Opioids are the most effective drugs for the treatment of severe pain, but they also cause addiction and overdose deaths, which have led to a worldwide opioid crisis. Therefore, the development of ...safer opioids is urgently needed. In this article, we provide a critical overview of emerging opioid-based strategies aimed at effective pain relief and improved side effect profiles. These approaches comprise biased agonism, the targeting of (i) opioid receptors in peripheral inflamed tissue (by reducing agonist access to the brain, the use of nanocarriers, or low pH-sensitive agonists); (ii) heteromers or multiple receptors (by monovalent, bivalent, and multifunctional ligands); (iii) receptor splice variants; and (iv) endogenous opioid peptides (by preventing their degradation or enhancing their production by gene transfer). Substantial advancements are underscored by pharmaceutical development of new opioids such as peripheral κ-receptor agonists, and by treatments augmenting the action of endogenous opioids, which have entered clinical trials. Additionally, there are several promising novel opioids comprehensively examined in preclinical studies, but also strategies such as biased agonism, which might require careful rethinking.
During the inflammation which occurs following nerve damage, macrophages are recruited to the site of injury. Phenotypic diversity is a hallmark of the macrophage lineage and includes ...pro-inflammatory M1 and anti-inflammatory M2 populations. Our aim in this study was to investigate the ability of polarized M0, M1, and M2 macrophages to secrete opioid peptides and to examine their relative contribution to the modulation of neuropathic pain.
Mouse bone marrow-derived cells were cultured as unstimulated M0 macrophages or were stimulated into an M1 phenotype using lipopolysaccharide and interferon-γ or into an M2 phenotype using interleukin-4. The macrophage phenotypes were verified using flow cytometry for surface marker analysis and cytokine bead array for cytokine profile assessment. Opioid peptide levels were measured by radioimmunoassay and enzyme immunoassay. As a model of neuropathic pain, a chronic constriction injury (CCI) of the sciatic nerve was employed. Polarized M0, M1, and M2 macrophages (5 × 10
cells) were injected perineurally twice, on days 14 and 15 following CCI or sham surgery. Mechanical and heat sensitivity were measured using the von Frey and Hargreaves tests, respectively. To track the injected macrophages, we also transferred fluorescently stained polarized cells and analyzed the surface marker profile of endogenous and injected cells in the nerves ex vivo.
Compared to M0 and M1 cells, M2 macrophages contained and released higher amounts of opioid peptides, including Met-enkephalin, dynorphin A (1-17), and β-endorphin. M2 cells transferred perineurally at the nerve injury site reduced mechanical, but not heat hypersensitivity following the second injection. The analgesic effect was reversed by the perineurally applied opioid receptor antagonist naloxone methiodide. M2 cells did not affect sensitivity following sham surgery. Neither M0 nor M1 cells altered mechanical and heat sensitivity in CCI or sham-operated animals. Tracing the fluorescently labeled M0, M1, and M2 cells ex vivo showed that they remained in the nerve and preserved their phenotype.
Perineural transplantation of M2 macrophages resulted in opioid-mediated amelioration of neuropathy-induced mechanical hypersensitivity, while M1 macrophages did not exacerbate pain. Therefore, rather than focusing on macrophage-induced pain generation, promoting opioid-mediated M2 actions may be more relevant for pain control.
Millisecond pulsars (MSPs) are a growing class of gamma-ray emitters. Pulsed gamma-ray signals have been detected from more than 40 MSPs with the Fermi Large Area Telescope (LAT). The wider radio ...beams and more compact magnetospheres of MSPs enable studies of emission geometries over a broader range of phase space than non-recycled radio-loud gamma-ray pulsars. We have modeled the gamma-ray light curves of 40 LAT-detected MSPs using geometric emission models assuming a vacuum retarded-dipole magnetic field. We modeled the radio profiles using a single-altitude hollow-cone beam, with a core component when indicated by polarimetry; however, for MSPs with gamma-ray and radio light curve peaks occurring at nearly the same rotational phase, we assume that the radio emission is co-located with the gamma rays and caustic in nature. The best-fit parameters and confidence intervals are determined using a maximum likelihood technique. We divide the light curves into three model classes, with gamma-ray peaks trailing (Class I), aligned (Class II), or leading (Class III) the radio peaks. Outer gap and slot gap (two-pole caustic) models best fit roughly equal numbers of Class I and II, while Class III are exclusively fit with pair-starved polar cap models. Distinguishing between the model classes based on typical derived parameters is difficult. We explore the evolution of the magnetic inclination angle with period and spin-down power, finding possible correlations. While the presence of significant off-peak emission can often be used as a discriminator between outer gap and slot gap models, a hybrid model may be needed.
Fundamental to our understanding of erosional and transport phenomena in earth-surface dynamics and engineering is knowledge of the conditions under which sediment motion will begin when subjected to ...turbulent flow. The onset criterion currently in use emphasizes the time-averaged boundary shear stress and therefore is incapable of accounting for the fluctuating forces encountered in turbulent flows. We have validated through laboratory experiments and analytical formulation of the problem a criterion based upon the impulse imparted to a sediment grain. We demonstrate that in addition to the magnitude of the instantaneous turbulent forces applied on a sediment grain, the duration of these turbulent forces is also important in determining the sediment grain's threshold of motion, and that their product, or impulse, is better suited for specifying such conditions.
Freeze-drying is a common method for preservation of probiotics, including bifidobacteria, for further industrial applications. However, the stability of freeze-dried bifidobacteria varies depending ...on the freeze-drying method and subsequent storage conditions. The primary goals of this study were to develop an optimized freeze-drying procedure and to determine the effects of temperature, water activity, and atmosphere on survival of freeze-dried bifidobacteria. To address these goals, a commercially used bifidobacteria strain that is resilient to stress, Bifidobacterium animalis ssp. lactis Bb-12, and a characterized intestinal strain that is more sensitive to stress conditions, Bifidobacterium longum DJO10A, were used. A freeze-drying protocol was developed using trehalose as the cryoprotectant, which resulted in almost no loss of viability during freeze-drying. Resuscitation medium, temperature, and time did not significantly influence recovery rates when this cryoprotectant was used. The effects of temperature (−80 to 45°C), water activity (0.02 to 0.92), and atmosphere (air, vacuum, and nitrogen) were evaluated for the stability of the freeze-dried powders during storage. Freeze-dried B. animalis ssp. lactis Bb-12 was found to survive under all conditions tested, with optimum survival at temperatures up to 21°C, water activities up to 0.44, and all 3 atmospheres tested. The intestinal-adapted strain B. longum DJO10A was much more sensitive to the different storage conditions, but could be adequately maintained using optimum conditions. These optimum storage conditions included frozen storage, replacement of oxygen with nitrogen, and water activities between 0.11 and 0.22. These results indicated that an optimized storage environment is required to maintain viability of stress-sensitive bifidobacteria strains, whereas stress-resilient bifidobacteria strains can maintain viability over a wide range of storage conditions, which is practical in countries where controlled cold storage conditions may not be readily available.
A new criterion for the onset of entrainment of coarse sediment grains is presented here. It is hypothesized that not only the magnitude, but also the duration of energetic near bed turbulent events ...is relevant in predicting grain removal from the bed surface. It is therefore proposed that the product of force and its duration, or impulse, is a more appropriate and universal criterion for identifying conditions for particle dislodgement. This conjecture is investigated utilizing two theoretical models, representative of two modes of entrainment: saltation and rolling. In these models, instantaneous, highly fluctuating turbulent forces are simulated as short‐lived pulses of characteristic magnitude and duration, which transfer adequate fluid momentum to the particle, to trigger its entrainment. The analytical solution of the respective equations of motion is employed in deriving representations of threshold conditions in terms of the impulse characteristics. It is shown that hydrodynamic forces of sufficiently high magnitude are capable of entraining a particle only when they last long enough so that their impulse exceeds a critical value. To illustrate further the validity of the critical impulse concept, as well as extend and generalize its application to different entrainment levels of an individual grain, a novel experimental setup is utilized. This setup facilitates observations of angular displacement of a steel mobile particle in air due to electromagnetic pulses of different magnitude and duration. The experimentally obtained conditions for partial or complete entrainment support the concept of a critical impulse.
To investigate the association between maternal serum neutrophil-to-lymphocyte ratios (NLRs) and pregnancy outcomes in women with familial mediterranean fever (FMF).
FMF exists worldwide, it ...primarily affects Mediterranean countries METHODS: We retrospectively analysed data from 269 pregnant women, who underwent a routine prenatal follow-up and delivery in our hospital from 2016 to 2020. Clinical and demographic data, including age, gravida, parity, abortus, proteinuria in the first trimester, NLR, obstetrical complications, gestational age at delivery, birthweight were retrieved from the patients' medical records. Data from 67 pregnant women with FMF and 202 healthy pregnant women were compared.
Patients with FMF showed higher rates of preeclampsia and primary caesarean delivery; however, there were no differences between the groups in terms of other obstetric complications or adverse neonatal outcomes. In both the FMF and control groups, NLRs in the third trimester were significantly higher than those in the first trimester. Additionally, patients in the FMF group demonstrated higher NLRs than patients in the control group in the third trimester.
The NLRs are a haematological parameter that can be used to predict subclinical inflammation and the effects of ongoing subclinical inflammation on the pregnancy outcomes in women with FMF (Tab. 4, Ref. 39).
Opioid receptors comprise μ (MOP), δ (DOP), κ (KOP), and nociceptin/orphanin FQ (NOP) receptors. Opioids are agonists of MOP, DOP, and KOP receptors, whereas nociceptin/orphanin FQ (N/OFQ) is an ...agonist of NOP receptors. Activation of all four opioid receptors in neurons can induce analgesia in animal models, but the most clinically relevant are MOP receptor agonists (e.g., morphine, fentanyl). Opioids can also affect the function of immune cells, and their actions in relation to immunosuppression and infections have been widely discussed. Here, we analyze the expression and the role of opioid receptors in peripheral immune cells and glia in the modulation of pain. All four opioid receptors have been identified at the mRNA and protein levels in immune cells (lymphocytes, granulocytes, monocytes, macrophages) in humans, rhesus monkeys, rats or mice. Activation of leukocyte MOP, DOP, and KOP receptors was recently reported to attenuate pain after nerve injury in mice. This involved intracellular Ca
-regulated release of opioid peptides from immune cells, which subsequently activated MOP, DOP, and KOP receptors on peripheral neurons. There is no evidence of pain modulation by leukocyte NOP receptors. More good quality studies are needed to verify the presence of DOP, KOP, and NOP receptors in native glia. Although still questioned, MOP receptors might be expressed in brain or spinal cord microglia and astrocytes in humans, mice, and rats. Morphine acting at spinal cord microglia is often reported to induce hyperalgesia in rodents. However, most studies used animals without pathological pain and/or unconventional paradigms (e.g., high or ultra-low doses, pain assessment after abrupt discontinuation of chronic morphine treatment). Therefore, the opioid-induced hyperalgesia can be viewed in the context of dependence/withdrawal rather than pain management, in line with clinical reports. There is convincing evidence of analgesic effects mediated by immune cell-derived opioid peptides in animal models and in humans. Together, MOP, DOP, and KOP receptors, and opioid peptides in immune cells can ameliorate pathological pain. The relevance of NOP receptors and N/OFQ in leukocytes, and of all opioid receptors, opioid peptides and N/OFQ in native glia for pain control is yet to be clarified.
Abstract Objective To determine the role of endometrial concentrations of heavy metals (cadmium, lead, mercury and arsenic) in the aetiology of unexplained infertility. Study design Thirty-three ...women with unexplained infertility and 32 fertile women were recruited. Endometrial biopsies were collected during the putative window of implantation (cycle days 20–24). The concentrations of cadmium, lead, mercury and arsenic were measured in endometrial biopsy specimens using atomic absorption spectrometry. Results Cadmium was detected in 91% (30/33) of women with unexplained infertility, compared with 34% (11/32) of fertile women. The median endometrial cadmium concentration was 19.58 (interquartile range 1.46–30.23) μg/l in women with unexplained infertility, compared with 0.00 (interquartile range 0.00–0.40) μg/l in fertile women. Lead was detected in 15% (5/33) of women with unexplained infertility and 3% (1/32) of fertile women. Mercury and arsenic were not detected in any endometrial samples from either group. Conclusion A significant difference in endometrial cadmium concentration was found between women with unexplained infertility and fertile women. This suggests that cadmium may be a contributing factor in the aetiology of unexplained infertility.
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