Aims.We report the results of an exploratory program to image the extended circumstellar envelopes of asymptotic giant branch (AGB) stars in dust-scattered galactic light. The goal is to characterize ...the morphology of the envelopes as a probe of the mass-loss process. Methods.The observations consist of short exposures with the VLT and longer exposures with 1–2 m telescopes, augmented with archival images from the Hubble Space Telescope. Results.We observed 12 AGB stars and detected the circumstellar envelopes in 7. The detected envelopes have mass loss rates ${\ga} 5\times 10^{-6}$ $M_{\odot}$ yr-1, and they can be seen out to distances ${\ga} 1$ kpc. The observations provide information on the mass loss history on time scales up to ${\sim} 10\,000$ yr. For the five AGB envelopes in which the circumstellar geometry is well determined by scattered light observations, all except one (OH348.2-19.7) show deviations from spherical symmetry. Two (IRC+10216 and IRC+10011) show roughly spherical envelopes at large radii but asymmetry or bipolarity close to the star; one (AFGL 2514) shows an extended, elliptical envelope, and one (AFGL 3068) shows a spiral pattern. The non-spherical structures are all consistent with the effects of binary interactions. Conclusions.Our observations are in accord with a scenario in which binary companions play a role in shaping planetary nebulae, and show that the circumstellar gas is already partly shaped on the AGB, before evolution to the proto-planetary nebula phase.
We investigate the time sequence for the appearance of jets and molecular tori in the transition of stars from the asymptotic giant branch to the planetary nebula phase. Jets and tori are prominent ...features of this evolution, but their origins are uncertain. Using optical and millimeter line kinematics, we determine the ejection history in a sample of well-observed cases. We find that jets and tori develop nearly simultaneously. We also find evidence that jets typically appear slightly later than tori, with a lag time of a few hundred years. These characteristics provide strong evidence that jets and tori are physically related, and they set new constraints on theories of jet formation. The ejection of a discrete torus followed by jets on a short timescale favors the class of models in which a companion interacts with the central star. Models with long timescales, or with jets followed by a torus, are ruled out.
The effect of PF-04457845, a potent and selective fatty acid amide hydrolase-1 (FAAH1) inhibitor, on pain due to osteoarthritis of the knee was investigated in a randomised placebo and ...active-controlled clinical trial. The trial involved 2 periods (separated by a 2-week washout) consisting of a 1-week wash-in phase followed by 2weeks double-blind treatment. Patients received single-blind placebo throughout the wash-in and washout periods. Patients were randomised to receive either 4mg q.d. PF-04457845 followed by placebo (or vice versa), or 500mg b.i.d. naproxen followed by placebo (or vice versa). The primary end point was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score. The trial had predefined decision rules based on likelihood that PF-04457845 was better or worse than the standard of care (considered to be a 1.8 reduction in WOMAC pain score compared to placebo). A total of 74 patients were randomised to 1 of 4 treatment sequences. The mean differences (80% confidence intervals) from placebo in WOMAC pain score were 0.04 (-0.63 to 0.71) for PF-04457845 and -1.13 (-1.79 to -0.47) for naproxen, indicating that whilst naproxen seemed efficacious, PF-04457845 was not differentiated from placebo. The study was stopped at the interim analysis for futility. PF-04457845 decreased FAAH activity by >96% and substantially increased 4 endogenous substrates (fatty acid amides). PF-04457845 was well tolerated in osteoarthritis patients, and there was no evidence of cannabinoid-type adverse events. The lack of analgesic effect of FAAH1 inhibition in humans is in contrast to data from animal models. This apparent disconnect between species needs further study.
Chronic pain remains a significant challenge for modern health care as its pathologic mechanisms are largely unknown and preclinical animal models suffer from limitations in assessing this complex ...subjective experience. However, human brain neuroimaging techniques enable the assessment of functional and neurochemical alterations in patients experiencing chronic pain and how these factors may dynamically change with pharmacologic treatment.
To identify the clinical action of pregabalin, a proven analgesic, the authors performed three complementary brain neuroimaging procedures: (proton magnetic resonance spectroscopy, functional magnetic resonance imaging, and functional connectivity magnetic resonance imaging) in 17 chronic pain patients diagnosed with fibromyalgia.
The authors found that pregabalin but not placebo reduces combined glutamate + glutamine levels within the posterior insula (pregabalin P = 0.016; placebo P = 0.71). Interestingly, reductions in clinical pain were associated with reductions in brain connectivity of this structure to brain regions within the default mode network during pregabalin (r = 0.82; P = 0.001) but not placebo (r = -0.13; P = 0.63). Response of default mode network regions to experimental pain was also reduced with pregabalin (P = 0.018) but not placebo (P = 0.182). Perhaps most importantly, baseline values for all three neuroimaging markers predicted subsequent analgesic response to pregabalin but not placebo.
The results of this study suggest that pregabalin works in part by reducing insular glutamatergic activity, leading to a reduction of the increased functional connectivity seen between brain regions in chronic pain states. The study also supports a role for human brain imaging in the development, assessment, and personalized use of central-acting analgesics.
Abnormal processing of somatosensory inputs in the central nervous system (central sensitization) is the mechanism accounting for the enhanced pain sensitivity in the skin surrounding tissue injury ...(secondary hyperalgesia). Secondary hyperalgesia shares clinical characteristics with neurogenic hyperalgesia in patients with neuropathic pain. Abnormal brain responses to somatosensory stimuli have been found in patients with hyperalgesia as well as in normal subjects during experimental central sensitization. The aim of this study was to assess the effects of gabapentin, a drug effective in neuropathic pain patients, on brain processing of nociceptive information in normal and central sensitization states. Using functional magnetic resonance imaging (fMRI) in normal volunteers, we studied the gabapentin-induced modulation of brain activity in response to nociceptive mechanical stimulation of normal skin and capsaicin-induced secondary hyperalgesia. The dose of gabapentin was 1,800 mg per os, in a single administration. We found that (i) gabapentin reduced the activations in the bilateral operculoinsular cortex, independently of the presence of central sensitization; (ii) gabapentin reduced the activation in the brainstem, only during central sensitization; (iii) gabapentin suppressed stimulus-induced deactivations, only during central sensitization; this effect was more robust than the effect on brain activation. The observed drug-induced effects were not due to changes in the baseline fMRI signal. These findings indicate that gabapentin has a measurable antinociceptive effect and a stronger antihyperalgesic effect most evident in the brain areas undergoing deactivation, thus supporting the concept that gabapentin is more effective in modulating nociceptive transmission when central sensitization is present.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Inhibition of fatty acid amide hydrolase‐1 (FAAH1) and the subsequent elevation of fatty acid amides has been proposed as a strategy to induce the analgesic ...properties of cannabinoids without the accompanying negative side effects such as impairment in cognition, motor control and predisposition to psychoses. PF‐04457845 is a potent and selective irreversible FAAH1 inhibitor which has been shown to elevate fatty acid amide concentrations in animal models and induce responses in behavioural models suggestive of analgesia.
WHAT THIS STUDY ADDS
• This study is the first to investigate a FAAH1 inhibitor in humans. PF‐04457845 is well tolerated following single and multiple dosing to healthy volunteers and has pharmacokinetic and pharmacodynamic properties that make nearly complete inhibition of FAAH1 possible with once daily dosing.
AIMS To evaluate the pharmacology and tolerability of PF‐04457845, an orally available fatty acid amide hydrolase‐1 (FAAH1) inhibitor, in healthy subjects.
METHODS
Double‐blind, randomized, placebo‐controlled single and multiple rising dose studies and an open‐label, randomized, food effect study were conducted. Plasma and urine PF‐04457845 concentrations, plasma fatty acid amide concentrations and FAAH1 activity in human leucocytes were measured. Tolerability, including effects on cognitive function, were assessed.
RESULTS
PF‐04457845 was rapidly absorbed (median tmax 0.5–1.2 h). Exposure increased supraproportionally to dose from 0.1 to 10 mg and proportionally between 10 and 40 mg single doses. The pharmacokinetics appeared dose proportional following 14 days once daily dosing between 0.5 and 8 mg. Steady‐state was achieved by day 7. Less than 0.1% of the dose was excreted in urine. Food had no effect on PF‐04457845 pharmacokinetics. FAAH1 activity was almost completely inhibited (>97%) following doses of at least 0.3 mg (single dose) and 0.5 mg once daily (multiple dose) PF‐04457845. Mean fatty acid amide concentrations increased (3.5‐ to 10‐fold) to a plateau and then were maintained following PF‐04457845. FAAH1 activity and fatty acid amide concentrations returned to baseline within 2 weeks following cessation of dosing at doses up to 4 mg. There was no evidence of effects of PF‐04457845 on cognitive function. PF‐04457845, at doses up to 40 mg single dose and 8 mg once daily for 14 days, was well tolerated.
CONCLUSIONS
PF‐04457845 was well tolerated at doses exceeding those required for maximal inhibition of FAAH1 activity and elevation of fatty acid amides.
We report the results of a search for gas phase atomic metals in the circumstellar envelope of the asymptotic giant branch carbon star IRC+10216. The search was made using high resolution (λ/Δ λ = 50 ...000) optical absorption spectroscopy of a background star that probes the envelope on a line of sight 35´´ from the center. The metal species that we detect in the envelope include $\ion{Na}{i}$, $\ion{K}{i}$, $\ion{Ca}{i}$, $\ion{Ca}{ii}$, $\ion{Cr}{i}$, and $\ion{Fe}{i}$, with upper limits for $\ion{Al}{i}$, $\ion{Mn}{i}$, $\ion{Ti}{i}$, $\ion{Ti}{ii}$, and $\ion{Sr}{ii}$. The observations are used to determine the metal abundances in the gas phase and the condensation onto grains. The metal depletions in the envelope range from a factor of 5 for Na to 300 for Ca, with some similarity to the depletion pattern in interstellar clouds. Our results directly constrain the condensation efficiency of metals in a carbon-rich circumstellar envelope and the mix of solid and gas phase metals returned by the star to the interstellar medium. The abundances of the uncondensed metal atoms that we observe are typically larger than the abundances of the metal-bearing molecules detected in the envelope. The metal atoms are therefore the major metal species in the gas phase and likely play a key role in the metal chemistry.
A lack of objective outcome measures and overreliance on subjective pain reports in early proof-of-concept studies contribute to the high attrition of potentially effective new analgesics. We studied ...the utility of neuroimaging in providing objective evidence of neural activity related to drug modulation or a placebo effect in a double-blind, randomized, placebo-controlled, three-way crossover trial.
We chronically administered pregabalin or tramadol (first-line and second-line analgesics, respectively), recommended for neuropathic pain, in 16 post-traumatic neuropathic pain patients. We measured subjective pain reports, allodynia-evoked neural activity, and brain resting state functional connectivity from patients during the three sessions and resting state data at baseline from patients after washout of their current medication. All data were collected using a 3 T MRI scanner.
When compared with placebo only, pregabalin significantly suppressed allodynia-evoked neural activity in several nociceptive and pain-processing areas of the brain, despite the absence of behavioural analgesia. Furthermore, placebo significantly increased functional connectivity between the rostral anterior cingulate and the brainstem, a core component of the placebo neural network.
Functional neuroimaging provided objective evidence of pharmacodynamic efficacy in a proof-of-concept study setting where subjective pain outcome measures are often unreliable. Additionally, we provide evidence confirming the neural mechanism underpinning placebo analgesia as identified in acute experimental imaging studies in patients during the placebo arm of a clinical trial. We explore how brain penetrant active drugs potentially interact with this mechanism.
NCT0061015
Cellular and molecular changes of the periodontium associated with a higher prevalence of oral diseases (e.g., chronic periodontitis) in aged populations have received little attention. Since ...impaired apoptosis during aging appears to be related to chronic inflammatory disorders, we hypothesized that the expression of genes associated with apoptotic processes are altered in aged healthy and periodontitis-affected gingival tissue. Ontology analysis of 88 genes related to apoptotic pathways was performed in gingival biopsies of healthy and periodontitis sites from young, adult, and aged non-human primates (Macaca mulatta), using the GeneChip® Rhesus Macaque Genome Array. Lower expression of anti-apoptotic and higher expression of pro-apoptotic genes were associated with healthy gingival tissue from young compared with aged animals. Few differences in gene expression were observed in healthy gingival tissue between adult and aged animals. Comparison between healthy and periodontitis gingival tissues showed that the up- or down-regulated apoptotic genes in diseased gingival tissue are different in adults compared with aged animals. These results suggest that apoptotic events normally occurring in gingival tissues could be reduced in aging,and unique aspects of apoptotic pathways are potentially involved in the pathophysiology of perio-dontal disease in adult vs. aged gingival tissues.
Translational regulation of mRNAs is critically important for proper gene expression in germ cells, gametes, and embryos. The ability of the nucleus to control gene expression in these systems may be ...limited due to spatial or temporal constraints, as well as the breadth of gene products they express to prepare for the rapid animal development that follows. During development germ granules are hubs of post-transcriptional regulation of mRNAs. They assemble and remodel messenger ribonucleoprotein (mRNP) complexes for translational repression or activation. Recently, mRNPs have been appreciated as discrete regulatory units, whose function is dictated by the many positive and negative acting factors within the complex. Repressed mRNPs must be activated for translation on ribosomes to introduce novel proteins into germ cells. The binding of eIF4E to interacting proteins (4EIPs) that sequester it represents a node that controls many aspects of mRNP fate including localization, stability, poly(A) elongation, deadenylation, and translational activation/repression. Furthermore, plants and animals have evolved to express multiple functionally distinct eIF4E and 4EIP variants within germ cells, giving rise to different modes of translational regulation.
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