Desynchronization of pathological low-frequency brain activity by the hypnotic drug zolpidem.

Reports of the beneficial effects of the hypnotic imidazopyridine, zolpidem, described in persistent vegetative state^1, 2^ have been replicated recently in brain-injured and cognitively impaired patients^3-7^. Previous single photon emission computed tomography (SPECT) studies have suggested that sub-sedative doses of zolpidem increased regional cerebral perfusion in affected areas^5, 8^, implying enhanced neuronal metabolic activity; which has led to speculation that zolpidem 'reawakens' functionally dormant cortex. However, a neuronal mechanism by which this hypnotic drug affords benefits to brain injured patients has yet to be demonstrated. Here, we report the action of sub-sedative doses of zolpidem on neuronal network oscillatory activity in human brain, measured using pharmaco-magnetoencephalography (pharmaco-MEG). Study participant JP suffered a stroke in 1996, causing major damage to the left hemisphere that impaired aspects of both motor and cognitive function. Pharmaco-MEG analyses revealed robust and persistent pathological theta (4-10Hz) and beta (15-30Hz) oscillations within the lesion penumbra and surrounding cortex. Administration of zolpidem (5mg) reduced the power of pathological theta and beta oscillations in all regions of the lesioned hemisphere. This desynchronizing effect correlated well with zolpidem uptake (occurring approximately 40 minutes after acute administration) and was coincident with marked improvements in cognitive and motor function. Control experiments revealed no effect of placebo, while a structurally unrelated hypnotic, zopiclone, administered at a comparable dose (3.5mg) elicited widespread increases in cortical oscillatory power in the beta (15-30Hz) band without functional improvement. These results suggest that in JP, specific motor and cognitive impairments are related to increased low-frequency oscillatory neuronal network activity. Zolpidem is unique amongst hypnotic drugs in its ability to desynchronize such pathological low-frequency activity, thereby restoring cognitive function

The views of general practitioners and practice nurses towards the barriers and facilitators of proactive, internet-based chlamydia screening for reaching young heterosexual men

Background: Chlamydia trachomatis is a common bacterial sexually transmitted infection (STI), which disproportionately affects young people under 25 years. Commonly, more women are offered screening than men. This study obtained the views of general practitioners and practice nurses towards Internet-based screening and assessed levels of support for the development of proactive screening targeting young heterosexual men via the Internet. Methods: Semi-structured telephone interviews with 10 general practitioners and 8 practice nurses, across Central Scotland. Topics covered: experience of screening heterosexual men for chlamydia, views on the use of the Internet as a way to reach young men for chlamydia screening, beliefs about the potential barriers and facilitators to Internet-based screening. Transcripts from audio recordings were analysed with Framework Analysis, using QSR NVivo10. Results: Experiences of chlamydia screening were almost exclusively with women, driven by the nature of consultations and ease of raising sexual health issues with female patients; few practice nurses reported seeing men during consultations. All participants spoke in favour of Internet-based screening for young men. Participants reported ease of access and convenience as potential facilitators of an Internet-based approach but anonymity and confidentiality could be potential barriers and facilitators to the success of an Internet approach to screening. Concerns over practical issues as well as those pertaining to gender and socio-cultural issues were raised. Conclusions: Awareness of key barriers and facilitators, such as confidentiality, practicality and socio-cultural influences, will inform the development of an Internet-based approach to screening. However, this approach may have its limits in terms of being able to tackle wider social and cultural barriers, along with shifts in young people's and health professionals' attitudes towards screening. Nevertheless, employing innovative efforts as part of a multi-faceted approach is required to ensure effective interventions reach the policy agenda

Young people’s perceptions of smartphone-enabled self-testing and online care for sexually transmitted infections: qualitative interview study

Background Control of sexually transmitted infections (STI) is a global public health priority. Despite the UK’s free, confidential sexual health clinical services, those at greatest risk of STIs, including young people, report barriers to use. These include: embarrassment regarding face-to-face consultations; the time-commitment needed to attend clinic; privacy concerns (e.g. being seen attending clinic); and issues related to confidentiality. A smartphone-enabled STI self-testing device, linked with online clinical care pathways for treatment, partner notification, and disease surveillance, is being developed by the eSTI2 consortium. It is intended to benefit public health, and could do so by increasing testing among populations which underutilise existing services and/or by enabling rapid provision of effective treatment. We explored its acceptability among potential users. Methods In-depth interviews were conducted in 2012 with 25 sexually-experienced 16–24 year olds, recruited from Further Education colleges in an urban, high STI prevalence area. Thematic analysis was undertaken. Results Nine females and 16 males participated. 21 self-defined as Black; three, mixed ethnicity; and one, Muslim/Asian. 22 reported experience of STI testing, two reported previous STI diagnoses, and all had owned smartphones. Participants expressed enthusiasm about the proposed service, and suggested that they and their peers would use it and test more often if it were available. Utilizing sexual healthcare was perceived to be easier and faster with STI self-testing and online clinical care, which facilitated concealment of STI testing from peers/family, and avoided embarrassing face-to-face consultations. Despite these perceived advantages to privacy, new privacy concerns arose regarding communications technology: principally the risk inherent in having evidence of STI testing or diagnosis visible or retrievable on their phone. Some concerns arose regarding the proposed self-test’s accuracy, related to self-operation and the technology’s novelty. Several expressed anxiety around the possibility of being diagnosed and treated without any contact with healthcare professionals. Conclusions Remote STI self-testing and online care appealed to these young people. It addressed barriers they associated with conventional STI services, thus may benefit public health through earlier detection and treatment. Our findings underpin development of online care pathways, as part of ongoing research to create this complex e-health intervention

A multimodal perspective on the composition of cortical oscillations:frontiers in human neuroscience

An expanding corpus of research details the relationship between functional magnetic resonance imaging (fMRI) measures and neuronal network oscillations. Typically, integratedelectroencephalography(EEG) and fMRI,orparallel magnetoencephalography (MEG) and fMRI are used to draw inference about the consanguinity of BOLD and electrical measurements. However, there is a relative dearth of information about the relationship between E/MEG and the focal networks from which these signals emanate. Consequently, the genesis and composition of E/MEG oscillations requires further clarification. Here we aim to contribute to understanding through a series of parallel measurements of primary motor cortex (M1) oscillations, using human MEG and in-vitro rodent local field potentials. We compare spontaneous activity in the ~10Hz mu and 15-30Hz beta frequency ranges and compare MEG signals with independent and integrated layers III and V(LIII/LV) from in vitro recordings. We explore the mechanisms of oscillatory generation, using specific pharmacological modulation with the GABA-A alpha-1 subunit modulator zolpidem. Finally, to determine the contribution of cortico-cortical connectivity, we recorded in-vitro M1, during an incision to sever lateral connections between M1 and S1 cortices. We demonstrate that frequency distribution of MEG signals appear have closer statistically similarity with signals from integrated rather than independent LIII/LV laminae. GABAergic modulation in both modalities elicited comparable changes in the power of the beta band. Finally, cortico-cortical connectivity in sensorimotor cortex (SMC) appears to directly influence the power of the mu rhythm in LIII. These findings suggest that the MEG signal is an amalgam of outputs from LIII and LV, that multiple frequencies can arise from the same cortical area and that in vitro and MEG M1 oscillations are driven by comparable mechanisms. Finally, corticocortical connectivity is reflected in the power of the SMC mu rhythm. © 2013 Ronnqvist, Mcallister, Woodhall, Stanford and Hall

A multimodal perspective on the composition of cortical oscillations.

An expanding corpus of research details the relationship between functional magnetic resonance imaging (fMRI) measures and neuronal network oscillations. Typically, integrated electroencephalography and fMRI, or parallel magnetoencephalography (MEG) and fMRI are used to draw inference about the consanguinity of BOLD and electrical measurements. However, there is a relative dearth of information about the relationship between E/MEG and the focal networks from which these signals emanate. Consequently, the genesis and composition of E/MEG oscillations requires further clarification. Here we aim to contribute to understanding through a series of parallel measurements of primary motor cortex (M1) oscillations, using human MEG and in vitro rodent local field potentials. We compare spontaneous activity in the ∼10 Hz mu and 15-30 Hz beta frequency ranges and compare MEG signals with independent and integrated layers III and V (LIII/LV) from in vitro recordings. We explore the mechanisms of oscillatory generation, using specific pharmacological modulation with the GABA-A alpha-1 subunit modulator zolpidem. Finally, to determine the contribution of cortico-cortical connectivity, we recorded in vitro M1, during an incision to sever lateral connections between M1 and S1 cortices. We demonstrate that frequency distribution of MEG signals appear have closer statistically similarity with signals from integrated rather than independent LIII/LV laminae. GABAergic modulation in both modalities elicited comparable changes in the power of the beta band. Finally, cortico-cortical connectivity in sensorimotor cortex (SMC) appears to directly influence the power of the mu rhythm in LIII. These findings suggest that the MEG signal is an amalgam of outputs from LIII and LV, that multiple frequencies can arise from the same cortical area and that in vitro and MEG M1 oscillations are driven by comparable mechanisms. Finally, cortico-cortical connectivity is reflected in the power of the SMC mu rhythm

Bradykinesia Is Driven by Cumulative Beta Power During Continuous Movement and Alleviated by Gabaergic Modulation in Parkinson's Disease

Spontaneous and "event-related" motor cortex oscillations in the beta (15-30 Hz) frequency range are well-established phenomena. However, the precise functional significance of these features is uncertain. An understanding of the specific function is of importance for the treatment of Parkinson's disease (PD), where attenuation of augmented beta throughout the motor network coincides with functional improvement. Previous research using a discrete movement task identified normalization of elevated spontaneous beta and postmovement beta rebound following GABAergic modulation. Here, we explore the effects of the gamma-aminobutyric acid type A modulator, zolpidem, on beta power during the performance of serial movement in 17 (15M, 2F; mean age, 66 ± 6.3 years) PD patients, using a repeated-measures, double-blinded, randomized, placebo-control design. Motor symptoms were monitored before and after treatment, using time-based Unified Parkinson's Disease Rating Scale measurements and beta oscillations in primary motor cortex (M1) were measured during a serial-movement task, using magnetoencephalography. We demonstrate that a cumulative increase in M1 beta power during a 10-s tapping trial is reduced following zolpidem, but not placebo, which is accompanied by an improvement in movement speed and efficacy. This work provides a clear mechanism for the generation of abnormally elevated beta power in PD and demonstrates that perimovement beta accumulation drives the slowing, and impaired initiation, of movement. These findings further indicate a role for GABAergic modulation in bradykinesia in PD, which merits further exploration as a therapeutic target.Peer reviewe

Human cytomegalovirus infection of langerhans-type dendritic cells does not require the presence of the gH/gL/UL128-131A complex and is blocked after nuclear deposition of viral genomes in immature cells

Human cytomegalovirus (CMV) enters its host via the oral and genital mucosae. Langerhans-type dendritic cells (LC) are the most abundant innate immune cells at these sites, where they constitute a first line of defense against a variety of pathogens. We previously showed that immature LC (iLC) are remarkably resistant to CMV infection, while mature LC (mLC) are more permissive, particularly when exposed to clinical-strain-like strains of CMV, which display a pentameric complex consisting of the viral glycoproteins gH, gL, UL128, UL130, and UL131A on their envelope. This complex was recently shown to be required for the infection of immature monocyte-derived dendritic cells. We thus sought to establish if the presence of this complex is also necessary for virion penetration of LC and if defects in entry might be the source of iLC resistance to CMV. Here we report that the efficiency of LC infection is reduced, but not completely abolished, in the absence of the pentameric complex. While virion penetration and nuclear deposition of viral genomes are not impaired in iLC, the transcription of the viral immediate early genes UL122 and UL123 and of the delayed early gene UL50 is substantially lower than that in mLC. Together, these data show that the UL128, UL130, and UL131A proteins are dispensable for CMV entry into LC and that progression of the viral cycle in iLC is restricted at the step of viral gene expression

Multicentre comparison of a diagnostic assay: Aquaporin-4 antibodies in neuromyelitis optica

Objective Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies. The assessment of antibody assays needs to reflect their clinical utility. We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD). Methods Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1). Results Results of tests on 92 controls identified 12assays as highly specific (0-1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD). On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5-100%) of all 21 assays. The specificities (85.8-100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples. Conclusions The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres. Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way. The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology

The role of GABAergic modulation in motor function related neuronal network activity

At rest, the primary motor cortex (M1) exhibits spontaneous neuronal network oscillations in the beta (15–30 Hz) frequency range, mediated by inhibitory interneuron drive via GABA-A receptors. However, questions remain regarding the neuropharmacological basis of movement related oscillatory phenomena, such as movement related beta desynchronisation (MRBD), post-movement beta rebound (PMBR) and movement related gamma synchronisation (MRGS). To address this, we used magnetoencephalography (MEG) to study the movement related oscillatory changes in M1 cortex of eight healthy participants, following administration of the GABA-A modulator diazepam. Results demonstrate that, contrary to initial hypotheses, neither MRGS nor PMBR appear to be GABA-A dependent, whilst the MRBD is facilitated by increased GABAergic drive. These data demonstrate that while movement-related beta changes appear to be dependent upon spontaneous beta oscillations, they occur independently of one other. Crucially, MRBD is a GABA-A mediated process, offering a possible mechanism by which motor function may be modulated. However, in contrast, the transient increase in synchronous power observed in PMBR and MRGS appears to be generated by a non-GABA-A receptor mediated process; the elucidation of which may offer important insights into motor processes

Animal Ethics and the Political

Some of the most important contributions to animal ethics over the past decade or so have come from political, as opposed to moral, philosophers. As such, some have argued that there been a ‘political turn’ in the field. If there has been such a turn, it needs to be shown that there is something which unites these contributions, and which sets them apart from previous work. We find that some of the features which have been claimed to be shared commitments of the turn are contested by key theorists working in the field. We also find that the originality of the turn can be exaggerated, with many of their ideas found in more traditional animal ethics. Nonetheless, we identify one unifying and distinctive feature of these contributions: the focus on justice; and specifically, the exploration of how political institutions, structures and processes might be transformed so as to secure justice for both human and nonhuman animals