Wellcome Witnesses to Twentieth Century Medicine: Volume 2

Annotated and edited transcripts of 4 Witness Seminars. Introduction by E M Tansey. First published by the Wellcome Trust, 1998 Occasional Publication no. 6, 1998. ©The Trustee of the Wellcome Trust, London, 1998.All volumes are freely available online following the links to Publications/Wellcome Witnesses at www.ucl.ac.uk/histmed.Annotated and edited transcripts of 4 Witness Seminars. Introduction by E M Tansey.Annotated and edited transcripts of 4 Witness Seminars. Introduction by E M Tansey.Annotated and edited transcripts of 4 Witness Seminars. Introduction by E M Tansey.Annotated and edited transcripts of 4 Witness Seminars. Introduction by E M Tansey.Annotated and edited transcripts of 4 Witness Seminars. Introduction by E M Tansey.Annotated and edited transcripts of 4 Witness Seminars. Introduction by E M Tansey.Second volume of four Witness Seminar transcripts of meetings held between 1996 and 1997: ‘Making the Human Body Transparent: The Impact of Nuclear Magnetic Resonance and Magnetic Resonance Imaging’ (Tansey E M, Christie D A, eds); ‘Research in General Practice’ (Tansey E M, Reynolds L A, eds); ‘Drugs in Psychiatric Practice’ (Tansey E M, Christie D A, eds); ‘The MRC Common Cold Unit (Tansey E M, Reynolds L A, eds). Tansey E M, Christie D A, Reynolds L A. (eds) (1998) Wellcome Witnesses to Twentieth Century Medicine: Volume 2. London: The Wellcome Trust.The Wellcome Trust is a registered charity, no. 210183

Wellcome Witnesses to Twentieth Century Medicine: Volume 1

Annotated and edited transcript of four Witness Seminars. Introduction by E M Tansey First published by the Wellcome Trust, 1997. ©The Trustee of the Wellcome Trust, London, 1997.In Volume One (Occasional Publication no. 4, 1997).All volumes are freely available online at: www.history.qmul.ac.uk/research/modbiomed/wellcome_witnesses/Annotated and edited transcript of four Witness Seminars. Introduction by E M Tansey.Annotated and edited transcript of four Witness Seminars. Introduction by E M Tansey.Annotated and edited transcript of four Witness Seminars. Introduction by E M Tansey.Annotated and edited transcript of four Witness Seminars. Introduction by E M Tansey.Four Witness Seminar transcripts of meetings held between 1993 and 1996: ‘Technology Transfer in Britain: The case of Monoclonal Antibodies’ (E M Tansey and P P Catterall, eds); ‘Self and Non-Self: A History of Autoimmunity’ (E M Tansey, S V Willhoft and D A Christie, eds); ‘Endogenous Opiates’ (E M Tansey and D A Christie, eds); ‘The Committee on Safety of Drugs’ (E M Tansey and L A Reynolds, eds). Introduction by E M Tansey, ‘What is a Witness Seminar’, separate index for each meeting. Tansey E M, Catterall P P, Christie D A, Willhoft S V, Reynolds L A. (eds) (1997) Wellcome Witnesses to Twentieth Century Medicine, volume 1. London: The Wellcome Trust.The Wellcome Trust is a registered charity, no. 210183

“It gave me something big in my life to wonder and think about which took over the space … and not MS”: Managing well-being in multiple sclerosis through art-making

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2014 Informa UK Ltd.Background and aim: Individuals living with Multiple Sclerosis (MS) often face progressive loss of function, uncertainty and disruption to self-image and valued roles. Previous studies show that creative self-expression is valued by some people living with long-term illness, yet its meaning for people living with MS is unclear. This research study explored the meanings of leisure-based visual art-making for people living with MS. Method: This qualitative study followed guidelines for Interpretative Phenomenological Analysis (IPA). Single semi-structured interviews were conducted with five adults (2 males; 3 females; 40–65 years), recruited from MS Ireland. Findings: Participants valued art-making for contributing to a more satisfying way of life; for filling occupational voids and using time well. Deep immersion offered respite from worry about illness. Creative classes offered social camaraderie and opportunities for learning and development. Art-making processes and products were highly affirmative, increasing emotional well-being and promoting self-worth. Most felt that they expressed valued aspects of self through their art. Art-making appeared to assist with identity maintenance, accommodating functional losses associated with MS whilst opening “new doors”. Conclusion: Art-making offered a multi-faceted means of supporting identity and increasing fulfilment in lives that were restricted in many ways by MS

Release probability increases towards distal dendrites boosting high-frequency signal transfer in the rodent hippocampus

Dendritic integration of synaptic inputs involves their increased electrotonic attenuation at distal dendrites, which can be counterbalanced by the increased synaptic receptor density. However, during network activity the influence of individual synapses depends on their release fidelity, the dendritic distribution of which remains poorly understood. Here, we employed classical optical quantal analyses and a genetically encoded optical glutamate sensor in acute hippocampal slices of rats and mice to monitor release at CA3-CA1 synapses. We find that their release probability increases with greater distances from the soma. Similar-fidelity synapses tend to group together whereas release probability shows no trends regarding the branch ends. Simulations with a realistic CA1 pyramidal cell hosting stochastic synapses suggest that the observed trends boost signal transfer fidelity, particularly at higher input frequencies. Because high-frequency bursting has been associated with learning, the release probability pattern we have found may play a key role in memory trace formation

Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles

Active neurons increase their energy supply by dilating nearby arterioles and capillaries. This neurovascular coupling underlies blood oxygen level-dependent functional imaging signals, but its mechanism is controversial. Canonically, neurons release glutamate to activate metabotropic glutamate receptor 5 (mGluR5) on astrocytes, evoking Ca(2+) release from internal stores, activating phospholipase A2 and generating vasodilatory arachidonic acid derivatives. However, adult astrocytes lack mGluR5, and knockout of the inositol 1,4,5-trisphosphate receptors that release Ca(2+) from stores does not affect neurovascular coupling. We now show that buffering astrocyte Ca(2+) inhibits neuronally evoked capillary dilation, that astrocyte [Ca(2+)]i is raised not by release from stores but by entry through ATP-gated channels, and that Ca(2+) generates arachidonic acid via phospholipase D2 and diacylglycerol kinase rather than phospholipase A2. In contrast, dilation of arterioles depends on NMDA receptor activation and Ca(2+)-dependent NO generation by interneurons. These results reveal that different signaling cascades regulate cerebral blood flow at the capillary and arteriole levels

Time-Resolved Imaging Reveals Heterogeneous Landscapes of Nanomolar Ca(2+) in Neurons and Astroglia

Maintaining low intracellular calcium is essential to the functioning of brain cells, yet the phenomenology and mechanisms involved remain an enigma. We have advanced a two-photon excitation time-resolved imaging technique, which exploits high sensitivity of the OGB-1 fluorescence lifetime to nanomolar Ca(2+) concentration ([Ca(2+)]) and enables a high data acquisition rate in situ. The [Ca(2+)] readout is not affected by dye concentration, light scattering, photobleaching, micro-viscosity, temperature, or the main known concomitants of cellular activity. In quiescent tissue, standard whole-cell configuration has little effect on resting [Ca(2+)] inside neuronal dendrites or inside astroglia dye-filled via gap junctions. Mapping basal [Ca(2+)] in neurons and astrocytes with submicron resolution unveils heterogeneous concentration landscapes that depend on age and preceding activity. The rich information content represented by such landscapes in acute slices and in vivo promises to unveil the hitherto unexplored, potentially fundamental aspects of brain cell physiology. VIDEO ABSTRACT

ANN-based energy reconstruction procedure for TACTIC gamma-ray telescope and its comparison with other conventional methods

The energy estimation procedures employed by different groups, for determining the energy of the primary $\gamma$-ray using a single atmospheric Cherenkov imaging telescope, include methods like polynomial fitting in SIZE and DISTANCE, general least square fitting and look-up table based interpolation. A novel energy reconstruction procedure, based on the utilization of Artificial Neural Network (ANN), has been developed for the TACTIC atmospheric Cherenkov imaging telescope. The procedure uses a 3:30:1 ANN configuration with resilient backpropagation algorithm to estimate the energy of a $\gamma$-ray like event on the basis of its image SIZE, DISTANCE and zenith angle. The new ANN-based energy reconstruction method, apart from yielding an energy resolution of $\sim$ 26%, which is comparable to that of other single imaging telescopes, has the added advantage that it considers zenith angle dependence as well. Details of the ANN-based energy estimation procedure along with its comparative performance with other conventional energy reconstruction methods are presented in the paper and the results indicate that amongst all the methods considered in this work, ANN method yields the best results. The performance of the ANN-based energy reconstruction has also been validated by determining the energy spectrum of the Crab Nebula in the energy range 1-16 TeV, as measured by the TACTIC telescope.Comment: 23pages, 9 figures Accepted for publication in NIM

Multiplexed calcium imaging of single-synapse activity and astroglial responses in the intact brain

All-optical registration of neuronal and astrocytic activities within the intact mammalian brain has improved significantly with recent advances in optical sensors and biophotonics. However, relating single-synapse release events and local astroglial responses to sensory stimuli in an intact animal has not hitherto been feasible. Here, we present a multiplexed multiphoton excitation imaging approach for assessing the relationship between presynaptic Ca2+ entry at thalamocortical axonal boutons and perisynaptic astrocytic Ca2+ elevations, induced by whisker stimulation in the barrel cortex of C57BL/6 mice. We find that, unexpectedly, Ca2+ elevations in the perisynaptic astrocytic regions consistently precede local presynaptic Ca2+ signals during spontaneous brain activity associated with anaesthesia. The methods described here can be adapted to a variety of optical sensors and are compatible with experimental designs that might necessitate repeated sampling of single synapses over a longitudinal behavioural paradigm

The quantitative surface analysis of an antioxidant additive in a lubricant oil matrix by desorption electrospray ionization mass spectrometry

Rationale Chemical additives are incorporated into commercial lubricant oils to modify the physical and chemical properties of the lubricant. The quantitative analysis of additives in oil-based lubricants deposited on a surface without extraction of the sample from the surface presents a challenge. The potential of desorption electrospray ionization mass spectrometry (DESI-MS) for the quantitative surface analysis of an oil additive in a complex oil lubricant matrix without sample extraction has been evaluated. Methods The quantitative surface analysis of the antioxidant additive octyl (4-hydroxy-3,5-di-tert-butylphenyl)propionate in an oil lubricant matrix was carried out by DESI-MS in the presence of 2-(pentyloxy)ethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate as an internal standard. A quadrupole/time-of-flight mass spectrometer fitted with an in-house modified ion source enabling non-proximal DESI-MS was used for the analyses. RESULTS An eight-point calibration curve ranging from 1 to 80 μg/spot of octyl (4-hydroxy-3,5-di-tert-butylphenyl)propionate in an oil lubricant matrix and in the presence of the internal standard was used to determine the quantitative response of the DESI-MS method. The sensitivity and repeatability of the technique were assessed by conducting replicate analyses at each concentration. The limit of detection was determined to be 11 ng/mm additive on spot with relative standard deviations in the range 3-14%. CONCLUSIONS The application of DESI-MS to the direct, quantitative surface analysis of a commercial lubricant additive in a native oil lubricant matrix is demonstrated

Astrocytes regulate brain extracellular pH via a neuronal activity-dependent bicarbonate shuttle

Brain cells continuously produce and release protons into the extracellular space, with the rate of acid production corresponding to the levels of neuronal activity and metabolism. Efficient buffering and removal of excess H+ is essential for brain function, not least because all the electrogenic and biochemical machinery of synaptic transmission is highly sensitive to changes in pH. Here, we describe an astroglial mechanism that contributes to the protection of the brain milieu from acidification. In vivo and in vitro experiments conducted in rodent models show that at least one third of all astrocytes release bicarbonate to buffer extracellular H+ loads associated with increases in neuronal activity. The underlying signalling mechanism involves activity-dependent release of ATP triggering bicarbonate secretion by astrocytes via activation of metabotropic P2Y1 receptors, recruitment of phospholipase C, release of Ca2+ from the internal stores, and facilitated outward HCO3− transport by the electrogenic sodium bicarbonate cotransporter 1, NBCe1. These results show that astrocytes maintain local brain extracellular pH homeostasis via a neuronal activity-dependent release of bicarbonate. The data provide evidence of another important metabolic housekeeping function of these glial cells