Morphine activates neuroinflammation in a manner parallel to endotoxin

Opioids create a neuroinflammatory response within the CNS, compromising opioid-induced analgesia and contributing to various unwanted actions. How this occurs is unknown but has been assumed to be via classic opioid receptors. Herein, we provide direct evidence that morphine creates neuroinflammation via the activation of an innate immune receptor and not via classic opioid receptors. We demonstrate that morphine binds to an accessory protein of Toll-like receptor 4 (TLR4), myeloid differentiation protein 2 (MD-2), thereby inducing TLR4 oligomerization and triggering proinflammation. Small-molecule inhibitors, RNA interference, and genetic knockout validate the TLR4/MD-2 complex as a feasible target for beneficially modifying morphine actions. Disrupting TLR4/MD-2 protein–protein association potentiated morphine analgesia in vivo and abolished morphine-induced proinflammation in vitro, the latter demonstrating that morphine-induced proinflammation only depends on TLR4, despite the presence of opioid receptors. These results provide an exciting, nonconventional avenue to improving the clinical efficacy of opioids.Xiaohui Wang, Lisa C. Loram, Khara Ramos, Armando J. de Jesus, Jacob Thomas, Kui Cheng, Anireddy Reddy, Andrew A. Somogyi, Mark R. Hutchinson, Linda R. Watkins and Hang Yi

Interpretation of sexual secondary characteristics (SSCs) in regulatory testing for endocrine activity in fish.

Secondary sexual characteristics (SSCs) are important features that have evolved in many fish species because of inter-individual competition for mates. SSCs are crucial not only for sexual selection, but also for other components of the reproductive process and parental care. Externally, they are especially clear in males (for instance, tubercles, fatpad, anal finnage, colouration) but are also externally present in the females (for instance, ovipositor). These characters are under hormonal control and as such there has been much interest in incorporating them as measures in fish test methods to assess the potential endocrine activity of chemicals. Here we describe the external SSCs in typical laboratory test species for endocrine testing - fathead minnow (Pimephales promelas), Japanese medaka (Oryzias latipes), zebrafish (Danio rerio) and the three-spined stickleback (Gasterosteus aculeatus L.). We also provide some examples and discuss the utility of SSC responses to the endocrine activity of chemicals in the field and the laboratory. This paper is not aimed to provide a comprehensive review of SSCs in fish but presents a view on the assessment of SSCs in regulatory testing. Due to the current regulatory importance of establishing an endocrine mode-of-action for chemicals, we also consider other, non-endocrine factors that may lead to SSC responses in fish. We conclude with recommendations for how the assessment of SSCs in fish could be usefully incorporated into the endocrine hazard and risk assessment of chemicals

Impact of previous hepatitis B infection on the clinical outcomes from chronic hepatitis C? A population-level analysis

Chronic coinfection with hepatitis C virus (HCV) and hepatitis B virus (HBV) is associated with adverse liver outcomes. The clinical impact of previous HBV infection on liver disease in HCV infection is unknown. We aimed at determining any association of previous HBV infection with liver outcomes using antibodies to the hepatitis B core antigen (HBcAb) positivity as a marker of exposure. The Scottish Hepatitis C Clinical Database containing data for all patients attending HCV clinics in participating health boards was linked to the HBV diagnostic registry and mortality data from Information Services Division, Scotland. Survival analyses with competing risks were constructed for time from the first appointment to decompensated cirrhosis, hepatocellular carcinoma (HCC) and liver‐related mortality. Records of 8513 chronic HCV patients were included in the analyses (87 HBcAb positive and HBV surface antigen [HBsAg] positive, 1577 HBcAb positive and HBsAg negative, and 6849 HBcAb negative). Multivariate cause‐specific proportional hazards models showed previous HBV infection (HBcAb positive and HBsAg negative) significantly increased the risks of decompensated cirrhosis (hazard ratio [HR]: 1.29, 95% CI: 1.01‐1.65) and HCC (HR: 1.64, 95% CI: 1.09‐2.49), but not liver‐related death (HR: 1.02, 95% CI: 0.80‐1.30). This is the largest study to date showing an association between previous HBV infection and certain adverse liver outcomes in HCV infection. Our analyses add significantly to evidence which suggests that HBV infection adversely affects liver health despite apparent clearance. This has important implications for HBV vaccination policy and indications for prioritization of HCV therapy

How to make large, void free dust clusters in dusty plasma under microgravity

Collections of micrometer sized solid particles immersed in plamsa are used to mimic many systems from solid state and fluid physics, due to their strong electrostatic interaction, their large inertia, and the fact that they are large enough to be visualized with ordinary optics. On Earth, gravity restricts the so called dusty plasma systems to thin, two-dimensional layers, unless special experimental geometries are used, involving heated or cooled electrons, and/or the use of dielectric materials.In micro-gravity experiments, the formation of a dust-free void breaks the isotropy of three-dimensional dusty plasma systems. In order to do real three-dimensional experiments, this void has somehow to be closed. In this paper, we use a fully self-consistent fluid model to study the closure of a void in a micro-gravity experiment, by lowering the driving potential. The analysis goes beyond the simple description of the virtual void, which describes the formation of a void without taking the dust into account. We show that self-organization plays an important role in void formation and void closure, which also allows a reversed scheme, where a discharge is run at low driving potentials and small batches of dust are added. No hysteresis is found this way. Finally, we compare our results to recent experiments and find good agreement,but only when we do not take charge-exchange collisions into account

Projections of the current and future disease burden of hepatitis C virus infection in Malaysia

The prevalence of hepatitis C virus (HCV) infection in Malaysia has been estimated at 2.5% of the adult population. Our objective, satisfying one of the directives of the WHO Framework for Global Action on Viral Hepatitis, was to forecast the HCV disease burden in Malaysia using modelling methods.An age-structured multi-state Markov model was developed to simulate the natural history of HCV infection. We tested three historical incidence scenarios that would give rise to the estimated prevalence in 2009, and calculated the incidence of cirrhosis, end-stage liver disease, and death, and disability-adjusted life-years (DALYs) under each scenario, to the year 2039. In the baseline scenario, current antiviral treatment levels were extended from 2014 to the end of the simulation period. To estimate the disease burden averted under current sustained virological response rates and treatment levels, the baseline scenario was compared to a counterfactual scenario in which no past or future treatment is assumed.In the baseline scenario, the projected disease burden for the year 2039 is 94,900 DALYs/year (95% credible interval (CrI): 77,100 to 124,500), with 2,002 (95% CrI: 1340 to 3040) and 540 (95% CrI: 251 to 1,030) individuals predicted to develop decompensated cirrhosis and hepatocellular carcinoma, respectively, in that year. Although current treatment practice is estimated to avert a cumulative total of 2,200 deaths from DC or HCC, a cumulative total of 63,900 HCV-related deaths is projected by 2039.The HCV-related disease burden is already high and is forecast to rise steeply over the coming decades under current levels of antiviral treatment. Increased governmental resources to improve HCV screening and treatment rates and to reduce transmission are essential to address the high projected HCV disease burden in Malaysia

Assessment of arsenic status and distribution in Usangu agro-ecosystem-Tanzania.

The research article published by Elsevier Ltd., 2021This study was conducted to assess arsenic (As) status and distribution in Usangu agroecosystem-Tanzania, including three land use. About 198 soil samples were collected in ten irrigation schemes in three land uses. Total and bioavailable As were determined by acid digestion (Aqua regia (AQ)) and Mehlich 3 method (M3) to estimate status, distribution and bioavailability. Arsenic concentration were variable among land use and irrigation schemes where total arsenic ranged 567.74-2909.84 μg/kg and bioavailable As ranged 26.17-712.37 μg/kg. About 12-16% of total arsenic were available for plant uptake. Approximately 86.53% of studied agricultural soils had total As concentration above Tanzania maximum allowable limit. Bioavailable As were lower compared to total As and were within the acceptable threshold. Total arsenic concentration were variable among schemes and higher values were observed in schemes which are highly intensified and mechanized. Thus, this study provides essential site specific preliminary baseline information for As status and distribution in agricultural soils to initiate monitoring and management strategies for increased land productivity and environmental safety

Convolution of multifractals and the local magnetization in a random field Ising chain

The local magnetization in the one-dimensional random-field Ising model is essentially the sum of two effective fields with multifractal probability measure. The probability measure of the local magnetization is thus the convolution of two multifractals. In this paper we prove relations between the multifractal properties of two measures and the multifractal properties of their convolution. The pointwise dimension at the boundary of the support of the convolution is the sum of the pointwise dimensions at the boundary of the support of the convoluted measures and the generalized box dimensions of the convolution are bounded from above by the sum of the generalized box dimensions of the convoluted measures. The generalized box dimensions of the convolution of Cantor sets with weights can be calculated analytically for certain parameter ranges and illustrate effects we also encounter in the case of the measure of the local magnetization. Returning to the study of this measure we apply the general inequalities and present numerical approximations of the D_q-spectrum. For the first time we are able to obtain results on multifractal properties of a physical quantity in the one-dimensional random-field Ising model which in principle could be measured experimentally. The numerically generated probability densities for the local magnetization show impressively the gradual transition from a monomodal to a bimodal distribution for growing random field strength h.Comment: An error in figure 1 was corrected, small additions were made to the introduction and the conclusions, some typos were corrected, 24 pages, LaTeX2e, 9 figure

Orbits and phase transitions in the multifractal spectrum

We consider the one dimensional classical Ising model in a symmetric dichotomous random field. The problem is reduced to a random iterated function system for an effective field. The D_q-spectrum of the invariant measure of this effective field exhibits a sharp drop of all D_q with q < 0 at some critical strength of the random field. We introduce the concept of orbits which naturally group the points of the support of the invariant measure. We then show that the pointwise dimension at all points of an orbit has the same value and calculate it for a class of periodic orbits and their so-called offshoots as well as for generic orbits in the non-overlapping case. The sharp drop in the D_q-spectrum is analytically explained by a drastic change of the scaling properties of the measure near the points of a certain periodic orbit at a critical strength of the random field which is explicitly given. A similar drastic change near the points of a special family of periodic orbits explains a second, hitherto unnoticed transition in the D_q-spectrum. As it turns out, a decisive role in this mechanism is played by a specific offshoot. We furthermore give rigorous upper and/or lower bounds on all D_q in a wide parameter range. In most cases the numerically obtained D_q coincide with either the upper or the lower bound. The results in this paper are relevant for the understanding of random iterated function systems in the case of moderate overlap in which periodic orbits with weak singularity can play a decisive role.Comment: The article has been completely rewritten; the title has changed; a section about the typical pointwise dimension as well as several references and remarks about more general systems have been added; to appear in J. Phys. A; 25 pages, 11 figures, LaTeX2