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Aging is a risk factor for the development of osteoarthritis (OA), a progressive joint disease leading to cartilage damage, pain, and loss of function. In a mouse model of OA, senolytic drugs to selectively clear senescent cells (SnCs) that accumulate with injury or aging yielded a chondroprotective effect; however, this therapeutic benefit was limited in aged mice. Due to inconsistency between cartilage destruction and pain-associated symptoms, we studied the therapeutic effect of senolytics on joint pain in spontaneous OA. We orally treated 21- and 22-month old mice with an ABT263 and Dasatinib and Quercetin (D+Q) drug combination. Selective elimination of the SnCs that accumulated in the articular cartilage and synovium by these two drugs did not alter cartilage degeneration and abnormal bone changes during spontaneous OA progression. Treatment reduced thermal and mechanical hyperalgesia associated with OA and peripheral sensitization through decreased expression of axon guidance proteins (nerve growth factor NGF/TrkA) and nociceptive neuron (calcitonin gene-related peptide, CGRP) projection to the synovium, subchondral bone marrow, and dorsal root ganglion, and knee joint angiogenesis. Selective removal of the SnCs fromiin vitro/icultures of synovial cells from human OA patients also decreased expression of senescent markers, axonal growth-promoting factors, such as NGF, and angiogenesis markers. We suggest that systemic administration of ABT263 and D+Q is an exciting therapeutic approach to age-related OA pain.

Purpose No study has been conducted to compare the clinicians' prediction of survival (CPS) with Palliative Prognostic Scores (PaP) across countries. We aimed to compare the performance of the CPS in PaP (PaP-CPS), the PaP without the CPS, and the PaP total scores in patients with advanced cancer in three East Asian countries. Methods We compared the discriminative accuracy of the three predictive models (the PaP-CPS [the score of the categorical CPS of PaP], the PaP without the CPS [sum of the scores of only the objective variables of PaP], and the PaP total score) in patients admitted to palliative care units (PCUs) in Japan, Korea, and Taiwan. We calculated the area under the receiver operating characteristic curve (AUROC) for 30-day survival to compare the discriminative accuracy of these three models. Results We analyzed 2,072 patients from three countries. The AUROC for the PaP total scores was 0.84 in patients in Japan, 0.76 in Korea, and 0.79 in Taiwan. The AUROC of the PaP-CPS was 0.82 in patients in Japan, 0.75 in Korea, and 0.78 in Taiwan. The AUROC of the PaP without the CPS was 0.75 in patients in Japan, 0.66 in Korea, and 0.67 in Taiwan. Conclusion The PaP total scores and the PaP-CPS consistently showed similar discriminative accuracy in predicting 30-day survival in patients admitted to PCUs in Japan, Korea, and Taiwan. It may be sufficient for experienced clinicians to use the CPS alone for estimating the short-term survival (less than one month) of patients with far-advanced cancer. The PaP may help to improve prognostic confidence and further reduce subjective variations.

The function of peripheral nociceptors is frequently tuned by the action of G protein-coupled receptors (GPRs) that are expressed in them, which contribute to pain alteration. Expanding new information on such GPRs and predicting their potential outcomes can help to construct new analgesic strategies based on their modulations. In this context, we attempted to present a new GPR not yet acknowledged for its pain association. Gpr83 exhibits relatively high expressions in the peripheral nervous system compared to other tissues when we mined and reconstructed Gene Expression Omnibus (GEO) metadata, which we confirmed using immunohistochemistry on murine dorsal root ganglia (DRG). When Gpr83 expression was silenced in DRG, neuronal and behavioral nociception were all downregulated. Pathologic pain in hind paw inflammation and chemotherapy-induced peripheral neuropathy were also alleviated by this Gpr83 knockdown. Dependent on exposure time, the application of a known endogenous Gpr83 ligand PEN showed differential effects on nociceptor responses in vitro. Localized PEN administration mitigated pain in vivo, probably following Gq/11-involved GPR downregulation caused by the relatively constant exposure. Collectively, this study suggests that Gpr83 action contributes to the tuning of peripheral pain sensitivity and thus indicates that Gpr83 can be among the potential GPR targets for pain modulation.

Objective Accurate prognostication is important for patients and their families to prepare for the end of life. Objective Prognostic Score (OPS) is an easy-to-use tool that does not require the clinicians’ prediction of survival (CPS), whereas Palliative Prognostic Score (PaP) needs CPS. Thus, inexperienced clinicians may hesitate to use PaP. We aimed to evaluate the accuracy of OPS compared with PaP in inpatients in palliative care units (PCUs) in three East Asian countries. Method This study was a secondary analysis of a cross-cultural, multicenter cohort study. We enrolled inpatients with far-advanced cancer in PCUs in Japan, Korea, and Taiwan from 2017 to 2018. We calculated the area under the receiver operating characteristics (AUROC) curve to compare the accuracy of OPS and PaP. Results A total of 1,628 inpatients in 33 PCUs in Japan and Korea were analyzed. OPS and PaP were calculated in 71.7% of the Japanese patients and 80.0% of the Korean patients. In Taiwan, PaP was calculated for 81.6% of the patients. The AUROC for 3-week survival was 0.74 for OPS in Japan, 0.68 for OPS in Korea, 0.80 for PaP in Japan, and 0.73 for PaP in Korea. The AUROC for 30-day survival was 0.70 for OPS in Japan, 0.71 for OPS in Korea, 0.79 for PaP in Japan, and 0.74 for PaP in Korea. Significance of results Both OPS and PaP showed good performance in Japan and Korea. Compared with PaP, OPS could be more useful for inexperienced physicians who hesitate to estimate CPS.

Background: Some factors associated with spiritual well-being in dying patients have previously been reported. However, there has been no cross-cultural study comparing factors related to spiritual well-being. The current investigation may shed light on this under-investigated area through a comparison of diverse factors. Aim: We aimed to (1) examine factors associated with spiritual well-being in the last days and (2) compare those factors across three East Asian countries. Design: This is an international multicenter prospective cohort study. Setting/participants: Newly admitted inpatients with far advanced cancer in palliative care units in Japan, Korea and Taiwan were enrolled. Each patient was classified into one of two groups based on spiritual well-being score in the last days of life. Univariate and multivariate analyses were performed to identify the factors related to better spiritual well-being score in each country. Results: A total of 1761 patients treated at 37 palliative care units from January 2017 to September 2018 were analyzed. Seven variables were significant in Japan, three in Korea, and five in Taiwan. “Good death scale [acceptance],” “fatigue” and “expressed wish for hastened death” were unique in Japan. “Visit from a pastoral care worker within 48 h of death” was unique in Korea. “Patient’s preferences for place of death,” “dyspnea” and “continuous deep sedation” were unique in Taiwan. Conclusions: This study found novel factors related to spiritual well-being in the last days of life, several of which differed according to country. Recognition of factors associated with spiritual well-being can improve the quality of palliative care.

Closed rupture of the flexor carpi radialis tendon in non-rheumatoid patients is uncommon. We report a case of a 53-year-old woman who developed painful pseudotendon after a complete rupture of the flexor carpi radialis tendon due to osteoarthritis of the scaphotrapezial trapezoidal joint.

Background: Symptoms are not typically part of established various prognostic factors and scoring systems but are among the most frequently assessed issues in patient care. Objectives: To evaluate ...

Purpose:No study has been conducted to compare the clinicians’ prediction of survival (CPS) with Palliative Prognostic Scores (PaP) across countries. We aimed to compare the performance of the CPS in PaP (PaP-CPS), the PaP without the CPS, and the PaP total scores in patients with advanced cancer in three East Asian countries.Methods:We compared the discriminative accuracy of the three predictive models (the PaP-CPS [the score of the categorical CPS of PaP], the PaP without the CPS [sum of the scores of only the objective variables of PaP], and the PaP total score) in patients in Japan, Korea, and Taiwan. We calculated the area under the receiver operating characteristic curve (AUROC) for 30-day survival to compare the discriminative accuracy of these three models.Results:We analyzed 2,072 patients from three countries. The AUROC for the PaP total scores was 0.84 in patients in Japan, 0.76 in Korea, and 0.79 in Taiwan. The AUROC of the PaP-CPS was 0.82 in patients in Japan, 0.75 in Korea, and 0.78 in Taiwan. The AUROC of the PaP without the CPS was 0.75 in patients in Japan, 0.66 in Korea, and 0.67 in Taiwan.Conclusion:The PaP total scores and the PaP-CPS consistently showed similar discriminative accuracy in predicting 30-day survival in patients in Japan, Korea, and Taiwan. It may be sufficient for experienced clinicians to use the CPS alone for estimating the short-term survival (less than one month) of patients with far-advanced cancer. The PaP may help to improve prognostic confidence and further reduce subjective variations.

Paradoxically, some TRPV1 agonists are, at the organismal level, both nonpungent and clinically useful as topical analgesics. Here, we describe the scaled-up synthesis and characterization in mouse models of a novel, nonpungent vanilloid. Potent analgesic activity was observed in models of neuropathic pain, and the compound blocked capsaicin induced allodynia, showing dermal accumulation with little transdermal absorption. Finally, it displayed much weaker systemic toxicity compared to capsaicin and was negative in assays of genotoxicity.

Objective:To evaluate the predicting value of99mTc-hydroxydiphosphonate (HDP) pinhole bone scan in development of osteonecrosis of femoral head (ONFH) in patients with femoral neck fracture after cannulated screw fixation.Methods:Pinhole bone scan of patients with metallically fixed femoral neck fracture from 2001 to 2015 were retrospectively reviewed. Initial pinhole bone scan was obtained within 2–3 weeks after surgery. Findings of initial pinhole bone scan were divided in to 4 groups. Group CU included cold defect in affected femoral head, group HU with no cold defect. Group PP with increased uptake along the inserted screws and group PN with no increased uptake along the inserted screws. More than 6 months of follow-up with pinhole bone scan and clinico-radiological evidence for ONFH was reviewed.Results:72 patients (mean age 54.01 years, male 22, female 50) were included. 19 patients were in group CU, 53 in group HU. 60 patients were in group PP, 12 in group PN. During the follow-up, 13 patients were diagnosed as ONFH. 9 (47.36%) patients in group CU developed ONFH and 4 (7.5%) in group HU. 4 (6.66%) patients in group PP developed ONFH and 9 (75%) in group PN.Conclusions:To predict ONFH of femoral head followed by neck fracture, many imaging techniques with variable results were known. In this study, cold defect in early postoperative pinhole bone scans could predict ONFH, and loss of increased uptake along screw inserted site could be a strong indicative sign of ONFH. Further evaluation with a larger population is necessary.

Purpose Isolated greater trochanteric (GT) fractures are often identified using plain radiography of patients with post-traumatic hip pain. In many cases, the fracture extends to form an occult intertrochanteric fracture. We conducted a study to determine the frequency of occult intertrochanteric fractures in patients diagnosed with isolated GT fractures using plain radiographs. Materials and methods Among 3,017 individuals who visited our emergency department with a trauma-induced pertrochanteric femur fracture between July 2004 and March 2018, 100 patients diagnosed with isolated GT fractures using plain radiographs were retrospectively analyzed. Patients were divided into two groups, those with: i) isolated GT fractures (group A) and ii) occult intertrochanteric fractures (group B). In addition, plain radiographs, magnetic resonance imaging results, and treatment methods were further analyzed in each group. If surgery treatment was needed, it was performed by one surgeon, and in all cases, a 2-hole dynamic hip screw was used. Results Among the 100 cases of isolated GT fractures diagnosed using plain radiograph, additional examinations revealed that 10 (10.0%) were suffering from isolated GT fractures alone, while the remaining 90 (90.0%) were further diagnosed with occult intertrochanteric fracture. Gender, age, mechanism of injury, and bone mineral density did not correlate with fracture type. Conclusion In our analysis, 90% of injuries initially diagnosed as isolated GT fractures were found to extend into occult intertrochanteric fractures upon further examination with additional imaging modalities. Therefore, additional evaluation should be performed to test for the potential presence of occult intertrochanteric fractures and to establish appropriate treatment plans.

Modulation of the function of somatosensory neurons is an important analgesic strategy, requiring the proposal of novel molecular targets. Many G-protein-coupled receptors (GPRs) have been deorphanized, but the receptor locations, outcomes due to their activations, and their signal transductions remain to be elucidated, regarding the somatosensory nociceptor function. Here we report that GPR171, expressed in a nociceptor subpopulation, attenuated pain signals via Gi/o-coupled modulation of the activities of nociceptive ion channels when activated by its newly found ligands. Administration of its natural peptide ligand and a synthetic chemical ligand alleviated nociceptor-mediated acute pain aggravations and also relieved pathologic pain at nanomolar and micromolar ranges. This study suggests that functional alteration of the nociceptor neurons by GPR171 signaling results in pain alleviation and indicates that GPR171 is a promising molecular target for peripheral pain modulation.

Objective We evaluated the clinical manifestation and surgical results following operative treatment of cubital tunnel syndrome (CuTS) caused by anconeus epitrochlearis (AE) muscle. Methods Among 142 patients who underwent surgery for CuTS from November 2007 to October 2015, 12 were assigned to the AE group based on discovery of AE muscle; 130 patients were assigned to the other group. We analyzed retrospectively; age, sex, dominant hand, symptom duration, and weakness in hand. Severity of the disease was evaluated using the Dellon classification and postoperative symptom were evaluated using disability of arm shoulder and hand (DASH) and visual analogue scale (VAS) scores. Surgery consisted of subfascial anterior transposition following excision of AE muscle. Results AE muscle was present in 8.5% of all patients, and was more common in patients who were younger and with involvement of their dominant hand; the duration of symptom was shorter in patients with AE muscle. All patients showed postoperative improvement in symptoms according to DASH and VAS scores. Conclusion The possibility of CuTS caused by AE muscle should be considered when younger patients have rapidly aggravated and activity-related cubital tunnel symptoms with a palpable mass in the cubital tunnel area. Excision of AE muscle and anterior ulnar nerve transposition may be considered effective surgical treatment.

Inflammation is one of the main causes of pathologic pain. Knowledge of the molecular links between inflammatory signals and pain-mediating neuronal signals is essential for understanding the mechanisms behind pain exacerbation. Some inflammatory mediators directly modulate the excitability of pain-mediating neurons by contacting the receptor molecules expressed in those neurons. For decades, many discoveries have accumulated regarding intraneuronal signals from receptor activation through electrical depolarization for bradykinin, a major inflammatory mediator that is able to both excite and sensitize pain-mediating nociceptor neurons. Here, we focus on the final effectors of depolarization, the neuronal ion channels, whose functionalities are specifically affected by bradykinin stimulation. Particular G-protein coupled signaling cascades specialized for each specific depolarizer ion channels are summarized. Some of these ion channels not only serve as downstream effectors but also play critical roles in relaying specific pain modalities such as thermal or mechanical pain. Accordingly, specific pain phenotypes altered by bradykinin stimulation are also discussed. Some members of the effector ion channels are both activated and sensitized by bradykinin-induced neuronal signaling, while others only sensitized or inhibited, which are also introduced. The present overview of the effect of bradykinin on nociceptor neuronal excitability at the molecular level may contribute to better understanding of an important aspect of inflammatory pain and help future design of further research on the components involved and pain modulating strategies.

Pain is a protective mechanism that enables us to avoid potentially harmful environments. However, when pathologically persisted and aggravated under severely injured or inflamed conditions, pain often reduces the quality of life and thus is considered as a disease to eliminate. Inflammatory and/or neuropathic mechanisms may exaggerate interactions between damaged tissues and neural pathways for pain mediation. Similar mechanisms also promote the communication among cellular participants in synapses at spinal or higher levels, which may amplify nociceptive firing and subsequent signal transmission, deteriorating the pain sensation. In this pathology, important cellular players are afferent sensory neurons, peripheral immune cells, and spinal glial cells. Arising from damage of injury, overloaded interstitial and intracellular reactive oxygen species (ROS) and intracellular Ca2+ are key messengers in the development and maintenance of pathologic pain. Thus, an ROS-sensitive and Ca2+-permeable ion channel that is highly expressed in the participant cells might play a critical role in the pathogenesis. Transient receptor potential melastatin subtype 2 (TRPM2) is the unique molecule that satisfies all of the requirements: the sensitivity, permeability, and its expressing cells. Notable progress in delineating the role of TRPM2 in pain has been achieved during the past decade. In the present review, we summarize the important findings in the key cellular components that are involved in pathologic pain. This overview will help to understand TRPM2-mediated pain mechanisms and speculate therapeutic strategies by utilizing this updated information.

Oxytocin and vasopressin are neurohypophyseal hormones with sequence similarity and play a central role in bodily homeostatic regulation. Pain is currently understood to be an important phenotype that those two neurohormones strongly downregulate. Nociceptors, the first component of the ascending neural circuit for pain signals, have constantly been shown to be modulated by those peptides. The nociceptor modulation appears to be critical in pain attenuation, which has led to a gradual increase in scientific interest about their physiological processes and also drawn attention to their translational potentials. This review focused on what are recently understood and stay under investigation in the functional modulation of nociceptors by oxytocin and vasopressin. Effort to produce a nociceptor-specific view could help to construct a more systematic picture of the peripheral pain modulation by oxytocin and vasopressin.

Animals must detect aversive compounds to survive. Bitter taste neurons express heterogeneous combinations of bitter receptors that diversify their response profiles, but this remains poorly understood. Here we describe groups of taste neurons in Drosophila that detect the same bitter compounds using unique combinations of gustatory receptors (GRs). These distinct complexes also confer responsiveness to non-overlapping sets of additional compounds. While either GR32a/GR59c/GR66a or GR22e/GR32a/GR66a heteromultimers are sufficient for lobeline, berberine, and denatonium detection, only GR22e/GR32a/GR66a responds to strychnine. Thus, despite minimal sequence-similarity, Gr22e and Gr59c show considerable but incomplete functional overlap. Since the gain- or loss-of-function of Gr22e or Gr59c alters bitter taste response profiles, we conclude a taste neuron’s specific combination of Grs determines its response profile. We suspect the heterogeneity of Gr expression in Drosophila taste neurons diversifies bitter compound detection, improving animal fitness under changing environmental conditions that present a variety of aversive compounds., Taste sensilla are Drosophila sensory organs containing taste neurons, which have differential tuning for bitter compounds. Here, the authors systematically examine what combinations of gustatory receptor genes confer a specific taste response profile in different bitter taste neurons.

Primary sensory afferent neurons detect environmental and painful stimuli at their peripheral termini. A group of transient receptor potential ion channels (TRPs) are expressed in these neurons and constitute sensor molecules for the stimuli such as thermal, mechanical, and chemical insults. We examined whether a mouse sensory neuronal line, N18D3, shows the sensory TRP expressions and their functionality. In Ca2+ imaging and electrophysiology with these cells, putative TRPV4-mediated responses were observed. TRPV4-specific sensory modalities including sensitivity to a specific agonist, hypotonicity, or an elevated temperature were reproduced in N18D3 cells. Electrophysiological and pharmacological profiles conformed to those from native TRPV4 of primarily cultured neurons. The TRPV4 expression in N18D3 was also confirmed by RT-PCR and Western blot analyses. Thus, N18D3 cells may represent TRPV4-expressing sensory neurons. Further, using this cell lines, we discovered a novel synthetic TRPV4-specific agonist, MLV-0901. These results suggest that N18D3 is a reliable cell line for functional and pharmacological TRPV4 assays. The chemical information from the novel agonist will contribute to TRPV4-targeting drug design.

Objective Prognostic Score (OPS) was developed as an easy and simple prognosticating tool in South Korea. It has been validated retrospectively in a single center in South Korea.We aimed to validate the OPS prospectively for advanced cancer inpatients in South Korea using a multicenter study.This was a prospective cohort study.We enrolled 243 advanced cancer patients admitted in five palliative care units in South Korea from May 2013 till March 2015. Seven members of the Korean Palliative Medicine Research Network who are experts of palliative care led the study.Clinical variables (dyspnea/anorexia/performance status) and laboratory variables (total leukocyte counts/serum total bilirubin/serum creatinine/lactate dehydrogenase) were collected at the enrollment. Survival time was calculated as days from enrollment to death during admission.A total of 217 patients were included in the final analysis (feasibility: 89.3%). Survival time of the higher OPS group (OPS ≥3) and the lower OPS group (OPS3) was 10.0 (95% confidence interval (CI) 7.72-12.28) days and 32.0 (95% CI 25.44-38.56) days, respectively. There were significant differences between the 2 groups (p 0.001). Overall accuracy of OPS ≥3 for predicting survival less than three weeks was 71.0%.OPS was successfully validated using a prospective multicenter study in South Korea. It is a useful method to predict three-week survival of Korean inpatients with advanced cancer.

Peripheral nociceptors and their synaptic partners utilize neuropeptides for signal transmission. Such communication tunes the excitatory and inhibitory function of nociceptor-based circuits, eventually contributing to pain modulation. Corticotropin-releasing hormone (CRH) is the initiator hormone for the conventional hypothalamic-pituitary-adrenal axis, preparing our body for stress insults. Although knowledge of the expression and functional profiles of CRH and its receptors and the outcomes of their interactions has been actively accumulating for many brain regions, those for nociceptors are still under gradual investigation. Currently, based on the evidence of their expressions in nociceptors and their neighboring components, several hypotheses for possible pain modulations are emerging. Here we overview the historical attention to CRH and its receptors on the peripheral nociception and the recent increases in information regarding their roles in tuning pain signals. We also briefly contemplate the possibility that the stress-response paradigm can be locally intrapolated into intercellular communication that is driven by nociceptor neurons. Such endeavors may contribute to a more precise view of local peptidergic mechanisms of peripheral pain modulation.

Nerve growth factor (NGF)-induced neuronal regeneration has emerged as a strategy to treat neuronal degeneration-associated disorders. However, direct NGF administration is limited by the occurrence of adverse effects at high doses of NGF. Therefore, development of a therapeutic strategy to promote the NGF trophic effect is required. In view of the lack of understanding of the mechanism for potentiating the NGF effect, this study investigated molecular targets of DA-9801, a well-standardized Dioscorea rhizome extract, which has a promoting effect on NGF. An increase in intracellular calcium ion level was induced by DA-9801, and chelation of extracellular calcium ions with ethylene-bis(oxyethylenenitrilo)tetraacetic acid (EGTA) suppressed the potentiating effect of DA-9801 on NGF-induced neurite outgrowth. In addition, EGTA treatment reduced the DA-9801-induced phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2), the major mediators of neurite outgrowth. To find which calcium ion-permeable...

Objective Limited research has examined the quality of life (QOL) and its correlates among family caregivers (FCs) during the final stage of terminal cancer. The purpose of this study was to investigate the determinants of overall QOL and its subdomains among Korean FCs at the very end of life. Methods For this cross-sectional study, we enrolled 299 FCs of terminal cancer patients from seven palliative care units. To assess FCs' QOL and its predictors, we used the Caregiver Quality Of Life Index-Cancer, which contains four domains. Possible determinants of caregiver QOL were categorized into patient, caregiver, and environmental factors. A multiple regression model was used to identify factors associated with FCs' QOL. Results Variance in each Caregiver Quality Of Life Index-Cancer domain was explained by different factors. FCs of younger patient felt more burden but were more likely to adapt positively. Emotional distress of FCs was strongly associated with total QOL, burdensomeness, and disruptiveness. Positive adaptation was related to more visits for care, FCs' religiousness, more social support, and satisfactory perceived quality of care. Financial concerns were more likely in married FCs, FCs with less social support, or low incomes. Conclusion Emotional distress of FCs was the most important factor determining the overall and negative aspects of FCs' QOL, whereas various environmental factors were associated with positive coping. Appropriate support programs directed at these factors are needed to maintain and improve FCs' QOL. Copyright © 2015 John Wiley & Sons, Ltd.

Ba ckground: To date, the medical environment has been undergoing continual changes. It is therefore imperative that clinicians recognize the changing trends in the degree of patient expectations for patient-centered care. We conducted this study to examine changes in the degree of patient expectations for patient-centered care and the related socio-demographic factors in a primary care setting over a 5-year period. Me thods: We evaluated patients’ attitudes toward patient-centered care using the Patient-Practitioner Orientation Scale, which provides ‘sharing’ and ‘caring’ scores. The study included 359 and 468 patients in phase I (March–July, 2005) and II (March–July, 2010). We also examined the relationship of their changes to their socio-demographic factors. Re sults: In phase II, as compared with phase I, the ‘sharing’ score was higher (3.67 ± 0.68 vs. 3.82 ± 0.44; P < 0.001) and ‘caring’ one was lower (4.01 ± 0.57 vs. 3.67 ± 0.58; P = 0.001). Further, ‘sharing’ and ‘caring’ scores were associated with age, monthly income, education level, marital status, and the functional health status of patients. Co nclusion: These results would be of help for providing patient-centered care for patients because it makes clinicians are aware of the degree to which patients’ expect it.

Endogenous pain-inhibitory substances have rarely been found. A group of powerful pain suppressor molecules that are endogenously generated are now emerging: resolvins and related compounds including neuroprotectins and maresins. These molecules began to be unveiled in a series of inflammation studies more than a decade ago, rapidly shifting the paradigm that explains the mechanism for the inflammatory phase switch. The resolution phase was considered a passive process as proinflammatory mediators disappeared; it is now understood to be actively drawn by the actions of resolvins. Surprisingly, these substances potently affect the pain state. Although this research area is not fully matured, consistently beneficial outcomes have been observed in a variousin vivoandin vitropain models. Furthermore, multiple hypotheses on the neuronal and molecular mechanisms for alleviating pain are being tested, deriving inspiration from existing inflammation and pain studies. This paper serves as a brief summary of the proresolving roles of resolvins and related lipid mediators in inflammation and also as a review for accumulated information of their painkilling actions. This also includes potential receptor-mediated mechanisms and discusses future scientific perspectives. Further diverse approaches will help to construct a hidden axis of natural protection principles and establish proofs of concept for pain relief.

Romo1 regulates mitochondrial reactive oxygen species production and acts as an essential redox sensor in mitochondrial dynamics. Lee et al. demonstrate that Romo1 is a unique mitochondrial ion channel with viroporin-like characteristics that distinguish Romo1 from other known eukaryotic ion channels., Reactive oxygen species (ROS) modulator 1 (Romo1) is a nuclear-encoded mitochondrial inner membrane protein known to regulate mitochondrial ROS production and to act as an essential redox sensor in mitochondrial dynamics. Although its physiological roles have been studied for a decade, the biophysical mechanisms that explain these activities of Romo1 are unclear. In this study, we report that Romo1 is a unique mitochondrial ion channel that differs from currently identified eukaryotic ion channels. Romo1 is a highly conserved protein with structural features of class II viroporins, which are virus-encoded nonselective cation channels. Indeed, Romo1 forms a nonselective cation channel with its amphipathic helical transmembrane domain necessary for pore-forming activity. Notably, channel activity was specifically inhibited by Fe2+ ions, an essential transition metal ion in ROS metabolism. Using structural bioinformatics, we designed an experimental data–guided structural model of Romo1 with a rational hexameric structure. We propose that Romo1 establishes a new category of viroporin-like nonselective cation channel in eukaryotes., Graphical Abstract

The mechanosensory neurons of Drosophila larvae are demonstrably activated by diverse mechanical stimuli, but the mechanisms underlying this function are not completely understood. Here we report a genetic, immunohistochemical, and electrophysiological analysis of the Ppk30 ion channel, a member of the Drosophila pickpocket (ppk) family, counterpart of the mammalian Degenerin/Epithelial Na+ Channel family. Ppk30 mutant larvae displayed deficits in proprioceptive movement and mechanical nociception, which are detected by class IV sensory (mdIV) neurons. The same neurons also detect heat nociception, which was not impaired in ppk30 mutant larvae. Similarly, Ppk30 mutation did not alter gentle touch mechanosensation, a distinct mechanosensation detected by other neurons, suggesting that Ppk30 has a functional role in mechanosensation in mdIV neurons. Consistently, Ppk30 was expressed in class IV neurons, but was not detectable in other larval skin sensory neurons. Mutant phenotypes were rescued by expressing Ppk30 in mdIV neurons. Electrophysiological analysis of heterologous cells expressing Ppk30 did not detect mechanosensitive channel activities, but did detect acid-induced currents. These data show that Ppk30 has a role in mechanosensation, but not in thermosensation, in class IV neurons, and possibly has other functions related to acid response.

Advanced cancer patients tend to present multiple concurrent sy mptoms which are often moderate or severe in intensity. To date, the majority of studies have focused on eit her a single symptom, such as pain, fatigue, or depression or associated symptoms. While this approach has adva nced understanding of some symptoms, it has offered clinicians not much guidance for treating several multi ple concurrent symptoms in cancer patients. So in recent years, a few symptom management studies attempted a new approach of focusing on symptom clusters instead of individual symptoms. A symptom cluster is defined as two or more concurrent symptoms that are related to each other. If we better understand symptom clusters, interrelations of symptoms, and their common mechanisms in advanced cancer patients, clinicians can more effectively control multiple, concurrent symptoms and reduce drug side effects. And clinicians can also predict any other symptom s, functional performance, and the relationship between symptom clusters and survival in advanced cancer patients. At present, there is inconsistency in symptom clusters due to many unexplained mechanisms and various means to assess and analyze symptoms. Still, with further study, the approach to symptom clusters rather than individual symptoms could more effectively control symptoms and improve patients’ quality of life.