Biocompatibility and proteomic profiling of DMSA-coated iron nanocubes in a human glioblastoma cell line.

Background: Superparamagnetic iron core iron oxide shell nanocubes have previously shown superior performance in magnetic resonance imaging T2 contrast enhancement compared with spherical nanoparticles. Methods: Iron core iron oxide shell nanocubes were synthesized, stabilized with dimercaptosuccinic acid (DMSA-NC) and physicochemically characterized. MRI contrast enhancement and biocompatibility were assessed in vitro. Results: DMSA-NC showed a transverse relaxivity of 122.59 mM-1·s-1 Fe. Treatment with DMSA-NC did not induce cytotoxicity or oxidative stress in U-251 cells, and electron microscopy demonstrated DMSA-NC localization within endosomes and lysosomes in cells following internalization. Global proteomics revealed dysregulation of iron storage, transport, transcription and mRNA processing proteins. Conclusion: DMSA-NC is a promising T2 MRI contrast agent which, in this preliminary investigation, demonstrates favorable biocompatibility with an astrocyte cell model.

MRI is a powerful tool used in the diagnosis of cancer, strokes and other injuries. An MRI scan can be improved with the use of iron oxide nanoparticles, which enhance the contrast of the image. In this study we have developed cube-shaped iron nanoparticles (nanocubes), which have been previously shown to be more effective at inducing contrast. We demonstrated that iron-based nanocubes do not damage or induce stress in cells and work effectively as an MRI contrast agent. We further analyzed how the nanocubes may affect cell functioning by investigating changes to protein levels in the cells. The results of this study are promising steps towards using iron-based nanocubes as a tool to improve the clarity of MRI scans for medical imaging and diagnosis. Future work must determine whether these nanocubes work effectively and safely in an animal model, which is a critical step in progressing to their use in clinical settings.

Evaluation of Dimercaptosuccinic Acid-Coated Iron Nanoparticles Immunotargeted to Amyloid Beta as MRI Contrast Agents for the Diagnosis of Alzheimer's Disease.

Nanoparticle-based magnetic contrast agents have opened the potential for magnetic resonance imaging (MRI) to be used for early non-invasive diagnosis of Alzheimer's disease (AD). Accumulation of amyloid pathology in the brain has shown association with cognitive decline and tauopathy; hence, it is an effective biomarker for the early detection of AD. The aim of this study was to develop a biocompatible magnetic nanoparticle targeted to amyloid beta (Aß) plaques to increase the sensitivity of T2-weighted MRI for imaging of amyloid pathology in AD. We presented novel iron core-iron oxide nanoparticles stabilized with a dimercaptosuccinic acid coating and functionalized with an anti-Aß antibody. Nanoparticle biocompatibility and cellular internalization were evaluated in vitro in U-251 glioblastoma cells using cellular assays, proteomics, and transmission electron microscopy. Iron nanoparticles demonstrated no significant in vitro cytotoxicity, and electron microscopy results showed their movement through the endocytic cycle within the cell over a 24 h period. In addition, immunostaining and bio-layer interferometry confirmed the targeted nanoparticle's binding affinity to amyloid species. The iron nanoparticles demonstrated favourable MRI contrast enhancement; however, the addition of the antibody resulted in a reduction in the relaxivity of the particles. The present work shows promising preliminary results in the development of a targeted non-invasive method of early AD diagnosis using contrast-enhanced MRI.

Recent Neurotherapeutic Strategies to Promote Healthy Brain Aging: Are we there yet?

Owing to the global exponential increase in population ageing, there is an urgent unmet need to develop reliable strategies to slow down and delay the ageing process. Age-related neurodegenerative diseases are among the main causes of morbidity and mortality in our contemporary society and represent a major socio-economic burden. There are several controversial factors that are thought to play a causal role in brain ageing which are continuously being examined in experimental models. Among them are oxidative stress and brain inflammation which are empirical to brain ageing. Although some candidate drugs have been developed which reduce the ageing phenotype, their clinical translation is limited. There are several strategies currently in development to improve brain ageing. These include strategies such as caloric restriction, ketogenic diet, promotion of cellular nicotinamide adenine dinucleotide (NAD+) levels, removal of senescent cells, 'young blood' transfusions, enhancement of adult neurogenesis, stem cell therapy, vascular risk reduction, and non-pharmacological lifestyle strategies. Several studies have shown that these strategies can not only improve brain ageing by attenuating age-related neurodegenerative disease mechanisms, but also maintain cognitive function in a variety of pre-clinical experimental murine models. However, clinical evidence is limited and many of these strategies are awaiting findings from large-scale clinical trials which are nascent in the current literature. Further studies are needed to determine their long-term efficacy and lack of adverse effects in various tissues and organs to gain a greater understanding of their potential beneficial effects on brain ageing and health span in humans.

Comparison of Joint Perception Between Posterior-Stabilized and Ultracongruent Total Knee Arthroplasty in the Same Patient.

BACKGROUND: Posterior-stabilized and ultracongruent designs are 2 common examples of posterior cruciate ligament-substituting total knee arthroplasty (TKA) prostheses. There is a lack of evidence regarding joint perception differences between ultracongruent and posterior-stabilized TKA. The purpose of this study was to compare the postoperative knee stability, function, and joint perception between ultracongruent and posterior-stabilized TKA in the same patients in order to determine whether there was a difference based on design. METHODS: This prospective, randomized controlled trial included 50 patients who underwent same-day bilateral TKA utilizing Persona (Zimmer Biomet) posterior-stabilized implants in 1 knee (posterior-stabilized group) and ultracongruent implants in the other knee (ultracongruent group). At 2 years postoperatively, patients were evaluated for knee stability, function, and joint perception. Postoperative static knee anteroposterior stability and femoral rollback were compared. Knee function was evaluated with use of the Knee Society Score and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Joint perception was compared by evaluating noise generation, side preference, satisfaction, and the Forgotten Joint Score. RESULTS: The ultracongruent group had more knee anteroposterior laxity (4.5 mm compared with 1.8 mm in the posterior-stabilized group; p < 0.001) and less femoral rollback (4.2 mm compared with 9.0 mm in the posterior-stabilized group; p < 0.001). Knee Society Score and WOMAC scores were not significantly different between groups (all p > 0.05). Although the ultracongruent group showed less noise generation than the posterior-stabilized group (18% compared with 38%, respectively; p = 0.026), there were no differences in side preference, satisfaction, or Forgotten Joint Score (all p > 0.05). CONCLUSIONS: Both groups had similar joint perception 2 years postoperatively, with obvious differences in noise generation and more sagittal laxity with less femoral rollback in the ultracongruent group. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Effects of allergic rhinitis on the progression and recovery of acute otitis media in a mouse model.

OBJECTIVES: The objective of this study was to evaluate the effects of allergic rhinitis (AR) on the development, progression, and recovery of acute otitis media (OM) in an animal model and investigate the secondary effects of bacterial infection. METHODS: BALB/c mice were divided into four groups: AR + OM, AR, OM, and control groups. AR + OM and AR groups were sensitized with ovalbumin (OVA) and alum and then challenged intranasally with OVA. Phosphate-buffered saline (PBS) was administered to the OM and control groups the same number of times. After AR induction, OM was induced by surgical inoculation of non-typeable Haemophilus influenza (NTHi) into the middle ear (ME) cavity of the mice in the AR + OM and OM groups. PBS was injected into the bulla in the AR and control groups. Each group was subdivided into sets of six mice, one for each of the four time points (0, 2, 7, and 10 days post-bacterial inoculation), at which point the mice were euthanized and ME and nasal cavity mucosa were obtained and evaluated. The occurrence of OM and the ME mucosa thickness were evaluated and compared among the four groups. Tissue expression of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α (TNF-α) in infected ME mucosa was assessed by immunohistochemical staining. We also investigated IgE, IL-4, and IL-5 in the nasal mucosa. RESULTS: Most of the ears showed OM on post-inoculation day 2 in both AR + OM and OM groups. In the AR + OM group, 58.3% of ears still had OM on post-inoculation day 10, while only 16.7% of the OM group had OM. The ME mucosa of all groups increased, and the AR + OM group exhibited the thickest mucosa. The OM group showed peak thickness on post-inoculation day 2 and then decreased, whereas the ME mucosa thickness of the AR + OM group continued to increase to day 7. In the OM group, the expression of IL-1ß, IL-6, and TNF-α in the ME also increased significantly, peaking on post-inoculation day 2, and then gradually decreased. In the AR + OM group, the expression of these proteins increased until day 7 and then decreased. The IgE and Th2 response (IL-4 and IL-5) cytokines were expressed at higher levels in the AR + OM and AR groups than in the OM and control groups. CONCLUSION: The inflammatory reaction to NTHi was more intense and lasted longer in the allergic group, which indicates that AR affects the progression and subsequent recovery of acute bacterial OM.

Cross-cultural adaptation and validation of the Korean version of the Central Sensitization Inventory in patients undergoing total knee arthroplasty for knee osteoarthritis.

The purpose of this study was to establish a Korean version of the Central Sensitization Inventory (CSI-K) for Korean-speaking patients facing total knee arthroplasty (TKA) for knee osteoarthritis (OA) and to investigate the psychometric characteristics of the CSI-K. We recruited a total of 269 patients with knee OA who were scheduled to undergo TKA for the study. CSI-K and pain-related outcomes, including the pain visual analog scale (VAS) and the Western Ontario and McMaster Universities OA Index (WOMAC) pain sub-scores, were measured. Since central sensitization (CS) is closely related to the quality of life (QOL) and limited functionality as well as pain, the patient's function was measured using the WOMAC function sub-scores, and QOL was measured using the EuroQol five-dimension test (EQ-5D). Reliability and validity were evaluated. Exploratory factor analysis (EFA) was conducted to begin the data reduction to validate the existing questionnaire translation. The internal consistency was excellent, with a Cronbach's alpha of 0.941. The test-retest reliability was acceptable-to-excellent with an ICC of 0.888. As expected, the CSI scores correlated strongly with the WOMAC pain scores (r = 0.524, p < 0.001) and moderately with the pain VAS (r = 0.496, p < 0.001), the WOMAC function (r = 0.408, p < 0.001), and the EQ-5D scores (r = 0.437, p < 0.001). EFA resulted in a six-factor model. The findings demonstrate that the CSI was successfully trans-culturally adapted into a simplified Korean version (CSI-K) that was reliable and valid for Korean-speaking patients who awaiting TKA for knee OA.

Patient Expectations and Satisfaction After Medial Opening Wedge High Tibial Osteotomy.

BACKGROUND: The objective of this study is to assess preoperative patient expectations of medial opening wedge high tibial osteotomy (MOWHTO) and related postoperative fulfillment, to increase understanding of associated factors of postoperative satisfaction. METHODS: One hundred fifteen patients who underwent MOWHTO were enrolled. Patients' expectations were measured using the Hospital for Special Surgery-Knee Replacement Expectations Survey. Fulfillment of expectations and satisfaction was evaluated using the Hospital for Special Surgery Knee Replacement Fulfillment of Expectations Survey and a 5-point Likert scale at 2 years, postoperatively. The discrepancies between preoperative expectation and postoperative fulfillment score were also assessed. Preoperative and postoperative patient-reported outcomes were evaluated using Western Ontario and McMaster Universities Arthritis Index (WOMAC) score. Univariate and multivariate analyses were performed to model predictions for satisfaction. RESULTS: The most expected items were "pain relief," "walking ability," and "perform daily activities." The top 3 items with the biggest discrepancies between expectation and fulfillment scores were "kneeling," "squatting," and "pain relief." Ninety patients (78.3%) were satisfied and 25 (21.7%) were dissatisfied at 2 years postoperative. Multivariate logistic regressions showed that patient expectations did not affect satisfaction. Small discrepancies between expectation and fulfillment scores (odds ratio [OR] 105.304, 95% confidence interval 20.974-528.714, P < .001), high postoperative fulfillment scores (OR 1.198, 95% CI 1.110-1.293, P < .001), and low postoperative Western Ontario and McMaster Universities Arthritis Index total scores (OR 0.932, 95% CI 0.894-0.971, P < .001) were significantly associated with patient satisfaction. CONCLUSION: The small discrepancy between preoperative expectations and postoperative fulfillment of expectations was a major contributor to patients' satisfaction following MOWHTO.

Preoperative Medial Meniscal Extrusion Is Associated With Patient-Reported Outcomes After Medial Opening Wedge High Tibial Osteotomy.

BACKGROUND: Although the medial compartment continues to sustain some loading after medial opening wedge high tibial osteotomy (MOWHTO) in varus-deformed knees, no studies have examined the relationship between medial meniscal extrusion (MME) and patient-reported outcome measures after MOWHTO. PURPOSE: To examine whether compartmental baseline MME was associated with patient-reported outcome measures after MOWHTO. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: This retrospective study was composed of 149 MOWHTOs in 147 patients with clinical and radiological assessments. Patients were grouped according to severity of MME in the medial compartment at the time of surgery. MME was categorized into 4 groups according to MOAKS (MRI [magnetic resonance imaging] Osteoarthritis Knee Score) criteria and relative value of MME. We compared preoperative characteristics, including Kellgren-Lawrence (KL) grading scale, meniscal tear pattern, and postoperative Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscores. Associations between extent of MME and WOMAC subscores at postoperative 1 and 2 years were assessed with generalized linear models. RESULTS: Pattern of meniscal tear (P < .05) and KL grade (P < .05) were associated with MME. Patients with KL grades 3 and 4 at the time of surgery had significantly greater MME than those with KL grade 2 (P < .05). When patients were divided into 4 groups according to MOAKS criteria at the time of surgery, there were significant differences in WOMAC pain scores among groups at 1 and 2 years after the operation (all P < .05). The WOMAC function score also differed among groups at postoperative 1 year (P < .05) but not postoperative 2 years (P > .05). When patients were divided into 4 groups according to relative MME at the time surgery, the WOMAC pain score differed significantly among groups at postoperative 1 and 2 years (all P < .05). Analysis of WOMAC pain score as the dependent variable in multivariate analyses revealed that severity of absolute and relative MME and KL grade were independent predictors of worse WOMAC pain score at postoperative 1 and 2 years (all P < .05). CONCLUSION: Greater preoperative MME at the time of surgery was associated with inferior patient-reported outcomes, especially pain, in patients with MOWHTO at 1 and 2 years after surgery.

Comparison of implant position and joint awareness between fixed- and mobile-bearing unicompartmental knee arthroplasty: a minimum of five year follow-up study.

PURPOSE: To compare the implant position and patient-reported outcomes (PROs) regarding joint awareness using the Forgotten Joint Score (FJS) following between fixed-bearing (FB) and mobile-bearing (MB) unicompartmental knee arthroplasty (UKA) with a minimum of five years' follow-up. METHODS: One hundred fifteen consecutive UKAs (58 FB UKAs and 57 MB UKAs) performed were retrospectively evaluated. We compared the radiographic parameters including component positions and relationships as well as lower extremity alignment. Post-operative clinical outcomes were assessed using Knee Society Score (KSS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, Tegner activity score, and FJS. RESULTS: The MB UKA group showed more convergent componentry relationship between femoral and tibial components (p < 0.001). The joint line of the MB UKA group was restored significantly better (p < 0.05). In addition, the positioning of femoral and tibial components of the MB UKA group showed less deviation from the weight-bearing line (WBL) (p < 0.05). Although there were no differences in KSS, WOMAC, and Tegner activity scores between the groups, the MB UKA group showed significantly better FJS than did the FB UKA group at five years post-operatively (p < 0.05). CONCLUSION: The MB UKA group had a more convergent componentry relationship, less deviation from WBL, better joint-line restoration, and reduced joint awareness than did the FB UKA group at five years follow-up.

Pseudarthrosis Repair Using Autologous Cultured Osteoblasts in Complex Type-1 Neurofibromatosis Spinal Deformity: A Case Report and Review of the Literature.

STUDY DESIGN: A case report and literature review. OBJECTIVE: To report a late dislocation of the vertebra caused by progressive dural ectasia combined with type-1 neurofibromatosis (NF-1) and the clinical results of pseudarthrosis repairs using autologous cultured osteoblasts. SUMMARY OF BACKGROUND DATA: NF-1 is a well-known genetic disorder that is commonly characterized by spinal deformities including kyphoscoliosis. Late dislocation of the vertebra resulting from progressive dural ectasia after surgical correction of NF-1 scoliosis is a very rare occurrence, and pseudarthrosis frequently develops after surgical intervention for this complex spinal deformity. METHODS: A 32-year-old female patient with NF-1 scoliosis underwent surgical correction with posterior instrumented fusion. Seventeen years later, dislocation of the lumbar spine with implant failure resulting from massive progressive dural ectasia was observed. She underwent anterior interbody fusion three times and posterior instrumented fusion four times for pseudarthrosis followed by surgical deformity correction. For the last operation, autologous cultured osteoblasts were used as a therapeutic approach to repair the pseudarthrosis, and a three-dimensional printing technique was used to understand the surgical anatomy of the dislocated lumbar spine in detail. RESULTS: After the final operation, bone union was achieved and confirmed by clinical and radiological examination. CONCLUSION: Spine surgeons should be knowledgeable about the possibility of late destabilization of the spine, due to pulsatile dural ectasia, and a high rate of pseudarthrosis in neurofibromatosis. Autologous cultured osteoblasts may prove to be a modality that can be applied pseudarthrosis repair to treat complex spinal deformity. LEVEL OF EVIDENCE: 5.

Surgical treatment of lesions of the long head of the biceps brachii tendon with rotator cuff tear: a prospective randomized clinical trial comparing the clinical results of tenotomy and tenodesis.

BACKGROUND: Tenotomy and tenodesis are common treatments for lesions in the long head of biceps tendon (LHBT); however, which treatment is superior is still controversial. This study compared the outcomes of tenotomy with outcomes of tenodesis for treatment of LHBT lesions with rotator cuff tears. METHODS: The study enrolled 128 patients with LHBT lesions and small- to medium-sized rotator cuff tear. Arthroscopic LHBT tenotomy was done in 56 patients (group I), and LHBT tenodesis was done for 72 patients (group II) with rotator cuff repair. American Shoulder and Elbow Surgeons Score, simple shoulder test, pain visual analog scale, range of motion, and cosmetic changes were assessed initially, at 3, 6, and 12 months postoperatively, and the last visit. The elbow motor power and magnetic resonance imaging were evaluated at 12 months. RESULTS: Both groups showed improvement in functional scores after treatments, but no significant difference was found between the 2 groups at each assessment. The rate of Popeye deformity was 3 times higher in group I (P = .04). Group II showed greater forearm supination power than group I (P = .02). On magnetic resonance imaging, 45 patients (80.4%) in group I showed maintenance of the LHBT cut end within the bicipital groove, whereas 65 patients (90.3%) in group II showed maintenance of fixated LHBT. CONCLUSION: For the treatment of LHBT lesions with rotator cuff tear, patients with tenotomy and tenodesis both showed significant improvements in functional scores. The incidence of Popeye deformity was about 3-times higher in tenotomy group. No significant differences in elbow motor power were observed except greater forearm supination power in the tenodesis group.

Anti-adipogenic effect of Artemisia annua in diet-induced-obesity mice model.

Obesity has increased continuously in western countries during the last several decades and recently become a problem in developing countries. Currently, anti-obesity drugs originating from natural products are being investigated for their potential to overcome adverse effects associated with chemical drugs. Artemisinic acid, which was isolated from the well-known anti-malaria herb Artemisia annua (AA) L., was recently shown to possess anti-adipogenic effects in vitro. However, the anti-adipogenic effects of AA in animal models have not yet been investigated. Therefore, we conducted daily oral administration with AA water extract in a diet-induced obesity animal model and treated 3T3-L1 cells with AA to confirm the anti-adipogenic effects in the related protein expressions. We then evaluated the physiology, adipose tissue histology and mRNA expressions of many related genes. Inhibition of adipogenesis by the AA water extract was observed in vitro. In the animal model, weight gain was significantly lower in the AA treated group, but there were no changes in food intake volume or calories. Reductions in lipid droplet size and mRNA expression associated with adipogenesis were also observed in animal epididymal fat. This study is the first to report that AA has an anti-obese effects in vivo.

Acanthopanax sessiliflorus stem confers increased resistance to environmental stresses and lifespan extension in Caenorhabditis elegans.

BACKGROUND/OBJECTIVES: Acanthopanax sessiliflorus is a native Korean plant and used as traditional medicine or an ingredient in many Korean foods. The free radical theory of aging suggests that cellular oxidative stress caused by free radicals is the main cause of aging. Free radicals can be removed by cellular anti-oxidants. MATERIALS/METHODS: Here, we examined the anti-oxidant activity of Acanthopanax sessiliflorus extract both in vitro and in vivo. Survival of nematode C. elegans under stress conditions was also compared between control and Acanthopanax sessiliflorus extract-treated groups. Then, anti-aging effect of Acanthopanax sessiliflorus extract was monitored in C. elegans. RESULTS: Stem extract significantly reduced oxidative DNA damage in lymphocyte, which was not observed by leaves or root extract. Survival of C. elegans under oxidative-stress conditions was significantly enhanced by Acanthopanax sessiliflorus stem extract. In addition, Acanthopanax sessiliflorus stem increased resistance to other environmental stresses, including heat shock and ultraviolet irradiation. Treatment with Acanthopanax sessiliflorus stem extract significantly extended both mean and maximum lifespan in C. elegans. However, fertility was not affected by Acanthopanax sessiliflorus stem. CONCLUSION: Different parts of Acanthopanax sessiliflorus have different bioactivities and stem extract have strong anti-oxidant activity in both rat lymphocytes and C. elegans, and conferred a longevity phenotype without reduced reproduction in C. elegans, which provides conclusive evidence to support the free radical theory of aging.

Neuroprotective effect of a new synthetic aspirin-decursinol adduct in experimental animal models of ischemic stroke.

Stroke is the second leading cause of death. Experimental animal models of cerebral ischemia are widely used for researching mechanisms of ischemic damage and developing new drugs for the prevention and treatment of stroke. The present study aimed to comparatively investigate neuroprotective effects of aspirin (ASA), decursinol (DA) and new synthetic aspirin-decursinol adduct (ASA-DA) against transient focal and global cerebral ischemic damage. We found that treatment with 20 mg/kg, not 10 mg/kg, ASA-DA protected against ischemia-induced neuronal death after transient focal and global ischemic damage, and its neuroprotective effect was much better than that of ASA or DA alone. In addition, 20 mg/kg ASA-DA treatment reduced the ischemia-induced gliosis and maintained antioxidants levels in the corresponding injury regions. In brief, ASA-DA, a new synthetic drug, dramatically protected neurons from ischemic damage, and neuroprotective effects of ASA-DA may be closely related to the attenuation of ischemia-induced gliosis and maintenance of antioxidants.