Progranulin contributes to endogenous mechanisms of pain defense after nerve injury in mice

Progranulin haploinsufficiency is associated with frontotemporal dementia in humans. Deficiency of progranulin led to exaggerated inflammation and premature aging in mice. The role of progranulin in adaptations to nerve injury and neuropathic pain are still unknown. Here we found that progranulin is up-regulated after injury of the sciatic nerve in the mouse ipsilateral dorsal root ganglia and spinal cord, most prominently in the microglia surrounding injured motor neurons. Progranulin knockdown by continuous intrathecal spinal delivery of small interfering RNA after sciatic nerve injury intensified neuropathic pain-like behaviour and delayed the recovery of motor functions. Compared to wild-type mice, progranulin-deficient mice developed more intense nociceptive hypersensitivity after nerve injury. The differences escalated with aging. Knockdown of progranulin reduced the survival of dissociated primary neurons and neurite outgrowth, whereas addition of recombinant progranulin rescued primary dorsal root ganglia neurons from cell death induced by nerve growth factor withdrawal. Thus, up-regulation of progranulin after neuronal injury may reduce neuropathic pain and help motor function recovery, at least in part, by promoting survival of injured neurons and supporting regrowth. A deficiency in this mechanism may increase the risk for injury-associated chronic pain

Learning and memory with neuropathic pain: impact of old age and progranulin deficiency

Persistent neuropathic pain is a frequent consequence of peripheral nerve injuries, particularly in the elderly. Using the IntelliCage we studied if sciatic nerve injury obstructed learning and memory in young and aged mice, each in wild type and progranulin deficient mice, which develop premature signs of brain aging. Both young and aged mice developed long-term nerve injury-evoked hyperalgesia and allodynia. In both genotypes, aged mice with neuropathic pain showed high error rates in place avoidance acquisition tasks. However, once learnt, these aged mice with neuropathic pain showed a significantly stronger maintenance of the aversive memory. Nerve injury did not affect place preference behavior in neither genotype, neither in young nor aged mice. However, nerve injury in progranulin deficient mice impaired the learning of spatial sequences of awarded places, particularly in the aged mice. This task required a discrimination of clockwise and anti-clockwise sequences. The chaining failure occurred only in progranulin deficient mice after nerve injury, but not in sham operated or wildtype mice, suggesting that progranulin was particularly important for compensatory adaptations after nerve injury. In contrast, all aged mice with neuropathic pain, irrespective of the genotype, had a long maintenance of aversive memory suggesting a negative alliance and possibly mutual aggravation of chronic neuropathic pain and aversive memory at old age

Inter-strain differences of serotonergic inhibitory pain control in inbred mice

Background: Descending inhibitory pain control contributes to the endogenous defense against chronic pain and involves noradrenergic and serotonergic systems. The clinical efficacy of antidepressants suggests that serotonin may be particularly relevant for neuropathic pain conditions. Serotonergic signaling is regulated by synthesis, metabolisms, reuptake and receptors. To address the complexity, we used inbred mouse strains, C57BL/6J, 129 Sv, DBA/2J and Balb/c, which differ in brain serotonin levels. Results: Serotonin analysis after nerve injury revealed inter-strain differences in the adaptation of descending serotonergic fibers. Upregulation of spinal cord and midbrain serotonin was apparent only in 129 Sv mice and was associated with attenuated nerve injury evoked hyperalgesia and allodynia in this strain. The increase of dorsal horn serotonin was blocked by hemisectioning of descending fibers but not by rhizotomy of primary afferents indicating a midbrain source. Para-chlorophenylalanine-mediated serotonin depletion in spinal cord and midbrain intensified pain hypersensitivity in the nerve injury model. In contrast, chronic inflammation of the hindpaw did not evoke equivalent changes in serotonin levels in the spinal cord and midbrain and nociceptive thresholds dropped in a parallel manner in all strains. Conclusion: The results suggest that chronic nerve injury evoked hypernociception may be contributed by genetic differences of descending serotonergic inhibitory control

Opto-mechanical eye models, a review on human vision applications and perspectives for use in industry

The purpose of this review is to aggregate technical information on existent optomechanical eye models (OME) described in the literature, for image quality assessment in different applications. Several physical eye models have been reviewed from peer-reviewed papers and patent applications. A typical eye model includes an artificial cornea, an intraocular lens or other lens to simulate the crystalline lens, an aperture as the pupil, and a posterior retinal surface, which may be connected to a light sensor. The interior of the eye model may be filled with a fluid to better emulate physiological conditions. The main focus of this review is the materials and physical characteristics used and the dimensional aspects of the main components including lenses, apertures, chambers, imaging sensors and filling medium. Various devices are described with their applications and technical details, which are systematically tabulated highlighting their main characteristics and applications. The models presented are detailed and discussed individually, and the features of different models are compared when applicable, highlighting strengths and limitations. In the end there is a brief discussion about the potential use of artificial eye models for industrial applications.This work is supported by European Structural and Investment Funds in the FEDER component, through the Operational Competitiveness and Internationalization Programme (COMPETE 2020) [Project nº 39479; Funding Reference: POCI-01-0247-FEDER-39479]

2017 recommendations of the Brazilian Society of Rheumatology for the pharmacological treatment of rheumatoid arthritis

The objective of this document is to provide a comprehensive update of the recommendations of Brazilian Society of Rheumatology on drug treatment of rheumatoid arthritis (RA), based on a systematic literature review and on the opinion of a panel of rheumatologists. Four general principles and eleven recommendations were approved. General principles: RA treatment should (1) preferably consist of a multidisciplinary approach coordinated by a rheumatologist, (2) include counseling on lifestyle habits, strict control of comorbidities, and updates of the vaccination record, (3) be based on decisions shared by the patient and the physician after clarification about the disease and the available therapeutic options; (4) the goal is sustained clinical remission or, when this is not feasible, low disease activity. Recommendations: (1) the first line of treatment should be a csDMARD, started as soon as the diagnosis of RA is established; (2) methotrexate (MTX) is the first-choice csDMARD; (3) the combination of two or more csDMARDs, including MTX, may be used as the first line of treatment; (4) after failure of first-line therapy with MTX, the therapeutic strategies include combining MTX with another csDMARD (leflunomide), with two csDMARDs (hydroxychloroquine and sulfasalazine), or switching MTX for another csDMARD (leflunomide or sulfasalazine) alone; (5) after failure of two schemes with csDMARDs, a bDMARD may be preferably used or, alternatively a tsDMARD, preferably combined, in both cases, with a csDMARD; (6) the different bDMARDs in combination with MTX have similar efficacy, and therefore, the therapeutic choice should take into account the peculiarities of each drug in terms of safety and cost; (7) the combination of a bDMARD and MTX is preferred over the use of a bDMARD alone; (8) in case of failure of an initial treatment scheme with a bDMARD, a scheme with another bDMARD can be used; in cases of failure with a TNFi, a second bDMARD of the same class or with another mechanism of action is effective and safe; (9) tofacitinib can be used to treat RA after failure of bDMARD; (10) corticosteroids, preferably at low doses for the shortest possible time, should be considered during periods of disease activity, and the risk-benefit ratio should also be considered; (11) reducing or spacing out bDMARD doses is possible in patients in sustained remission

Dehydroepiandrosterone sulfate mediates activation of transcription factors CREB and ATF-1 via a Gα11-coupled receptor in the spermatogenic cell line GC-2

AbstractDehydroepiandrosterone sulfate (DHEAS) is a circulating steroid produced in the adrenal cortex, brain, and gonads. Whereas a series of investigations attest to neuroprotective effects of the steroid in the brain, surprisingly little is known about the physiological effects of DHEAS on cells of the reproductive system. Here we demonstrate that DHEAS acting on the spermatogenic cell line GC-2 induces a time- and concentration-dependent phosphorylation of c-Src and Erk1/2 and activates the transcription factors activating transforming factor-1 (ATF-1) and cyclic AMP-responsive element binding protein (CREB). These actions are consistent with the non-classical signaling pathway of testosterone and suggest that DHEAS is a pro-androgen that is converted into testosterone in order to exert its biological activity. The fact, however, that steroid sulfatase mRNA was not detected in the GC-2 cells and the clear demonstration of DHEAS-induced activation of Erk1/2, ATF-1 and CREB after silencing the androgen receptor by small interfering RNA (siRNA) clearly contradict this assumption and make it appear unlikely that DHEAS has to be converted in the cytosol into a different steroid in order to activate the kinases and transcription factors mentioned. Instead, it is likely that the DHEAS-induced signaling is mediated through the interaction of the steroid with a membrane-bound G-protein-coupled receptor, since silencing of Guanine nucleotide-binding protein subunit alpha-11 (Gnα11) leads to the abolition of the DHEAS-induced stimulation of Erk1/2, ATF-1, and CREB. The investigation presented here shows a hormone-like activity of DHEAS on a spermatogenic cell line. Since DHEAS is produced in male and female reproductive organs, these findings could help to define new roles for DHEAS in the physiology of reproduction

THE APPLICATION OF SPEED READING AT INTERMEDIATE LEVEL (A Case Study of Qualitative Research in One of Senior High School at Majalengka)

Muhammad Salim Pajri. 14111330143. THE APPLICATION OF SPEED READING AT INTERMEDIATE LEVEL (A Case Study of Qualitative Research in One of Senior High School at Majalengka) Reading is the important things in education, because people can get knowledge and information from reading. Without reading people cannot absorb many sciences. Here, the researcher use speed reading technique as the tool of analyzing to know the learning and teaching process at intermediate level. Moreover, the aims of this research are (1). To know the teaching and learning process of speed reading. (2). To know students’ attitude towards teaching and learning speed reading. (3). To know overcome of the difficulties of speed reading. Theoretically, is regarding to the reading area, especially in the reading comprehension by using speed reading technique. Practically, the researcher will analyze of speed reading in one of Senior High School at Majalengka which has benefit for teacher to know students’ ability in school. The research finding and discussion told about the teaching and learning process of speed reading at intermediate level. There are three activities of speed reading techniques. (1) Preparation Activity: teacher begins with greetings, deliver material and prepare students by warming up to focuss in learning process. (2) Core Activity: teacher teaches all the materials of speed reading. (3) Follow-up Activity: teacher gives exercise as the activity to know students score of speed reading test. The result of the analysis shows there are 5 students’ attitude towards teaching and learning speed reading. then, the finding shows that (1). Students’ feeling towards teaching and learning using speed reading in general: students like speed reading then also comfortable. (2). Students’ feeling towards the process of teaching and learning speed reading: they get comprehension of this technique. (3). Students’ difficulties in learning using speed reading: there are unfamiliar word on athe text. (4). Students’ feeling towards their comprehension in learning using speed reading: they get purpose in speed reading learning. (5). Students’ motivation in learning using speed reading: they can read books in fast time. It was found the overcome of difficulties of speed reading technique they are the process of the teaching speed reading and response the students’ response towards it, difficulties, disadvantages and teaching using speed reading technique and the result, usefulness, critics, and suggestions of teaching using speed reading technique. From the research that has been done, it can be concluded that there is way to apply speed reading by using steps of speed reading. From this technique will increase students’ ability in reading process. It can help students to read fast and efficient time. Keywords: Reading Comprehension, Speed Reading, Intermediate Leve

Study of J/ψ azimuthal anisotropy at forward rapidity in Pb-Pb collisions at √sNN=5.02 TeV

The second (v2) and third (v3) flow harmonic coefficients of J/ψ mesons are measured at forward rapidity (2.5 < y < 4.0) in Pb-Pb collisions at √ sNN = 5.02 TeV with the ALICE detector at the LHC. Results are obtained with the scalar product method and reported as a function of transverse momentum, pT, for various collision centralities. A positive value of J/ψ v3 is observed with 3.7σ significance. The measurements, compared to those of prompt D0 mesons and charged particles at mid-rapidity, indicate an ordering with vn(J/ψ) < vn(D0 ) < vn(h±) (n = 2, 3) at low and intermediate pT up to 6 GeV/c and a convergence with v2(J/ψ) ≈ v2(D0 ) ≈ v2(h±) at high pT above 6–8 GeV/c. In semicentral collisions (5–40% and 10–50% centrality intervals) at intermediate pT between 2 and 6 GeV/c, the ratio v3/v2 of J/ψ mesons is found to be significantly lower (4.6σ) with respect to that of charged particles. In addition, the comparison to the prompt D0 -meson ratio in the same pT interval suggests an ordering similar to that of the v2 and v3 coefficients. The J/ψ v2 coefficient is further studied using the Event Shape Engineering technique. The obtained results are found to be compatible with the expected variations of the eccentricity of the initial-state geometry.publishedVersio

Spin alignment measurements using vector mesons with ALICE detector at the LHC

We present new measurements related to spin alignment of K*0 vector mesons at mid-rapidity for Pb–Pb collisions at √sNN = 2.76 and 5.02 TeV. The spin alignment measurements are carried out with respect to production plane and 2nd order event plane. At low pT the spin density matrix element ρ00 for K*0 is found to have values slightly below 1/3, while it is consistent with 1/3, i.e. no spin alignment, at high pT. Similar values of ρ00 are observed with respect to both production plane and event plane. Within statistical and systematic uncertainties, ρ00 values are also found to be independent of √sNN. ρ00 also shows centrality dependence with maximum deviation from 1/3 for mid-central collisions with respect to both the kinematic planes. The measurements for K*0 in pp collisions at √s = 13 TeV and for K0S (a spin 0 hadron) in 20-40% central Pb–Pb collisions at √sNN = 2.76 TeV are consistent with no spin alignment.publishedVersio

Mid-Staffordshire:a case study of failed governance and leadership?

Hadronic resonances are unique tools to investigate the interplay of re-scattering and regeneration effects during the hadronization phase in heavy-ion collisions. Measurements in small collision systems provide a necessary baseline for heavy-ion data, help to tune pQCD inspired event generators and give insight into the search for the onset of collective effects. As the ϕ meson has a longer lifetime compared to other resonances, it is expected that its production would be much less affected by regeneration and re-scattering processes. We report on measurements of ϕ meson production in minimum bias pp collisions at different beam energies and as a function of charged particle multiplicity with the ALICE detector at the LHC. The results include the transverse momentum (pT) distributions of ϕ as well as the particle yield ratios. Finally, we have also studied the ϕ effective strangeness content by comparing our results to theoretical calculations