NIR-II-Responsive CeO2-x@HA Nanotheranostics for Photoacoustic Imaging-Guided Sonodynamic-Enhanced Synergistic Phototherapy.

The therapeutic effect of photothermal therapy (PTT) and photodynamic therapy (PDT) is severely limited because of the shallow tissue penetration depth of the first near-infrared (NIR-I) light. Multifunctional nanotheranostics irradiated by the second near-infrared (NIR-II) light have received wide interest with respect to deeper tissue penetration, and sonodynamic therapy (SDT) synergistic phototherapy can achieve the complete elimination of tumors. Herein, we successfully constructed a single NIR-II light-induced nanotheranostic using cerium oxide (CeO2-x) with abundant oxygen vacancies for photoacoustic imaging-guided SDT-enhanced phototherapy for the first time. CeO2-x with surface crystalline disorder showed extensive NIR-II region absorption and an outstanding photothermal conversion ability. In addition, the CeO2-x layer with numerous oxygen defects can promote the separation of holes and electrons by ultrasound irradiation, which can remarkably enhance the efficacy of phototherapy to achieve high-efficiency tumor ablation. CeO2-x was surface modified with hyaluronic acid (HA) to prepare CeO2-x@HA to allow active tumor targeting efficiency. Both cell and animal experiments confirmed that all-in-one CeO2-x@HA exhibited a high therapeutic efficacy of SDT-enhanced PDT/PTT under 1064 nm laser irradiation, which achieved complete tumor eradication without systemic toxicity. This study significantly broadened the application of NIR-II-responsive CeO2-x for photoacoustic imaging-mediated SDT-enhanced phototherapy to the highly efficient and precise elimination of tumors.

Topical Spilanthol Inhibits MAPK Signaling and Ameliorates Allergic Inflammation in DNCB-Induced Atopic Dermatitis in Mice.

Atopic dermatitis (AD) is a recurrent allergic skin disease caused by genetic and environmental factors. Patients with AD may experience immune imbalance, increased levels of mast cells, immunoglobulin (Ig) E and pro-inflammatory factors (Cyclooxygenase, COX-2 and inducible NO synthase, iNOS). While spilanthol (SP) has anti-inflammatory and analgesic activities, its effect on AD remains to be explored. To develop a new means of SP, inflammation-related symptoms of AD were alleviated, and 2,4-dinitrochlorobenzene (DNCB) was used to induce AD-like skin lesions in BALB/c mice. Histopathological analysis was used to examine mast cells and eosinophils infiltration in AD-like skin lesions. The levels of IgE, IgG1 and IgG2a were measured by enzyme-linked immunosorbent assay (ELISA) kits. Western blot was used for analysis of the mitogen-activated protein kinase (MAPK) pathways and COX-2 and iNOS protein expression. Topical SP treatment reduced serum IgE and IgG2a levels and suppressed COX-2 and iNOS expression via blocked mitogen-activated protein kinase (MAPK) pathways in DNCB-induced AD-like lesions. Histopathological examination revealed that SP reduced epidermal thickness and collagen accumulation and inhibited mast cells and eosinophils infiltration into the AD-like lesions skin. These results indicate that SP may protect against AD skin lesions through inhibited MAPK signaling pathways and may diminish the infiltration of inflammatory cells to block allergic inflammation.

Flexible Wearable Electrochemical Sensors Based on AuNR/PEDOT:PSS for Simultaneous Monitoring of Levodopa and Uric Acid in Sweat.

As a facile substitute for the invasive technique of blood testing, wearable electrochemical sensors exhibit high potential for the noninvasive and real-time monitoring of biomarkers in human sweat. However, owing to enzyme specificity, the simultaneous detection of multiple biomarkers by enzymatic analysis is challenging. Moreover, sweat accumulation under sensors causes sweat contamination, which hinders real-time biomarker detection from sweat. This study reports the design and fabrication of flexible wearable electrochemical sensors containing a composite comprising Au nanorods (AuNRs) and poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) for the nonenzymatic detection of levodopa (LD) and uric acid (UA) in sweat. Each sensor was integrated with a flexible three-electrode system and a microfluidic patch for sweat sampling. AuNRs immobilized by PEG-doped PEDOT:PSS showed excellent analytical performance for LD and UA at different potentials. Thus, the newly fabricated sensors could detect LD and UA over a broad detection range with high sensitivity and showed a low limit of detection for both species. On-body assessments confirmed the ability of these sensors to simultaneously detect LD and UA in real time. Therefore, this study could open new frontiers in the fabrication of wearable electrochemical sensors for the pharmacokinetic profile tracking of LD and gout management.

Improved microcalcification visualization using dual-energy digital mammography.

BACKGROUND: Dual-energy digital mammography (DEDM), involving a combination of high-energy (HE) and low-energy (LE) images, has been investigated as offering a potential improvement in microcalcification detection obscured by overlapping tissue structures. PURPOSE: To explore the possibility to improve detection of microcalcifications using the DEDM technique. MATERIAL AND METHODS: Three DEDM protocols were performed by adjusting the effective tube current time product (mAs) of LE image at the same (100%), one half (50%), and one-quarter (25%) of that used in HE image acquisition, named DEDM100%, DEDM50%, and DEDM25%, respectively. A single-energy digital mammography (SEDM) method was also used as a control. A total of 525 regions of interest (ROIs) were used to compare the performance of the DEDM to that of SEDM using free-response receiver-operating characteristic (FROC) and areas under the FROC curve (Az). RESULTS: All DEDM protocols ranked significantly higher than the SEDM method (P < 0.001). The true-positive fraction was 0.90 for an average of 0.017-0.042 false-positive per image using the DEDM100%, 0.017-0.114 using the DEDM50%, 0.021-0.148 using the DEDM25%, and 0.134-0.422 using the SEDM. The estimated Az values were 0.915-0.940, 0.867-0.935, 0.824-0.930, and 0.567-0.673, respectively. CONCLUSION: The DEDM50% protocol provided a trade-off benefit between accurate microcalcification detectability and radiation dose for any tissue density. Therefore, the DEDM50% has the potential to minimize excess radiation dose without a negative impact on image quality which could improve earlier diagnosis of breast cancer.

Pt/MXene-Based Flexible Wearable Non-Enzymatic Electrochemical Sensor for Continuous Glucose Detection in Sweat.

Wearable non-invasive sensors facilitate the continuous measurement of glucose in sweat for the treatment and management of diabetes. However, the catalysis of glucose and sweat sampling are challenges in the development of efficient wearable glucose sensors. Herein, we report a flexible wearable non-enzymatic electrochemical sensor for continuous glucose detection in sweat. We synthesized a catalyst (Pt/MXene) by the hybridization of Pt nanoparticles onto MXene (Ti3C2Tx) nanosheets with a broad linear range of glucose detection (0-8 mmol/L) under neutral conditions. Furthermore, we optimized the structure of the sensor by immobilizing Pt/MXene with a conductive hydrogel to enhance the stability of the sensor. Based on Pt/MXene and the optimized structure, we fabricated a flexible wearable glucose sensor by integrating a microfluidic patch for sweat collection onto a flexible sensor. We evaluated the utility of the sensor for the detection of glucose in sweat, and the sensor could detect the glucose change with the replenishment and consumption of energy by the body, and a similar trend was observed in the blood. An in vivo glucose test in sweat indicated that the fabricated sensor is promising for the continuous measurement of glucose, which is essential for the treatment and management of diabetes.

Feasibility study for the improvement of microcalcification visualization in different breast thicknesses and tissue components using a dual-energy approach in digital mammography.

OBJECTIVE: The purpose of this study was to improve detectability of microcalcifications using a dual-energy digital mammographic (DEDM) technique. METHODS: Slabs of uniform breast-equivalent plastic and an additional plate were used to mimic various breast thicknesses, from 3 to 7 cm, and to simulate microcalcification with diameters from 0.16 to 0.39 mm. Free-response receiver operating characteristics and area under the curves (Az) were used to evaluate the sensitivity of detecting microcalcifications using the DEDM compared with using the conventional single-energy digital mammography (SEDM). RESULTS: The mean number of false-positives per image was 0.0198 (Az = 0.956 ± 0.027) using DEDM compared with 0.292 (Az = 0.681 ± 0.235) using SEDM. A lower radiation dose could be possibly obtained for the DEDM technique with a thickness of less than 5 cm compared with the SEDM with a thickness larger than 5 cm. CONCLUSIONS: Microcalcifications could be more accurately and efficiently detected using the DEDM, which might bring reliable and promising applications on early computer-aided diagnosis of breast cancer.

Unusual imaging features of completely isolated enteric duplication in a child.

We report a case of completely isolated enteric duplication in an 18-month-old boy in whom US revealed a reniform abdominal mass with a pseudokidney sign that had no connection to adjacent organs. Distinctive histopathological changes of the duplication account for these unusual imaging features. Our case represents a diagnostic challenge in this rare entity. To our knowledge, this is a unique case.

Genetic Disruption of KLF1 K74 SUMOylation in Hematopoietic System Promotes Healthy Longevity in Mice.

The quest for rejuvenation and prolonged lifespan through transfusion of young blood has been studied for decades with the hope of unlocking the mystery of the key substance(s) that exists in the circulating blood of juvenile organisms. However, a pivotal mediator has yet been identified. Here, atypical findings are presented that are observed in a knockin mouse model carrying a lysine to arginine substitution at residue 74 of Krüppel-like factor 1 (KLF1/EKLF), the SUMOylation-deficient Klf1K74R/K74R mouse, that displayed significant improvement in geriatric disorders and lifespan extension. Klf1K74R/K74R mice exhibit a marked delay in age-related physical performance decline and disease progression as evidenced by physiological and pathological examinations. Furthermore, the KLF1(K74R) knockin affects a subset of lymphoid lineage cells; the abundance of tumor infiltrating effector CD8+ T cells and NKT cells is increased resulting in antitumor immune enhancement in response to tumor cell administration. Significantly, infusion of hematopoietic stem cells (HSCs) from Klf1K74R/K74R mice extends the lifespan of the wild-type mice. The Klf1K74R/K74R mice appear to be an ideal animal model system for further understanding of the molecular/cellular basis of aging and development of new strategies for antiaging and prevention/treatment of age-related diseases thus extending the healthspan as well as lifespan.

Two new species of genus Svistella Gorochov, 1987 from China (Orthoptera: Trigonidiidae: Trigonidiinae).

The genus Svistella contains 8 species worldwide with 7 recorded from China. In this study, we reconstructed the gene tree based on COI gene, and reported two new species, S. wuyong He sp. nov. and S. malu He sp. nov. The new species differs from allied species in color, male genitalia, songs and molecular study. The type specimens are deposited in the Museum of Biology, East China Normal University (ECNU).

A new species of genus Homoeoxipha Saussure, 1874 from China (Orthoptera: Trigonidiidae: Trigonidiinae).

The genus Homoeoxipha contains 11 species worldwide with 4 recorded from China. In this study, we reconstructed the gene tree based on COI gene, and reported one new species, H. oscillantenna He sp. nov. The new species is similar to H. eurylobus Ma, Liu Zhang, but differs in the color of fore femur and the structure of male genitalia. Calling songs and nymph morphology are also provided. The type specimens are deposited in the Museum of Biology, East China Normal University (ECNU).

Spilanthol from Traditionally Used Spilanthes acmella Enhances AMPK and Ameliorates Obesity in Mice Fed High-Fat Diet.

Spilanthol (SP) is a bioactive compound found in Spilanthes acmella, giving the flowers and leaves a spicy taste. Studies found that phyto-ingredients stored in spice plants act against obesity-related diseases. SP has antimicrobial, anti-inflammatory, and analgesic properties, but the effects on obesity are not yet known. We investigated the effects of SP in differentiated adipocytes (3T3-L1 cells) and mice fed a high-fat diet (HFD). SP significantly inhibited intracellular lipid accumulation and significantly reduced the expression of lipogenesis-related proteins, including acetyl-CoA carboxylase (ACC) and fatty-acid synthase (FAS). In contrast, SP increased the expression of carnitine palmitoyltransferase (CPT)1 and AMP-activated protein kinase (AMPK) in adipocytes. However, SP suppressed the levels of cyclooxygenase-2 (COX-2), phospho-p38 (pp38), and phospho-JNK (c­Jun N-terminal kinase) (pJNK) in LPS (lipopolysaccharide)-stimulated murine pre-adipocytes. SP administered to HFD-induced obese mice via intraperitoneal injections twice a week for 10 weeks decreased body weight gain, visceral adipose tissue weight, and adipocyte size. SP inhibited lipogenic proteins FAS and ACC, and suppressed adipogenic transcription factors, enhancing lipolysis and AMPK protein expression in the liver. SP has anti-obesity effects, upregulating AMPK to attenuate lipogenic and adipogenic transcription factors.

Short-term effects of customized arch support insoles on symptomatic flexible flatfoot in children: A randomized controlled trial.

BACKGROUND: Limited evidence is available regarding the effects of insoles on pediatric flexible flatfoot because of the heterogeneity and low methodological quality of previous studies. The purpose of this prospective trial is to examine the short-term effects of customized arch support insoles on symptomatic flexible flatfoot in children by using the International Classification of Functioning, randomized controlled Disability, and Health (ICF) framework. METHODS: This study was conducted in a rehabilitation outpatient clinic of a teaching hospital. Fifty-two children with symptomatic flexible flatfoot were included. The children in the treatment group wore customized arch support insoles for 12 weeks, whereas those in the control group did not wear the insoles. Both clinical and radiographic measurements, including the navicular drop, foot posture index, Beighton hypermobility score, talonavicular coverage angle, calcaneal inclination angle, and calcaneal-first metatarsal angle, were used for diagnosing flexible flatfoot. Physical activity (10-m normal and fast walking, stair ascent, stair descent, and chair rising), physical function, and psychometric properties (Pediatric Outcome Data Collection Instrument and Pediatric Quality of Life Inventory) were evaluated at the baseline and 12 weeks after the intervention. RESULTS: Compared with the control group, the treatment group exhibited significant improvement in pain/comfort (P = .048), physical health (P = .035), stair ascent time (P = .015), upper extremity and physical function (P = .016), and transfer and basic mobility (P = .042) during the intervention period. CONCLUSION: Children with flexible flatfoot who wore customized arch support insoles for 12 weeks exhibited significantly improved pain/comfort, physical health, stair ascent time, upper extremity and physical function, and transfer and basic mobility. These variables belong to the domains of body functions and structures and activity and participation in the ICF framework. However, because the groups were not comparable, additional studies with larger sample sizes should be conducted.

Fisetin inhibits the generation of inflammatory mediators in interleukin-1ß-induced human lung epithelial cells by suppressing the NF-κB and ERK1/2 pathways.

Fisetin, a flavone that can be isolated from fruits and vegetables, has anti-tumor and anti-oxidative properties and ameliorates airway hyperresponsiveness in asthmatic mice. This study investigated whether fisetin can suppress the expression of inflammatory mediators and intercellular adhesion molecule 1 (ICAM-1) in A549 human lung epithelial cells that were stimulated with interleukin-1ß (IL-1ß) to induce inflammatory responses. A549 cells were treated with fisetin (3-30 µM) and then with IL-1ß. Fisetin significantly inhibited COX-2 expression and reduced prostaglandin E2 production, and it suppressed the levels of IL-8, CCL5, monocyte chemotactic protein 1, tumor necrosis factor α, and IL-6. Fisetin also significantly attenuated the expression of chemokine and inflammatory cytokine genes and decreased the expression of ICAM-1, which mediates THP-1 monocyte adhesion to inflammatory A549 cells. Fisetin decreased the translocation of nuclear transcription factor kappa-B (NF-κB) subunit p65 into the nucleus and inhibited the phosphorylation of proteins in the ERK1/2 pathway. Co-treatment of IL-1ß-stimulated A549 cells with ERK1/2 inhibitors plus fisetin reduced ICAM-1 expression. Furthermore, fisetin significantly increased the effects of the protective antioxidant pathway by promoting the expression of nuclear factor erythroid-2-related factor-2 and heme oxygenase 1. Taken together, these data suggest that fisetin has anti-inflammatory effects and that it suppresses the expression of chemokines, inflammatory cytokines, and ICAM-1 by suppressing the NF-κB and ERK1/2 signaling pathways in IL-1ß-stimulated human lung epithelial A549 cells.

Sonographic imaging of meniscal subluxation in patients with radiographic knee osteoarthritis.

BACKGROUND/PURPOSE: This study was undertaken to describe the sonographic features of meniscal subluxation in the weight-bearing position and to determine any association between meniscal subluxation and radiographic osteoarthritis. METHODS: In total, 238 knees with symptoms were examined successfully with weight-bearing anteroposterior and lateral radiographs and high resolution ultrasonography. The radiographs were examined to determine whether participants had radiographic osteoarthritis, graded using the Kellgren-Lawrence Scale. The degree of subluxation of the medial meniscus in each knee was measured using high resolution ultrasound with a 10-MHz linear transducer, at the level of the medial collateral ligament in weight-bearing condition. The degree of subluxation was compared in knees with the presence or absence of radiographic osteoarthritis using Students t test. Additional analysis between knees with early and advanced radiographic osteoarthritis was also performed. RESULTS: Meniscal subluxation for knees with (n = 141) and without (n = 97) radiographic signs of osteoarthritis were 4.3 1.9 mm and 0.7 0.6 mm, respectively. The difference was highly significant (p < 0.001). After age adjustment, the medial meniscal subluxation of age-matched subjects were 4.8 1.7 mm for knees with radiographic osteoarthritis (n = 43) and 1.0 0.8 mm for knees without such changes (n = 43). The difference between the two groups was still significant (p < 0.001). The greatest meniscal subluxation was seen in knees with advanced radiographic signs of osteoarthritis; no knee with osteoarthritic changes on radiographs had an undisplaced meniscus. CONCLUSION: Meniscal subluxation is a prominent feature on weight-bearing sonographic imaging in patients with radiographic osteoarthritis and could be considered as a risk factor for the development of knee osteoarthritis. By using musculoskeletal ultrasonography, one can detect this occult meniscal derangement early before the appearance of radiographic signs of osteoarthritis.

Cell-free methylation markers with diagnostic and prognostic potential in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a highly malignant tumor with poor prognosis and high mortality. There is a dearth of effective early diagnostic tools, so liver resection surgery and liver transplantation are the only effective medical treatments. The most commonly used marker for HCC detection is serum alpha fetoprotein (AFP), which has low sensitivity and specificity. Because aberrant DNA methylation of genes and miRNAs occurs early in most cancers, we explored whether circulating methylation markers could be promising clinical tools for HCC diagnosis. Using a whole-genome approach, we identified many hyper-methylated miRNAs in HCC. Furthermore, three abnormally methylated genes and one miRNA were combined to establish a methylation predictive model and tested for its diagnostic and prognostic potential in HCC. Using plasma samples, the predictive model exhibited high sensitivity and specificity (> 80%) for HBV-related HCC. Most importantly, nearly 75% of patients who could not be diagnosed with AFP at 20 ng/mL were detected by this model. Further, the predictive model exhibited an exceedingly high ability to predict 5-year overall survival in HCC patients. These data demonstrate the high diagnostic and prognostic potential of methylation markers in the plasma of HCC patients.

Effectiveness of Vestibular Rehabilitation in Hemodialysis Patients With Dizziness.

PURPOSE: This study evaluated the effectiveness of vestibular rehabilitation (VR) for hemodialysis (HD) patients with chronic dizziness. DESIGN: A single-blind, randomized controlled study was performed. METHODS: Cluster-randomized sampling was used to select the experimental group from two outpatient dialysis clinics. A total of 26 patients participated in the study. Dizziness Handicap Inventory (DHI) and falls were used as outcome measures. Data were collected at baseline (T1), 3 months (T2), and 6 months (T3). FINDINGS: Two-way repeated-measures ANOVA of DHI revealed a statistically significant group and time interaction. Dizziness handicap outcome was significantly reduced over time in the experimental group (DHI total score, T1 = 35.29, T2 = 32.86, T3 = 27.86, p = .001). CONCLUSIONS: VR exercise instructed by nurses can be effective in alleviating handicap imposed by dizziness in dialysis patients. CLINICAL RELEVANCE: Nurses are encouraged to learn VR as a simple exercise to improve well-being in dialysis patients with chronic dizziness.

Phloretin ameliorates chemokines and ICAM-1 expression via blocking of the NF-κB pathway in the TNF-α-induced HaCaT human keratinocytes.

Previous studies found that phloretin had anti-oxidant, anti-inflammatory, and anti-tumor properties. In this study, we investigated whether phloretin could suppress the production of the intercellular adhesion molecule (ICAM)-1 and chemokines through downregulation of the nuclear transcription factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways in TNF-α-stimulated HaCaT human keratinocytes. HaCaT cells were treated with phloretin and then the cells were stimulated by TNF-α. Phloretin treatment decreased the production of IL-6, IL-8, CCL5, MDC, and TARC. Phloretin decreased ICAM-1 protein and mRNA expression, and also suppressed the adhesion of monocyte THP-1 cells to inflammatory HaCaT cells. Phloretin inhibited NF-κB translocation into the nucleus and also suppressed the phosphorylation of Akt and MAPK signal. In addition, phloretin increased heme oxygenase-1 production in a concentration-dependent manner. These results demonstrated that phloretin has anti-inflammatory effects to inhibit chemokines and ICAM-1 expressions through suppression of the NF-κB and MAPK pathways in human keratinocytes.

AVATAR: a database for genome-wide alternative splicing event detection using large scale ESTs and mRNAs.

UNLABELLED: In the past years, identification of alternative splicing (AS) variants has been gaining momentum. We developed AVATAR, a database for documenting AS using 5,469,433 human EST sequences and 26,159 human mRNA sequences. AVATAR contains 12000 alternative splicing sites identified by mapping ESTs and mRNAs with the whole human genome sequence. AVATAR also contains AS information for 6 eukaryotes. We mapped EST alignment information into a graph model where exons and introns are represented with vertices and edges, respectively. AVATAR can be queried using, (1) gene names, (2) number of identified AS events in a gene, (3) minimal number of ESTs supporting a splicing site, etc. as search parameters. The system provides visualized AS information for queried genes. AVAILABILITY: The database is available for free at http://avatar.iecs.fcu.edu.tw/

Community-based multiple screening model: design, implementation, and analysis of 42,387 participants.

BACKGROUND: Multiple disease screening may have several advantages over single disease screening because of the economics of scale, with the high yield of detecting asymptomatic diseases, the identification of multiple diseases or risk factors simultaneously, the enhancement of the attendance rate, and the efficiency of follow-up. METHODS: An integrated model of community-based multiple screening was designed and conducted between 1999 and 2001 in Keelung, Taiwan. The authors used a Papanicolaou (Pap) smear screening program as a base to integrate other screening regimens encompassing four other neoplastic diseases and three nonneoplastic chronic diseases. Screening methods, the interscreening interval, and the follow-up for each screening regimen were designed based on evidence-based literature and current national screening policy. RESULTS: A total of 42,387 subjects participated in the screening activities. A 25% increase in the attendance rate for Pap smear screening was demonstrated after the introduction of multiple disease screening programs. At the first screen, this program yielded a total of 677 asymptomatic neoplasms (16.0 per 1000), including a large proportion of precancerous lesions and small presymptomatic tumors without lymph node involvement. The association between the occurrence of neoplasm and the presence of comorbid nonneoplastic chronic disease was found to be statistically significant (odds ratio, 1.64; 95% confidence interval, 1.38-1.94 [P < 0.05]). The authors also identified 5314 subjects with metabolic syndrome who were at a greater risk for colorectal and oral neoplasias. CONCLUSIONS: The results of the current study demonstrate that an outreach and community-based multiple screening program not only enhances attendance rates but also has a high yield of early cases of various diseases simultaneously, and provides a natural opportunity to elucidate the correlation between neoplastic disease and nonneoplastic chronic disease.