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Supplemental Digital Content is Available in the Text. Activity of gamma-aminobutyric acid-ergic neurons in the right-side central amygdala determines ectopic mechanical allodynia in the bilateral hind limbs in rats with orofacial inflammation., Widespread or ectopic sensitization is a hallmark symptom of chronic pain, characterized by aberrantly enhanced pain sensitivity in multiple body regions remote from the site of original injury or inflammation. The central mechanism underlying widespread sensitization remains unidentified. The central nucleus of the amygdala (also called the central amygdala, CeA) is well situated for this role because it receives nociceptive information from diverse body sites and modulates pain sensitivity in various body regions. In this study, we examined the role of the CeA in a novel model of ectopic sensitization of rats. Injection of formalin into the left upper lip resulted in latent bilateral sensitization in the hind paw lasting >13 days in male Wistar rats. Chemogenetic inhibition of gamma–aminobutyric acid-ergic neurons or blockade of calcitonin gene-related peptide receptors in the right CeA, but not in the left, significantly attenuated this sensitization. Furthermore, chemogenetic excitation of gamma-aminobutyric acid-ergic neurons in the right CeA induced de novo bilateral hind paw sensitization in the rats without inflammation. These results indicate that the CeA neuronal activity determines hind paw tactile sensitivity in rats with remote inflammatory pain. They also suggest that the hind paw sensitization used in a large number of preclinical studies might not be simply a sign of the pain at the site of injury but rather a representation of the augmented CeA activity resulting from inflammation/pain in any part of the body or from activities of other brain regions, which has an active role of promoting defensive/protective behaviors to avoid further bodily damage.

Background. Neuropsychological symptoms are common complications among patients with rheumatoid arthritis (RA), while it is largely unexplored how RA pathology spread to brain protected by blood-brain barrier (BBB). The sensory circumventricular organs (sCVOs) (brain regions lacking a blood–brain barrier) is the brain site that peripheral inflammatory signals, such as blood cytokines and chemokines, can directly access and modulate cell activities in the brain parenchyma. To determine whether microglia, resident immune cells in neuronal tissue, in the sCVOs can function as an interface between peripheral inflammation and brain under the autoimmune-arthritis conditions, we analyzed microglia in the sCVOs of a mouse model of collagen-induced arthritis (CIA).Methods. Microglial number and morphology were analyzed in the sCVOs of CIA and control mice (controls were administrated Freund’s adjuvant [FA] and/or saline). Immunostaining for ionized calcium-binding adaptor molecule-1 was performed at various disease phases: “pre-onset” (post-immunization day [PID] 21), ”establishment” (PID 35), and “chronic” (PID 56 and 84). Quantitative analyses on microglial number and morphology were performed, with principal component analysis used to classify microglia. Interleukin-1β (IL-1β) mRNA expression in microglia was also analyzed by multiple fluorescent in situ hybridization.Results. In the area postrema (AP), one of the sCVOs located in the medulla, microglia significantly increased in density (CIA, n = 15; FA, n = 6; saline: n = 10) with changes in morphology during the establishment and chronic phases. In other sCVOs (subfornical organs [SFO] and organum vasculosum laminae terminalis [OVLT]), microglial changes were not significant. In the AP microglia, non-subjective clustering classification of cell morphology (CIA, 1,256 cells; saline, 852 cells) showed that the proportion of microglia in a highly activated form was increased in the CIA group. Also, the density of IL-1β-positive microglia, a hallmark of functional activation, increased in the AP. These microglial changes in the AP persisted until the chronic phase.Conclusions. Our findings indicate that an increase and activation of microglia is sustained in the AP during chronic arthritis. This suggests that there is a direct physiological pathway linking peripheral arthritis to the brain through the AP.

BackgroundCentral nervous system (CNS)-mediated symptoms, such as fatigue, depression, and hyperalgesia, are common complications among patients with rheumatoid arthritis (RA). However, it remains unclear how the peripheral pathology of RA spreads to the brain. Accumulated evidence showing an association between serum cytokine levels and aberrant CNS function suggests that humoral factors participate in this mechanism. In contrast to the well-known early responses of microglia (CNS-resident immune cells) in the area postrema [AP; a brain region lacking a blood–brain barrier (BBB)] to experimental inflammation, microglial alterations in the AP during chronic inflammation like RA remain unclear. Therefore, to determine whether microglia in the AP can react to persistent autoimmune-arthritis conditions, we analyzed these cells in a mouse model of collagen-induced arthritis (CIA).MethodsMicroglial number and morphology were analyzed in the AP of CIA and control mice (administered Freund’s adjuvant or saline). Immunostaining for ionized calcium-binding adaptor molecule-1 was performed at various disease phases: “pre-onset” [post-immunization day (PID) 21], “establishment” (PID 35), and “chronic” (PID 56 and 84). Quantitative analyses of microglial number and morphology were performed, with principal component analysis used to classify microglia. Interleukin-1β (IL-1β) mRNA expression was analyzed by multiple fluorescent in situ hybridization and real-time polymerase chain reaction. Behavioral changes were assessed by sucrose preference test.ResultsMicroglia in the AP significantly increased in density and exhibited changes in morphology during the establishment and chronic phases, but not the pre-onset phase. Non-subjective clustering classification of cell morphology (CIA, 1,256 cells; saline, 852 cells) showed that the proportion of highly activated microglia increased in the CIA group during establishment and chronic phases. Moreover, the density of IL-1β-positive microglia, a hallmark of functional activation, was increased in the AP. Sucrose preferences in CIA mice negatively correlated with IL-1β expression in brain regions containing the AP.ConclusionsOur findings demonstrate that microglia in the AP can sustain their activated state during persistent autoimmune arthritis, which suggests that chronic inflammation, such as RA, may affect microglia in brain regions lacking a BBB and have various neural consequences.

Background Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovitis and bone destruction at the joints, causing pain and motor disturbance. Despite the better control of inflammation and joint deformity afforded by modern disease-modifying anti-rheumatic drugs, many patients with RA remain dissatisfied with their treatment, primarily because of sensory-emotional distress. Pre-clinical tests that can evaluate not only the symptoms of arthritis but also the associated pain as sensory-emotional experience are urgently needed. Methods Here, we introduce two types of novel methods for evaluation of voluntary behavior in a commonly used model of RA (collagen-induced arthritis; CIA) in male mice. First, spontaneous motor activity was assessed with a running wheel placed in home cages and the number of rotations was continuously recorded in a 12:12-h light environment. Second, temperature preference was assessed by measuring the time spent in either of the floor plates with augmenting (25 to 49 °C) or fixed temperature (25 °C). We also evaluated the effects of tofacitinib on CIA-associated changes in voluntary wheel running and temperature preference. Results We detected a significant decrease in voluntary wheel running, a significant shift in the distribution of movement in the dark phase, and a significant increase in the time spent in warmer environments than the room temperature in the mice with CIA. These alterations in voluntary behavior have never been described with conventional methods. We also revealed tofacitinib-resistant significant changes in the voluntary behavior and choice of temperature despite significant mitigation of the symptoms of arthritis. Conclusions We described for the first time significant alterations of the voluntary behavior of the mice with CIA during the clinical periods, indicating that the overall physical/motivational states and its circadian variation, as well as the specific preference to a certain environmental temperature, are modified in the mice with CIA, as observed in human patients. Some of these did not parallel with the conventional arthritis scores, particularly during the pharmacotherapy suggesting that mice with CIA show not only the peripheral symptoms but also the central consequences. The use of these approaches would also help clarify the biological mechanisms underlying physician-patient discordance in the assessment of RA.

Chronic pain is a major health problem, affecting 10-30% of the population in developed countries. While chronic pain is defined as "a persistent complaint of pain lasting for more than the usual period for recovery," recently accumulated lines of evidence based on human brain imaging have revealed that chronic pain is not simply a sustained state of nociception, but rather an allostatic state established through gradually progressing plastic changes in the central nervous system. To visualize the brain activity associated with spontaneously occurring pain during the shift from acute to chronic pain under anesthetic-free conditions, we used manganese-enhanced magnetic resonance imaging (MEMRI) with a 9.4-T scanner to visualize neural activity-dependent accumulation of manganese in the brains of mice with hind paw inflammation. Time-differential analysis between 2- and 6-h after formalin injection to the left hind paw revealed a significantly increased MEMRI signal in various brain areas, including the right insular cortex, right nucleus accumbens, right globus pallidus, bilateral caudate putamen, right primary/secondary somatosensory cortex, bilateral thalamus, right amygdala, bilateral substantial nigra, and left ventral tegmental area. To analyze the role of the right amygdala in these post-formalin MEMRI signals, we repeatedly inhibited right amygdala neurons during this 2-6-h period using the "designer receptors exclusively activated by designer drugs" (DREADD) technique. Pharmacological activation of inhibitory DREADDs expressed in the right amygdala significantly attenuated MEMRI signals in the bilateral infralimbic cortex, bilateral nucleus accumbens, bilateral caudate putamen, right globus pallidus, bilateral ventral tegmental area, and bilateral substantia nigra, suggesting that the inflammatory pain-associated activation of these structures depends on the activity of the right amygdala and DREADD-expressing adjacent structures. In summary, the combined use of DREADD and MEMRI is a promising approach for revealing regions associated with spontaneous pain-associated brain activities and their causal relationships.

In addition to the canonical spino-thalamo-cortical pathway, lines of recently accumulated anatomical and physiological evidence suggest that projections originating in nociception-specific neurons in lamina I of the dorsal horn or the spinal nucleus of the trigeminal nerve to the lateral parabrachial nucleus (LPB) and then to the central amygdala (CeA) play essential roles in the nociception-emotion link and its tightening in chronic pain. With recent advances in the artificial manipulation of central neuronal activity, such as those with optogenetics, it is now possible to address many unanswered questions regarding the molecular and cellular mechanisms underlying the plastic changes in this pathway and their role in the pain chronification process.

Background Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) are rare causes of pulmonary hypertension. Although diagnosis is based on pathological findings, an early diagnosis is crucial because of poor prognosis compared to other types of pulmonary hypertension. Furthermore, vasodilators may cause fatal pulmonary edema in patients with PVOD/PCH. This study aimed to identify specific characteristics for patients with PVOD/PCH to clinically diagnose PVOD/PCH. Methods Clinical data were obtained at baseline and were compared between 19 patients with PVOD/PCH and 55 patients with idiopathic/heritable pulmonary arterial hypertension. Receiver operating characteristic analyses were used to determine characteristics specific for patients with PVOD/PCH and a scoring system to diagnose PVOD/PCH was developed. Results Patients with PVOD/PCH had a smoking history and were predominantly male. Six-minute walk distance was significantly lower and oxygen desaturation was severe during the walk. Diffusion capacity of carbon monoxide was significantly low. Radiological findings included ground glass opacity on chest high-resolution computed tomography (CT) in all patients with PVOD/PCH, and thickened septal lines in 90% of the patients. Lung perfusion scintigraphy showed defect in >70% of the patients. Pulmonary edema after initiation of vasodilation therapy was frequently observed in PVOD/PCH patients. Based on these results, we identified nine important clinical characteristics and a novel scoring system was designed to clinically diagnose PVOD/PCH: male sex, smoking history, 6-minute walk distance Conclusions Our novel prediction rule for diagnosing PVOD/PCH may offer an early clinical diagnosis of these diseases.

Objective: To understand technical nursing students' meaning of interacting with family members of hospitalized children. Method: Symbolic Interactionism was used as the theoretical framework and Qualitative Content Analysis was the methodological procedure. A total of eight graduates from an institution situated in the city of Osasco, Sao Paulo state, participated in this study. Data were collected through semi-structured interviews. Results: A total of five representative themes were revealed: Dealing with difficult situations with family members; Perceiving oneself to be unprepared to interact with family members; Family members being a helpful tool; Developing strategies to obtain a good interaction with family members; and Teachers being facilitators of the interaction with family members. Final considerations: To be acquainted with this experience has led to the understanding of the need to include the theme of family care in the curriculum of the Technical Nursing Course. Additionally, the present study contributed to reflections on the importance of such knowledge for this population and to the development of future studies, as this theme has been scarcely explored in the literature.

CH3NH3SnI3 is a metal halide perovskite that shows metallic conductivity over a wide temperature range, although ab initio calculations and optical absorption indicate that its band structure is consistent with that of an intrinsic semiconductor. Hall effect measurements of as-grown crystals give a hole concentration of about 9×1017 cm−3 with rather high Hall mobility of about 200 cm2 V−1 s−1 at 250 K. Artificial hole doping enhances the electrical conductivity of the crystals without influencing mobility. These observations indicate that the electronic structure in stoichiometric CH3NH3SnI3 can be described as that of an intrinsic semiconductor with a wide valence band. This situation leads to metal-like conduction with even a trace amount of spontaneous hole doping in the as-grown crystal.

The organic–inorganic hybrid tin iodide perovskites, A2SnI4 (A = organic ammonium), consist of inorganic layers bearing electronic functionality and organic layers that act as a template for the structure and are also able to tune the band structure. These hybrids are soluble in a wide range of solvents. Charge-transport measurements performed on single crystals indicate that the conductivity is high, despite band gaps of more than 1 eV, and strongly influenced by the type of cationic species A. The high conductivity is assumed to be due to spontaneous p-type doping in the as-grown crystals. The conductivity can be further enhanced by artificial hole doping. Since these materials can be processed in solution and display electronic performance comparable to conventional inorganic semiconductors, they show promise as a new class of tunable semiconductors of future technological importance.

The purpose of this study is to reveal the determinants of the amortization period of negative goodwill in order to determine whether the choice of amortization period reflects the management’s perception of the future outlook. The analysis results suggest that the management chooses a shorter amortization period when the case resulting in negative goodwill is relief-oriented and a longer amortization period when the transaction is under common control. This indicates that the choice of amortization period for negative goodwill may reflect the management’s perception of the duration in which the business combination will incur costs or loss and that systematic amortization—which was a requirement before the Accounting Standard for Business Combinations in Japan was revised—might have offered useful information on the future outlook of the company.

Crystals of the title compound are prepared by transferring EtOH into a flask containing stoichiometric quantities of SnI2 and MeNH3I (65 °C followed by cooling to 5 °C, 10—30% yield).

Absorption coefficient measurements of strongly scattering and weakly absorbing media have been performed using time resolved transmittance of a 100 fs pulse through a 30 mm slab containing latex spheres suspended in water and absorbing ink solutions. The scattering and absorption coefficients were selected so that the optical properties of the media were similar to those of biological tissues. Measured curves of time-resolved transmittance of the pulse through the media were used to estimate the optical properties of the media. The experiment was made at two different wavelengths, 784 nm and 810 nm. Estimated absorption coefficients were in good agreement with those measured in a nonscattering case by a spectrophotometer.

Near-infrared light is promising for measuring oxygenation of living bodies. Understanding of photon migration through living bodies is necessary, because light is strongly scattered by biological tissues. Among various simulation methods, a Monte Carlo method is regarded to be accurate because it can simulate all the paths of photon migration in strongly scattering media. Picosecond time-resolved transmittance measurement has been carried out to validate the Monte Carlo simulation results. However, differences have been observed between the measured and the Monte Carlo results where the reflection at the cell interfaces was neglected. In this research, a Monte Carlo simulation with consideration of reflection at the cell interfaces is carried out. The results are compared with the results of the time-resolved measurement, and good agreement is observed.

Characteristics of suprathermal ions and neutral particles from a laser-produced tin plasma by use of a colloidal microjet target containing tin dioxide (SnO 2 ) nanoparticles were investigated. Suprathermal ion emissions were reduced by producing a low-density preplasma. Simultaneously, the maximum conversion efficiency of 1.2% at 13.5 nm with a bandwidth of 2% and a solid angle of 2p sr was observed. Neutral particles, however, were not suppressed under the optimum laser-plasma conditions.

Background Painful diabetic neuropathy (PDN) is a serious complication of diabetes mellitus that affects a large number of patients in many countries. The molecular mechanisms underlying the exaggerated nociception in PDN have not been established. Recently, duloxetine (DLX), a serotonin and noradrenaline re-uptake inhibitor, has been recommended as one of the first-line treatments of PDN in the United States Food and Drug Administration, the European Medicines Agency and the Japanese Guideline for the Pharmacologic Management of Neuropathic pain. Because selective serotonin re-uptake inhibitors show limited analgesic effects in PDN, we examined whether the potent analgesic effect of DLX contributes toward improving the pathologically aberrant noradrenaline homeostasis in diabetic models. Results In streptozotocin (STZ) (50 mg/kg, i.v.)-induced diabetic rats that exhibited robust mechanical allodynia and thermal hyperalgesia, DLX (10 mg/kg, i.p.) significantly and markedly increased the nociceptive threshold. The analgesic effect of DLX was nullified by the prior administration of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) (50 mg/kg, i.p.), which drastically eliminated dopamine-beta-hydroxylase- and norepinephrine transporterimmunopositive fibers in the lumbar spinal dorsal horn and significantly reduced the noradrenaline content in the lumbar spinal cord. The treatment with DSP-4 alone markedly lowered the nociceptive threshold in vehicle-treated non-diabetic rats; however, this pro-nociceptive effect was occluded in STZ-treated diabetic rats. Furthermore, STZ-treated rats exhibited a higher amount of dopamine-beta-hydroxylase- and norepinephrine transporterimmunopositive fibers in the dorsal horn and noradrenaline content in the spinal cord compared to vehicle-treated rats. Conclusions Impaired noradrenaline-mediated regulation of the spinal nociceptive network might underlie exaggerated nociception in PDN. DLX might exert its analgesic effect by selective enhancement of noradrenergic signals, thus counteracting this situation.