Debris disks are tenuous, dust-dominated disks commonly observed around stars over a wide range of ages. Those around main sequence stars are analogous to the Solar System's Kuiper Belt and zodiacal ...light. The dust in debris disks is believed to be continuously regenerated, originating primarily with collisions of planetesimals. Observations of debris disks provide insight into the evolution of planetary systems; and the composition of dust, comets, and planetesimals outside the Solar System; as well as placing constraints on the orbital architecture and potentially the masses of exoplanets that are not otherwise detectable. This review highlights recent advances in multiwavelength, high-resolution scattered light and thermal imaging that have revealed a complex and intricate diversity of structures in debris disks and discusses how modeling methods are evolving with the breadth and depth of the available observations. Two rapidly advancing subfields highlighted in this review include observations of atomic and molecular gas around main sequence stars and variations in emission from debris disks on very short (days to years) timescales, providing evidence of non-steady-state collisional evolution particularly in young debris disks.
The chemical synthesis of DNA oligonucleotides and their assembly into synthons, genes, circuits, and even entire genomes by gene synthesis methods has become an enabling technology for modern ...molecular biology and enables the design, build, test, learn, and repeat cycle underpinning innovations in synthetic biology. In this perspective, we briefly review the techniques and technologies that enable the synthesis of DNA oligonucleotides and their assembly into larger DNA constructs with a focus on recent advancements that have sought to reduce synthesis cost and increase sequence fidelity. The development of lower-cost methods to produce high-quality synthetic DNA will allow for the exploration of larger biological hypotheses by lowering the cost of use and help to close the DNA read-write cost gap.
Background
Duloxetine is a balanced serotonin and noradrenaline reuptake inhibitor licensed for the treatment of major depressive disorders, urinary stress incontinence and the management of ...neuropathic pain associated with diabetic peripheral neuropathy. A number of trials have been conducted to investigate the use of duloxetine in neuropathic and nociceptive painful conditions. This is the first update of a review first published in 2010.
Objectives
To assess the benefits and harms of duloxetine for treating painful neuropathy and different types of chronic pain.
Search methods
On 19th November 2013, we searched The Cochrane Neuromuscular Group Specialized Register, CENTRAL, DARE, HTA, NHSEED, MEDLINE, and EMBASE. We searched ClinicalTrials.gov for ongoing trials in April 2013. We also searched the reference lists of identified publications for trials of duloxetine for the treatment of painful peripheral neuropathy or chronic pain.
Selection criteria
We selected all randomised or quasi‐randomised trials of any formulation of duloxetine, used for the treatment of painful peripheral neuropathy or chronic pain in adults.
Data collection and analysis
We used standard methodological procedures expected by The Cochrane Collaboration.
Main results
We identified 18 trials, which included 6407 participants. We found 12 of these studies in the literature search for this update. Eight studies included a total of 2728 participants with painful diabetic neuropathy and six studies involved 2249 participants with fibromyalgia. Three studies included participants with depression and painful physical symptoms and one included participants with central neuropathic pain. Studies were mostly at low risk of bias, although significant drop outs, imputation methods and almost every study being performed or sponsored by the drug manufacturer add to the risk of bias in some domains. Duloxetine at 60 mg daily is effective in treating painful diabetic peripheral neuropathy in the short term, with a risk ratio (RR) for ≥ 50% pain reduction at 12 weeks of 1.73 (95% CI 1.44 to 2.08). The related NNTB is 5 (95% CI 4 to 7). Duloxetine at 60 mg daily is also effective for fibromyalgia over 12 weeks (RR for ≥ 50% reduction in pain 1.57, 95% CI 1.20 to 2.06; NNTB 8, 95% CI 4 to 21) and over 28 weeks (RR 1.58, 95% CI 1.10 to 2.27) as well as for painful physical symptoms in depression (RR 1.37, 95% CI 1.19 to 1.59; NNTB 8, 95% CI 5 to 14). There was no effect on central neuropathic pain in a single, small, high quality trial. In all conditions, adverse events were common in both treatment and placebo arms but more common in the treatment arm, with a dose‐dependent effect. Most adverse effects were minor, but 12.6% of participants stopped the drug due to adverse effects. Serious adverse events were rare.
Authors' conclusions
There is adequate amounts of moderate quality evidence from eight studies performed by the manufacturers of duloxetine that doses of 60 mg and 120 mg daily are efficacious for treating pain in diabetic peripheral neuropathy but lower daily doses are not. Further trials are not required. In fibromyalgia, there is lower quality evidence that duloxetine is effective at similar doses to those used in diabetic peripheral neuropathy and with a similar magnitude of effect. The effect in fibromyalgia may be achieved through a greater improvement in mental symptoms than in somatic physical pain. There is low to moderate quality evidence that pain relief is also achieved in pain associated with depressive symptoms, but the NNTB of 8 in fibromyalgia and depression is not an indication of substantial efficacy. More trials (preferably independent investigator led studies) in these indications are required to reach an optimal information size to make convincing determinations of efficacy.
Minor side effects are common and more common with duloxetine 60 mg and particularly with 120 mg daily, than 20 mg daily, but serious side effects are rare.
Improved direct comparisons of duloxetine with other antidepressants and with other drugs, such as pregabalin, that have already been shown to be efficacious in neuropathic pain would be appropriate. Unbiased economic comparisons would further help decision making, but no high quality study includes economic data.
The reduction of 4-nitrophenol to 4-aminophenol by borohydride is one of the foremost model catalytic reactions because it allows for a straightforward assessment of catalysts using the kinetic ...parameters extracted from the real-time spectroscopic monitoring of an aqueous solution. Crucial to its standing as a model reaction is a comprehensive mechanistic framework able to explain the entire time evolution of the reaction. While much of this framework is in place, there is still much debate over the cause of the induction period, an initial time interval where no reaction seemingly occurs. Here, we report on the simultaneous monitoring of the spectroscopic signal and the dissolved oxygen content within the aqueous solution. It reveals that the induction period is the time interval required for the level of dissolved oxygen to fall below a critical value that is dependent upon whether Au, Ag, or Pd nanoparticles are used as the catalyst. With this understanding, we are able to exert complete control over the induction period, being able to eliminate it, extend it indefinitely, or even induce multiple induction periods over the course of a single reaction. Moreover, we have determined that the reaction product, 4-aminophenol, in the presence of the same catalyst reacts with dissolved oxygen to form 4-nitrophenolate. The implication of these results is that the induction period relates, not to some activation of the catalyst, but to a time interval where the reaction product is being rapidly transformed back into a reactant by a side reaction.
Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (Hdc), the key enzyme for ...the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. Hdc knockout mice exhibited potentiated tic-like stereotypies, recapitulating core phenomenology of TS; these were mitigated by the dopamine (DA) D2 antagonist haloperidol, a proven pharmacotherapy, and by HA infusion into the brain. Prepulse inhibition was impaired in both mice and humans carrying Hdc mutations. HA infusion reduced striatal DA levels; in Hdc knockout mice, striatal DA was increased and the DA-regulated immediate early gene Fos was upregulated. DA D2/D3 receptor binding was altered both in mice and in humans carrying the Hdc mutation. These data confirm histidine decarboxylase deficiency as a rare cause of TS and identify HA-DA interactions in the basal ganglia as an important locus of pathology.
Aims
To determine clinical outcomes and explore prognostic factors related to ulcer healing in people with a clinically infected diabetic foot ulcer.
Methods
This multicentre, prospective, ...observational study reviewed participants’ data at 12 months after culture of a diabetic foot ulcer requiring antibiotic therapy. From participants’ notes, we obtained information on the incidence of wound healing, ulcer recurrence, lower extremity amputation, lower extremity revascularization and death. We estimated the cumulative incidence of healing at 6 and 12 months, adjusted for lower extremity amputation and death using a competing risk analysis, and explored the relationship between baseline factors and healing incidence.
Results
In the first year after culture of the index ulcer, 45/299 participants (15.1%) had died. The ulcer had healed in 136 participants (45.5%), but recurred in 13 (9.6%). An ipsilateral lower extremity amputation was recorded in 52 (17.4%) and revascularization surgery in 18 participants (6.0%). Participants with an ulcer present for ~2 months or more had a lower incidence of healing (hazard ratio 0.55, 95% CI 0.39 to 0.77), as did those with a PEDIS (perfusion, extent, depth, infection, sensation) perfusion grade of ≥2 (hazard ratio 0.37, 95% CI 0.25 to 0.55). Participants with a single ulcer on their index foot had a higher incidence of healing than those with multiple ulcers (hazard ratio 1.90, 95% CI 1.18 to 3.06).
Conclusions
Clinical outcomes at 12 months for people with an infected diabetic foot ulcer are generally poor. Our data confirm the adverse prognostic effect of limb ischaemia, longer ulcer duration and the presence of multiple ulcers.
What's new?
This is the first prospective study to estimate the incidence of healing and prognostic factors associated with healing in people with a clinically infected diabetic foot ulcer, and specifically in the presence of competing risks of amputation and death.
Outcomes for people with a clinically infected diabetic foot ulcer are poorer than previously thought; in the first year after presentation with an infected ulcer, 15.1% of our participants had died and 17.4% underwent at least partial lower extremity amputation.
Healing incidence within 1 year was 44.5% (95% CI 38.9 to 50.1). Three key factors served as the best independent predictors of healing: PEDIS (perfusion, extent, depth, infection, sensation) perfusion grade; the absence of multiple foot ulcers; and shorter ulcer duration.
The defining feature of a classical black hole is being a perfect absorber. Any evidence showing otherwise would indicate a departure from the standard black-hole picture. Energy and angular momentum ...absorption by the horizon of a black hole is responsible for tidal heating in a binary. This effect is particularly important in the latest stages of an extreme mass ratio inspiral around a spinning supermassive object, one of the main targets of the future LISA mission. We study how this effect can be used to probe the nature of supermassive objects in a model independent way. We compute the orbital dephasing and the gravitational-wave signal emitted by a point particle in circular, equatorial motion around a spinning supermassive object to the leading order in the mass ratio. Absence of absorption by the central object can affect the gravitational-wave signal dramatically, especially at high spin. This effect will make it possible to put an unparalleled upper bound on the reflectivity of exotic compact objects, at the level of O(0.01)%. This stringent bound would exclude the possibility of observing echoes in the ringdown of a supermassive binary merger.
The untranslated regions of mRNAs can determine gene expression by influencing mRNA stability and translational efficiency. Recent reports show that gene expression can be regulated by the ...differential use of alternative untranslated regions. Tissue-specific expression of transcripts that have different untranslated regions (UTRs) can control protein expression enabling developmental, physiological and pathological regulation. Several examples of alternative UTRs have been characterized, including those found in
AXIN2,
FGF1 and
BRCA1. Results from bioinformatics studies indicate that this mechanism is more common than previously appreciated.
Autism is a complex spectrum of disorders characterized by core behavioral deficits in social interaction, communication, repetitive stereotyped behaviors and restricted interests. Autism frequently ...presents with additional cognitive symptoms, including attentional deficits and intellectual disability. Preclinical models are important tools for studying the behavioral domains and biological underpinnings of autism, and potential treatment targets. The inbred BTBR T+tf/J (BTBR) mouse strain has been used as an animal model of core behavioral deficits in autism. BTBR mice exhibit repetitive behaviors and deficits in sociability and communication, but other aspects of their cognitive phenotype, including attentional performance, are not well characterized. We examined the attentional abilities of BTBR mice in the 5-choice serial reaction time task (5-CSRTT) using an automated touchscreen testing apparatus. The 5-CSRTT is an analogue of the human continuous performance task of attention, and so both the task and apparatus have translational relevance to human touchscreen cognitive testing. We also measured basal extracellular levels of a panel of neurotransmitters within the medial prefrontal cortex, a brain region critically important for performing the 5-CSRTT. We found that BTBR mice have increased impulsivity, defined as an inability to withhold responding, and decreased motivation, as compared to C57Bl/6J mice. Both of these features characterize attentional deficit disorders in humans. BTBR mice also display decreased accuracy in detecting short stimuli, lower basal levels of extracellular acetylcholine and higher levels of kynurenic acid within the prefrontal cortex. Intact cholinergic transmission in prefrontal cortex is required for accurate performance of the 5-CSRTT, consequently this cholinergic deficit may underlie less accurate performance in BTBR mice. Based on our findings that BTBR mice have attentional impairments and alterations in a key neural substrate of attention, we propose that they may be valuable for studying mechanisms for treatment of cognitive dysfunction in individuals with attention deficits and autism.
The importance of microglia in immune homeostasis within the brain is undisputed. Their role in a diversity of neurological and psychiatric diseases as well as CNS injury is the subject of much ...investigation. Cyclic adenosine monophosphate (AMP) is a critical regulator of microglia homeostasis; as the predominant negative modulator of cyclic AMP signaling within microglia, phosphodiesterase 4 (PDE4) represents a promising target for modulating immune function. PDE4 expression is regulated by inflammation, and in turn, PDE4 inhibition can alter microglia reactivity. As the prototypic PDE4 inhibitor, rolipram, was tested clinically in the 1980s, drug discovery and clinical development of PDE4 inhibitors have been severely hampered by tolerability issues involving nausea and emesis. The two PDE4 inhibitors approved for peripheral inflammatory disorders (roflumilast and apremilast) lack brain penetration and are dose‐limited by side effects making them unsuitable for modulating microglial function. Subtype selective inhibitors targeting PDE4B are of high interest given the critical role PDE4B plays in immune function versus the association of PDE4D with nausea and emesis. The challenges and requirements for successful development of a novel brain‐penetrant PDE4B inhibitor are discussed in the context of early clinical development strategies. Furthermore, the challenges of monitoring the state of microglia in vivo are highlighted, including a description of the currently available tools and their limitations. Continued drug discovery efforts to identify safe and well‐tolerated, brain‐penetrant PDE4 inhibitors are a reflection of the confidence in the rationale for modulation of this target to produce meaningful therapeutic benefit in a wide range of neurological conditions and injury. GLIA 2016;64:1698–1709
Main Points
Cyclic AMP is a critical regulator of microglial cell homeostasis, its hydrolysis by PDE4B is one of the triggers for neuroinflammation.
PDE4B is a promising drug target for modulating microglia reactivity, though efforts remain ongoing to identify safe and well‐tolerated, brain‐penetrant PDE4 inhibitors for clinical use.
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