PACAP and migraine headache: immunomodulation of neural circuits in autonomic ganglia and brain parenchyma.

The discovery that intravenous (IV) infusions of the neuropeptide PACAP-38 (pituitary adenylyl cyclase activating peptide-38) induced delayed migraine-like headaches in a large majority of migraine patients has resulted in considerable excitement in headache research. In addition to suggesting potential therapeutic targets for migraine, the finding provides an opportunity to better understand the pathological events from early events (aura) to the headache itself. Although PACAP-38 and the closely related peptide VIP (vasoactive intestinal peptide) are well-known as vasoactive molecules, the dilation of cranial blood vessels per se is no longer felt to underlie migraine headaches. Thus, more recent research has focused on other possible PACAP-mediated mechanisms, and has raised some important questions. For example, (1) are endogenous sources of PACAP (or VIP) involved in the triggering and/or propagation of migraine headaches?; (2) which receptor subtypes are involved in migraine pathophysiology?; (3) can we identify specific anatomical circuit(s) where PACAP signaling is involved in the features of migraine? The purpose of this review is to discuss the possibility, and supportive evidence, that PACAP acts to induce migraine-like symptoms not only by directly modulating nociceptive neural circuits, but also by indirectly regulating the production of inflammatory mediators. We focus here primarily on postulated extra-dural sites because potential mechanisms of PACAP action in the dura are discussed in detail elsewhere (see X, this edition)

Microflow of fluorescently labelled red blood cells in tumours expressing single isoforms of VEGF and their response to VEGF-R tyrosine kinase inhibition

This paper was presented at the 2nd Micro and Nano Flows Conference (MNF2009), which was held at Brunel University, West London, UK. The conference was organised by Brunel University and supported by the Institution of Mechanical Engineers, IPEM, the Italian Union of Thermofluid dynamics, the Process Intensification Network, HEXAG - the Heat Exchange Action Group and the Institute of Mathematics and its Applications.In this work we studied the functional differences between the microcirculation of murine tumours that only express single isoforms of vascular endothelial growth factor-A (VEGF), VEGF120 and VEGF188, and the effect of VEGF receptor tyrosine kinase (VEGF-R TK) inhibition on their functional response to the vascular disrupting agent, combretastatin A-4 phosphate (CA-4-P). We used measurement of fluorescentlylabelled red blood cell (RBC) velocities in tumour microvessels to study this functional response. RBC velocity for control VEGF120-expressing tumours was over 50% slower than for control VEGF188-expressing tumours, which may be due to the immature and haemorrhagic vasculature of the VEGF120 tumour. After chronic treatment with a VEGF-R tyrosine kinase inhibitor, SU5416, RBC velocities in VEGF120 tumours were significantly increased compared to control VEGF120 tumours, and similar to velocities in both VEGF188 treatment groups. Control and SU5416 treated VEGF188 tumours were not different from each other. Treatment of VEGF120 tumours with SU5416 reduced their vascular response to CA-4-P to a similar level to the VEGF188 tumours. Differential expression of VEGF isoforms not only affected vascular function in untreated tumours but also impacted on response to a vascular disrupting drug, CA-4-P, alone and in combination with an anti-angiogenic approach involving VEGF-R TK inhibition. Analysis of RBC velocities is a useful tool in measuring functional responses to vascular targeted treatments.This study is funded by the Cancer Research UK

High-fidelity state detection and tomography of a single ion Zeeman qubit

We demonstrate high-fidelity Zeeman qubit state detection in a single trapped 88 Sr+ ion. Qubit readout is performed by shelving one of the qubit states to a metastable level using a narrow linewidth diode laser at 674 nm followed by state-selective fluorescence detection. The average fidelity reached for the readout of the qubit state is 0.9989(1). We then measure the fidelity of state tomography, averaged over all possible single-qubit states, which is 0.9979(2). We also fully characterize the detection process using quantum process tomography. This readout fidelity is compatible with recent estimates of the detection error-threshold required for fault-tolerant computation, whereas high-fidelity state tomography opens the way for high-precision quantum process tomography

Measuring Red Blood Cell Velocity with a Keyhole Tracking Algorithm

A tracking algorithm is proposed to measure the velocity of red blood cells traveling through microvessels of tumors growing in skin flaps implanted on mice. The tracking is based on a keyhole model that describes the probable movement of a segmented cell between contiguous frames in a video sequence. When a history of movements exists, past, present and a predicted landing position define two regions of probability with a keyhole shape. This keyhole is used to de- termine if cells in contiguous frames should be linked to form tracks. Pre-processing segments cells from background and post-processing joins tracks and discards links that could have been formed due to noise or uncertainty. The algorithm pre- sents several advantages over traditional methods such as kymographs or particle image velocimetry: manual interven- tion is restricted to the thresholding, several vessels can be analyzed simultaneously, algorithm is robust to noise and a wealth of statistical measures can be obtained. Two tumors with different geometries were analyzed; average velocities were 211±136 [μm/s] (mean±std) with a range 15.9-797 [μm/s], and 89±62 [μm/s] with a range 5.5-300 [μm/s] respec- tively, which are consistent with previous results in the litera- ture

A scale-space tracing algorithm for analysis of tumour blood vessel morphology from transmitted light optical images

Background Limited contrast in optical images is problematic for analysing tumour vascular morphology. We describe an algorithm for segmenting tumour vasculature in transmitted light optical images, without the need for contrast enhancement. Effects of angiopoietin-1 (Ang-1) and -2 (Ang-2) ± treatment with the vascular disrupting agent combretastatin A4P (CA4P) were investigated. Method SW1222 human colorectal carcinoma cells were transfected with Ang-1 or Ang-2 cDNA, or with empty vector and implanted into ‘window’ chamber-bearing mice. Transmitted light images of tumours (x10 objective) were acquired before and up to 24h after treatment with 30 mg/kg CA4P or saline. Vessel tracing used a scale-space approach, employing differences in intensity of transmitted light between the vessels and surrounding tissues, as well as differences in the chromatic components, hue and saturation. The centreline of vessels was detected as a “ridge” in a topographical analogy and successive levels of filtering provided different scales to detect sharp to diffuse ridges. Morphological parameters were measured from the traced images - average vessel length (AL) width (AW), and relative vascular area (RA). Results The algorithm successfully identified the majority of tumour microvessels. CA4P-treated tumours showed a decrease in RA and increase in saturation balance up to 1-3h, with recovery by 24h. Saline had no effect. Ang-2 over-expressing tumours had lower values of AL, AW and RA than Ang-1 and wild-type (WT) tumours. Ang-1 tumours were similar to the WT except that AL was longer

An on-line chromatic and scale-space microvasculature-tracing analysis for transmitted light optical images

Limited contrast in optical images from intravital microscopy is problematic for analysing tumour vascular morphology. Moreover, in some cases, changes in vasculature are visible to a human observer but are not easy to quantify. In this paper two quantitative on-line algorithms are presented: scale-space vessel tracing and chromatic decomposition for tumour vasculature from in-vivo transmitted light optical images. The algorithms were tested on intravital window chamber images of the vasculature from SW1222 human colorectal carcinomas, which were treated with a vascular disrupting agent combretastatin-A-4-phosphate (CA-4-P) or saline. The results confirmed the well-known effects of CA-4-P on the constriction of vessels. Furthermore, changes in the chromaticity suggest a deoxygenation of the blood with a recovery to initial levels in CA-4-P-treated tumours relative to the controls. The algorithms can be freely applied to any vascular image through the CAIMAN (CAncer IMage ANalysis: http://www.caiman.org.uk)

Microflow of fluorescently labelled red blood cells in tumours expressing single isoforms of VEGF and their response to VEGF-R tyrosine kinase inhibition

In this work we studied the functional differences between the microcirculation of murine tumours that only express single isoforms of vascular endothelial growth factor-A (VEGF), VEGF120 and VEGF188, and the effect of VEGF receptor tyrosine kinase (VEGF-R TK) inhibition on their functional response to the vascular disrupting agent, combretastatin A-4 phosphate (CA-4-P). We used measurement of fluorescently- labelled red blood cell (RBC) velocities in tumour microvessels to study this functional response. RBC velocity for control VEGF120-expressing tumours was over 50% slower than for control VEGF188- expressing tumours, which may be due to the immature and haemorrhagic vasculature of the VEGF120 tumour. After chronic treatment with a VEGF-R tyrosine kinase inhibitor, SU5416, RBC velocities in VEGF120 tumours were significantly increased compared to control VEGF120 tumours, and similar to velocities in both VEGF188 treatment groups. Control and SU5416 treated VEGF188 tumours were not different from each other. Treatment of VEGF120 tumours with SU5416 reduced their vascular response to CA-4-P to a similar level to the VEGF188 tumours. Differential expression of VEGF isoforms not only affected vascular function in untreated tumours but also impacted on response to a vascular disrupting drug, CA-4-P, alone and in combination with an anti-angiogenic approach involving VEGF-R TK inhibition. Analysis of RBC velocities is a useful tool in measuring functional responses to vascular targeted treatments

Quantum control of 88^{88}Sr+^+ in a miniature linear Paul trap

We report on the construction and characterization of an apparatus for quantum information experiments using $^{88}$Sr$^+$ ions. A miniature linear radio-frequency (rf) Paul trap was designed and built. Trap frequencies above 1 MHz in all directions are obtained with 50 V on the trap end-caps and less than 1 W of rf power. We encode a quantum bit (qubit) in the two spin states of the $S_{1/2}$ electronic ground-state of the ion. We constructed all the necessary laser sources for laser cooling and full coherent manipulation of the ions' external and internal states. Oscillating magnetic fields are used for coherent spin rotations. High-fidelity readout as well as a coherence time of 2.5 ms are demonstrated. Following resolved sideband cooling the average axial vibrational quanta of a single trapped ion is $\bar n=0.05$ and a heating rate of $\dot{\bar n}=0.016$ ms$^{-1}$ is measured.Comment: 8 pages,9 figure