is fundamental to neurodegeneration, and concepts based around such a concept may better explain the overlap between their clinical and pathological phenotypes. In this Review, promoters of overlap in neurodegeneration incorporating behavioural, cognitive, metabolic, motor, and extrapyramidal presentations will be critically appraised. In addition, evidence that may support the existence of large-scale networks that might be contributing to phenotypic differentiation will be considered across a neurodegenerative spectrum. Disintegration of neuronal networks through different pathological processes, such as prion-like spread, may provide a better paradigm of disease and thereby facilitate the identification of novel therapies for neurodegeneration

Tackling clinical heterogeneity across the Amyotrophic Lateral Sclerosis-Frontotemporal Dementia spectrum using a transdiagnostic approach

The disease syndromes of amyotrophic lateral sclerosis and frontotemporal dementia display considerable clinical, genetic and pathological overlap, yet mounting evidence indicates substantial differences in progression and survival. To date, there has been limited examination of how profiles of brain atrophy might differ between clinical phenotypes. Here, we address this longstanding gap in the literature by assessing cortical and subcortical grey and white matter volumes on structural MRI in a large cohort of 209 participants. Cognitive and behavioural changes were assessed using the Addenbrooke’s Cognitive Examination and the Cambridge Behavioural Inventory. Relative to 58 controls, behavioural variant frontotemporal dementia (n = 58) and amyotrophic lateral sclerosis-frontotemporal dementia (n = 41) patients displayed extensive atrophy of frontoinsular, cingulate, temporal and motor cortices, with marked subcortical atrophy targeting the hippocampus, amygdala, thalamus, and striatum, with atrophy further extended to the brainstem, pons and cerebellum in the latter group. At the other end of the spectrum, pure-amyotrophic lateral sclerosis patients (n = 52) displayed considerable frontoparietal atrophy, including right insular and motor cortices and pons and brainstem regions. Subcortical regions included the bilateral pallidum and putamen, but to a lesser degree than in the amyotrophic lateral sclerosis-frontotemporal dementia and behavioural variant frontotemporal dementia groups. Across the spectrum the most affected region in all three groups was the insula, and specifically the anterior part (76-90% lower than controls). Direct comparison of the patient groups revealed disproportionate temporal atrophy and widespread subcortical involvement in amyotrophic lateral sclerosis-frontotemporal dementia relative to pure-amyotrophic lateral sclerosis. In contrast, pure-amyotrophic lateral sclerosis displayed significantly greater parietal atrophy. Both behavioural variant frontotemporal dementia and amyotrophic lateral sclerosis-frontotemporal dementia were characterised by volume decrease in the frontal lobes relative to pure-amyotrophic lateral sclerosis. The motor cortex and insula emerged as differentiating structures between clinical syndromes, with bilateral motor cortex atrophy more pronounced in amyotrophic lateral sclerosis-frontotemporal dementia compared to pure-amyotrophic lateral sclerosis, and greater left motor cortex and insula atrophy relative to behavioural variant frontotemporal dementia. Taking a transdiagnostic approach, we found significant associations between abnormal behaviour and volume loss in a predominantly frontoinsular network involving the amygdala, striatum and thalamus. Our findings demonstrate the presence of distinct atrophy profiles across the amyotrophic lateral sclerosis-frontotemporal dementia spectrum, with key structures including the motor cortex and insula, Notably, our results point to subcortical involvement in the origin of behavioural disturbances, potentially accounting for the marked phenotypic variability typically observed across the spectrum

A time-resolved imaging system for the diagnosis of x-ray self-emission in high energy density physics experiments

A diagnostic capable of recording spatially and temporally resolved x-ray self-emission data was developed to characterize experiments on the MAGPIE pulsed-power generator. The diagnostic used two separate imaging systems: a pinhole imaging system with two-dimensional spatial resolution and a slit imaging system with one-dimensional spatial resolution. The two-dimensional imaging system imaged light onto the image plate. The one-dimensional imaging system imaged light onto the same piece of image plate and a linear array of silicon photodiodes. This design allowed the cross-comparison of different images, allowing a picture of the spatial and temporal distribution of x-ray self-emission to be established. The design was tested in a series of pulsed-power-driven magnetic-reconnection experiments

Biomarkers in dementia: clinical utility and new directions.

Imaging, cerebrospinal fluid (CSF) and blood-based biomarkers have the potential to improve the accuracy by which specific causes of dementia can be diagnosed in vivo, provide insights into the underlying pathophysiology, and may be used as inclusion criteria and outcome measures for clinical trials. While a number of imaging and CSF biomarkers are currently used for each of these purposes, this is an evolving field, with numerous potential biomarkers in varying stages of research and development. We review the currently available biomarkers for the three most common forms of neurodegenerative dementia, and give an overview of research techniques that may in due course make their way into the clinic

Retinopathy of prematurity and risk factors: a prospective cohort study

BACKGROUND: Increased survival of extremely low birth infants due to advances in antenatal and neonatal care has resulted in a population of infants at high risk of developing retinopathy of prematurity (ROP). Therapeutic interventions include the use of antenatal and postnatal steroids however, their effects on the severity of ROP is in dispute. In addition, it has not been investigated whether severe ROP is due to therapeutic interventions or due to the severity of illness. The aim of the present study was to assess the association between the incidence of severe retinopathy of prematurity (greater than stage 2 – International classification of ROP) and mechanical ventilation, oxygen therapy, gestational age, antenatal and postnatal steroids in extremely low birth weight infants. METHODS: Neonates admitted to the neonatal intensive care unit in Lansing, Michigan, during 1993–2000 were followed to determine factors influencing the development of severe retinopathy of prematurity. Ophthalmologic examinations were started at 6 weeks and followed until resolution. We used logistic regression to estimate the relative risk (odds ratio) associated with risk factors of ROP. RESULTS: Of the neonates with ≤ 1500 g birth weight, admitted to the neonatal intensive care unit, 85% (616/725) survived. Severe retinopathy of prematurity was detected in 7.8% of 576 neonates who had eye examinations. Neonates of lower gestational age (≤ 25 weeks and 26–28 weeks) had an increased odds ratio of 8.49 and 3.19 for the development of severe retinopathy of prematurity, respectively, compared to those 29 weeks and older. Late postnatal steroid treatment starting after 3 weeks of life showed 2.9-fold increased odds ratio, in particular administration for two weeks and more (OR: 4.09, 95% CI: 1.52–11.03). With increasing antenatal steroids courses the risk of severe retinopathy of prematurity decreased, however, it was not significant. Lower gestational age, dependence on ventilation, and use of postnatal steroids were intertwined. Simultaneous presence of these factors seems to indicate severe disease status. CONCLUSION: Prolonged and late postnatal steroids treatment in very low birth weight infants may pose an increased risk for the development of severe retinopathy of prematurity; however, use of postnatal steroids may also be a marker for severity of illness. Further studies need to focus on biologic markers in the pathogenesis of retinopathy of prematurity and to better understand the influence of therapies

Developmental origin underlies evolutionary rate variation across the placental skull

The placental skull has evolved into myriad forms, from longirostrine whales to globular primates, and with a diverse array of appendages from antlers to tusks. This disparity has recently been studied from the perspective of the whole skull, but the skull is composed of numerous elements that have distinct developmental origins and varied functions. Here, we assess the evolution of the skull's major skeletal elements, decomposed into 17 individual regions. Using a high-dimensional morphometric approach for a dataset of 322 living and extinct eutherians (placental mammals and their stem relatives), we quantify patterns of variation and estimate phylogenetic, allometric and ecological signal across the skull. We further compare rates of evolution across ecological categories and ordinal-level clades and reconstruct rates of evolution along lineages and through time to assess whether developmental origin or function discriminate the evolutionary trajectories of individual cranial elements. Our results demonstrate distinct macroevolutionary patterns across cranial elements that reflect the ecological adaptations of major clades. Elements derived from neural crest show the fastest rates of evolution, but ecological signal is equally pronounced in bones derived from neural crest and paraxial mesoderm, suggesting that developmental origin may influence evolutionary tempo, but not capacity for specialisation. This article is part of the theme issue 'The mammalian skull: development, structure and function'

Nature of the Earth's earliest crust from hafnium isotopes in single detrital zircons

Continental crust forms from, and thus chemically depletes, the Earth's mantle. Evidence that the Earth's mantle was already chemically depleted by melting before the formation of today's oldest surviving crust has been presented in the form of Sm-Nd isotope studies of 3.8-4.0 billion years old rocks from Greenland(1-5) and Canada(5-7). But this interpretation has been questioned because of the possibility that subsequent perturbations may have re-equilibrated the neodymium-isotope compositions of these rocks(8). Independent and more robust evidence for the origin of the earliest crust and depletion of the Archaean mantle can potentially be provided by hafnium-isotope compositions of zircon, a mineral whose age can be precisely determined by U-Pb dating, and which can survive metamorphisms(4). But the amounts of hafnium in single zircon grains are too small for the isotopic composition to be precisely analysed by conventional methods. Here we report hafnium-isotope data, obtained using the new technique of multiple-collector plasma-source mass spectrometry(9), for 37 individual grains of the oldest known terrestrial zircons (from the Narryer Gneiss Complex, Australia, with U-Pb ages of up to 4.14 Gyr (refs 10-13)). We find that none of the grains has a depleted mantle signature, but that many were derived from a source with a hafnium-isotope composition similar to that of chondritic meteorites. Furthermore, more than half of the analysed grains seem to have formed by remelting of significantly older crust, indicating that crustal preservation and subsequent reworking might have been important processes from earliest times.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62681/1/399252a0.pd