Renal failure and the neural control of the kidney

Renal failure (RF) is associated with an over activation of the sympathetic nervous system. The aim of this thesis was to investigate the hypothesis that as the kidney progresses into RF there is an inappropriate and sustained activation of renal afferent nerves which results in a dysregulation of basal RSNA and reflexly controlled RSNA by the high and low pressure baroreceptors. Baroreflex gain curves for both RSNA and HR were generated in control and RF rats. This study clearly showed a blunted high-pressure baroreflex in RF rats, an impairment which was almost completely corrected by bilateral renal denervation. The integrity of the low-pressure cardiopulmonary receptors to inhibit RSNA was investigated using acute saline volume. Again, a blunted reflex sympatho-inhibition of RSNA was observed, which was corrected by renal denervation. Finally a functional study to examine how the renal excretory response to volume expansion differed in RF was carried out. This study revealed an impairment of the low-pressure baroreflex control of the sympathetic outflow. The result of these studies suggest that cisplatin induced RF initiates a neural signal from within the kidney, which over rides the normal reflex regulation of RSNA by the high and low – pressure baroreceptors and that this impairment in function can be normalised by renal denervation. This raises further questions as to the mechanisms involved in the afferent over activation arising from the diseased kidneys.

Differential mechanisms of morphine antinociceptive tolerance revealed in (beta)arrestin-2 knock-out mice.

Morphine induces antinociception by activating mu opioid receptors (muORs) in spinal and supraspinal regions of the CNS. (Beta)arrestin-2 (beta)arr2), a G-protein-coupled receptor-regulating protein, regulates the muOR in vivo. We have shown previously that mice lacking (beta)arr2 experience enhanced morphine-induced analgesia and do not become tolerant to morphine as determined in the hot-plate test, a paradigm that primarily assesses supraspinal pain responsiveness. To determine the general applicability of the (beta)arr2-muOR interaction in other neuronal systems, we have, in the present study, tested (beta)arr2 knock-out ((beta)arr2-KO) mice using the warm water tail-immersion paradigm, which primarily assesses spinal reflexes to painful thermal stimuli. In this test, the (beta)arr2-KO mice have greater basal nociceptive thresholds and markedly enhanced sensitivity to morphine. Interestingly, however, after a delayed onset, they do ultimately develop morphine tolerance, although to a lesser degree than the wild-type (WT) controls. In the (beta)arr2-KO but not WT mice, morphine tolerance can be completely reversed with a low dose of the classical protein kinase C (PKC) inhibitor chelerythrine. These findings provide in vivo evidence that the muOR is differentially regulated in diverse regions of the CNS. Furthermore, although (beta)arr2 appears to be the most prominent and proximal determinant of muOR desensitization and morphine tolerance, in the absence of this mechanism, the contributions of a PKC-dependent regulatory system become readily apparent.

Is there an association between angiotensin-converting enzyme gene variants and chronic nonproductive cough?

Background: It is unclear why some patients develop a chronic nonproductive cough. Angiotensin-converting enzyme (ACE) inactivates tussive peptides in the airways such as bradykinin and tachykinins. An insertion/deletion polymorphism in the ACE gene accounts for variation in ACE levels, and patients with the II genotype have lowest serum ACE levels compared with ID and DD genotypes. We hypothesized that the II genotype would be associated with increased risk of developing a chronic cough.

Materials and methods: We recruited 47 patients (33 women), referred for evaluation of cough (median cough duration, 24 months; range, 2 to 240 months). Cough patients were evaluated using a comprehensive diagnostic protocol, and cough reflex sensitivity was measured using a capsaicin inhalation challenge. ACE genotyping was performed on DNA samples from patients using the polymerase chain reaction followed by agarose gel electrophoresis. ACE genotypes in patients with chronic cough were compared with those in 199 healthy control subjects. Serum ACE levels were determined using a colorimetric assay.

Results: Genotype frequencies for the ACE gene were similar between patients and control subjects. There was no correlation between capsaicin sensitivity and ACE genotypes or serum ACE levels.

Conclusion: Susceptibility to develop chronic cough is not associated with ACE genotype.

WASP-1b and WASP-2b: Two new transiting exoplanets detected with SuperWASP and SOPHIE

We have detected low-amplitude radial-velocity variations in two stars, USNO-B1.0 1219-0005465 (GSC 02265-00107 = WASP-1) and USNO-B1.0 0964-0543604 (GSC 00522-01199 = WASP-2). Both stars were identified as being likely host stars of transiting exoplanets in the 2004 SuperWASP wide-field transit survey. Using the newly commissioned radial-velocity spectrograph SOPHIE at the Observatoire de Haute-Provence, we found that both objects exhibit reflex orbital radial-velocity variations with amplitudes characteristic of planetary-mass companions and in-phase with the photometric orbits. Line-bisector studies rule out faint blended binaries as the cause of either the radial-velocity variations or the transits. We perform preliminary spectral analyses of the host stars, which together with their radial-velocity variations and fits to the transit light curves yield estimates of the planetary masses and radii. WASP-1b and WASP-2b have orbital periods of 2.52 and 2.15 d, respectively. Given mass estimates for their F7V and K1V primaries, we derive planet masses 0.80-0.98 and 0.81-0.95 times that of Jupiter, respectively. WASP-1b appears to have an inflated radius of at least 1.33 RJup, whereas WASP-2b has a radius in the range 0.65-1.26 RJup.

WASP-3b: a strongly irradiated transiting gas-giant planet

We report the discovery of WASP-3b, the third transiting exoplanet to be discovered by the WASP and SOPHIE collaboration. WASP-3b transits its host star USNO-B1.01256-0285133 every 1.846834 +/- 0.000002 d. Our high-precision radial velocity measurements present a variation with amplitude characteristic of a planetary-mass companion and in phase with the light curve. Adaptive optics imaging shows no evidence for nearby stellar companions, and line-bisector analysis excludes faint, unresolved binarity and stellar activity as the cause of the radial velocity variations. We make a preliminary spectroscopic analysis of the host star and find it to have Teff = 6400 +/- 100K and log g = 4.25 +/- 0.05 which suggests it is most likely an unevolved main-sequence star of spectral type F7-8V. Our simultaneous modelling of the transit photometry and reflex motion of the host leads us to derive a mass of 1.76+0.08-0.14 MJ and radius 1.31+0.07-0.14 RJ for WASP-3b. The proximity and relative temperature of the host star suggests that WASP-3b is one of the hottest exoplanets known, and thus has the potential to place stringent constraints on exoplanet atmospheric models.

Phasic modulation of corticomotor excitability during passive movement of the upper limb: effects of movement frequency and muscle specificity

Modulations in the excitability of spinal reflex pathways during passive rhythmic movements of the lower limb have been demonstrated by a number of previous studies [4]. Less emphasis has been placed on the role of supraspinal pathways during passive movement, and on tasks involving the upper limb. In the present study, transcranial magnetic stimulation (TMS) was delivered to subjects while undergoing passive flexion-extension movements of the contralateral wrist. Motor evoked potentials (MEPs) of flexor carpi radialis (FCR) and abductor pollicus brevis (APB) muscles were recorded. Stimuli were delivered in eight phases of the movement cycle during three different frequencies of movement. Evidence of marked modulations in pathway excitability was found in the MEP amplitudes of the FCR muscle, with responses inhibited and facilitated from static values in the extension and flexion phases, respectively. The results indicated that at higher frequencies of movement there was greater modulation in pathway excitability. Paired-pulse TMS (sub-threshold conditioning) at short interstimulus intervals revealed modulations in the extent of inhibition in MEP amplitude at high movement frequencies. In the APE muscle, there was some evidence of phasic modulations of response amplitude, although the effects were less marked than those observed in FCR. It is speculated that these modulatory effects are mediated via Ia afferent pathways and arise as a consequence of the induced forearm muscle shortening and lengthening. Although the level at which this input influences the corticomotoneuronal pathway is difficult to discern, a contribution from cortical regions is suggested. (C) 2001 Published by Elsevier Science B.V.

DNA and chromosomal damage in response to intermittent extremely low-frequency magnetic fields.

Considerable controversy still exists as to whether electric and magnetic fields (MF) at extremely low frequencies are genotoxic to humans. The aim of this study was to test the ability of alternating magnetic fields to induce DNA and chromosomal damage in primary human fibroblasts. Single- and double-strand breaks were quantified using the alkaline comet assay and the gammaH2AX-foci assay, respectively. Chromosomal damage was assayed for unstable aberrations, sister chromatid exchange and micronuclei. Cells were exposed to switching fields - 5min on, 10min off - for 15h over the range 50-1000microT. Exposure to ionizing radiation was used as a positive-effect calibration. In this study two separate MF exposure systems were used. One was based on a custom-built solenoid coil system and the other on a commercial system almost identical to that used in previous studies by the EU REFLEX programme. With neither system could DNA damage or chromosomal damage be detected as a result of exposure of fibroblasts to switching MF. The sensitive gammaH2AX assay could also not detect significant DNA damage in the MF-exposed fibroblasts, although the minimum threshold for this assay was equivalent to an X-ray dose of 0.025Gy. Therefore, with comparable MF parameters employed, this study could not confirm previous studies reporting significant effects for both the alkaline and neutral comet assays and chromosomal aberration induction.

Humour: Stylistic Approaches

An important focus in contemporary stylistics has been on the connections between style and verbal humor, and this article charts the ways in which stylisticians have used a variety of linguistic models to analyze humorous discourse. The idea of stylistic incongruity is identified as being especially important in triggering the humor reflex. The principle of incongruity applies to any level of language or discourse, as is illustrated here by examples of puns and related forms of humor as well as by incongruities that are more to do with mismatches between text and discourse context. The principle of incongruity is also aligned with the concept of irony, through which a number of points are made about the stylistic analysis of both parody and satire.

Nociception or pain in a decapod crustacean?

Nociception is the ability to perceive a noxious stimulus and react in a re flexive manner and occurs across a wide range of taxa. However, the ability to experience the associated aversive sensation and feeling, known as pain, is not widely accepted to occur in nonvertebrates. We examined the responses of a decapod crustacean, the prawn, Palaemon elegans, to different noxious stimuli applied to one antenna to assess reflex responses (nociception) and longer-term, specifically directed behavioural responses that might indicate pain. We also examined the effects of benzocaine, a local anaesthetic, on these responses. Noxious stimuli elicited an immediate reflex tail flick response, followed by two prolonged activities, grooming of the antenna and rubbing of the antenna against the side of the tank, with both activities directed specifically at the treated antenna. These responses were inhibited by benzocaine; however, benzocaine did not alter general swimming activity and thus the decline in grooming and rubbing is not due to general anaesthesia. Mechanical stimulation by pinching also resulted in prolonged rubbing, but this was not inhibited by benzocaine. These results indicate an awareness of the location of the noxious stimuli, and the prolonged complex responses indicate a central involvement in their organization. The inhibition by a local anaesthetic is similar to observations on vertebrates and is consistent with the idea that these crustaceans can experience pain.

Motivational trade-offs and potential pain experience in hermit crabs

One criterion of pain experience is that the emotional response to pain may be traded-off against other motivational requirements. This was tested in hermit crabs, housed in either preferred or unpreferred species of shells, by subjecting their abdomens to electric shocks of gradually increasing intensity. The first observable response was not affected by shell species but those in preferred shells evacuated at a higher shock level than those in poor quality shells. Thus, they seem to trade-off the requirement to retain a high quality shell with that of avoidance of the noxious stimulus. Some crabs returned to their shells and those that got back into the preferred species did so with less probing of the aperture before getting in and subsequently thrust their abdomen in and out less often in further investigation, thus confirming their shell species preference. Not all crabs returned to the vicinity of the shell and some attempted to climb the wall of the experimental chamber. Others engaged in shell rapping as if in a fight and grooming of the abdomen was noted. These findings are consistent with the idea of a pain experience rather than a nociceptive reflex. (C) 2009 Elsevier B.V. All rights reserved.

Line-profile tomography of exoplanet transits - II. A gas-giant planet transiting a rapidly rotating A5 star

Most of our knowledge of extrasolar planets rests on precise radial-velocity measurements, either for direct detection or for confirmation of the planetary origin of photometric transit signals. This has limited our exploration of the parameter space of exoplanet hosts to solar- and later-type, sharp-lined stars. Here we extend the realm of stars with known planetary companions to include hot, fast-rotating stars. Planet-like transits have previously been reported in the light curve obtained by the SuperWASP survey of the A5 star HD15082 (WASP-33 V = 8.3, v sini = 86 km s-1). Here we report further photometry and time-series spectroscopy through three separate transits, which we use to confirm the existence of a gas-giant planet with an orbital period of 1.22d in orbit around HD15082. From the photometry and the properties of the planet signal travelling through the spectral line profiles during the transit, we directly derive the size of the planet, the inclination and obliquity of its orbital plane and its retrograde orbital motion relative to the spin of the star. This kind of analysis opens the way to studying the formation of planets around a whole new class of young, early-type stars, hence under different physical conditions and generally in an earlier stage of formation than in sharp-lined late-type stars. The reflex orbital motion of the star caused by the transiting planet is small, yielding an upper mass limit of 4.1MJupiter on the planet. We also find evidence of a third body of substellar mass in the system, which may explain the unusual orbit of the transiting planet. In HD 15082, the stellar line profiles also show evidence of non-radial pulsations, clearly distinct from the planetary transit signal. This raises the intriguing possibility that tides raised by the close-in planet may excite or amplify the pulsations in such stars.

Future Directions in Treating Cough

Cough is a common and troublesome symptom that can be difficult to treat. New therapeutic options that are safe and more effective than those currently available are needed. In this article, the authors offer opinion on future directions in the treatment of cough, with a particular emphasis on the clinical syndrome associated with cough reflex hypersensitivity. In addition, the article provides an overview of some of the diagnostic technologies and promising drug targets likely to emerge from current clinical and scientific endeavor.

Pain and suffering in invertebrates?

All animals face hazards that cause tissue damage and most have nociceptive reflex responses that protect them from such damage. However, some taxa have also evolved the capacity for pain experience, presumably to enhance longterm protection through behavior modification based on memory of the unpleasant nature of pain. In this article I review various criteria that might distinguish nociception from pain. Because nociceptors are so taxonomically widespread, simply demonstrating their presence is not sufficient. Furthermore, investigation of the central nervous system provides limited clues about the potential to experience pain. Opioids and other analgesics might indicate a central modulation of responses but often peripheral effects could explain the analgesia; thus reduction of responses by analgesics and opioids does not allow clear discrimination between nociception and pain. Physiological changes in response to noxious stimuli or the threat of a noxious stimulus might prove useful but, to date, application to invertebrates is limited. Behavior of the organism provides the greatest insights. Rapid avoidance learning and prolonged memory indicate central processing rather than simple reflex and are consistent with the experience of pain. Complex, prolonged grooming or rubbing may demonstrate an awareness of the specific site of stimulus application. Tradeoffs with other motivational systems indicate central processing, and an ability to use complex information suggests sufficient cognitive ability for the animal to have a fitness benefit from a pain experience. Available data are consistent with the idea of pain in some invertebrates and go beyond the idea of just nociception but are not definitive. In the absence of conclusive data, more humane care for invertebrates is suggested.

Brain activity during ankle proprioceptive stimulation predicts balance performance in young and older adults

Proprioceptive information from the foot/ankle provides important information regarding body sway for balance control, especially in situations where visual information is degraded or absent. Given known increases in catastrophic injury due to falls with older age, understanding the neural basis of proprioceptive processing for balance control is particularly important for older adults. In the present study, we linked neural activity in response to stimulation of key foot proprioceptors (i.e., muscle spindles) with balance ability across the lifespan. Twenty young and 20 older human adults underwent proprioceptive mapping; foot tendon vibration was compared with vibration of a nearby bone in an fMRI environment to determine regions of the brain that were active in response to muscle spindle stimulation. Several body sway metrics were also calculated for the same participants on an eyes-closed balance task. Based on regression analyses, multiple clusters of voxels were identified showing a significant relationship between muscle spindle stimulation-induced neural activity and maximum center of pressure excursion in the anterior-posterior direction. In this case, increased activation was associated with greater balance performance in parietal, frontal, and insular cortical areas, as well as structures within the basal ganglia. These correlated regions were age- and foot-stimulation side-independent and largely localized to right-sided areas of the brain thought to be involved in monitoring stimulus-driven shifts of attention. These findings support the notion that, beyond fundamental peripheral reflex mechanisms, central processing of proprioceptive signals from the foot is critical for balance control.

Clinical cough II:therapeutic treatments and management of chronic cough

Chronic cough is a common and frequently disruptive symptom which can be difficult to treat with currently available medicines. Asthma/eosinophilic airway disease and gastro-oesophageal reflux disease are most commonly associated with chronic cough but it may also trouble patients with chronic obstructive pulmonary disease, pulmonary fibrosis and lung cancer. Over the last three decades there have been a number of key advances in the clinical approach to cough and a number of international guidelines on the management of cough have been developed. Despite the undoubted benefit of such initiatives, more effective treatments for cough are urgently needed. The precise pathophysiological mechanisms of chronic cough are unknown but central to the process is sensitization (upregulation) of the cough reflex. One well-recognized clinical consequence of this hypersensitive state is bouts of coughing triggered by apparently trivial provocation such as scents and odours and changes in air temperature. The main objective of new treatments for cough would be to identify ways to downregulate this heightened cough reflex but yet preserve its crucial role in protecting the airway. The combined efforts of clinicians, scientists and the pharmaceutical industry offer most hope for such a treatment breakthrough. The aim of this chapter is to provide some rationale for the current treatment recommendations and to offer some reflections on the management of patients with chronic cough.