Effects of ON101 for Hard-to-Heal Diabetic Foot Ulcers in A Randomized Phase III Trial: A Post hoc Analysis.

OBJECTIVE: Hard-to-heal diabetic foot ulcers (DFUs) are associated with higher mortality rates and an increased medical burden for patients. ON101, a new topical cream, exhibited better healing efficacy than the control dressing in a Phase III trial. In this post-hoc analysis, we further identify whether ON101 can improve the healing of ulcers with hard-to-heal risk factors in this cohort of DFU patients. APPROACH: To compare the efficacy of ON101 with absorbent dressing among various hard-to-heal wounds in patients with DFU, a post hoc analysis of a randomized phase III trial included 276 DFU patients was performed by subgrouping those patients based on ulcer depth, location, size, duration, and patients' glycated hemoglobin (HbA1c) levels and body mass index (BMI). RESULTS: In the full analysis set, the proportion of patients achieving healing was 61.7% in the ON101 group and 37.0% in the comparator (P =0.0001). In sub-group analysis according to risk factors, ON101 demonstrated superior healing capacity on Wagner grade 2 ulcers (P < 0.0001); plantar ulcers (P = 0.0016), ulcers size ≥5 cm² (P = 0.0122), ulcers duration ≥3 months (P = 0.0043); for patients with HbA1c ≥9% (P = 0.0285); and patients with BMI ≥25 (P = 0.0005). INNOVATION: ON101, a novel therapeutic drug, can modulate the functions of macrophages and demonstrate superior healing rates to conventional absorbent dressing in patients with hard-to-heal DFUs. CONCLUSIONS: The results of this post hoc study suggest that ON101 is a better therapeutic option than conventional dressing used in treatment for DFU patients with higher HbA1c, BMI, or ulcers with complex conditions such as longer duration, deeper wounds, larger size, and plantar location.

Hyperbaric oxygen therapy suppresses hypoxia and reoxygenation injury to retinal pigment epithelial cells through activating peroxisome proliferator activator receptor-alpha signalling.

Retinal ischemia followed by reperfusion (IR) is a common cause of many ocular disorders, such as age-related macular degeneration (AMD), which leads to blindness in the elderly population, and proper therapies remain unavailable. Retinal pigment epithelial (RPE) cell death is a hallmark of AMD. Hyperbaric oxygen (HBO) therapy can improve IR tissue survival by inducing ischemic preconditioning responses. We conducted an in vitro study to examine the effects of HBO preconditioning on oxygen-glucose deprivation (OGD)-induced IR-injured RPE cells. RPE cells were treated with HBO (100% O2 at 3 atmospheres absolute for 90 min) once a day for three consecutive days before retinal IR onset. Compared with normal cells, the IR-injured RPE cells had lower cell viability, lower peroxisome proliferator activator receptor-alpha (PPAR-α) expression, more severe oxidation status, higher blood-retinal barrier disruption and more elevated apoptosis and autophagy rates. HBO preconditioning increased PPAR-α expression, improved cell viability, decreased oxidative stress, blood-retinal barrier disruption and cellular apoptosis and autophagy. A specific PPAR-α antagonist, GW6471, antagonized all the protective effects of HBO preconditioning in IR-injured RPE cells. Combining these observations, HBO therapy can reverse OGD-induced RPE cell injury by activating PPAR-α signalling.

The Clinical Application of Pulsed Radiofrequency Induces Inflammatory Pain via MAPKs Activation: A Novel Hint for Pulsed Radiofrequency Treatment.

Pulsed radiofrequency (PRF) works by delivering short bursts of radiofrequency to a target nerve, thereby affecting nerve signal transduction to reduce pain. Although preliminary clinical investigations have shown that PRF treatment can be used safely as an alternative interventional treatment in patients with refractory pain conditions, unexpected damage to a normal nerve/ganglion is still one of the possible complications of using the PRF strategy. Noxious pain may also be triggered if PRF treatment accidentally damages an intact nerve. However, few studies in the literature have described the intracellular modifications that occur in neuronal cells after PRF stimulation. Therefore, in this study, we evaluated the effects of PRF on unimpaired nerve function and investigated the potential mechanisms of PRF-induced pain. Wistar rats were stimulated with 30-60 V of PRF for 6 min, and mechanical allodynia, cold hypersensitivity, cytokine and matrix metalloproteinase (MMP) production, and mitogen-activated protein kinase activity (p38 MAPK, ERK1/2, JNK/SAPK) were analyzed. The results indicated that PRF stimulation induced a significant algesic effect and nociceptive response. In addition, the protein array and Western blotting analyses showed that the clinical application of 60 V of PRF can induce the activation of MAPKs and the production of inflammatory cytokines and MMPs in the lumbar dorsal horn, which is necessary for nerve inflammation, and it can be suppressed by MAPK antagonist treatment. These results indicate that PRF stimulation may induce inflammation of the intact nerve, which in turn causes inflammatory pain. This conclusion can also serve as a reminder for PRF treatment of refractory pain.

Effect of a Novel Macrophage-Regulating Drug on Wound Healing in Patients With Diabetic Foot Ulcers: A Randomized Clinical Trial.

Importance: Delayed healing of diabetic foot ulcers (DFUs) is known to be caused by dysregulated M1/M2-type macrophages, and restoring the balance between these macrophage types plays a critical role in healing. However, drugs used to regulate M1/M2 macrophages have not yet been studied in large randomized clinical trials. Objective: To compare the topical application of ON101 cream with use of an absorbent dressing (Hydrofiber; ConvaTec Ltd) when treating DFUs. Design, Setting, and Participants: This multicenter, evaluator-blinded, phase 3 randomized clinical trial was performed in 21 clinical and medical centers across the US, China, and Taiwan from November 23, 2012, to May 11, 2020. Eligible patients with debrided DFUs of 1 to 25 cm2 present for at least 4 weeks and with Wagner grade 1 or 2 were randomized 1:1 to receive ON101 or control absorbent dressings. Interventions: Twice-daily applications of ON101 or a absorbent dressing changed once daily or 2 to 3 times a week for 16 weeks, with a 12-week follow-up. Main Outcomes and Measures: The primary outcome was the incidence of complete healing, defined as complete re-epithelialization at 2 consecutive visits during the treatment period assessed on the full-analysis set (FAS) of all participants with postrandomization data collected. Safety outcomes included assessment of the incidences of adverse events, clinical laboratory values, and vital signs. Results: In the FAS, 236 eligible patients (175 men [74.2%]; mean [SD] age, 57.0 [10.9] years; mean [SD] glycated hemoglobin level, 8.1% [1.6%]) with DFUs classified as Wagner grade 1 or 2 (mean [SD] ulcer area, 4.8 [4.4] cm2) were randomized to receive either the ON101 cream (n = 122) or the absorbent dressing (n = 114) for as long as 16 weeks. The incidence of complete healing in the FAS included 74 patients (60.7%) in the ON101 group and 40 (35.1%) in the comparator group during the 16-week treatment period (difference, 25.6 percentage points; odds ratio, 2.84; 95% CI, 1.66-4.84; P < .001). A total of 7 (5.7%) treatment-emergent adverse events occurred in the ON101 group vs 5 (4.4%) in the comparator group. No treatment-related serious adverse events occurred in the ON101 group vs 1 (0.9%) in the comparator group. Conclusions and Relevance: In this multicenter randomized clinical trial, ON101 exhibited better healing efficacy than absorbent dressing alone in the treatment of DFUs and showed consistent efficacy among all patients, including those with DFU-related risk factors (glycated hemoglobin level, ≥9%; ulcer area, >5 cm2; and DFU duration, ≥6 months). Trial Registration: ClinicalTrials.gov Identifier: NCT01898923.

Detection rate of breast malignancy of needle localization biopsy of breast microcalcification.

OBJECTIVE: The current study aimed to retrospectively assess the cancer detection rate of needle localization biopsy of breast microcalcifications undetectable on sonography. MATERIALS AND METHODS: Patients who underwent mammography-guided needle localization biopsy of breast microcalcifications undetectable on sonography from January 2005 to December 2017 were included in the study. Patients with incomplete medical records were excluded from the study. Patient mammograms were categorized using the Breast Imaging-Reporting and Data System (BI-RADS) assessment criteria. The percentages of benign and malignant lesions were determined by pathological examination of surgically recovered specimens. Correlation between preoperative imaging assessment and final diagnosis was investigated, and the complications associated with the procedures were recorded. RESULTS: A total of 301 needle-localized biopsies were performed under mammographic guidance. The mean age of the patients was 58.18 ± 7.73 years. The overall ductal carcinoma in situ (DCIS) and cancer detection rate was 23.3%. The proportion of patients with BI-RADS 0 category and undergoing second mammography was higher in the DCIS and cancer group. A total of 227 patients did not undergo second mammography. Of these patients, 70 demonstrated BI-RADS 4 category, 34 were diagnosed with DCIS, and 5 were diagnosed with breast cancer during subsequent follow-up. CONCLUSION: Needle-localized excision of microcalcifications undetectable on sonography has high detection rate for early stage of breast cancer with low risk of associated complications. Regular mammography is a satisfactory follow-up tool for female patients with microcalcifications in the breasts. Additional studies should be performed to compare between needle-localized excision and vacuum-assisted breast biopsy.

Anti-inflammatory effects of powdered product of Bu Yang Huan Wu decoction: Possible role in protecting against Transient Focal Cerebral Ischemia.

Bu Yang Huan Wu decoction (BYHW) is a traditional Chinese medicine (TCM) that consists of several herbs and has been used in patients with ischemic stroke for centuries. Although powdered formula of BYHW has widely been prescribed in clinic nowadays, evidence-based effectiveness and mechanism of action of BYHW powdered product in stroke remain to be characterized. Adult male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 90 min followed by reperfusion for 24 h (ischemia/reperfusion; I/R) or sham surgery. After I/R, the rats were then given low dose (0.5 g/kg) and high dose (2.5 g/kg) of BYHW or vehicle by oral gavage twice a day for seven consecutive days. The results showed that I/R induced obvious cerebral infarction and neurobehavioral defects, in parallel with histological aberrations and extensive signaling of proinflammatory cytokines, including tumor necrosis factor (TNF-α) and interleukin-6 (IL-6), in the stroke model. Post-I/R treatment with BYHW powdered product significantly reduced the infarct area and ameliorated neurofunctional defects in a dose-dependent manner. The dose dependence was associated with TNF-α downregulation and interleukin-10 (IL-10) induction. In summary, the present findings demonstrated that BYHW powdered product exhibited therapeutic efficacy for experimental stroke and a higher dose treatment may strengthen the effectiveness via inflammatory modulation.

Hydrogen Protons Modulate Perivascular Axo-axonal Interactions in the Middle Cerebral Artery of Rats.

Previous studies have demonstrated that nicotine can induce relaxation of the middle cerebral artery (MCA). However, whether this relaxation is associated with the activity of sensory calcitonin gene-related peptide (CGRP) nerves and whether this is modulated by hydrogen protons (H), facilitating the release of CGRP from sensory CGRPergic nerve terminals in the MCA, remains unclear. In this study, we examined the role of H in the modulation of neurogenic vasomotor responses in the rat-isolated endothelium-denuded MCA. Wire myography was used to measure vasoreactivity and indicated that nicotine-induced relaxation was sensitive to tetrodotoxin and lidocaine and drastically reduced levels of guanethidine (an adrenergic neuronal blocker), N-nitro-L-arginine (L-NNA), CGRP8-37, vasoactive intestinal polypeptide (VIP)6-28, capsaicin, capsazepine (a transient receptor potential vanilloid-1 inhibitor), and tetraethylammonium. However, this nicotine-induced relaxation was not sensitive to propranolol. Lowering the pH of the buffer solution with HCl caused pH-dependent vasorelaxation and deceased intracellular pH in the MCA rings, which was sensitive to L-NNA, CGRP8-37, VIP6-28, capsazepine, 4-aminopyridine (a voltage-gated potassium channel antagonist), and paxilline (a large conductance Ca-activated K channel antagonist). However, HCl-induced relaxation was not inhibited by glibenclamide (an ATP-sensitive K channel blocker). These results suggested that electrical and chemical activation of cerebral perivascular adrenergic nerves led to the release of H, which then facilitated the release of NO, VIP, and CGRP, resulting in vasorelaxation. Lowering the pH of the buffer solution caused potassium channels of vascular smooth muscle cells and perivascular nerves to open. In conclusion, our results demonstrated that H may act as a modulator on MCA perivascular nerves and/or smooth muscles.

Immuohistochemical score of matrix metalloproteinase-1 may indicate the severity of symptomatic cervical and lumbar disc degeneration.

BACKGROUND CONTEXT: Intervertebral disc (IVD) degeneration is related to numerous risk factors, including obesity. Leptin, one of the commonly measured adipokines, is proven to play an important role in the pathogenesis of IVD degeneration. In the context of IVD degeneration, matrix metalloproteinase-1 (MMP-1), which is upregulated and activated by leptin, is the most abundant catabolic enzyme. It remains unclear which of the factors mentioned above is most strongly associated with IVD degeneration. PURPOSE: To investigate the influence of MMP-1 in IVD degeneration, we determined the strength of different predictors, including age, sex, magnetic resonance imaging (MRI), Modic changes (MCs), body mass index (BMI), leptin, and MMP-1. This was achieved by assessing the correlation among these factors and histologic degeneration score (HDS). STUDY DESIGN: This study included 89 patients undergoing cervical discectomy for disc herniation, 93 who underwent lumbar discectomy, and 90 control subjects. Herniated disc tissue and plasma were used after the study was approved by the Human Ethics Review Committee at the authors' institution. METHODS: Hematoxylin and eosin (H&E), Alcian blue-PAS and immunohistochemical (IHC) staining were performed to measure the expression levels of leptin and MMP-1. Circulating plasma levels of leptin and MMP-1 were measured using an enzyme-linked immunosorbent assay. To assess the correlation with HDS, measurements of age, sex, BMI, MRI scale, MCs scale, leptin/MMP-1 plasma concentration, and leptin/MMP-1 IHC expression were analyzed. RESULTS: Patients with cervical or lumbar discectomy had significantly higher BMI than controls. Significantly more men than women were involved in the lumbar patients as compared with the cervical patients and the control subjects. After adjustment for age and sex, plasma leptin and leptin IHC score correlated significantly with BMI in patients with cervical or lumbar discectomy. Age, sex, MRI scale, MCs scale, and leptin/MMP-1 plasma concentration were not positively correlated with HDS. HDS was significantly associated with BMI, leptin IHC score, and MMP-1 IHC score. After a stepwise-multiple linear regression analysis to evaluate the strength of the correlations between HDS and various factors, only the MMP-1 IHC score demonstrated an independent association with HDS in patients with degeneration of the cervical or lumbar disc. CONCLUSIONS: MMP-1 IHC score is an independent predictor of the severity of cervical or lumbar IVD degeneration. CLINICAL SIGNIFICANCE: MMP-1 IHC score may be used as an indicator of IVD degeneration.

Distant Intramuscular Metastases of Head and Neck Squamous Cell Carcinoma.

OBJECTIVES: Metastasis of head and neck squamous cell carcinoma (HNSCC) usually occurs regionally in the neck lymph nodes, but also more infrequently at distant organs (eg, the lungs, bone, and liver). Intramuscular metastasis (IMM) has rarely been described. Therefore, we aimed to identify this disease characteristic and to evaluate available medical management options. METHODS: Data of surgically treated HNSCC patients (n = 1150) at the Chi Mei Medical Center, Taiwan (2005-2015), were retrospectively reviewed. Literature searches were also conducted (1985-2015) to analyze the behavior of HNSCC with distant IMMs. RESULTS: We identified 1 HNSCC patient with histopathologically proven IMMs. Ten similar cases were also identified in the available literature. Two-thirds of lesions arose in patients with laryngeal/hypopharyngeal malignancies, and two-thirds of lesions were located in the lower limbs. Lesions were subjectively painful and usually had rim enhancement with central hypoattenuation in contrast-enhanced computed tomography/magnetic resonance imaging. The mean duration between primary tumor diagnosis and secondary lesion detection was 13.7 months. No patient survived more than 2 years after establishing a diagnosis of HNSCC with IMMs. CONCLUSIONS: Distant IMMs are extremely rare in HNSCC patients and have a poor clinical outcome. Differentiating this disease from sarcoma via anatomic distribution or diagnostic imaging studies is not straightforward. Biopsies for histopathologic examination are mandatory. Treatment of HNSCC patients with IMMs is mainly palliative for life quality preservation and not lifetime prolongation. Radiotherapy is established as a first-line treatment for symptom control with surgical intervention usually preserved for refractory cases.

Ultraviolet B irradiation induced Nrf2 degradation occurs via activation of TRPV1 channels in human dermal fibroblasts.

Ultraviolet (UV) irradiation causes cellular oxidative stress. Under redox imbalance, Keap1-dependent Nrf2 degradation is minimal. In this study, we examined the role of Ca2+ in Nrf2 homeostasis after UVB irradiation using human dermal fibroblasts. UVB irradiation stimulates 12-lipoxygenase and the product 12-hydroxyeicosatetraenoic acid then activates TRPV1 increasing the cell's cytosolic Ca2+ concentration. UVB irradiation induced reactive oxygen species generation and apoptosis are inhibited in the absence of Ca2+ or in the presence of either a 12-lipoxygenase inhibitor or a TRPV1 inhibitor during and after UVB irradiation. Thus, the Ca2+ increase via TRPV1 is a critical factor in UVB irradiation induced oxidative stress. UVB irradiation induces a Ca2+ dependent Nrf2 degradation and thus activation of TRPV1 with 12-hydroxyeicosatetraenoic acid also decreasing Nrf2 levels. UVB irradiation induced Nrf2 degradation is inhibited by co-treatment of cells with W-7, cyclosporin A, SB-216763 or MG-132, which are inhibitors of calmodulin, calcineurin, GSK3ß and the proteasome, respectively. Furthermore, UVB irradiation in parallel induces GSK3ß dephosphorylation in a Ca2+ dependent manner. Co-immunoprecipitation showed that UVB irradiation induces an increase in Nrf2 phosphorylation, an increase in the binding of ß-TrCP and Nrf2, and an increase in Nrf2 ubiquitination; these effects are all Ca2+ dependent. These findings suggest that UVB irradiation induced GSK3ß activation in a Ca2+ dependent manner, which then stimulates the phosphorylation and ubiquitination of Nrf2 via ß-TrCP. Indeed, silencing of ß-TrCP was found to inhibit UVB irradiation-induced oxidative stress, Nrf2 degradation and apoptosis, while it had no effect on the Ca2+ increase. Taken together, our results suggest that a Ca2+ influx via TRPV1 is responsible for UVB irradiation-induced Nrf2 degradation and that modulation of the Ca2+-calmodulin-calcineurin-GSK3ß-Nrf2-ß-TrCP-Cullin-1 pathway may explain Ca2+ dependent Nrf2 degradation.

Baicalein inhibits matrix metalloproteinase 1 expression via activation of TRPV1-Ca-ERK pathway in ultraviolet B-irradiated human dermal fibroblasts.

Increased matrix metalloproteinase 1 (MMP-1) expression is a feature of photo-aged skin. We investigated the effects of baicalein and sulphoraphane on ultraviolet B (UVB) irradiation-induced MMP-1 expression and apoptosis using human dermal fibroblasts. UVB irradiation not only increased MMP-1 expression, but also caused apoptosis. Both baicalein and sulphoraphane protected cells from UVB irradiation-induced apoptosis, but only baicalein inhibited MMP-1 expression. UVB irradiation activated 12-lipoxygenase, and its product, 12-hydroxyeicosatetraenoic acid, activated TRPV1 channels. The resulting UVB irradiation-induced Ca2+ increase was blocked by the 12-lipoxygenase inhibitor baicalein and the TRPV1 blocker capsazepine, but not by the Nrf2 inducer sulphoraphane. UVB irradiation also increased ROS generation and decreased Nrf2 protein levels. UVB irradiation-induced MMP-1 expression was blocked by the Ca2+ chelator BAPTA, by capsazepine and by TRPV1 silencing. However, induction was unaffected by the antioxidant N-acetylcysteine. ERK phosphorylation and JNK phosphorylation were induced by UVB irradiation, but only ERK phosphorylation was Ca2+ sensitive. Increased MMP-1 expression was blocked by PD98059, but not by SP600125. Thus, increased MMP-1 expression is mediated by increased cytosolic Ca2+ and ERK phosphorylation. UVB irradiation-induced ROS generation is also Ca2+ sensitive, and UVB irradiation-induced apoptosis is caused by increased ROS. Thus, baicalein, by blocking the UVB irradiation-induced cytosolic Ca2+ increase, protects cells from UVB irradiation-induced MMP-1 expression and apoptosis. In contrast, sulphoraphane, by decreasing cellular ROS, protects cells from only UVB-induced apoptosis. Thus, targeting 12-lipoxygenase may provide a therapeutic approach to improving the health of photo-aged human skin.

Neuroprotective Effects of Collagen-Glycosaminoglycan Matrix Implantation following Surgical Brain Injury.

BACKGROUND: Neurological deficits following neurosurgical procedures are inevitable; however, there are still no effective clinical treatments. Earlier reports revealed that collagen-glycosaminoglycan (CG) matrix implantation promotes angiogenesis, neurogenesis, and functional recovery following surgical brain injury (SBI). The present study was conducted to further examine the potential neuroprotective effects of collagen-glycosaminoglycan (CG) matrix implantation following neurosurgery. METHODS: CG implantation was performed in the lesion cavity created by surgical trauma. The Sprague-Dawley rat model of SBI was used as established in the previous study by the author. The rats were divided into three groups as follows: (1) sham (SHAM), (2) surgery-induced lesion cavity (L), and (3) CG matrix implantation following surgery-induced lesion cavity (L+CG). Proinflammatory (tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells)) and anti-inflammatory (IL-10 and granulocyte-macrophage colony-stimulating factor (GMCSF)) cytokine expression was evaluated by enzyme-linked immunosorbent assays. Microglial activation was evaluated by immunohistochemistry, and the neuroprotective effect of CG matrix implantation was evaluated by an immunohistochemical study of microglia ED-1 and IBA-1 (activated microglia) and myeloperoxidase (MPO) and by the analysis of IL-6, IL-10, TNF-α, NF-κB, and GMCSF cytokine levels. Apoptosis was also assessed using a TUNEL assay. RESULTS: The results showed that CG matrix implantation following surgically induced lesions significantly decreased the density of ED-1, IBA-1, and MPO (activated microglia). The tissue concentration of proinflammatory cytokines, such as TNF-α, IL-6, and NF-κB was significantly decreased. Conversely, the anti-inflammatory cytokines GMCSF and IL-10 were significantly increased. CONCLUSIONS: Implantation of the CG matrix following SBI has neuroprotective effects, including the suppression of microglial activation and the production of inflammatory-related cytokines.

Manipulating exchange bias by spin-orbit torque.

Exchange bias, a shift in the hysteresis loop of a ferromagnet arising from interfacial exchange coupling between adjacent ferromagnetic and antiferromagnetic layers, is an integral part of spintronic devices. Here, we show that spin-orbit torque generated from spin current, a promising approach to switch the ferromagnetic magnetization of next-generation magnetic random access memory, can also be used to manipulate the exchange bias. Applying current pulses to a Pt/Co/IrMn trilayer causes concurrent switching of ferromagnetic magnetization and exchange bias, but with different underlying mechanisms. This implies that the ferromagnetic magnetization and exchange bias can be manipulated independently. Our work demonstrates that spin-orbit torque in ferromagnet/antiferromagnet heterostructures facilitates independent manipulations of distinct magnetic properties, motivating innovative designs for future spintronics devices.

Impact of a 3-Day High-Altitude Trek on Xue Mountain (3886 m), Taiwan, on the Emotional States of Children: A Prospective Observational Study.

AIMS: Changes in emotions associated with mountain treks have rarely been reported. This study examined emotional state changes in sixth-grade elementary school students before and after a 3-day high-altitude mountain trek from the trailhead (2140 m) to Xue Mountain (3886 m) in Taiwan. METHODS: In June 2011, 201 students participated in the trek. The round-trip distance was 21.8 km. The age, gender, blood group, and family configuration of the participants were documented before the trek. A 36-item short-form survey instrument, including the Mood and Anxiety Symptom Questionnaire and the Positive and Negative Affect Scale for Children, was used to evaluate the participants' emotional states (happiness, anticipation, sadness, and anger). The participants answered the questionnaires 1 month before and 1 week after the trek. A Likert scale was used to evaluate individual items (range 1-4; from strongly disagree to strongly agree). We calculated scores for each index before and after the trek. The incidence and presentation of acute mountain sickness (AMS) among the participants was also studied and published previously. RESULTS: In total, 187 (112 boys and 75 girls) participants (mean age 11.9 ± 0.4 years) completed the trek and the survey. The sadness and anger scores (negative emotions) were significantly lower after than before the trek (39.5 vs. 36.6; p < 0.01). The happiness and anticipation scores (positive emotions) before and after the trek did not differ significantly (49.9 vs. 48.9; p = 0.11). No participant used AMS prophylaxis, while 78 participants met the AMS criteria. Negative emotions decreased more in those with AMS than without AMS (-4.6 vs. -1.8; p = 0.04), and the use of medications or acetazolamide did not alter the emotions. CONCLUSIONS: A 3-day high-altitude mountain trek can reduce children's negative emotions. Negative emotions decreased more in those with AMS, whereas medications or acetazolamide did not alter their emotions.

A new copper ionophore DPMQ protects cells against ultraviolet B irradiation by inhibiting the TRPV1 channel.

Copper is more likely than iron to generate reactive oxygen species (ROS) in a redox reaction due to its higher electrochemical reactivity. This study examined the effect of a newly synthesized Cu2+ binding compound, (E)-2-(4-(dimethylamino)phenylimino)methyl)quinolin-8-ol (DPMQ), on ultraviolet B (UVB) irradiation-induced cytotoxicity in human dermal fibroblasts. DPMQ induced Cu2+ influx as effectively as disulfiram, a Cu2+ ionophore anticancer drug. However, disulfiram induced ROS generation, mitochondrial dysfunction, and apoptosis in fibroblasts in a Cu2+ -dependent manner, whereas DPMQ was not only nontoxic, but protected cells against UVB irradiation-induced apoptosis in a Cu2+ -independent manner. UVB irradiation induced a Ca2+ -dependent increase in ROS generation, a decrease in Nrf2 levels, and activation of the mitochondrial apoptotic pathway, and these effects were prevented by DPMQ, which also increased Nrf2 nuclear translocation in a Cu2+ -independent manner. UVB irradiation activated 12-lipoxygenase and 12-hydroxyeicosatetraenoic acid (12-HETE), a product of 12-lipoxygenase, activated the TRPV1 channel. DMPQ did not act as a Ca2+ chelator, but inhibited the cytosolic Ca2+ increase induced by 12-HETE or capsaicin, but not that induced by bradykinin or ATP. Blockade of Ca2+ influx by pharmacological inhibition or silencing of the TRPV1 channel or chelation of cytosolic Ca2+ inhibited the UVB irradiation-induced Nrf2 reduction, ROS generation, mitochondrial dysfunction, and apoptosis. Taken together, our results suggest that Ca2+ influx via the TRPV1 channel is responsible for UVB irradiation-induced cytotoxicity and that DPMQ protects cells against UVB irradiation by inhibiting the TRPV1 channel and stabilizing Nrf2, and could thus be a potentially useful compound for the treatment of free radical-induced diseases.

Enhancement of matrix metalloproteinases 2 and 9 accompanied with neurogenesis following collagen glycosaminoglycan matrix implantation after surgical brain injury.

Surgical brain injury may result in irreversible neurological deficits. Our previous report showed that partial regeneration of a traumatic brain lesion is achieved by implantation of collagen glycosaminoglycan (CGM). Matrix metalloproteinases (MMPs) may play an important role in neurogenesis but there is currently a lack of studies displaying the relationship between the stimulation of MMPs and neurogenesis after collagen glycosaminoglycan implantation following surgical brain trauma. The present study was carried out to further examine the expression of MMP2 and MMP9 after implantation of collagen glycosaminoglycan (CGM) following surgical brain trauma. Using the animal model of surgically induced brain lesion, we implanted CGM into the surgical trauma. Rats were thus divided into three groups: (1) sham operation group: craniotomy only; (2) lesion (L) group: craniotomy + surgical trauma lesion; (3) lesion + CGM (L + CGM) group: CGM implanted following craniotomy and surgical trauma lesion. Cells positive for SOX2 (marker of proliferating neural progenitor cells) and matrix metalloproteinases (MMP2 and MMP9) in the lesion boundary zone were assayed and analyzed by immunofluorescence and ELISA commercial kits, respectively. Our results demonstrated that following implantation of CGM after surgical brain trauma, significant increases in MMP2+/SOX2+ cells and MMP9+/SOX2+ cells were seen within the lesion boundary zone in the L + CGM group. Tissue protein concentrations of MMP2 and MMP9 also increased after CGM scaffold implantation. These findings suggest that implantation of a CGM scaffold alone after surgical brain trauma can enhance the expression of MMP2 and MMP9 accompanied by neurogenesis.

Incidence and severity of acute mountain sickness and associated symptoms in children trekking on Xue Mountain, Taiwan.

BACKGROUND: Acute mountain sickness (AMS) occurs in non-acclimatized people after an acute ascent to an altitude of 2,500 m or higher. The aim of this study was to examine the incidence and severity of AMS and associated symptoms in children. METHODS: The prospective observational study included 197 healthy, non-acclimatized 11 and 12-year-old children trekking the round-trip from the trailhead to the summit of Xue Mountain, Taiwan (2,179 m to 3,886 m) over 3 days. AMS was evaluated at Qika Hut (2,460 m) on Day 1, at Sanliujiu Hut on Day 2 (3,100 m), and at the same altitude (3,100 m) after reaching the summit on Day 3. We used the Lake Louise Score (LLS) to diagnose AMS and record daily AMS-associated symptoms. We gave acetazolamide to children with mild to moderate AMS. Dexamethasone was reserved for individuals suffering from severe AMS. Acetaminophen was administrated to children with headache, and metoclopramide for those with nausea or vomiting. RESULTS: There were 197 subjects eligible for analysis. The overall incidence of AMS was 40.6%, which was higher in males and in subjects with a higher body mass index (BMI) (p < 0.05). The prevalence of AMS on Day 1 was 5.6%, which was significantly lower than that on Day 2 (29.4%) and Day 3 (23.4%). The mean LLS of all subjects was 1.77 ± 2.08. The overall incidence of severe AMS (LLS ≥ 5) was 12.5%. The mean LLS of the AMS group (3.02 ± 2.46) was significantly higher than that of the non-AMS group (0.92 ± 1.16, p < 0.001). Among the AMS group, the mean LLS was 1.00 ± 1.55 on Day 1, 4.09 ± 1.97 on Day 2, and 3.98 ± 2.42 on Day 3. The most common symptom was sleep disturbance followed by dizziness, and headache. The prevalence of headache was 46.2% on Day 2 at 3,100 m, and 31.3% on Day 3 at the same altitude after climbing the summit (3,886 m). Males experienced significantly more headache and fatigue than females (p < 0.05). The LLS and prevalence of all AMS symptoms were significantly higher in the AMS than the non-AMS group (p < 0.05). CONCLUSIONS: The AMS incidence among children trekking to Xue Mountain was 40.6%. AMS is common and mostly manifests as mild symptoms. Gender (male) and a higher BMI could be considered two independent risk factors of higher AMS incidence. Sleep disturbance is the most common symptom, and the lower prevalence of headache on Day 3 may be due to the effects of medication and/or acclimatization.

Quality of life of breast and cervical cancer survivors.

BACKGROUND: Breast and cervical cancer are the most common cancers affecting women. The symptom distresses experienced by cancer survivors are critical factors influencing their quality of life (QOL). This study investigated the QOL of breast and cervical cancer survivors, their physical, psychological and social conditions. METHODS: The participants were older than 20 years, had been diagnosed with breast or cervical cancer for more than 2 years, and had completed their cancer treatment. The survey incorporated the QOL questionnaires developed by the European Organization of Research and Treatment for Cancer and a self-designed questionnaire. RESULTS: The mean age at diagnosis was 48.89 ± 8.53 years for the breast cancer survivors and 49.00 ± 10.30 years for the cervical cancer survivors. The corresponding QOL scores were 75.33 ± 20.25 and 75.56 ± 17.93. The factors influencing QOL of breast cancer survivors were household income, number of comorbidities, stage of cancer, type of cancer treatment and duration of illness, whereas the factor related to QOL of cervical cancer survivors was only household income. CONCLUSIONS: The QOL of the two groups was similar. Healthcare providers should demonstrate greater concern toward breast and cervical cancer survivors.

Initialization-Free Multilevel States Driven by Spin-Orbit Torque Switching.

By engineering multidomain formation in Co/Pt multilayers, it is demonstrated how multilevel storage can be achieved by spin-orbit torque switching. It is rather remarkable that, by modulating the writing pulse conditions, the final magnetization states can be controlled, independent of the initial configurations. The initialization-free multilevel memory advances the spin-orbit-torque magnetic random access memory to higher storage density for practical applications.