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Objective: This study aimed to understand the effectiveness of regular care in reducing the incidence of severe peristomal skin disorders, as well as to identify their risk factors., Summary Background Data: Peristomal skin disorders occur frequently in outpatient settings and require appropriate intervention. It remains, however, to be demonstrated when the need to follow up these patients decreases and whether assessing severity of peristomal skin disorders is useful., Methods: This prospective, multicenter, observational cohort study was conducted in six regional high-volume Japanese hospitals. The primary endpoint of the study was the effectiveness of regular follow-up in reducing the incidence of severe peristomal skin disorders via a scoring system at a defined regular outpatient visit. Propensity score matching was performed to compare a control group and patients with severe peristomal skin disorders., Results: In total, 217 patients between December 2019 and December 2021 were enrolled, and 191 patients were analyzed. Multivariate analysis showed that loop stoma (odds ratio [OR], 5.017; 95% confidence interval [CI], 1.350-18.639; P=0.016) and stoma height of <10 mm (OR, 7.831; 95% CI, 1.760-34.838; P=0.007) were independent risk factors for all peristomal skin disorders. After propensity score matching, the incidence of the disorders was not significantly different between the specified evaluation timing and historical control groups (75.7% vs. 77.2%, P=0.775), and the incidence of the severe disorders based on the ABCD and DET scores (5.9% vs. 19.1%, P<0.001 and 1.5% vs. 29.4%, P<0.001, respectively) was significantly lower in the specified evaluation timing group than in the historical control group., Conclusion: Regular peristomal skin disease follow-up and scoring, as well as appropriate stoma care at the stoma outpatient visit did not change the frequency of peristomal skin disease, but severe peristomal skin disorders were prevented. Additionally, risk factors for peristomal skin disorders were found to be height <10 mm and loop stoma., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

TCF3-HLF-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has an extremely poor prognosis. A 2-year-old boy with TCF3-HLF-positive BCP-ALL had an isolated extramedullary relapse in multiple bones after allogeneic hematopoietic stem cells transplantation (HSCT) from a human leukocyte antigen-matched unrelated donor. In this study, he received a T-cell-replete haploidentical HSCT (TCR-haplo-HSCT) from his father when in nonremission state, which resulted in a sustained complete remission for over 3 years. Immune therapies for patients with an extramedullary relapse of TCF3-HLF-positive BCP-ALL have been attempted; however, long-term efficacies of these therapies remain unknown. Our TCR-haplo-HSCT may be an effective therapeutic option for such patients., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Genetic factors play a role in individual differences in pain experience. Here, we performed a genome-wide association study (GWAS) to identify novel loci regulating pain processing. We conducted a 2-stage GWAS and the candidate single-nucleotide polymorphisms (SNPs) association study on pain experience using an exploratory cohort of patients with cancer pain. The confirmatory cohort comprised of participants from the general population with and without habitual use of analgesic medication. In the exploratory cohort, we evaluated pain intensity using a numerical rating scale, recorded daily opioid dosages, and calculated pain reduction rate. In the confirmatory cohort, pain experience was defined as habitual nonsteroidal anti-inflammatory drug usage. Using linear regression models, we identified candidate SNP in the exploratory samples, and tested the association between phenotype and experienced pain in the confirmatory samples. We found 1 novel SNP (rs11764598)-located on the gene encoding for pleiotrophin on chromosome 7-that passed the genome-wide suggestive significance at 20% false discovery rate (FDR) correction in the exploratory samples of patients with cancer pain (P = 1.31 × 10-7, FDR = 0.101). We confirmed its significant association with daily analgesic usage in the confirmatory cohort (P = .028), although the minor allele affected pain experience in an opposite manner. We identified a novel genetic variant associated with pain experience. Further studies are required to validate the role of pleiotrophin in pain processing., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Competing Interests: The authors declare no conflict of interest.

Abstract: Nasomaxillary fracture is a characteristic mid-facial fracture, and there are no reports showing the fracture damaging the nasolacrimal system (NLS). This report described nasomaxillary fracture cases with NLS damages, which were assessed by computed tomographic dacryocystography (CT-DCG). A retrospective cohort study of nasomaxillary fractures diagnosed by CT was conducted from 2007 to 2015. Twelve patients (mean age: 27.5 years) were found, and their clinical symptoms were as follows: nasal deformity in 10 patients, infra-orbital hypoesthesia in 7, epiphora in 5, and diplopia in one. CT-DCG was performed for 2 patients who complained epiphora, and obstruction was found in 1 patient. All patients underwent open reduction and internal fixation (ORIF), and epiphora in 5 patients was improved. One patient, however, complained epiphora postoperatively, which was supposed to be due to the unsuitable screw insertion. Since nasomaxillary fracture could give NLS obstruction, CT-DCG is useful for diagnosis. Although ORIF is an optimal treatment, attention is needed to avoid the lacrimal canal in screwing on the nasomaxillary buttress., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by Mutaz B. Habal, MD.)

Rationale: Although single organ vasculitis (SOV) is a rare occurrence and it is difficult to diagnose, its possibility as a cause of fever of unknown origin (FUO) must be considered. Recently, the usefulness of 18F-fluorodeoxyglucose positron emission tomography computed tomography (FDG PET/CT) in the diagnosis of unknown fevers due to vasculitis, especially in cases of small and medium-sized vasculitis, has begun to be pointed out., Patient Concerns: We report the case of an 84-year-old woman with persisting fever for more than 2 weeks. She had no accompanying symptoms, other than fever, and the physical examination, echocardiography, and contrast-enhanced CT did not reveal any diagnostic clue., Diagnoses: The FDG PET/CT revealed positive uptakes of FDG in the left breast, with a standardized uptake value (SUV) of 2.9. The biopsy specimen of the left breast lesion revealed rupture of the elastic plate and evidence of fibrinoid necrosis of arteries, leading to the diagnosis of polyarteritis (PAN). Further angiographic examination and additional imaging did not reveal the presence of other lesions. Therefore, the diagnosis was established as a PAN-SOV of the left breast., Interventions: This patient has improved with follow-up only., Outcomes: There has been no evidence of a relapse of PAN over a 5-year follow-up period., Lessons: SOV presenting with unspecific local symptoms is difficult to diagnose based on the medical history and clinical examination. Our findings show that early "Combination of PET-CT and biopsy" can be a powerful diagnostic tool in patients with FUO for whom diagnosis of the underlying cause is difficult despite appropriate clinical examination., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Chondroitin sulfate proteoglycans are the primary constituents of the macrophage glycosaminoglycan and extracellular microenvironment. To examine their potential role in atherogenesis, we investigated the biological importance of one of the chondroitin sulfate glycosaminoglycan biosynthesis gene, ChGn-2 (chondroitin sulfate N -acetylgalactosaminyltransferase-2), in macrophage foam cell formation. Approach and Results: ChGn-2-deficient mice showed decreased and shortened glycosaminoglycans. ChGn-2 -/- /LDLr -/- (low-density lipoprotein receptor) mice generated less atherosclerotic plaque after being fed with Western diet despite exhibiting a metabolic phenotype similar to that of the ChGn-2 +/+ /LDLr -/- littermates. We demonstrated that in macrophages, ChGn-2 expression was upregulated in the presence of oxLDL (oxidized LDL), and glycosaminoglycan was substantially increased. Foam cell formation was significantly altered by ChGn-2 in both mouse peritoneal macrophages and the RAW264.7 macrophage cell line. Mechanistically, ChGn-2 enhanced oxLDL binding on the cell surface, and as a consequence, CD36-an important macrophage membrane scavenger receptor-was differentially regulated., Conclusions: ChGn-2 alteration on macrophages conceivably influences LDL accumulation and subsequently accelerates plaque formation. These results collectively suggest that ChGn-2 is a novel therapeutic target amenable to clinical translation in the future. Graphic Abstract: A graphic abstract is available for this article.

Background: The feasibility and safety of laparoscopic extensive resection (ER) for complicated appendicitis (CA) has not been clarified. We assessed the feasibility of laparoscopic ER versus open ER for CA., Methods: We retrospectively enrolled consecutive 983 patients who underwent emergency surgery for appendicitis, including 91 patients who underwent ER for CA, between April 2007 and October 2019., Results: Thirty-three patients underwent laparoscopic ER, and 58 patients underwent open ER. There were no significant differences in the reasons for performing ER between laparoscopic ER and open ER. The rates of suspicious for malignant tumor did not differ between laparoscopic and open ER [15.2% (5/33) vs. 17.2% (10/58)]. Blood loss was less in laparoscopic ER than in open ER (P=0.028). Superficial surgical site infection was less frequent in laparoscopic ER than in open ER (P=0.047). In addition, laparoscopic ER tended to be associated with a shorter hospital stay, lower rate of postoperative ileus, and higher rate of intra-abdominal abscess., Conclusion: Laparoscopic ER is feasible, and it is associated with less intraoperative blood loss and a lower frequency of postoperative superficial surgical site infection than open ER., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Acute pancreatitis (AP) guidelines for adult patients do not recommend routine prophylactic use of antibiotics because of no clinical merit on mortality, infectious complications, or length of stay. Although the mortality of pediatric AP is low, no studies have explored the rationale for antibiotic use in pediatric patients. The aim of this study was to evaluate the effects of early prophylactic antibiotics on length of stay and total costs in pediatric patients., Methods: Using the Japanese Diagnosis Procedure Combination database from 2010 to 2017, we used the stabilized inverse probability of treatment weighting method using propensity scores to balance the background characteristics in the antibiotics group and the control group, and compared length of stay and total costs between the groups., Results: We found significant differences between the antibiotics group (n = 652) and the control group (n = 467) in length of stay (11 days vs 9 days; percent difference, 15.4%; 95% confidence interval, 5.0%-26.8%) and total costs (US $4085 vs US $3648; percent difference, 19.8%; 95% confidence interval, 8.0%-32.9%)., Conclusions: Prophylactic antibiotics were associated with longer length of stay and higher total costs. Our results do not support routine use of prophylactic antibiotics in pediatric AP populations.

In this pilot study, we aimed to determine the safety and feasibility of a 15-day protocol consisting of in-hospital repetitive peripheral magnetic stimulation (rPMS) combined with intensive physical therapy for the recovery of the gait disturbance in chronic stroke patients with lower limb hemiparesis. Seven hemorrhagic stroke patients with lower limb hemiparesis and gait disturbance (age: 50-78; time from onset of stroke: 7-107 months) were enrolled. rPMS was applied to the muscles of the paretic lower limb with a parabolic coil. A train of stimuli at a frequency of 20 Hz was applied for 3 s followed by a 27-s rest interval. Therapy with rPMS was performed with eighty such trains of stimuli (total 4800 pulses). Following rPMS therapy, 120 min of physical therapy was administrated daily. Each patient received this combination treatment over fifteen consecutive days, with the walking function of all participants assessed before and after the intervention. The proposed treatment protocol resulted in significant improvements in the walking speed, ambulation ability, and balance ability, but showed no significant effects on the endurance capacity, step length, and spasticity. No rPMS-related side effects were noted. Our protocol consisting of rPMS and intensive physical therapy appears well tolerated and feasible for therapy in hemorrhagic stroke patients with gait disturbance. Further large-scale studies are required to confirm its efficacy.

Introduction: Repetitive peripheral magnetic stimulation (rPMS) therapy is an innovative and minimally invasive neurorehabilitative technique and has been shown to facilitate neural plasticity. However, there is at present no research that clarifies the dose-response of rPMS therapy on the recovery of upper limb hemiparesis after stroke. This trial aims to clarify the dose-response of rPMS therapy combined with intensive occupational therapy (OT) for chronic stroke patients with moderate to severe upper limb hemiparesis., Methods and Analysis: This multicenter, prospective, assessor-blinded, randomized controlled study with 3 parallel groups will be conducted from January 20, 2020 to September 30, 2022. Fifty patients will be randomly assigned in a ratio of 1:2:2 to the control group, the group receiving daily 2400 pulses of rPMS, or the group receiving daily 4800 pulses of rPMS, respectively. From the day after admission (Day 1), rPMS therapy and intensive OT will be initiated. The primary outcome is the change in the motor function of the affected upper extremity (Fugl-Meyer Assessment) between the time of admission (Day 0) and the day after 2 weeks of treatment (Day 14). Secondary outcomes will include the changes in spasticity, active range of motion, motor evoked potential, and activity of daily living., Ethics and Dissemination: The study was approved by the Jikei University Certified Review Board for all institutions (reference number: JKI19-020). Results of the primary and secondary outcomes will be published in a peer-reviewed journal and presented at international congresses. The results will also be disseminated to patients., Trial Registration Number: jRCTs032190191.

We present 3 cases of extrapulmonary lymphangioleiomyomatosis (LAM) identified incidentally in the uterine corpus and pelvic nodes resected for other reasons. One patient, a 47-yr-old female with corpus cancer, underwent a total hysterectomy and nodal dissection; the other 2 patients, aged 44 and 49 yr, underwent simple hysterectomy for corpus leiomyomas. None of the patients had evidence of tuberous sclerosis complex or any significant lesions in other organs. An area of spindle cell proliferation, intimately associated with dilated and tortuous lymphatic vessels, was found in the myometrium of all 3 patients, and nodal involvement with spindle cell proliferation was observed in the patient with corpus cancer. The spindle cells had faintly eosinophilic cytoplasm and a bland appearance. They were immunoreactive for α-SMA, gp100 (HMB45), and Melan-A. Tumor cell clusters lined with a single layer of lymphatic endothelium were floating in the lymphatic vessel lumen. These lesions were diagnosed as lymphangioleiomyoma in the uterine corpus and associated lymph nodes. Two of the cases seemed to be the earliest manifestations of extrapulmonary LAM, and the other case represents early-phase metastasis of LAM from the uterus. The present cases support the speculation that the uterus is the primary source of LAM cells.

The patient was a 5-year-old boy who was found in a state of cardiorespiratory arrest in the tub of a washing machine without water with the door closed. The autopsy findings included severe facial congestion and petechiae of the facial skin and palpebral conjunctiva. Several organs exhibited congestion. Hemorrhagic spots were seen on the serous membranes of various organs, with particularly marked hemorrhagic spots seen on the lungs. The heart contained fluid blood without soft clots. There were no findings indicative of marked trauma, intoxication, or hyperthermia. The examination results suggested that asphyxia had occurred in this case. However, there were no findings indicative of cervical compression, oronasal obstruction, or the presence of a foreign body in the respiratory tract. Image analysis showed the child could make postural changes inside the washing machine tub. Consequently, impaired thoracic movement and postural asphyxia were considered unlikely to have occurred. The results of blood gas analysis showed no evidence of marked hypercapnia. We, therefore, concluded that the cause of the child's death was asphyxia due to hypoxia caused by being in a closed space, that is, a washing machine tub.

Mismatched HLA loss is a cause of leukemia relapse after HLA-haploidentical stem cell transplantation (haplo-SCT). We report a patient with a history of 2 occurrences of leukemia relapse due to mismatched HLA loss after haplo-SCT. He received haplo-SCT from his father but showed leukemia relapse with loss of the maternal HLA haplotype. He then underwent haplo-SCT from his mother, and developed relapse with loss of the paternal HLA haplotype. Both donors had killer cell immunoglobulin-like receptor-ligand mismatch but alloreactive natural killer cells could not prevent relapse. Second haplo-SCT should be conducted carefully for patients with relapse due to mismatched HLA loss.

Adiponectin is an adipose tissue-derived cytokine that exerts its antiinflammatory effects by binding to 2 adiponectin receptors, adiponectin receptor 1 (ADIPOR1) and adiponectin receptor 2 (ADIPOR2). However, the role of these adiponectin receptors on inflammatory pain remains unclear. We investigated the association between single nucleotide polymorphisms (SNPs) of these genes and inflammatory pain, such as postoperative pain and cancer pain.We analyzed 17 SNPs of the ADIPOR1 gene and 27 SNPs of the ADIPOR2 gene in 56 adult patients with postlaparotomy pain. We compared these genotypes with pain intensity and opioid consumption, adjusting for multiple testing. We analyzed the genotypes of 88 patients with cancer pain and examined the association of the relevant SNP(s) with pain intensity and opioid consumption.One variant of the ADIPOR1 gene (rs12045862) showed significant association with postoperative pain intensity; patients with minor allele homozygote (n = 7) demonstrated significantly worse pain intensity than that of combined patient group exhibiting major allele homozygote or the heterozygote (n = 49; Mann-Whitney test, P < .00002), although their opioid consumptions were comparable. Cancer pain intensity between minor allele homozygote patients (n = 7) and other 2 genotype patients (n = 81) were comparable.The rs12045862 SNP of the ADIPOR1 gene was associated with postoperative pain but not cancer pain. This might result from functional alteration of the ADIPOR1 signalling pathways, which influence the inflammatory process. ADIPOR1 may be a novel potential target for developing analgesics of postoperative pain.

Background: Cytochrome aa3, the terminal component of the electron transport chain, absorbs near-infrared radiation (NIR) differentially depending on its oxidation state (Cytox), which can in theory be measured using near-infrared spectroscopy (NIRS) by relating light absorption at specific wavelengths to chromophore concentrations. Some NIRS algorithms use discrete wavelengths, while others analyze a band of NIR (broadband NIRS). The purpose of this study was to test the ability of discrete wavelength and broadband algorithms to measure changes in Cytox (primary outcome), and to determine whether or not a discreet wavelength NIRS algorithm could perform similarly to a broadband NIRS algorithm for the measurement of Cytox in a staged hypoxia-cyanide model (hypoxia and cyanide have oppositional effects on tissue saturation, but both cause cytochrome reduction)., Methods: Twenty Sprague-Dawley rats were anesthetized with isoflurane, intubated, and instrumented. Blood pressure, end-tidal carbon dioxide, and arterial oxygen saturation were measured. A halogen light source transmitted NIR transcranially. NIR from the light source and the skull was transmitted to 2 cooled charge-coupled device spectrometers. Rats were subjected to anoxia (fraction of inspired oxygen, 0.0) until arterial oxygen saturation decreased to 70%. After recovery, 5 mg/kg sodium cyanide was injected intravenously. The cycle was repeated until cardiac arrest occurred. Relative concentrations of hemoglobin and cytochrome aa3 were calculated using discreet wavelength and broadband NIRS algorithms., Results: Hypoxia led to an increase in calculated deoxyhemoglobin (0.20 arbitrary units [AUs]; 95% confidence interval [CI], 0.17-0.22; P < .0001), a decrease in calculated oxyhemoglobin (-0.16 AUs; 95% CI, -0.19 to -0.14; P < .0001), and a decrease in calculated Cytox (-0.057 AUs; 95% CI, -0.073 to 0.0040; P < .001). Cyanide led to a decrease in calculated deoxyhemoglobin (-0.037 AUs; 95% CI, 0.046 to -0.029; P < .001), an increase in calculated oxyhemoglobin (0.053 AUs; 95% CI, 0.040-0.065; P < .001), and a decrease in calculated Cytox (-0.056 AUs; 95% CI, -0.064 to -0.048; P < .001). The correlations between "discreet" wavelength algorithms (using 4, 6, 8, and 10 wavelengths) and the broadband algorithm for the measurement of calculated Cytox were 0.54 (95% CI, 0.52-0.56), 0.87 (0.87-0.88), 0.88 (0.88-0.89), and 0.95 (0.95-0.95), respectively., Conclusions: The broadband and 10 wavelength algorithm were able to accurately track changes in Cytox for all experiments.

Background: Pro- and anti-inflammatory cytokines (adipokines) associated with adipose tissue can modulate inflammatory processes and lead to systemic inflammatory conditions such as metabolic syndrome. In the present pilot study, we investigated 3 major adipokines (leptin, adiponectin, and resistin) and 2 nonspecific proinflammatory cytokines (tumor necrosis factor α and interleukin-6) with regard to their association with postoperative pain intensity., Methods: We analyzed a total of 45 single-nucleotide polymorphisms of the adipokines in 57 patients with postlaparotomy pain. We adjusted for multiple testing to reduce the chance of false-positive results by controlling the false discovery rate. Serum levels of the adipokines and proinflammatory cytokines were measured in another 36 patients undergoing laparotomy. A stepwise multiple linear regression analysis using these measurements and opioid dosages as independent variables was performed to explore the factors associated with postoperative pain., Results: Only 1 variant of the resistin gene (rs3745367) demonstrated a significant association with postoperative pain (P < .002). Patients exhibiting homozygosity for the minor alleles (n = 7; numerical rating scale [NRS], 2.3 ± 1.3) demonstrated lower pain intensity compared with those exhibiting homozygosity for the major alleles (n = 29; NRS, 3.8 ± 1.0; P = .004) and heterozygosity for the minor alleles (n = 21; NRS, 4.2 ± 0.8; P < .001). Only serum resistin levels showed a positive association with postoperative pain., Conclusions: A genetic variant of resistin and serum resistin levels were associated with postoperative pain intensity, while other adipokines and cytokines exhibit no such association. Resistin can alter the inflammatory responses in postoperative wounds, although it could be a determinant factor that is independent of inflammatory processes. Resistin may be a novel marker for postoperative pain intensity.

If a representation of an auditory attention channel was present in the auditory cortices but not in the subcortical structures, it would be predicted that the early event-related brain potential (ERP) would disagree with the late ERP in selective attention effects. To examine this idea, the present study recorded the auditory brain stem response (ABR) as an early ERP and also the negative difference, the processing negativity and the irrelevant positive difference waves as late ERPs during dichotic listening. Each participant experienced two dichotic conditions: (i) 500-Hz standard tones to the left ear and 1000-Hz ones to the right ear (L500/R1000), (ii) 1000-Hz standard tones to the left ear and 500-Hz ones to the right ear (L1000/R500). In a control task, participants performed visual detection and ignored auditory stimuli. Although the negative difference and processing negativity were found to be identical between the two dichotic conditions, the ABR demonstrated a significant difference between relevant and irrelevant tasks only for the L500/R1000 condition. A response preference to lower-frequency tones was found for behavioural measures and late ERPs but not for the ABR. These results suggest difficulty in representing attention channels in the auditory brain stem. In addition, a weak effect of dichotic sound combination in behaviours corresponded only with earlier ERPs.

Objectives: To report cases of chronic autoimmune necrotizing myopathy with anti-signal recognition particle antibodies (anti-SRP myopathy) initially misdiagnosed as muscular dystrophy, in particular, facioscapulohumeral muscular dystrophy (FSHD)., Methods: Medical records of patients with anti-SRP myopathy in our institution were retrospectively reviewed., Results: All 6 patients were initially diagnosed with muscular dystrophy because of the long-term clinical course and lack of inflammation on biopsy; 5 were diagnosed with FSHD based on a winged scapula. However, the following features suggested an alternative diagnosis, leading to anti-SRP antibody measurement: (1) lack of family history, (2) lack of facial involvement and asymmetry, (3) prominent dysphagia, and (4) profuse spontaneous activities on needle electromyography. All patients showed improvement with immunomodulating therapy., Conclusions: Anti-SRP antibody measurement should be considered in patients diagnosed with FSHD if they present with diagnostic hallmarks of anti-SRP myopathy listed above, to avoid oversight of this potentially treatable disorder.

Rationale: The regulation of calcium (Ca(2+)) homeostasis by β-adrenergic receptor (βAR) activation provides the essential underpinnings of sympathetic regulation of myocardial function, as well as a basis for understanding molecular events that result in hypertrophic signaling and heart failure. Sympathetic stimulation of the βAR not only induces protein phosphorylation but also activates nitric oxide-dependent signaling, which modulates cardiac contractility. Nonetheless, the role of nitric oxide in βAR-dependent regulation of Ca(2+) handling has not yet been explicated fully., Objective: To elucidate the role of protein S-nitrosylation, a major transducer of nitric oxide bioactivity, on βAR-dependent alterations in cardiomyocyte Ca(2+) handling and hypertrophy., Methods and Results: Using transgenic mice to titrate the levels of protein S-nitrosylation, we uncovered major roles for protein S-nitrosylation, in general, and for phospholamban and cardiac troponin C S-nitrosylation, in particular, in βAR-dependent regulation of Ca(2+) homeostasis. Notably, S-nitrosylation of phospholamban consequent upon βAR stimulation is necessary for the inhibitory pentamerization of phospholamban, which activates sarcoplasmic reticulum Ca(2+)-ATPase and increases cytosolic Ca(2+) transients. Coincident S-nitrosylation of cardiac troponin C decreases myocardial sensitivity to Ca(2+). During chronic adrenergic stimulation, global reductions in cellular S-nitrosylation mitigate hypertrophic signaling resulting from Ca(2+) overload., Conclusions: S-Nitrosylation operates in concert with phosphorylation to regulate many cardiac Ca(2+)-handling proteins, including phospholamban and cardiac troponin C, thereby playing an essential and previously unrecognized role in cardiac Ca(2+) homeostasis. Manipulation of the S-nitrosylation level may prove therapeutic in heart failure., (© 2015 American Heart Association, Inc.)

Background: An intriguing potential clinical use of cerebral oximeter measurements (SctO2) is the ability to noninvasively estimate jugular bulb venous oxygen saturation (SjvO2). Our purpose in this study was to determine the accuracy of the FORE-SIGHT(®) (CAS Medical Systems, Branford, CT), which is calibrated to a weighted average of 70% (SjvO2) and 30% arterial saturation, for Food and Drug Administration pre-market approval 510(k) certification by adapting an industry standard protocol, ISO 9919:2005 (www.ISO.org) (used for pulse oximeters), and to evaluate the use of SctO2 and SpO2 measurements to noninvasively estimate jugular venous oxygen saturation (SnvO2)., Methods: Paired blood gas samples from the radial artery and the jugular venous bulb were collected from 20 healthy volunteers undergoing progressive oxygen desaturation from 100% to 70%. The blood sample pairs were analyzed via co-oximetry and used to calculate the approximate mixed vascular cerebral blood oxygen saturation, or reference SctO2 values (refSctO2), during increasing hypoxia. These reference values were compared to bilateral FORE-SIGHT SctO2 values recorded simultaneously with the blood gas draws to determine its accuracy. Bilateral SctO2 and SpO2 measurements were then used to calculate SnvO2 values which were compared to SjvO2., Results: Two hundred forty-six arterial and 253 venous samples from 18 subjects were used in the analysis. The ipsilateral FORE-SIGHT SctO2 values showed a tolerance interval (TI) of [-10.72 to 10.90] and Lin concordance correlation coefficient (CCC) with standard error (SE) of 0.83 ± 0.073 with the refSctO2 values calculated using arterial and venous blood gases. The ipsilateral data had a CCC of 0.81 + 0.059 with TI of [-9.22 to 9.40] with overall bias of 0.09%, and amplitude of the root mean square of error after it was corrected with random effects analysis was 2.92%. The bias and variability values between the ipsilateral and the contralateral FORE-SIGHT SctO2 measurements varied from person to person. The SnvO2 calculated from the ipsilateral SctO2 and SpO2 data showed a CCC ± SE of 0.79 ± 0.088, TI = [-14.93 to 15.33], slope of 0.98, y-intercept of 1.14% with SjvO2 values with a bias of 0.20% and an Arms of 4.08%. The SnvO2 values calculated independently from contralateral forehead FORE-SIGHT SctO2 values were not as correlated with the SjvO2 values (contralateral side CCC + SE = 0.72 ± 0.118, TI = [-14.86 to 15.20], slope of 0.66, and y-intercept of 20.36%)., Conclusions: The FORE-SIGHT cerebral oximeter was able to estimate oxygen saturation within the tissues of the frontal lobe under conditions of normocapnia and varying degrees of hypoxia (with 95% confidence interval of [-5.60 to 5.78] with ipsilateral blood sample data). These findings from healthy volunteers also suggest that the use of the calculated SnvO2 derived from SctO2 and SpO2 values may be a reasonable noninvasive method of estimating SjvO2 and therefore global cerebral oxygen consumption in the clinical setting. Further laboratory and clinical research is required to define the clinical utility of near-infrared spectroscopy determination of SctO2 and SnvO2 in the operating room setting.

Advanced complex surgery performed with the natural orifice translumenal endoscopic surgery technique requires use of a multitasking platform. The aim of this study is to evaluate the basic functionality of a prototype multitasking platform "EndoSAMURAI" with the use of a biosimulation model and ex vivo porcine stomach. We compared the performance of basic surgical skill tasks between the EndoSAMURAI and standard laparoscopic instrumentation. Basic surgical tasks include cutting, dissection, and suturing and knot tying. Main outcome measurements were the time to complete each task and leak pressure to evaluate the quality of the suturing and knot tying. Although it took longer to perform all basic surgical tasks with the EndoSAMURAI than with laparoscopic instrumentation, all tasks could be performed precisely and with an accuracy comparable to that of the laparoscopic technique. Leak pressures of the gastric closure site between both techniques were also comparable.

The GSK-3β gene, GSK3B, codes for an enzyme that is a target for the action of mood stabilizers, lithium and possibly valproic acid.In this study, the relationship between haplotypes consisting of single nucleotide polymorphisms (SNPs) of GSK3B -50T/C and -1727A/T and the effect of lithium was studied among Japanese bipolar disorder lithium nonresponders and responders.The distributions of the GSK3B haplotypes (-50T/C and -1727A/T) showed a trend for significant difference between the lithium nonresponders and responders (global P=0.07074). Haplotype 1 (T-A) was associated with a higher lithium response (haplotype-specific P=0.03477), whereas haplotype 2 (C-A) was associated with a lower lithium response (haplotype-specific P=0.03443).The pairwise D' and r values between the 2 SNPs in this study were 1.0 and 0.097, respectively. The 2 SNPs showed weak linkage disequilibrium with each other.

Purpose: Endoscopic retrograde cholangiopancreatography (ERCP) has played a major role in the diagnosis of biliary and pancreatic diseases. The prevalence and mortality rate of post-ERCP pancreatitis (PEP) remains a serious issue that needs to be resolved. Here, we report the first ERCP study that was conducted at a high-volume center of an educational institution in Japan., Methods: This study investigated patients with suspected biliary and pancreatic diseases who had undergone ERCP between April 2006 and June 2009. We created a database and analyzed preoperative and postoperative data. Patients who had undergone surgery and those with a history of undergoing duodenal papilla treatment were excluded., Results: Mild (n=62) or moderate (n=3) pancreatitis was present in 65 cases (6.21%; 36 men and 29 women). A univariate analysis identified age under 50 years (P=0.01), pancreatography (P<0.001), and biliary stent placement (P<0.001). A Multivariate analysis was performed for evaluating the risk factors associated with PEP. This analysis identified age of the patients under 50 years [P=0.003; odds ratio (OR), 0.37; 95% confidence interval (CI), 0.19-0.71], endoscopic papillary balloon dilation (P=0.012; OR, 4.69; 95% CI, 1.41-15.54), pancreatography (P<0.001; OR, 5.55; 95% CI, 2.98-10.33), and plastic stent placement (P<0.001; OR, 3.77; 95% CI, 2.17-6.54). Descriptive statistics showed that only pancreatography was associated with PEP. An additional sphincterotomy did not increase the risk of PEP (P=0.306; OR, 2.03; 95% CI, 0.52-7.84), and even adjusted for pancreatography., Conclusions: We changed the size of the stent to 7-Fr. In the future, we plan to repeat the same study with a higher number of cases.

Yu et al.(1) reported that iron levels in the temporal cortex were reduced in patients with Parkinson disease (PD) compared with age-matched controls. They also determined that patients with Alzheimer disease (AD) had no change in iron levels in the temporal cortex. We would like to know whether Yu et al.(1) included any patients with memory disturbance in this study.

Objective: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a childhood encephalopathy following severe febrile seizures, leaving neurologic sequelae in many patients. However, its pathogenesis remains unclear. In this study, we clarified that genetic variation in the adenosine A2A receptor (ADORA2A), whose activation is involved in excitotoxicity, may be a predisposing factor of AESD., Methods: We analyzed 4 ADORA2A single nucleotide polymorphisms in 85 patients with AESD. The mRNA expression in brain samples, mRNA and protein expression in lymphoblasts, as well as the production of cyclic adenosine monophosphate (cAMP) by lymphoblasts in response to adenosine were compared among ADORA2A diplotypes., Results: Four single nucleotide polymorphisms were completely linked, which resulted in 2 haplotypes, A and B. Haplotype A (C at rs2298383, T at rs5751876, deletion at rs35320474, and C at rs4822492) frequency in patients was significantly higher than in controls (p = 0.005). Homozygous haplotype A (AA diplotype) had a higher risk of developing AESD (odds ratio 2.32, 95% confidence interval 1.32-4.08; p = 0.003) via a recessive model. mRNA expression was significantly higher in AA than AB and BB diplotypes, both in the brain (p = 0.003 and 0.002, respectively) and lymphoblasts (p = 0.035 and 0.003, respectively). In lymphoblasts, ADORA2A protein expression (p = 0.024), as well as cellular cAMP production (p = 0.0006), was significantly higher in AA than BB diplotype., Conclusions: AA diplotype of ADORA2A is associated with AESD and may alter the intracellular adenosine/cAMP cascade, thereby promoting seizures and excitotoxic brain damage in patients.

Background: Rapid delivery of potent opioid to the systemic circulation is an important feature for the effective treatment of acute and acute-on-chronic breakthrough pain. The delivery of different opioids by the pulmonary route has been inconsistent, usually resulting in low bioavailability of the drug. Staccato® Fentanyl for Inhalation is a handheld inhaler producing a single metered dose of aerosolized fentanyl during a single inspiration. The aerosol is of high purity (≥98%) at a particle size (1 to 3.5 microns) shown to be best for pulmonary absorption., Methods: We conducted the study in healthy volunteers in 2 stages. In the crossover stage, 10 subjects received IV fentanyl 25 µg and inhaled fentanyl 25 µg on separate occasions. The dose escalation stage was a multidose, randomized, double-blind, placebo-controlled, single-period dose escalation study of inhaled fentanyl (50 to 300 µg). Serial blood sampling was performed over an 8-hour period after drug administration to determine the pharmacokinetic profile, and serial pupillometry was performed as a measure of pharmacodynamic effect., Results: In the crossover stage the pharmacokinetic profiles of the inhaled and IV fentanyl showed similar peak arterial concentrations and areas under the curve. The time to maximum concentration was slightly shorter for the inhaled than IV fentanyl, 20.5 and 31.5 seconds, respectively. In the dose escalation stage the administration of repeated doses resulted in predictable, dose-dependent serum concentrations., Conclusions: This study has demonstrated that the pharmacokinetic profile of single doses of inhaled fentanyl is comparable to IV administration.

Hypothesis: The present study assessed how to inject a gene into the mouse vestibule and which is the optimum gene to the mouse vestibule adenovirus (AdV) vector or adeno-associated virus (AAV) vector., Background: Loss of vestibular hair cell is seen in various balance disorder diseases. There have been some reports concerning gene delivery to the mouse vestibule in recent years. To effectively induce transgene expression at the vestibule, we assessed the efficiency of inoculating the mouse inner ear using various methods., Methods: We employed an AdV- and AAV-carrying green fluorescent protein using a semicircular canal approach (via a canalostomy) and round window approach., Results: AAV injection via canalostomy induced gene expression at the hair cells, supporting cells, and fibrocytes at the vestibular organs without auditory or balance dysfunction, suggesting it was the most suitable transfection method. This method is thus considered to be a promising strategy to prevent balance dysfunction., Conclusion: AAV injection via canalostomy to the vestibule is the noninvasive and highly efficient transfection method, and this study may have the potential to repair balance disorders in human in the future.

The effect of visual and auditory enhancements of finger movement on corticospinal excitability during motor imagery (MI) was investigated using the transcranial magnetic stimulation technique. Motor-evoked potentials were elicited from the abductor digit minimi muscle during MI with auditory, visual and, auditory and visual information, and no information. Ten healthy participants were instructed to imagine repetitive abduction and adduction of the fifth finger. After each condition, the extent of vividness of MI was rated using a visual analogue scale. The results showed that the mean visual analogue scale score and motor-evoked potentials amplitude for the auditory and visual condition were higher than those of other conditions, indicating an enhanced excitability of the primary motor cortex with a clearer image of motor action during MI.

Background: Diabetic cardiomyopathy is characterized by energetic dysregulation caused by glucotoxicity, lipotoxicity, and mitochondrial alterations. p53 and its downstream mitochondrial assembly protein, synthesis of cytochrome c oxidase 2 (SCO2), are important regulators of mitochondrial respiration, whereas the involvement in diabetic cardiomyopathy remains to be determined., Methods and Results: The role of p53 and SCO2 in energy metabolism was examined in both type I (streptozotocin [STZ] administration) and type II diabetic (db/db) mice. Cardiac expressions of p53 and SCO2 in 4-week STZ diabetic mice were upregulated (185% and 152% versus controls, respectively, P<0.01), with a marked decrease in cardiac performance. Mitochondrial oxygen consumption was increased (136% versus control, P<0.01) in parallel with augmentation of mitochondrial cytochrome c oxidase (complex IV) activity. Reactive oxygen species (ROS)-damaged myocytes and lipid accumulation were increased in association with membrane-localization of fatty acid translocase protein FAT/CD36. Antioxidant tempol reduced the increased expressions of p53 and SCO2 in STZ-diabetic hearts and normalized alterations in mitochondrial oxygen consumption, lipid accumulation, and cardiac dysfunction. Similar results were observed in db/db mice, whereas in p53-deficient or SCO2-deficient diabetic mice, the cardiac and metabolic abnormalities were prevented. Overexpression of SCO2 in cardiac myocytes increased mitochondrial ROS and fatty acid accumulation, whereas knockdown of SCO2 ameliorated them., Conclusions: Myocardial p53/SCO2 signal is activated by diabetes-mediated ROS generation to increase mitochondrial oxygen consumption, resulting in excessive generation of mitochondria-derived ROS and lipid accumulation in association with cardiac dysfunction.

Burn injury initiates an enhanced inflammatory condition referred to as the systemic inflammatory response syndrome or the two-hit response phenotype. Prior reports indicated that macrophages respond to injury and demonstrate a heightened reactivity to Toll-like receptor stimulation. Since we and others observed a significant increase in splenic GR-1 F4/80 CD11b macrophages in burn-injured mice, we wished to test if these macrophages might be the primary macrophage subset that shows heightened LPS reactivity. We report here that burn injury promoted higher level TNF-α expression in GR-1, but not GR-1 macrophages, after LPS activation both in vivo and ex vivo. We next tested whether CD4 T cells, which are known to suppress injury-induced inflammatory responses, might control the activation and expansion of GR-1 macrophages. Interestingly, we found that GR-1 macrophage expansion and LPS-induced TNF-α expression were not significantly different between wild-type and CD4 T cell-deficient CD4(-/-) mice. However, further investigations showed that LPS-induced TNF-α production was significantly influenced by CD4 T cells. Taken together, these data indicate that GR-1 F4/80 CD11b macrophages represent the primary macrophage subset that expands in response to burn injury and that CD4 T cells do not influence the GR-1 macrophage expansion process, but do suppress LPS-induced TNF-α production. These data suggest that modulating GR-1 macrophage activation as well as CD4 T cell responses after severe injury may help control the development of systemic inflammatory response syndrome and the two-hit response phenotype.

Objective: Reactive oxygen species (ROS) are involved in the initial process of atherosclerosis, whereas it remains to be determined how atherogenic stimulus causes ROS-mediated proinflammatory reactions. Here, we focused on proline-rich tyrosine kinase (PYK2)-mediated ROS generation and examined how atherogenic stimulus causes early proinflammatory reactions., Methods and Results: PYK2-deficient (knockout [KO]) (PYK2-KO) mice were crossbred with apolipoprotein E (ApoE)-deficient (PYK2-KO/ApoE-KO) mice. PYK2-KO/ApoE-KO mice and endothelial cells (EC) were used for the study. Aortic atherogenic lesions in PYK2-KO/ApoE-KO mice were markedly decreased (55% versus ApoE-KO) after 8 weeks of a Western diet. Aortic PYK2 was activated as early as 7 days after the Western diet, when inflammatory cells were not yet activated. Addition of the proatherogenic oxidized phospholipid lysophosphatidylcholine caused activation of endothelial PYK2. Lysophosphatidylcholine-activated PYK2 induced NADPH oxidase-mediated ROS generation and ROS-mediated synthesis of tumor necrosis factor-α (TNFα), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemotactic protein-1 (MCP-1), and p21Cip1/Ets-1. Neutralizing anti-TNFα antibody or knockdown of p21Cip1/Ets-1 system blocked the induction of VCAM-1 and MCP-1. PYK2 deficiency abolished these ROS-mediated proinflammatory reactions. Further analysis revealed that PYK2/ROS-mediated p21Cip1/Ets-1 activation upregulated the transcription of the MCP-1 gene in collaboration with p300 transcription coactivator., Conclusions: PYK2 is a key tyrosine kinase activated by high cholesterol exposure, which causes ROS-mediated TNFα release and induces TNFα-dependent expression of proinflammatory molecules via the p21Cip1/Ets-1/p300 transcription system.

Objective: The goal of this study was to investigate the effects of stimulants for a nucleotide-binding domain, leucine-rich repeat-containing (NLR) protein family on human artery endothelial cells and murine arteries., Methods and Results: Human coronary artery endothelial cells were challenged in vitro with microbial components that stimulate NLRs or Toll-like receptors. We found stimulatory effects of NLR and Toll-like receptor ligands on the adhesion molecule expression and cytokine secretion by human coronary artery endothelial cells. On the basis of these results, we examined the in vivo effects of these ligands in mice. Among them, FK565, 1 of the nucleotide-binding oligomerization domain (Nod)-1 ligands induced strong site-specific inflammation in the aortic root. Furthermore, coronary arteritis/valvulitis developed after direct oral administration or ad libitum drinking of FK565. The degree of the respective vascular inflammation was associated with persistent high expression of proinflammatory chemokine/cytokine and matrix metallopeptidase (Mmp) genes in each tissue in vivo by microarray analysis., Conclusions: This is the first coronary arteritis animal model induced by oral administration of a pure synthetic Nod1 ligand. The present study has demonstrated an unexpected role of Nod1 in the development of site-specific vascular inflammation, especially coronary arteritis. These findings might lead to the clarification of the pathogenesis and pathophysiology of coronary artery disease in humans.

Although it is known that injury enhances the regulatory activity of CD4 regulatory T cells (Tregs), the cellular and molecular mechanisms responsible for injury-induced Treg activation remain unclear. This study was designed to investigate and compare injury-induced T-cell receptor (TCR) signaling in Tregs, non-Tregs, and CD8 T cells. Specifically, we used phospho-flow cytometry to measure the expression and phosphorylation of ZAP-70, protein kinase C θ, nuclear factor of activated T cells, and glycogen synthase kinase 3β in FoxP3 Tregs versus FoxP3 non-Tregs versus CD8 T cells. Groups of male C57BL/6J mice underwent burn or sham injury, and lymph nodes and spleens were harvested at early time points-15, 30, 60, 120, and 240 min-to measure TCR signaling. As early as 15 min after burn injury, we observed a significant upregulation and phosphorylation of ZAP-70, protein kinase C θ, nuclear factor of activated T cells, and glycogen synthase kinase 3β in Tregs prepared from injury-site-draining lymph nodes. Burn injury did not activate TCR signaling in Tregs from the spleen or in CD4 non-Tregs and CD8 T cells. In conclusion, the results of this study demonstrate that burn injury activates TCR signaling in Tregs, but not non-Tregs or CD8 T cells. These findings suggest that injury provides an early TCR-activating signal to Tregs and supply new insights into how injury influences the adaptive immune system.

Menthol is known as an agonist for cold-sensitive transient receptor potential channels (TRPM8) and also as a direct modulator of GABA channels. We examined the effects of menthol on respiratory rhythm generation in the brainstem-spinal cord preparations isolated from newborn rats. Menthol decreased respiratory rhythm dose-dependently (0.1-1 mM). Effects of menthol were reversed by the GABAA antagonist, bicuculline. Menthol caused pronounced reduction in the driving potential of pre-inspiratory but not inspiratory neurons. Expression of the TRPM8 channel protein was not detected in the respiratory related region of the rostral ventrolateral medulla by immunohistochemistry. The results suggest that the potent inhibitory action of menthol on burst generation of pre-inspiratory neurons is because of direct activation of tonic GABA channels by menthol.

Objective: Vascular calcification is an important risk factor for cardiovascular diseases. Here, we investigated a role of dedifferentiated vascular smooth muscle cells (VSMCs) in the atherosclerotic intimal calcification., Methods and Results: We prepared human cultured VSMCs in either redifferentiatiated or dedifferentiated state and analyzed the gene expressions of bone-calcification regulatory factors. Expression of bone morphogenetic protein-2 (BMP-2), a potent initiator for osteoblast differentiation, was significantly enhanced in dedifferentiated VSMCs. Furthermore, endogenous BMP-2 antagonists, such as noggin, chordin, and matrix gamma-carboxyglutamic acid protein, were all downregulated in the dedifferentiated VSMCs. Conditioned medium from dedifferentiated VSMCs, but not from redifferentiated VSMCs, stimulated the osteoblastic differentiation of the mesenchymal progenitor C2C12 cells, which was abolished by BMP-2 knockdown. In atherosclerotic intima from apolipoprotein (apo)E-deficient mice, αSM-actin-positive cells, presumably dedifferentiated VSMCs, expressed BMP-2. We generated BMP-2-transgenic mice using αSM-actin promoter and crossed them with apoE-deficient mice (BMP-2-transgenic/apoE-knockout). Significantly accelerated atherosclerotic intimal calcification was detected in BMP-2-transgenic/apoE-knockout mice, although serum lipid concentration and atherosclerotic plaque size were not different from those in apoE-knockout mice. Enhanced calcification appeared to be associated with the frequent emergence of osteoblast-like cells in atherosclerotic intima in BMP-2-transgenic/apoE-knockout mice., Conclusions: Our findings collectively demonstrate an important role of dedifferentiated VSMCs in the pathophysiology of atherosclerotic calcification through activating paracrine BMP-2 osteogenic signals.

This study examined the basis for introducing an ignoring task during cortical evoked response audiometry (CERA) using the N1-P2 response. Healthy hearing participants were assigned to two groups with and without an ignoring task (ignoring and listening groups) during CERA whose outcomes were compared with the pure-tone audiometry (PTA) in response to tone frequencies at 500-4000 Hz. The ignoring but not the listening group exhibited positive correlations between the PTA and CERA thresholds, and further showed negative correlations between the PTA threshold and the N1-P2 amplitude as the tone intensity decreased particularly for lower tone frequencies. Within the healthy hearing levels at least, conducting an ignoring task is thus considered to improve the validity of CERA for lower tone frequencies.

This study examined a notion that auditory discrimination is a requisite for attention-related modulation of the auditory brainstem response (ABR) during contralateral noise exposure. Given that the right ear was exposed continuously with white noise at an intensity of 60-80 dB sound pressure level, tone pips at 80 dB sound pressure level were delivered to the left ear through either single-stimulus or oddball procedures. Participants conducted reading (ignoring task) and counting target tones (attentive task) during stimulation. The oddball but not the single-stimulus procedures elicited task-related modulations in both early (ABR) and late (processing negativity) event-related potentials simultaneously. The elicitation of the attention-related ABR modulation during contralateral noise exposure is thus considered to require auditory discrimination and have the corticofugal nature evidently.

Objective: Bone marrow (BM)-derived endothelial progenitor cells (EPCs) and vascular smooth muscle progenitor cells (VPCs) contribute to neointima formation, whereas the angiotensin II (Ang II) type 1 receptor (AT(1))-mediated action on BM-derived progenitors remains undefined., Methods and Results: A wire-induced vascular injury was performed in the femoral artery of BM-chimeric mice whose BM was repopulated with AT(1)-deficient (BM-Agtr1(-/-)) or wild-type (BM-Agtr1(+/+)) cells. Neointima formation was profoundly reduced by 38% in BM-Agtr1(-/-) mice. Although the number of circulating EPCs (Sca-1(+)Flk-1(+)) and extent of reendothelialization did not differ between the 2 groups, the numbers of both circulating VPCs (c-Kit(-)Sca-1(+)Lin(-)) and tissue VPCs (Sca-1(+)CD31(-)) incorporated into neointima were markedly decreased in BM-Agtr1(-/-) mice. The accumulation of aggregated platelets and their content of stromal cell-derived factor-1alpha (SDF-1alpha) were significantly reduced in BM-Agtr1(-/-) mice, accompanied by a decrease in the serum level of SDF-1alpha. Thrombin-induced platelets aggregation was dose-dependently inhibited (45% at 0.1 IU/mL, P<0.05) in Agtr1(-/-) platelets compared with Agtr1(+/+) platelets, accompanied by the reduced expression and release of SDF-1alpha., Conclusions: The BM-AT(1) receptor promotes neointima formation by regulating the mobilization and homing of BM-derived VPCs in a platelet-derived SDF-1alpha-dependent manner without affecting EPC-mediated reendothelialization.

Individual differences in sensitivity to fentanyl, a widely used opioid analgesic, can hamper effective pain treatment. Still controversial is whether the single nucleotide polymorphisms (SNPs) of the human OPRM1 gene encoding the mu-opioid receptor influence the analgesic effects of opioids. We examined associations between fentanyl sensitivity and the two SNPs, A118G and IVS3+A8449G, in the human OPRM1 gene in 280 Japanese patients undergoing painful orofacial cosmetic surgery, including bone dissection. Regarding the A118G SNP in exon 1, in a cold pressor-induced pain test before surgery, less analgesic effects of fentanyl were shown in subjects carrying the minor G allele of the A118G SNP (median of difference between pain perception latencies before and after fentanyl injection [PPLpost-PPLpre]: 12s) compared with subjects not carrying this allele (PPLpost-PPLpre: 15s, p=0.046). Furthermore, the IVS3+A8449G SNP in intron 3, which represents a complete linkage disequilibrium block with more than 30 SNPs from intron 3 to the 3' untranslated region, was associated with 24-h postoperative fentanyl requirements. Subjects carrying the minor G allele of the IVS3+A8449G SNP required significantly less fentanyl for 24-h postoperative pain control (median: 1.5microg/kg) compared with subjects not carrying this allele (median: 2.5microg/kg, p=0.010). Although further validation is needed, the present findings shed light on the involvement of OPRM1 3' untranslated region polymorphisms in fentanyl sensitivity in addition to the A118G SNP and open new avenues for personalized pain treatment with fentanyl.

Background: We propose a new phototherapy using polarized light from light emitting diode (LED). The purpose of this study is to clarify the effect of polarized LED irradiation on wound healing., Methods: Five groups were classified: control (C), unpolarized (U), linearly polarized (L), right circularly polarized (RC), and left circularly polarized (LC) LED irradiation. In vitro study, fibroblast cell cultures were irradiated, and cellular proliferation was evaluated with a WST-8 assay. In vivo study, full-thickness skin defect of 20 mm diameter was created on the dorsal side of rats. The ratio of the residual wound area was measured, and expression of type 1 and type 3 procollagen mRNA in granulation tissue was determined by real-time reverse transcription polymerase chain reaction method., Results: The cellular proliferation rates of group RC and L were significantly higher than other groups. The ratio of the residual wound area of group RC and L was significantly reduced than group C and U. Expression of type 1 procollagen mRNA in group RC was found to be significantly increased about 1.5-fold in comparison with the group C. There were no significant differences for type 3 procollagen., Conclusions: The right circularly polarized light and linearly polarized light promoted the process of wound healing by increasing the proliferation of fibroblasts, and the right circularly polarized light increased the expression of type 1 procollagen mRNA. The effectiveness of right circularly polarized light suggests that some optical active material, which has a circular dichroic spectrum, takes part in a biochemical reaction.

The precise movement of human fingers requires continuous and reciprocal interaction between motor and sensory systems. Similar to other primates, there is double representation of the digits and wrists within the human primary motor cortex (M1), which are generally referred to as area 4 anterior (M1-4a) and area 4 posterior (M1-4p). In this high-field (3.0 T) functional magnetic resonance imaging (fMRI) study, we hypothesized that M1-4p is more important for initiation of motion, whereas M1-4a is important for execution of a given motion involving more complex sensoriomotor interaction. We investigated M1-4a and M1-4p activation associated with two representative motor tasks, namely, finger tapping (voluntary motion, VM) and passive finger movement accomplished by continuous pressure (passive motor, PM), and two representative sensory stimulations, namely, simple stimulation of flutter vibration (simple sensory, SS), and complex stimulation by a row of pins moving either vertically or horizontally (complex sensory, CS). Both M1-4a and M1-4p were activated in both motor tasks, VM and PM. M1-4p was not activated by either of the two sensory tasks, whereas M1-4a was activated by CS but not by SS. Analysis of the center of gravities (COG) of the activated areas showed that VM and PM moved COG towards M1-4p and 3a. SS moved COG towards somatosensory cortex Brodmann areas 1, 2, and 3b, whereas CS towards M1-4a. The result clearly showed that M1-4a represents the area of secondary motor execution, which actively participates in CS processing.