The search for novel analgesics: re-examining spinal cord circuits with new tools

In this perspective, we propose the absence of detailed information regarding spinal cord circuits that process sensory information remains a major barrier to advancing analgesia. We highlight recent advances showing that functionally discrete populations of neurons in the spinal cord dorsal horn play distinct roles in processing sensory information. We then discuss new molecular, electrophysiological, and optogenetic techniques that can be employed to understand how dorsal horn circuits process tactile and nociceptive information. We believe this information can drive the development of entirely new classes of pharmacotherapies that target key elements in spinal circuits to selectively modify sensory function and blunt pain

Unpulsed UBV Optical Emission from the Crab Pulsar

Based on observations of the Crab pulsar using the TRIFFID high speed imaging photometer in the UBV bands using the Special Astrophysical Observatory's 6m telescope in the Russian Caucasus, we report the detection of pronounced emission during the so-called `off' phase of emission. Following de-extinction, this unpulsed component of emission is shown to be consistent with a power law with an exponent of alpha = -0.60 +/- 0.37, the uncertainty being dominated by the error associated with the independent CCD photometry used to reference the TRIFFID data. This suggests a steeper power law form than that reported elsewhere in the literature for the total integrated spectrum, which is essentially flat with alpha ~ 0.1, although the difference in this case is only significant at the ~ 2 sigma level. Deeper reference integrated and TRIFFID phase-resolved photometry in these bands in conjunction with further observations in the UV and R region would constrain this fit further.Comment: 26 pages, 2 figures, uses aasms4.sty, accepted for publication in the Astrophysical Journa

Mode Switching and Subpulse Drifting in PSR B0826-34

We present high-quality observations of PSR B0826-34 at 1374 MHz. The emission from this pulsar exhibits strong bursts of pulses followed by long periods of `null' pulses. When it is strong, the radiation extends through the whole pulse period. We show for the first time that there is weak emission during the `null' phases, which should therefore be considered to be a different mode rather than a null. During this weak mode the profile is similar to that observed in the strong mode at low radio frequency. Using a phase-tracking method, the pattern of drifting subpulses during the strong mode is seen to be coherent across the whole profile. The drift rate is variable and includes positive and negative values. Thirteen subpulse bands have been directly observed, covering the whole longitude range. The subpulses and their spacings ($P_2$) are wider in one half of the profile than those in the other half. This difference, and the variation of observed $P_2$ within the two regions, can be accounted for if the magnetic pole is inclined to the rotation axis by about 0.5 degrees. These two regions appear to represent radiation from outer and inner cones. The intensity modulation of subpulses in all longitude ranges is related to the magnitude of the drift rate.Comment: 8 pages, 10 figures. Accepted for publication in MNRA

The 1997 event in the Crab pulsar revisited

A complex event observed in the radio pulses from the Crab pulsar in 1997 included echoes, a dispersive delay, and large changes in intensity. It is shown that these phenomena were due to refraction at the edge of a plasma cloud in the outer region of the Crab Nebula. Several similar events have been observed, although in less detail. It is suggested that the plasma cloud is in the form of filaments with diameter around 3 x 10^11m and electron density of order 10^4 cm-3Comment: 5 pages 4 figs Accepted by MNRA

Phase-resolved Crab Studies with a Cryogenic TES Spectrophotometer

We are developing time- and energy-resolved near-IR/optical/UV photon detectors based on sharp superconducting-normal transition edges in thin films. We report observations of the Crab pulsar made during prototype testing at the McDonald 2.7m telescope with a fiber-coupled transition-edge sensor (TES) system. These data show substantial (d[alpha]~0.3), rapid variations in the spectral index through the pulse profile, with a strong phase-varying IR break across our energy band. These variations correlate with X-ray spectral variations, but no single synchrotron population can account for the full Spectral Energy Distribution (SED). We also describe test spectrophotopolarimetry observations probing the energy dependence of the polarization sweep; this may provide a new key to understanding the radiating particle population.Comment: 12 pages, 10 figures -- to appear in ApJ V56

Pulsar Jets: Implications for Neutron Star Kicks and Initial Spins

We study implications for the apparent alignment of the spin axes, proper-motions, and polarization vectors of the Crab and Vela pulsars. The spin axes are deduced from recent Chandra X-ray Observatory images that reveal jets and nebular structure having definite symmetry axes. The alignments indicate these pulsars were born either in isolation or with negligible velocity contributions from binary motions. We examine the effects of rotation and the conditions under which spin-kick alignment is produced for various models of neutron star kicks. If the kick is generated when the neutron star first forms by asymmetric mass ejection or/and neutrino emission, then the alignment requires that the protoneutron star possesses an original spin with period $P_s$ much less than the kick timescale, thus spin-averaging the kick forces. The kick timescale ranges from 100 ms to 10 s depending on whether the kick is hydrodynamically driven or neutrino-magnetic field driven. For hydrodynamical models, spin-kick alignment further requires the rotation period of an asymmetry pattern at the radius near shock breakout (>100 km) to be much less than ~100 ms; this is difficult to satisfy unless rotation plays a dynamically important role in the core collapse and explosion (P_s\lo 1 ms). Aligned kick and spin vectors are inherent to the slow process of asymmetric electromagnetic radiation from an off-centered magnetic dipole. We reassess the viability of this effect, correcting a factor of 4 error in Harrison and Tademaru's calculation that increases the size of the effect. To produce a kick velocity of order a few hundred km/s requires that the neutron star be born with an initial spin close to 1 ms and that spindown due to r-mode driven gravitational radiation be inefficient compared to standard magnetic braking.Comment: Small changes/additions; final version to be published in ApJ, Vol.549 (March 10, 2001

Differential gene expression in multiple neurological, inflammatory and connective tissue pathways in a spontaneous model of human small vessel stroke

Aims: Cerebral small vessel disease (SVD) causes a fifth of all strokes plus diffuse brain damage leading to cognitive decline, physical disabilities and dementia. The aetiology and pathogenesis of SVD are unknown, but largely attributed to hypertension or microatheroma. Methods: We used the spontaneously hypertensive stroke-prone rat (SHRSP), the closest spontaneous experimental model of human SVD, and age-matched control rats kept under identical, non-salt-loaded conditions, to perform a blinded analysis of mRNA microarray, qRT-PCRand pathway analysis in two brain regions (frontal and midcoronal) commonly affected by SVD in the SHRSP at age five, 16 and 21 weeks. Results: We found gene expression abnormalities, with fold changes ranging from 2.5 to 59 for the 10 most differentially expressed genes, related to endothelial tight junctions (reduced), nitric oxide bioavailability (reduced), myelination (impaired), glial and microglial activity (increased), matrix proteins (impaired), vascular reactivity (impaired) and albumin (reduced), consistent with protein expression defects in the same rats. All were present at age 5 weeks thus pre-dating blood pressure elevation. ‘Neurological’ and ‘inflammatory’ pathways were more affected than ‘vascular’ functional pathways. Conclusions: This set of defects, although individually modest, when acting in combination could explain the SHRSP's susceptibility to microvascular and brain injury, compared with control rats. Similar combined, individually modest, but multiple neurovascular unit defects, could explain susceptibility to spontaneous human SVD

A missing dimension in measures of vaccination impacts

Immunological protection, acquired from either natural infection or vaccination, varies among hosts, reflecting underlying biological variation and affecting population-level protection. Owing to the nature of resistance mechanisms, distributions of susceptibility and protection entangle with pathogen dose in a way that can be decoupled by adequately representing the dose dimension. Any infectious processes must depend in some fashion on dose, and empirical evidence exists for an effect of exposure dose on the probability of transmission to mumps-vaccinated hosts [1], the case-fatality ratio of measles [2], and the probability of infection and, given infection, of symptoms in cholera [3]. Extreme distributions of vaccine protection have been termed leaky (partially protects all hosts) and all-or-nothing (totally protects a proportion of hosts) [4]. These distributions can be distinguished in vaccine field trials from the time dependence of infections [5]. Frailty mixing models have also been proposed to estimate the distribution of protection from time to event data [6], [7], although the results are not comparable across regions unless there is explicit control for baseline transmission [8]. Distributions of host susceptibility and acquired protection can be estimated from dose-response data generated under controlled experimental conditions [9]–[11] and natural settings [12], [13]. These distributions can guide research on mechanisms of protection, as well as enable model validity across the entire range of transmission intensities. We argue for a shift to a dose-dimension paradigm in infectious disease science and community health

Onset of experimental severe cardiac fibrosis is mediated by overexpression of angiotensin-converting enzyme 2

Angiotensin-converting enzyme (ACE) 2 is a recently identified homologue of ACE. There is great interest in the therapeutic benefit for ACE2 overexpression in the heart. However, the role of ACE2 in the regulation of cardiac structure and function, as well as maintenance of systemic blood pressure, remains poorly understood. In cell culture, ACE2 overexpression led to markedly increased myocyte volume, assessed in primary rabbit myocytes. To assess ACE2 function in vivo, we used a recombinant adeno-associated virus 6 delivery system to provide 11-week overexpression of ACE2 in the myocardium of stroke-prone spontaneously hypertensive rats. ACE2, as well as the ACE inhibitor enalapril, significantly reduced systolic blood pressure. However, in the heart, ACE2 overexpression resulted in cardiac fibrosis, as assessed by histological analysis with concomitant deficits in ejection fraction and fractional shortening measured by echocardiography. Furthermore, global gene expression profiling demonstrated the activation of profibrotic pathways in the heart mediated by ACE2 gene delivery. This study demonstrates that sustained overexpression of ACE2 in the heart in vivo leads to the onset of severe fibrosis