Aspects of monoclonal antibody technology in diagnosis and therapy of neoplastic meningitis

This study includes an introductory review of current diagnostic, clinical and therapeutic aspects of neoplastic meningitis. Emphasis is placed on the importance of early detection of leptomeningeal tumour, as current therapeutic strategies are more effective against minimal disease. The enhancement of conventional diagnostic cytology by the addition of monoclonal antibody immunocytochemistry is discussed and, subsequently illustrated in a study of 12 patients with neoplastic meningitis. The use of monoclonal antibodies in radioimmunoassay methods is then demonstrated by the development of an immunoradiometric assay for the detection of Polymorphic Epithelial Mucin (PEM) in cerebrospinal fluid (CSF). This high molecular weight glycoprotein has not been previously assayed for in CSF and its potential value as a new diagnostic biochemical marker for carcinomatous meningitis is assessed. Finally, in a study of 15 patients with neoplastic meningitis, the potential therapeutic application of monoclonal antibodies as vectors of targeted radiation is explored. Monoclonal antibodies labelled with I-131 were administered directly into ventricular CSF, and demonstrable therapeutic responses were seen in 3/15 patients. Toxicity was seen in the form of bone marrow suppression in 3/15 patients and epilepsy in 2/15 patients

Cognitive and neural mechanisms underlying auditory verbal hallucinations in a non-clinical sample

Auditory verbal hallucinations (AVHs) are the experience of hearing a voice in the absence of any speaker. Cognitive models of AVHs have suggested that they may occur when an internal mental event, such as inner speech, is misattributed to an external source. This has variously been explained by reference to biases in self-monitoring, source monitoring, or reality discrimination processes. Evidence suggests that, mechanistically, this may be related to atypical functioning of a forward model system which usually predicts the outcome of self-generated actions, attenuating activity in sensory cortices to the resulting perceptual input. At a higher level, excessive vividness and low cognitive effort associated with internal mental events may be associated with external misattributions of inner speech. Chapter 1 reviews inner speech models of AVH, as well as recent attempts to reduce the frequency of AVHs using neurostimulation. Chapter 2 then provides a methodological overview of techniques used in this thesis. The first two empirical studies presented in this thesis, in Chapters 3 and 4, explore the cognitive mechanisms underlying AVHs by investigating the associations between self-reported hallucination-proneness and phenomenology of inner speech, and performance on source monitoring and self-monitoring tasks, in a non-clinical, student sample. The results indicated that hallucination-prone participants were more likely to misattribute self-generated auditory verbal imagery, both when instructed to generate imagery and when they retrospectively reported using imagery. Regression analysis also indicated that a tendency to use dialogic inner speech, biased performance on reality discrimination and self-monitoring tasks, and a tendency to perceive meaning in jumbled speech independently predicted hallucination-proneness. The studies presented in Chapters 5 and 6 investigated the neural basis of performance on auditory signal detection and source monitoring tasks using transcranial direct current stimulation (tDCS). Results indicated that modulating activity in the superior temporal gyrus/temporoparietal junction (STG/TPJ) affected the number of false perceptions on the signal detection task. However, stimulation to the left STG or medial prefrontal cortex did not affect performance on a source monitoring task. These results indicate that different cortical regions may be involved in the two tasks, and hence that they may reflect different aspects of how self-generated actions are experienced as such. Together, the four experimental chapters 1) provide evidence for inner speech accounts of AVH, 2) indicate the need for a more complex account of self-monitoring and reality discrimination in which both are seen as independent predictors of AVHs, and 3) suggest that the left STG plays a key role in reality discrimination, but less so in source monitoring tasks (at least in the encoding stage). The thesis concludes with a general discussion of these issues, and recommendations for future research

It's time we put agency into Behavioural Public Policy

Promoting agency - people's ability to form intentions and to act on them freely - must become a primary objective for Behavioural Public Policy (BPP). Contemporary BPPs do not directly pursue this objective, which is problematic for many reasons. From an ethical perspective, goals like personal autonomy and individual freedom cannot be realised without nurturing citizens' agency. From an efficacy standpoint, BPPs that override agency - for example, by activating automatic psychological processes - leave citizens 'in the dark', incapable of internalising and owning the process of behaviour change. This may contribute to non-persistent treatment effects, compensatory negative spillovers or psychological reactance and backfiring effects. In this paper, we argue agency-enhancing BPPs can alleviate these ethical and efficacy limitations to longer-lasting and meaningful behaviour change. We set out philosophical arguments to help us understand and conceptualise agency. Then, we review three alternative agency-enhancing behavioural frameworks: (1) boosts to enhance people's competences to make better decisions; (2) debiasing to encourage people to reduce the tendency for automatic, impulsive responses; and (3) nudge+ to enable citizens to think alongside nudges and evaluate them transparently. Using a multi-dimensional framework, we highlight differences in their workings, which offer comparative insights and complementarities in their use. We discuss limitations of agency-enhancing BPPs and map out future research directions

The MicroRNA, miR‐18a, Regulates NeuroD and Photoreceptor Differentiation in the Retina of Zebrafish

During embryonic retinal development, six types of retinal neurons are generated from multipotent progenitors in a strict spatiotemporal pattern. This pattern requires cell cycle exit (i.e. neurogenesis) and differentiation to be precisely regulated in a lineage‐specific manner. In zebrafish, the bHLH transcription factor NeuroD governs photoreceptor genesis through Notch signaling but also governs photoreceptor differentiation though distinct mechanisms that are currently unknown. Also unknown are the mechanisms that regulate NeuroD and the spatiotemporal pattern of photoreceptor development. Members of the miR‐17‐92 microRNA cluster regulate CNS neurogenesis, and a member of this cluster, miR‐18a, is predicted to target neuroD mRNA. The purpose of this study was to determine if, in the developing zebrafish retina, miR‐18a regulates NeuroD and if it plays a role in photoreceptor development. Quantitative RT‐PCR showed that, of the three miR‐18 family members (miR‐18a, b, and c), miR‐18a expression most closely parallels neuroD expression. Morpholino oligonucleotides and CRISPR/Cas9 gene editing were used for miR‐18a loss‐of‐function (LOF) and both resulted in larvae with more mature photoreceptors at 70 hpf without affecting cell proliferation. Western blot showed that miR‐18a LOF increases NeuroD protein levels and in vitro dual luciferase assay showed that miR‐18a directly interacts with the 3′ UTR of neuroD. Finally, tgif1 mutants have increased miR‐18a expression, less NeuroD protein and fewer mature photoreceptors, and the photoreceptor deficiency is rescued by miR‐18a knockdown. Together, these results show that, independent of neurogenesis, miR‐18a regulates the timing of photoreceptor differentiation and indicate that this occurs through post‐transcriptional regulation of NeuroD.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147840/1/dneu22666.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147840/2/dneu22666_am.pd

Measurement practices in hallucinations research

In several sub-fields of psychology, there has been a renewed focus on measurement practices. As far as we are aware, this has been absent in hallucinations research. Thus, we investigated (a) cross-study variation in how hallucinatory experiences are measured and (b) the reliability of measurements obtained using two tasks that are widely employed in hallucinations research

Mexico-UK Sub-millimeter Camera for AsTronomy

MUSCAT is a large format mm-wave camera scheduled for installation on the Large Millimeter Telescope Alfonso Serrano (LMT) in 2018. The MUSCAT focal plane is based on an array of horn coupled lumped-element kinetic inductance detectors optimised for coupling to the 1.1mm atmospheric window. The detectors are fed with fully baffled reflective optics to minimize stray-light contamination. This combination will enable background-limited performance at 1.1 mm across the full 4 arcminute field-of-view of the LMT. The easily accessible focal plane will be cooled to 100 mK with a new closed cycle miniature dilution refrigerator that permits fully continuous operation. The MUSCAT instrument will demonstrate the science capabilities of the LMT through two relatively short science programmes to provide high resolution follow-up surveys of Galactic and extra-galactic sources previously observed with the Herschel space observatory, after the initial observing campaigns. In this paper, we will provide an overview of the overall instrument design as well as an update on progress and scheduled installation on the LMT.Comment: Accepted for publication in the Journal of Low Temperature Detector

A Focusing Metamaterial Based Wollaston Prism

By using existing metal mesh technology we propose a new lens design that behaves in a similar way to a Wollaston Prism. That is, a device that separates out the two linear polarised states of the incident field and then focuses them separately on same focal plane. The design is an evolution of an existing GRIN lens based on the same technology. The proposed lens design has a diameter of 75mm while only being 2mm thick. This will focus two beams at a distance of 250mm with a separation of 10mm, over the frequency range of 100-200GHZ. Such a device would be useful where space and weight are an issue and would allow the use of incoherent detectors

Pins & Needles: Towards Limb Disownership in Augmented Reality

The seemingly stable construct of our bodily self depends on the continued, successful integration of multisensory feedback about our body, rather than its purely physical composition. Accordingly, pathological disruption of such neural processing is linked to striking alterations of the bodily self, ranging from limb misidentification to disownership, and even the desire to amputate a healthy limb. While previous embodiment research has relied on experimental setups using supernumerary limbs in variants of the Rubber Hand Illusion, we here used Augmented Reality to directly manipulate the feeling of ownership for one's own, biological limb. Using a Head-Mounted Display, participants received visual feedback about their own arm, from an embodied first-person perspective. In a series of three studies, in independent cohorts, we altered embodiment by providing visuotactile feedback that could be synchronous (control condition) or asynchronous (400ms delay, Real Hand Illusion). During the illusion, participants reported a significant decrease in ownership of their own limb, along with a lowered sense of agency. Supporting the right-parietal body network, we found an increased illusion strength for the left upper limb as well as a modulation of the feeling of ownership during anodal transcranial direct current stimulation. Extending previous research, these findings demonstrate that a controlled, visuotactile conflict about one's own limb can be used to directly and systematically modulate ownership - without a proxy. This not only corroborates the malleability of body representation but questions its permanence. These findings warrant further exploration of combined VR and neuromodulation therapies for disorders of the bodily self