MYRF: A unique transmembrane transcription factor- from proteolytic self-processing to its multifaceted roles in animal development.

The Myelin Regulator Factor (MYRF) is a master regulator governing myelin formation and maintenance in the central nervous system. The conservation of MYRF across metazoans and its broad tissue expression suggest it has functions extending beyond the well-established role in myelination. Loss of MYRF results in developmental lethality in both invertebrates and vertebrates, and MYRF haploinsufficiency in humans causes MYRF-related Cardiac Urogenital Syndrome, underscoring its importance in animal development; however, these mechanisms are largely unexplored. MYRF, an unconventional transcription factor, begins embedded in the membrane and undergoes intramolecular chaperone mediated trimerization, which triggers self-cleavage, allowing its N-terminal segment with an Ig-fold DNA-binding domain to enter the nucleus for transcriptional regulation. Recent research suggests developmental regulation of cleavage, yet the mechanisms remain enigmatic. While some parts of MYRF's structure have been elucidated, others remain obscure, leaving questions about how these motifs are linked to its intricate processing and function.

In vivo three-dimensional brain imaging with chemiluminescence probes in Alzheimer's disease models.

Optical three-dimensional (3D) molecular imaging is highly desirable for providing precise distribution of the target-of-interest in disease models. However, such 3D imaging is still far from wide applications in biomedical research; 3D brain optical molecular imaging, in particular, has rarely been reported. In this report, we designed chemiluminescence probes with high quantum yields, relatively long emission wavelengths, and high signal-to-noise ratios to fulfill the requirements for 3D brain imaging in vivo. With assistance from density-function theory (DFT) computation, we designed ADLumin-Xs by locking up the rotation of the double bond via fusing the furan ring to the phenyl ring. Our results showed that ADLumin-5 had a high quantum yield of chemiluminescence and could bind to amyloid beta (Aß). Remarkably, ADLumin-5's radiance intensity in brain areas could reach 4 × 107 photon/s/cm2/sr, which is probably 100-fold higher than most chemiluminescence probes for in vivo imaging. Because of its strong emission, we demonstrated that ADLumin-5 could be used for in vivo 3D brain imaging in transgenic mouse models of Alzheimer's disease.

Endoplasmic reticular stress as an emerging therapeutic target for chronic pain: a narrative review.

Chronic pain is a severely debilitating condition with enormous socioeconomic costs. Current treatment regimens with nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, or opioids have been largely unsatisfactory with uncertain benefits or severe long-term side effects. This is mainly because chronic pain has a multifactorial aetiology. Although conventional pain medications can alleviate pain by keeping several dysfunctional pathways under control, they can mask other underlying pathological causes, ultimately worsening nerve pathologies and pain outcome. Recent preclinical studies have shown that endoplasmic reticulum (ER) stress could be a central hub for triggering multiple molecular cascades involved in the development of chronic pain. Several ER stress inhibitors and unfolded protein response modulators, which have been tested in randomised clinical trials or apprpoved by the US Food and Drug Administration for other chronic diseases, significantly alleviated hyperalgesia in multiple preclinical pain models. Although the role of ER stress in neurodegenerative disorders, metabolic disorders, and cancer has been well established, research on ER stress and chronic pain is still in its infancy. Here, we critically analyse preclinical studies and explore how ER stress can mechanistically act as a central node to drive development and progression of chronic pain. We also discuss therapeutic prospects, benefits, and pitfalls of using ER stress inhibitors and unfolded protein response modulators for managing intractable chronic pain. In the future, targeting ER stress to impact multiple molecular networks might be an attractive therapeutic strategy against chronic pain refractory to steroids, NSAIDs, or opioids. This novel therapeutic strategy could provide solutions for the opioid crisis and public health challenge.

Preoperative decreased physical activity is associated with greater postoperative pain: the mediating role of preoperative sleep disturbance.

PURPOSE: Engagement in physical activity (PA) is often associated with better sleep quality and less pain severity among patients diagnosed with breast cancer. However, less research has focused on whether patients' PA prior to breast surgery, including their perceived decrease in PA level, is associated with worse preoperative sleep quality, and subsequently, greater postoperative pain. This longitudinal study investigated whether patients' preoperative PA was associated with their postoperative pain. We also explored whether preoperative sleep disturbance partially mediated the relationship between preoperative PA and postoperative pain. METHODS: Prior to breast surgery, patients self-reported both their overall level of PA and whether they perceived a decrease in their PA since the diagnosis/onset of treatment for cancer. Patients also completed a measure of preoperative sleep disturbance. Two weeks after surgery, patients completed a measure of postoperative surgical-area pain severity. RESULTS: Our results showed that preoperatively perceiving a decrease in PA level was significantly associated with greater preoperative sleep disturbance and postoperative pain. A mediation analysis revealed that the association between preoperative decreased PA and postoperative pain was partially mediated by preoperative sleep disturbance. Notably, patients' overall preoperative level of PA was not related to preoperative sleep disturbance or postoperative pain. CONCLUSION: These findings suggest that maintaining, or even increasing, PA after diagnosis/treatment may be more important than the absolute amount of PA that women engage in during the preoperative period. Potentially, some patients with breast cancer may benefit from a preoperative intervention focused on both maintaining PA and bolstering sleep quality.

Half-curcumin-based chemiluminescence probes and their applications in detecting quasi-stable oxidized protein.

Numerous methods have been reported for detecting ROS/RNS in vitro and in vivo; however, detecting methods for the secondary products of the ROS/RNS reactions, particularly quasi-stable oxidized products, have been much less explored. In this report, we observed that half-curcumins could generate chemiluminescence. In contrast to other chemiluminescence scaffolds, the distinguishing feature of a half-curcumin is the formation of a carbanion intermediate of its acetylacetone moiety, opening unique avenues for applications. In this study, we designed a series of half-curcumins CRANAD-Xs and found that CRANAD-164 could be used to detect quasi-stable oxidized proteins (QSOP) in vivo and in patient serum samples. We illustrated that CRANAD-164 could be used to monitor the responses of taurine, an amino acid with newly reported anti-aging capacity, in an inflammatory mouse model. Remarkably, we further demonstrated that the QSOP levels were much higher in the disease serum samples, including Alzheimer's disease, compared to the samples from healthy controls. Moreover, our results revealed that the sera chemiluminescence intensities were higher in aged healthy controls compared to young healthy subjects, suggesting that CRANAD-164 can be used to monitor the increase of QSOP during aging.

Indole-3-Propionic Acid, a Gut Microbiota Metabolite, Protects Against the Development of Postoperative Delirium.

OBJECTIVE: The aim was to determine preoperative gut microbiota metabolites that may be associated with postoperative delirium (POD) development in patients and further study in rodents. SUMMARY BACKGROUND DATA: POD occurs in 9% to 50% of older patients undergoing anesthesia/surgery but lacks effective treatments or prevention. High-throughput metabolomics using liquid chromatography with tandem mass spectrometry has accelerated disease-related biomarkers discovery. We performed metabolomic studies in humans to identify potential metabolite biomarkers linked to POD and examined potential mechanisms in rodents. METHODS: We performed a prospective observational cohort study to examine the metabolomic changes that were associated with the development of POD. Then the gut microbiota-related metabolomic changes were recapitulated by gut microbiota perturbation in rodents. POD was assessed in mice using a battery of behavioral tests including novel objective test, Y-maze test, open-field test, and buried food test. The mechanisms through which gut microbiota-related metabolomic changes influenced POD were examined using chemogenetics. RESULTS: Indole-3-propionic acid (IPA) is a gut microbiota metabolite that belongs to the indole family. Baseline plasma levels of IPA were significantly inversely correlated with the onset of POD in 103 (17 cases) human individuals. This relationship was validated in preclinical mouse models for POD: reducing IPA levels through gut microbiota perturbation promoted POD-like behavior. More importantly, IPA administration deterred POD-like behavior. Colonization of germ-free mice with mutant Clostridium sporogenes that did not produce IPA-promoted POD-like behavior. Chemogenetic studies revealed that the protective effect of IPA in mice was mediated, in part, by peroxisome proliferator-activated receptor gamma coactivator 1-alpha in hippocampal interneurons. CONCLUSIONS: Gut microbiota-derived IPA is an important molecule implicated in the pathogenesis of POD, which could potentially be harnessed for POD prevention.

Bioluminescence Imaging with Functional Amyloid Reservoirs in Alzheimer's Disease Models.

Bioluminescence imaging has changed the daily practice of preclinical research on cancer and other diseases over the last few decades; however, it has rarely been applied in preclinical research on Alzheimer's disease (AD). In this Article, we demonstrated that bioluminescence imaging could be used to report the levels of amyloid beta (Aß) species in vivo. We hypothesized that AkaLumine, a newly discovered substrate for luciferase, could bind to Aß aggregates and plaques. We further speculated that the Aß aggregates/fibrils/plaques could be considered as "functional amyloids", which have a reservoir function to sequester and release AkaLumine to control the bioluminescence intensity, which could be used to report the levels of Aßs. Our hypotheses have been validated via in vitro solution tests, mimic studies with brain tissues and mice, two-photon imaging with AD mice, and in vivo bioluminescence imaging using transgenic AD mice that were virally transduced with AkaLuciferase (AkaLuc), a new luciferase that generates bioluminescence in the near-infrared window. As expected, compared to the control group, we observed that the Aß group showed lower bioluminescence intensity due to AkaLumine sequestering at early time points, while higher intensity was due to AkaLumine releasing at later time points. Lastly, we demonstrated that this method could be used to monitor AD progression and the therapeutic effectiveness of avagacestat, a well-studied gamma-secretase inhibitor. Importantly, a good correlation (R2 = 0.81) was established between in vivo bioluminescence signals and Aß burdens of the tested AD mice. We believe that our approach can be easily implemented into daily imaging experiments and has tremendous potential to change the daily practice of preclinical AD research.

Repeated early-life exposure to anaesthesia and surgery causes subsequent anxiety-like behaviour and gut microbiota dysbiosis in juvenile rats.

BACKGROUND: Early exposure to general anaesthetics for multiple surgeries or procedures might negatively affect brain development. Recent studies indicate the importance of microbiota in the development of stress-related behaviours. We determined whether repeated anaesthesia and surgery in early life cause gut microbiota dysbiosis and anxiety-like behaviours in rats. METHODS: Sprague Dawley rats received skin incisions under sevoflurane 2.3 vol% three times during the first week of life. After 4 weeks, gut microbiota, anxiety-related behaviours, hippocampal serotonergic activity, and plasma stress hormones were tested. Subsequently, we explored the effect of faecal microbiota transplantation from multiple anaesthesia/surgery exposed rats after administration of a cocktail of antibiotics on anxiety-related behaviours. RESULTS: Anxiety-like behaviours were observed in rats with repeated anaesthesia/surgery exposures: In the OF test, multiple anaesthesia/surgery exposures induced a decrease in the time spent in the centre compared to the Control group (P<0.05, t=3.05, df=16, Cohen's d=1.44, effect size=0.58). In the EPM test, rats in Multiple AS group travelled less (P<0.05, t=5.09, df=16, Cohen's d=2.40, effective size=0.77) and spent less time (P<0.05, t=3.58, df=16, Cohen's d=1.69, effect size=0.65) in the open arms when compared to the Control group. Repeated exposure caused severe gut microbiota dysbiosis, with exaggerated stress response (P<0.01, t=4.048, df=16, Cohen's d=-1.91, effect size=-0.69), a significant increase in the hippocampal concentration of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) (P<0.05; for 5-HT: t=3.33, df=18, Cohen's d=-1.49, effect size=-0.60; for 5-HIAA: t=3.12, df=18, Cohen's d=-1.40, effect size=-0.57), and changes in gene expression of serotonergic receptors later in life (for Htr1a: P<0.001, t=4.49, df=16, Cohen's d=2.24, effect size=0.75; for Htr2c: P<0.01, t=3.72, df=16, Cohen's d=1.86, effect size=0.68; for Htr6: P<0.001, t=7.76, df=16, Cohen's d=3.88, effect size=0.89). Faecal microbiota transplantation led to similar anxiety-like behaviours and changes in the levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid. CONCLUSIONS: Gut microbiota dysbiosis caused by early repeated exposure to anaesthesia and surgery affects long-term anxiety emotion behaviours in rats.

A Photolabile Curcumin-Diazirine Analogue Enables Phototherapy with Physically and Molecularly Produced Light for Alzheimer's Disease Treatment.

The development of Alzheimer's disease (AD) drugs has recently witnessed substantial achievement. To further enhance the pool of drug candidates, it is crucial to explore non-traditional therapeutic avenues. In this study, we present the use of a photolabile curcumin-diazirine analogue, CRANAD-147, to induce changes in properties, structures (sequences), and neurotoxicity of amyloid beta (Aß) species both in cells and in vivo. This manipulation was achieved through irradiation with LED light or molecularly generated light, dubbed as "molecular light", emitted by the chemiluminescence probe ADLumin-4. Next, aided by molecular chemiluminescence imaging, we demonstrated that the combination of CRANAD-147/LED or CRANAD-147/ADLumin-4 (molecular light) could effectively slow down the accumulation of Aßs in transgenic 5xFAD mice in vivo. Leveraging the remarkable tissue penetration capacity of molecular light, phototherapy employing the synergistic effect of a photolabile Aß ligand and molecular light emerges as a promising alternative to conventional AD treatment interventions.

Gut Microbiome in Anesthesiology and Pain Medicine.

The gut microbiome plays critical roles in human health and disease. Recent studies suggest it may also be associated with chronic pain and postoperative pain outcomes. In animal models, the composition of the gut microbiome changes after general anesthesia and affects the host response to medications, including anesthetics and opioids. In humans, the gut microbiome is associated with the development of postoperative pain and neurocognitive disorders. Additionally, the composition of the gut microbiome has been associated with pain conditions including visceral pain, nociplastic pain, complex regional pain syndrome, and headaches, partly through altered concentration of circulating bacterial-derived metabolites. Furthermore, animal studies demonstrate the critical role of the gut microbiome in neuropathic pain via immunomodulatory mechanisms. This article reviews basic concepts of the human gut microbiome and its interactions with the host and provide a comprehensive overview of the evidence linking the gut microbiome to anesthesiology, critical care, and pain medicine.

Nonopioid GTS-21 Mitigates Burn Injury Pain in Rats by Decreasing Spinal Cord Inflammatory Responses.

BACKGROUND: Burn injury (BI) pain consists of inflammatory and neuropathic components and activates microglia. Nicotinic alpha 7 acetylcholine receptors (α7AChRs) expressed in microglia exhibit immunomodulatory activity during agonist stimulation. Efficacy of selective α7AChR agonist GTS-21 to mitigate BI pain and spinal pain-mediators was tested. METHODS: Anesthetized rats after hind-paw BI received intraperitoneal GTS-21 or saline daily. Allodynia and hyperalgesia were tested on BI and contralateral paw for 21 days. Another group after BI receiving GTS-21 or saline had lumbar spinal cord segments harvested (day 7 or 14) to quantify spinal inflammatory-pain transducers or microglia activation using fluorescent marker, ionized calcium-binding adaptor protein (Iba1). RESULTS: BI significantly decreased allodynia withdrawal threshold from baseline of ~9-10 to ~0.5-1 g, and hyperalgesia latency from ~16-17 to ~5-6 seconds by day 1. Both doses of GTS-21 (4 or 8 mg/kg) mitigated burn-induced allodynia from ~0.5-1 to ~2-3 g threshold (P = .089 and P = .010), and hyperalgesia from ~5-6 to 8-9 seconds (P < .001 and P < .001) by day 1. The GTS-21 group recovered to baseline pain threshold by day 15-17 compared to saline-treated, where the exaggerated nociception persisted beyond 15-17 days. BI significantly (P < .01) increased spinal cord microgliosis (identified by fluorescent Iba1 staining), microglia activation (evidenced by the increased inflammatory cytokine), and pain-transducer (protein and/or messenger RNA [mRNA]) expression (tumor necrosis factor-α [TNF-α], interleukin-1ß [IL-1ß], nuclear factor-kappa B [NF-κB], interleukin-6 [IL-6], Janus-associated kinase signal transducer and activator of transcription 3 [JAK-STAT3], and/or N-methyl-D-aspartate receptor [NMDAR]). GTS-21 mitigated pain-transducer changes. The α7AChR antagonist methyllycaconitine nullified the beneficial effects of GTS-21 on both increased nociception and pain-biomarker expression. CONCLUSIONS: Nonopioid, α7AChR agonist GTS-21 elicits antinociceptive effects at least in part by decreased activation spinal-cord pain-inducers. The α7AChR agonist GTS-21 holds promise as potential therapeutic adjunct to decrease BI pain by attenuating both microglia changes and expression of exaggerated pain transducers.

Gut Microbiota Influences Neuropathic Pain Through Modulating Proinflammatory and Anti-inflammatory T Cells.

BACKGROUND: Gut microbiota, a consortium of diverse microorganisms residing in the gastrointestinal tract, has emerged as a key player in neuroinflammatory responses, supporting the functional relevance of the "gut-brain axis." Chronic-constriction injury of the sciatic nerve (CCI) is a commonly used animal model of neuropathic pain with a major input from T cell-mediated immune responses. In this article, we sought to examine whether gut microbiota influences CCI neuropathic pain, and, if so, whether T-cell immune responses are implicated. METHODS: We used a mixture of wide-spectrum oral antibiotics to perturbate gut microbiota in mice and then performed CCI in these animals. Nociceptive behaviors, including mechanical allodynia and thermal hyperalgesia, were examined before and after CCI. Additionally, we characterized the spinal cord infiltrating T cells by examining interferon (IFN)-γ, interleukin (IL)-17, and Foxp3. Using a Foxp3-GFP-DTR "knock-in" mouse model that allows punctual depletion of regulatory T cells, we interrogated the role of these cells in mediating the effects of gut microbiota in the context of CCI neuropathic pain. RESULTS: We found that oral antibiotics induced gut microbiota changes and attenuated the development of CCI neuropathic pain, as demonstrated by dampened mechanical allodynia and thermal hyperalgesia. Percentages of IFN-γ-producing Th1 cells and Foxp3+ regulatory T cells were significantly different between animals that received oral antibiotics (Th1 mean = 1.0, 95% confidence interval [CI], 0.9-1.2; Foxp3 mean = 8.1, 95% CI, 6.8-9.3) and those that received regular water (Th1 mean = 8.4, 95% CI, 7.8-9.0, P < .01 oral antibiotics versus water, Cohen's d = 18.8; Foxp 3 mean = 2.8, 95% CI, 2.2-3.3, P < .01 oral antibiotics versus water, Cohen's d = 6.2). These T cells characterized a skewing from a proinflammatory to an anti-inflammatory immune profile induced by gut microbiota changes. Moreover, we depleted Foxp3+ regulatory T cells and found that their depletion reversed the protection of neuropathic pain mediated by gut microbiota changes, along with a dramatic increase of IFN-γ-producing Th1 cell infiltration in the spinal cord (before depletion mean = 2.8%, 95% CI, 2.2-3.5; after depletion mean = 9.1%, 95% CI, 7.2-11.0, p < .01 before versus after, Cohen's d = 5.0). CONCLUSIONS: Gut microbiota plays a critical role in CCI neuropathic pain. This role is mediated, in part, through modulating proinflammatory and anti-inflammatory T cells.

Proliferator-Activated Receptor-Gamma Coactivator-1α Haploinsufficiency Promotes Pain Chronification After Burn Injury.

BACKGROUND: Tissue injuries such as surgery and trauma are usually accompanied by simultaneous development of acute pain, which typically resolves along with tissue healing. However, in many cases, acute pain does not resolve despite proper tissue repair; rather, it transitions to chronic pain. In this study, we examined whether proliferator-activated receptor-gamma coactivator-1α (PGC-1α), a master regulator of mitochondria biogenesis, is implicated in pain chronification after burn injury in mice. METHODS: We used PGC-1α and littermates PGC-1α mice of both sex. Burn injury was induced on these mice. Hindpaw mechanical withdrawal thresholds and thermal withdrawal latency were examined. RESULTS: Hindpaw mechanical withdrawal thresholds and thermal withdrawal latencies were comparable at baseline between PGC-1α and PGC-1α mice. After burn injury, both PGC-1α and PGC-1α mice exhibited an initial dramatic decrease of withdrawal parameters at days 3 and 5 after injury. While PGC-1α mice fully recovered their withdrawal parameters to preinjury levels by days 11-14, PGC-1α mice failed to recover those parameters during the same time frame, regardless of sex. Moreover, we found that PGC-1α mice resolved tissue inflammation in a similar fashion to PGC-1α mice using a chemiluminescence-based reactive oxygen species imaging technique. CONCLUSIONS: Taken together, our data suggest that PGC-1α haploinsufficiency promotes pain chronification after burn injury.

Methylphenidate and Morphine Combination Therapy in a Rat Model of Chronic Pain.

BACKGROUND: The incremental dose of opioids used in chronic pain management often leads to a reduced opioid analgesic effect, opioid misuse, and addiction. Central dopamine (DA) dysfunction contributes to the chronicity of pain and a decreased opioid analgesic effect. Methylphenidate (MPH/Ritalin) enhances central DA function by inhibiting DA reuptake. In this study, we used a rat model of chronic pain to examine whether combination of MPH with morphine (MOR) would improve the MOR analgesic effect under a chronic pain condition. METHODS: Tibiotarsal joint Complete Freund's Adjuvant (CFA) injection in rats was utilized to induce chronic nociception. The analgesic effect of low-dose MPH (0.25 mg/kg), low-dose MOR (2.5 mg/kg), and their combination was examined in CFA rats. Nociceptive behavior was assessed by von Frey test. Conditioned place preference (CPP) and open field tests (OFTs) were used to examine the rewarding behavior and locomotor activity in rats, respectively. RESULTS: Our findings are as follows: (1) in CFA rats with chronic pain, 2.5 mg/kg of MOR had less analgesic effect than 10 mg/kg of MOR at 28 days after injury (95% confidence intervals [CIs] for difference of means of von Frey threshold in gram: -11.9 [-6.5 to -17.3]); (2) in the 1-hour time window of 30-90 minutes after injection, the combination of MPH (0.25 mg/kg) with MOR (2.5 mg/kg) increased synergistically and prolonged the analgesic effect in CFA rats as compared with MPH or MOR alone (P = .01 for MPH by MOR interaction, and 95% CIs for difference of means of von Frey threshold in gram: 3.3 [1.37-6.12] for the combination versus MPH and 3.2 [1.35-5.74] for the combination versus MOR); (3) at the low dose (0.25 mg/kg), MPH did not increase locomotor activity (MOR + MPH versus MOR, P = .13) nor significantly enhanced MOR reward behavior (MOR + MPH versus MOR, P = .63) in CFA rats. CONCLUSIONS: Our data suggest that a combination therapy using low-dose MPH and MOR may produce a MOR-sparing effect in chronic pain management.

Persistent Nociception Facilitates the Extinction of Morphine-Induced Conditioned Place Preference.

BACKGROUND: As opioid abuse and addiction have developed into a major national health crisis, prescription of opioids for pain management has become more controversial. However, opioids do help some patients by providing pain relief and improving the quality of life. To better understand the addictive properties of opioids under chronic pain conditions, we used a conditioned place preference (CPP) paradigm to examine the rewarding properties of morphine in rats with persistent nociception. METHODS: Spared nerve injury (SNI) model was used to induce persistent nociception in rats. Nociceptive behavior was assessed by von Frey test. CPP test was used to examine the rewarding properties of morphine. RESULTS: Our findings are as follows: (1) SNI rats did not show a difference compared with sham rats in magnitude of morphine-induced CPP 1 day after last morphine injection (2-way analysis of variance; for SNI versus sham, F[1,42] = 0.014, P = .91; and 95% confidence intervals for difference of means, -5.9 [-58 to 46], 0.76 [-51 to 53], and 0.90 [-51 to 53] for 2.5, 5, and 10 mg/kg, respectively); (2) increasing morphine dosage (2.5, 5, and 10 mg/kg) did not further increase the magnitude of CPP in both sham and SNI rats (for dosage: F[2,42] = 0.94, P = .40); and (3) morphine-induced CPP persisted in sham rats but extinguished in SNI rats when tested at 8 days after last morphine injection (for sham versus SNI: Bonferroni correction, P < .006 for both 5 and 10 mg/kg doses; and 95% confidence intervals for difference of means, 80.3 [19.7-141] and 87.0 [26.3-148] for 5 and 10 mg/kg, respectively). CONCLUSIONS: Our data provide new evidence supporting the notion that the brain's reward circuitry changes in the context of persistent pain. This observational study suggests that future investigation into the neurobiology of opioid reward requires consideration of the circumstances in which opioid analgesics are administered.

Ultrasmall Superparamagnetic Iron Oxide Imaging Identifies Tissue and Nerve Inflammation in Pain Conditions.

Objective: Correlation between radiologic structural abnormalities and clinical symptoms in low back pain patients is poor. There is an unmet clinical need to image inflammation in pain conditions to aid diagnosis and guide treatment. Ferumoxytol, an ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle, is clinically used to treat iron deficiency anemia and showed promise in imaging tissue inflammation in human. We explored whether ferumoxytol can be used to identify tissue and nerve inflammation in pain conditions in animals and humans. Methods: Complete Freud's adjuvant (CFA) or saline was injected into mice hind paws to establish an inflammatory pain model. Ferumoxytol (20 mg/kg) was injected intravenously. Magnetic resonance imaging (MRI) was performed prior to injection and 72 hours postinjection. The changes in the transverse relaxation time (T2) before and after ferumoxytol injection were compared between mice that received CFA vs saline injection. In the human study, we administered ferumoxytol (4 mg/kg) to a human subject with clinical symptoms of lumbar radiculopathy and compared the patient with a healthy subject. Results: Mice that received CFA exhibited tissue inflammation and pain behaviors. The changes in T2 before and after ferumoxytol injection were significantly higher in mice that received CFA vs saline (20.8 ± 3.6 vs 2.2 ± 2.5, P = 0.005). In the human study, ferumoxytol-enhanced MRI identified the nerve root corresponding to the patient's symptoms, but the nerve root was not impinged by structural abnormalities, suggesting the potential superiority of this approach over conventional structural imaging techniques. Conclusions: Ferumoxytol-enhanced MRI can identify tissue and nerve inflammation and may provide a promising diagnostic tool in assessing pain conditions in humans.

Anaesthesia for chest wall reconstruction in a patient with Poland syndrome: CARE-compliant case report and literature review.

BACKGROUND: Poland syndrome is a rare congenital disease, characterized by agenesis/hypoplasia of the pectoralis major muscle, usually associated with variable thoracic anomalies that needed chest wall reconstruction under general anesthesia. Anaesthetic management in Poland syndrome has scarcely been described. CASE PRESENTATION: Here, we present our anaesthetic management of Nuss procedure for chest wall correction in a 5 years old patient with Poland syndrome. We also reviewed the reports of anaesthetic management of Poland syndrome by searching Pubmed, and summarize the perioperative procedures that may warrant a safe surgery. CONCLUSIONS: Examinations before surgery, intraoperative monitoring, choice of general anesthetics and pain management after surgery should all be contemplated.

Adaptive Foxp3+ regulatory T cell-dependent and -independent control of allergic inflammation.

Adaptive Foxp3(+) regulatory T (Treg) cells develop during induction of mucosal tolerance and after immunization. Large numbers of Foxp3(+) T cells have been found in inflamed tissues. We investigated the role of adaptive Foxp3(+) Treg cells in mucosal tolerance and in chronic allergic lung inflammation. We used two strains of mice that are devoid of naturally occurring Treg cells; one is capable of generating adaptive Foxp3(+) Treg cells upon exposure to antigen, whereas the other is deficient in both naturally occurring and adaptive Foxp3(+) Treg cells. We found that adaptive Foxp3(+) Treg cells were essential for establishing mucosal tolerance and for suppressing IL-4 production and lymphoid neogenesis in chronic inflammation, whereas IL-5 production and eosinophilia could be controlled by Foxp3-independent, IFN-gamma-dependent mechanisms. Thus, whereas adaptive Foxp3(+) Treg cells regulate sensitization to allergens and the severity of chronic inflammation, IFN-gamma-producing cells can play a beneficial role in inflammatory conditions involving eosinophils.

Development and Patient Satisfaction of a New Telemedicine Service for Pain Management at Massachusetts General Hospital to the Island of Martha's Vineyard.

OBJECTIVE: Patients in remote areas lack access to specialist care and pain management services. In order to provide pain management care to patients remote from our center, we created a telemedicine pain clinic (telepain) at Massachusetts General Hospital (MGH) in Boston, MA to extend services to the Island of Martha's Vineyard. DESIGN: Over 13 months, 238 telepain video clinic evaluations were conducted. A pain physician visited the island 1-2 days per month and performed 121 interventions. Given the novelty of telemedicine clinics, we surveyed patients to gauge satisfaction and identify perceived weaknesses in our approach that could be addressed. Forty-nine consecutive patients answered a 14-question, 5-point balanced Likert-scale survey with 1 (no, definitely not) being most negative and 5 (yes, definitely) being most positive. SETTING: Patients on Martha's Vineyard referred for pain management consultation services via telemedicine. PATIENTS: Forty-nine consecutive patients evaluated via telemedicine. INTERVENTIONS: Likert-scale survey administered. MEASURES: Questions measured patient impressions of video-based visits with their doctor, convenience of the visit, concerns about privacy, and whether they would recommend such a visit, among other items. RESULTS: Mean respondent scores for each question were >4.3 indicating a favorable impression of the telepain clinic experience. Lowest mean scores were found when respondents were asked to compare the care they received by telepain versus an in-person visit, or whether they were able to develop a friendly relationship with the doctor. CONCLUSIONS: The results suggest an overall positive reception of telepain by patients, yet highlight the challenge of building a patient-physician relationship remotely.