Generalized optical signal-to-noise ratio monitoring using a convolutional neural network for digital coherent receivers.

In this Letter, we propose a generalized optical signal-to-noise ratio (GOSNR) monitoring scheme using a convolutional neural network trained on constellation density features acquired from a back-to-back setup and demonstrate accurate GOSNR estimations for links having different nonlinearities. The experiments were carried over dense wavelength division multiplexing links configured on 32-Gbaud polarization division multiplexed 16-quadrature amplitude modulation (QAM) and demonstrated that the GOSNRs are estimated within 0.1 dB mean absolute error with maximum estimation errors below 0.5 dB on metro class links. The proposed technique does not require any information about the noise floor in the conventional spectrum-based means and therefore is readily deployable for real-time monitoring.

Arrested Pneumatization of the Sphenoid Sinus.

The sphenoid bone is a complex structure in terms of its embryological origin. At birth, the sphenoid sinus is nonpneumatized. Arrested pneumatization of the sphenoid sinus is considered a normal anatomic variant but may be mistaken for disease in imaging studies. We report 2 cases of arrested pneumatization of the sphenoid sinus, a normal variant commonly misdiagnosed as a serious disease of the skull base. A 29-year-old man with a complaint of dizziness visited a local clinic for assessment. Computed tomography (CT) of the paranasal sinuses (PNS) showed a noneroding, nonexpansile, and nonhomogenous lesion in the sphenoid bone. Magnetic resonance imaging (MRI) of the brain revealed a high-signal lesion on both T1-weighted and T2-weighted images. Given these typical findings in the CT of PNS and MRI of the brain, the lesion was diagnosed as arrested pneumatization of the sphenoid sinus. In the second case, a 60-year-old woman with a complaint of headache visited a local clinic for assessment. CT of PNS showed a fibro-osseous lesion (with features of sclerosis and osteolysis) in the skull base. Brain MRI revealed a low-signal lesion on a T1-weighted image containing a high-signal intensity around the sphenoid bone, thereby suggesting internal fat contents. A precise interpretation of CT of PNS and brain MRI is essential to distinguish arrested pneumatization of the sphenoid sinus and to help establish a differential diagnosis and avoid needless biopsy.

Constellation-based identification of linear and nonlinear OSNR using machine learning: a study of link-agnostic performance.

We demonstrate accurate estimation of generalized optical signal to noise ratio (GOSNR) for wavelength division multiplexed fiber communication systems using an experimentally trained multi-tasking convolutional neural network while simultaneously estimating linear and nonlinear noise contributions. Using dual-polarized 32-GBaud 16QAM DWDM links we extract learnable features from constellation density matrices and accurately estimate GOSNR while simultaneously estimating linear and nonlinear contributions. Estimation of the OSNRASE, OSNRNL and GOSNR are demonstrated with < 0.5 dB mean absolute error. We also assess the universality of our model within the regime of metro networks by cross-training with data from such links comprised of different fiber types. We demonstrate a path to a practical universal training method that includes additional link parameters. The methods do not require contiguous high-speed sampling, additional hardware nor transmission of special symbols or patterns and are readily implemented in deployed systems.

Quantitative susceptibility mapping and R1 measurement: Determination of the myelin volume fraction in the aging ex vivo rat corpus callosum.

In studies of the white matter (WM) in aging brains, both quantitative susceptibility mapping (QSM) and direct R1 measurement offer potentially useful ex vivo MRI tools that allow volumetric characterization of myelin content changes. Despite the technical importance of such MRI methods in numerous age-related diseases, the supposed linear relationship between the estimates of either the QSM or R1 method and age-affected myelin contents has not been validated. In this study, the absolute myelin volume fraction (MVF) was determined by transmission electron microscopy (TEM) as a gold standard measure for comparison with the values obtained by the aforementioned MR methods. To theoretically evaluate and understand the MR signal characteristics, QSM simulations were performed using the finite perturber method (FPM). Specifically, the simulation geometry modeling was based on TEM-derived structures aligned orthogonally to the main magnetic field, the construct of which was used to estimate the magnetic field shift (ΔB) changes arising from the conjectured myelin structures. Experimentally, ex vivo corpus callosum (CC) samples from rat brains obtained at 6 weeks (n = 3), 4 months (n = 3), and 20 months (n = 3) after birth were used to establish the relationship between changes quantified by either QSM or R1 with the absolute MVF by TEM. From the ex vivo brain samples, the scatterplot of mean MVF versus R1 was fitted to a linear equation, where R1mean = 0.7948 × MVFmean + 0.8118 (Pearson's correlation coefficient r = 0.9138; p < 0.01), while the scatterplot of mean MVF versus MRI-derived magnetic susceptibility (χ) was also fitted to a line where χmeasured,mean = -0.1218 × MVFmean - 0.006345 (r = -0.8435; p < 0.01). As a result of the FPM-based QSM simulations, a linearly proportional relationship between the simulated magnetic susceptibility, χsimulated,mean , and MVF (r = -0.9648; p < 0.01) was established. Such a statistically significant linear correlation between MRI-derived values by the QSM (or R1 ) method and MVF demonstrated that variable myelin contents in the WM (i.e., CC) can be quantified across multiple stages of aging. These findings further support that both techniques based on QSM and R1 provide an efficient means of studying the brain-aging process with accurate volumetric quantification of the myelin content in WM.

Sex-Specific Multiparameter Blood Test for the Early Diagnosis of Alzheimer's Disease.

Blood-based biomarkers are needed for the early diagnosis of Alzheimer's disease (AD). We analyzed longitudinal human plasma samples from AD and control cases to identify biomarkers for the early diagnosis of AD. Plasma samples were grouped based on clinical diagnosis at the time of collection: AD, mild cognitive impairment (MCI), and pre-symptomatic (preMCI). Samples were analyzed by ELISA using a panel of reagents against nine different AD-related amyloid-ß (Aß), tau, or TDP-43 variants. Receiver operating characteristic (ROC) curves of different biomarker panels for different diagnostic sample groups were determined. Analysis of all of the samples gave a sensitivity of 92% and specificity of 76% for the diagnosis of AD. Early-stage diagnosis of AD, utilizing only the preMCI and MCI samples, identified 88% of AD cases. Using sex-biased biomarker panels, early diagnosis of AD cases improved to 96%. Using the sex-biased panels, we also identified 6 of the 25 control group cases as being at high risk of AD, which is consistent with what is expected given the advanced age of the control cases. Specific AD-associated protein variants are effective blood-based biomarkers for the early diagnosis of AD. Notably, significant differences were observed in biomarker profiles for the early detection of male and female AD cases.

Extracellular vesicles regulate gap junction-mediated intercellular communication and HIV-1 infection of human neural progenitor cells.

Human immunodeficiency virus-1 (HIV-1) has been shown to cross the blood-brain barrier and cause HIV-associated neurocognitive disorders (HAND) through a process that may involve direct or indirect interactions with the central nervous system (CNS) cells and alterations of amyloid ß (Aß) homeostasis. The present study focused on the mechanisms of HIV-1 infecting human neural progenitor cells (hNPCs) and affecting NPC intercellular communications with human brain endothelial cells (HBMEC). Despite the lack of the CD4 receptor, hNPCs were effectively infected by HIV-1 via a mechanism involving the chemokine receptors, CXCR4 and CCR5. HIV-1 infection increased expression of connexin-43 (Cx43), phosphorylated Cx43 (pCx43), and pannexin 2 (Panx2) protein levels in hNPCs, suggesting alterations in gap-junction (GJ) and pannexin channel communication. Indeed, a functional GJ assay indicated an increase in communication between HIV-infected hNPCs and non-infected HBMEC. We next analyzed the impact of HBMEC-derived extracellular vesicles (EVs) and EVs carrying Aß (EV-Aß) on the expression of Cx43, pCx43, and Panx2 in HIV-1 infected and non-infected hNPCs. Exposure to EV-Aß resulted in significant reduction of Cx43 and pCx43 protein expression in non-infected hNPCs when compared to EV controls. Interestingly, EV-Aß treatment significantly increased levels of Cx43, pCx43, and Panx2 in HIV-1-infected hNPCs when compared to non-infected controls. These results were confirmed in a GJ functional assay and an ATP release assay, which is an indicator of connexin hemichannel and/or pannexin channel functions. Overall, the current study demonstrates the importance of hNPCs in HIV-1 infection and indicates that intercellular communications between infected hNPCs and HBMEC can be effectively modulated by EVs carrying Aß as their cargo.

Model-free leakage index estimation of the blood-brain barrier using dual dynamic susceptibility contrast MRI acquisition.

Pharmacokinetic K2 mapping from dynamic susceptibility contrast (DSC)-MRI can be a sensitive technique for evaluating the vascular permeability of the subtly damaged blood-brain barrier (BBB) in ischemic regions. However, the K2 values of ischemic lesions depend upon the selection of the intact BBB reference region. As previous observations suggest that the ΔR2* curve of pre-loaded DSC-MRI is not significantly affected by the extravasation of contrast agent, dual DSC-MRI acquisitions can be performed to derive the BBB leakage index from the voxel-wise reference input function for ischemic regions. This study aims to demonstrate the robustness of such model-free leakage index estimation in ischemic brains. By configuring the relationship between dual ΔR2* curves of the intact contralateral brain, the deviation of the measured ΔR2* curve from the unloaded DSC-MRI with respect to the non-deviated ΔR2* curve in the pre-loaded DSC-MRI can be quantified as the BBB leakage index. Such model-free leakage index values from rats with transient middle carotid artery occlusion (tMCAO) (n = 17) and normal controls (n = 3) were evaluated and compared with conventional K2 values with multiple reference regions. Inter-subject leakage index values were also compared with the corresponding ΔT1 map. Evans-blue-stained images were used to validate the leakage index. For the tMCAO group, leakage index values correlated well with ΔT1 (Pearson's r = 0.828). The hyperintense area on the leakage index map matched well with the corresponding Evans-blue-stained area (Dice correlation = 0.626). The slopes of the scatter-plot from the leakage index (0.97-1.00) were observed to be more robust against changes in the reference region than those from conventional K2 values (0.94-1.07). In a subtly damaged BBB tMCAO model, model-free evaluation of vascular permeability using dual DSC-MRIs would provide a consistent measure of inter-subject vascular permeability.

Clinical outcomes of otogenic skull base osteomyelitis.

PURPOSE: Skull base osteomyelitis (SBO) is an uncommon and a potentially life-threatening condition if not promptly recognized and properly treated. The aim of our study was to present a 32-case series of patients diagnosed with SBO at a single center. METHODS: In this retrospective study, we reviewed the data of patients diagnosed with otogenic SBO between January 2011 and January 2020. 32 patients were enrolled in the study. SBO diagnosis was based on a combination of symptoms and physical examination, bone scan, brain magnetic resonance imaging, and pathologic examination findings. The following clinical data were collected during the follow-up period: types of antibiotics used, duration of antibiotic treatment, C-reactive protein level, presence of disease control, duration from the onset of symptoms to diagnosis, and patient survival. RESULTS: The mean follow-up period was 11 (1-110) months. The mean duration of antibiotic treatment was 115 (19-223) days. The mean C-reactive protein levels at the time of diagnosis and at the endpoint of follow-up were 3.05 (0.56-18.31) and 0.21 (0.03-33.61) mg/dL, respectively (P < 0.001). Disease control rate was 34.9% at 1-year and 83.7% at 5-year follow-up. Patient survival rate was 90.6% at 1- and 3-year follow-ups. At the endpoint of follow-up, three patients died. The mean durations from the onset of symptoms to diagnosis were 50 (5-360) and 90 (30-480) days in patients with the controlled disease and in those with the uncontrolled disease, respectively, at the endpoint of follow-up (P = 0.043). CONCLUSION: Comprehensive assessment and aggressive treatment of patients exhibiting symptoms suggestive of SBO would help in the rapid diagnosis of otogenic SBO, resulting in an improvement in prognosis.

Optical performance monitoring using digital coherent receivers and convolutional neural networks.

We experimentally demonstrate accurate modulation format identification, optical signal to noise ratio (OSNR) estimation, and bit error ratio (BER) estimation of optical signals for wavelength division multiplexed optical communication systems using convolutional neural networks (CNN). We assess the benefits and challenges of extracting information at two distinct points within the demodulation process: immediately after timing recovery and immediately prior to symbol unmapping. For the former, we use 3D Stokes-space based signal representations. For the latter, we use conventional I-Q constellation images created using demodulated symbols. We demonstrate these methods on simulated and experimental dual-polarized waveforms for 32-GBaud QPSK, 8QAM, 16QAM, and 32QAM. Our results show that CNN extracts distinct and learnable features at both the early stage of demodulation where the information can be used to optimize subsequent stages and near the end of demodulation where the constellation images are readily available. Modulation format identification is demonstrated with >99.8% accuracy, OSNR estimation with <0.5 dB average discrepancy and BER estimation with percentage error of <25%.

Blood-brain barrier pericytes as a target for HIV-1 infection.

Pericytes are multifunctional cells wrapped around endothelial cells via cytoplasmic processes that extend along the abluminal surface of the endothelium. The interactions between endothelial cells and pericytes of the blood-brain barrier are necessary for proper formation, development, stabilization, and maintenance of the blood-brain barrier. Blood-brain barrier pericytes regulate paracellular flow between cells, transendothelial fluid transport, maintain optimal chemical composition of the surrounding microenvironment, and protect endothelial cells from potential harmful substances. Thus, dysfunction or loss of blood-brain barrier pericytes is an important factor in the pathogenesis of several diseases that are associated with microvascular instability. Importantly, recent research indicates that blood-brain barrier pericytes can be a target of HIV-1 infection able to support productive HIV-1 replication. In addition, blood-brain barrier pericytes are prone to establish a latent infection, which can be reactivated by a mixture of histone deacetylase inhibitors in combination with TNF. HIV-1 infection of blood-brain barrier pericytes has been confirmed in a mouse model of HIV-1 infection and in human post-mortem samples of HIV-1-infected brains. Overall, recent evidence indicates that blood-brain barrier pericytes can be a previously unrecognized HIV-1 target and reservoir in the brain.

Open reduction and internal fixation of comminuted patellar fractures with headless compression screws and wiring technique.

BACKGROUND: Management of a displaced comminuted patellar fractures is challenging, and various surgical fixation methods have been suggested. However, issues of loss of reduction and breakage of fixatives have not yet been resolved. In the current study, we describe a new technique for exposure and stabilization of comminuted patellar fractures and evaluate the clinical and radiologic outcomes of this new treatment. MATERIALS AND METHODS: Thirteen patellar fractures with articular comminution, which were treated by headless compression screws with additional separate vertical wiring were enrolled in this study. Loose articular fragments were fixed with headless compression screws under direct visual reduction of the articular surface, which was facilitated by the superior everting of the patella. Radiographs of the knee were obtained at routine follow-up to assess fracture healing and widening of articular step-off. Clinical outcomes including range of motion, quadriceps circumference, visual analog scale (VAS) related pain score, Lysholm, and Bostman grading scales were measured at the last follow-up. RESULTS: All the fractures healed at a mean of 15 weeks. No patient had loss of reduction, evidence of implant migration, or metallic failure. Articular step-off larger than 2 mm was not seen in any of the cases. The average range of motion arc was 134.2° (range, 120°-145°), and the mean Lysholm and Bostman scores were 94.4 (range, 84-100 points) and 28.7 (range, 25-30 points), respectively. Thigh muscle wasting was observed in four patients (33.3%), but no patient had >1.5 cm difference in thigh circumference girth between the injured and uninjured lower limbs. The average VAS-related pain score was 0.4. CONCLUSIONS: Articular fixations with headless compression screws under direct visual reduction of the articular surface resulted in good clinical outcomes and were considered clinically effective for comminuted patellar fractures.

Variations in sagittal locations of anterior cruciate ligament tibial footprints and their association with radiographic landmarks: a human cadaveric study.

BACKGROUND: This cadaveric study aimed to demonstrate variation of the anterior cruciate ligament (ACL) tibial attachment in the sagittal plane, and to analyze the radiographic landmarks which predict the sagittal location of the ACL tibial attachment. METHODS: In 20 cadaveric knees, native ACLs were removed and the centers of the ACL tibial and femoral attachments were marked with metal pins. Full extension lateral radiographs were then obtained in each cadaveric knee. Using the full extension lateral radiographs, the sagittal location of the ACL tibial footprint center was estimated as a percentage in the Amis and Jakob's line. Several radiographic landmarks including the geometry of Blumensaat's line and the apex of the tibial eminence were measured. Then, the relationship between the variation of the sagittal location of the ACL tibial footprint and several radiographic landmarks were analyzed using Pearson's correlation analysis. RESULTS: The average sagittal position of the native ACL tibial footprint was 40.9% (range: 38.0-45.0%). The line connecting the centers of the ACL footprint was nearly parallel to Blumensaat's line, with an average angle of 1.7° (range: 0-4.1°). In addition, the distance from the point where Blumensaat's line meets the tibial articular surface to the center of the ACL tibial footprint was almost consistent, at 7.6 mm on average (range: 6.4-8.7 mm). The correlation analysis revealed that the geometry of Blumensaat's line was significantly correlated with the sagittal location of the ACL tibial footprint. CONCLUSION: The radiographic landmark that showed a significant correlation with the ACL tibial footprint in the full extension lateral radiographs was Blumensaat's line.

Simultaneous evaluation of vascular morphology, blood volume and transvascular permeability using SPION-based, dual-contrast MRI: imaging optimization and feasibility test.

Exploiting ultrashort-T(E) (UTE) MRI, T1-weighted positive contrast can be obtained from superparamagnetic iron oxide nanoparticles (SPIONs), which are widely used as a robust T2-weighted, negative contrast agent on conventional MR images. Our study was designed (a) to optimize the dual-contrast MRI method using SPIONs and (b) to validate the feasibility of simultaneously evaluating the vascular morphology, blood volume and transvascular permeability using the dual-contrast effect of SPIONs. All studies were conducted using 3 T MRI. According to numerical simulation, 0.15 mM was the optimal blood SPION concentration for visualizing the positive contrast effect using UTE MRI (T(E) = 0.09 ms), and a flip angle of 40° could provide sufficient SPION-induced enhancement and acceptable measurement noise for UTE MR angiography. A pharmacokinetic study showed that this concentration can be steadily maintained from 30 to 360 min after the injection of 29 mg/kg of SPIONs. An in vivo study using these settings displayed image quality and CNR of SPION-enhanced UTE MR angiography (image quality score 3.5; CNR 146) comparable to those of the conventional, Gd-enhanced method (image quality score 3.8; CNR 148) (p > 0.05). Using dual-contrast MR images obtained from SPION-enhanced UTE and conventional spin- and gradient-echo methods, the transvascular permeability (water exchange index 1.76-1.77), cerebral blood volume (2.58-2.60%) and vessel caliber index (3.06-3.10) could be consistently quantified (coefficient of variation less than 9.6%; Bland-Altman 95% limits of agreement 0.886-1.111) and were similar to the literature values. Therefore, using the optimized setting of combined SPION-based MRI techniques, the vascular morphology, blood volume and transvascular permeability can be comprehensively evaluated during a single session of MR examination.

Prevalence and Risk Factors of Spine, Shoulder, Hand, Hip, and Knee Osteoarthritis in Community-dwelling Koreans Older Than Age 65 Years.

BACKGROUND: Osteoarthritis (OA) is common and disabling among older patients around the world. Data exploring the prevalence and risk factors of OA are of paramount importance in establishing healthcare policies. However, few studies have evaluated these topics among Asian populations. QUESTIONS/PURPOSES: This study was conducted to determine the prevalence and risk factors of radiographic OA in the spine, shoulder, hand, hip, and knee in Koreans older than age 65 years. METHODS: A simple random sample (N = 1118) was drawn from a roster of elderly individuals older than age 65 years in Seongnam. Of the 1118 invited subjects, 696 (males = 298, females = 398) participated in this study (a response rate of 62%). The mean age of respondents was 72 ± 5 years (range, 65-91 years). Radiographs of the lumbar spine, shoulder, hand, hip, and knee were taken and afterward evaluated for radiographic OA. The Kellgren-Lawrence grading system was used for all mentioned joints, and radiographic OA was defined as Grade 2 changes or higher. The association of sex, aging, and obesity with OA in each of the mentioned joints was determined with the help of multivariate logistic regression. RESULTS: The highest prevalence of radiographic OA was seen in the spine (number of subjects with OA/number of whole population = 462 of 696 [66%]) followed by the hand (415 of 692 [60%]), knee (265 of 696 [38%]), shoulder (36 of 696 [5%]), and hip (15 of 686 [2%]). Female sex was associated with knee OA (odds ratio [OR], 5.7; 95% confidence interval [CI], 3.9-8.4; p < 0.001) and hand OA (OR, 2.3; 95% CI, 1.6-3.1; p < 0.001), and male sex was associated with spine OA (OR, 0.7; 95% CI, 0.5-1.0; p = 0.025). Aging was associated with radiographic OA in the spine, knee, and hand (OR per 5-year increments, 1.3 [95% CI, 1.1-1.6; p = 0.001], 1.6 [95% CI, 1.4-1.9; p < 0.001], and 1.4 [95% CI, 1.2-1.7; p < 0.001]), respectively) but not associated with OA in the hip and shoulder. Obesity was associated with knee OA (OR, 3.4; 95% CI, 2.4-5.0; p < 0.001) and spine OA (OR, 1.5; 95% CI, 1.1-2.2; p = 0.014) but not with OA in other joints. CONCLUSIONS: OA of the spine, hand, and knee is likely to become a major public health problem rather than shoulder and hip OA in Korea. Associations of demographic factors with radiographic OA differed among each joint, and that would be valuable information to assess the role and influence of risk factors of OA in various joints. LEVEL OF EVIDENCE: Level III, prognostic study.

Synthesis and cellular uptake of folic acid-conjugated cellulose nanocrystals for cancer targeting.

Elongated nanoparticles have recently been shown to have distinct advantages over spherical ones in targeted drug delivery applications. In addition to their oblong geometry, their lack of cytotoxicity and numerous surface hydroxyl groups make cellulose nanocrystals (CNCs) promising drug delivery vectors. Herein we report the synthesis of folic acid-conjugated CNCs for the targeted delivery of chemotherapeutic agents to folate receptor-positive cancer cells. Folate receptor-mediated cellular binding/uptake of the conjugate was demonstrated on human (DBTRG-05MG, H4) and rat (C6) brain tumor cells. Folate receptor expression of the cells was verified by immunofluorescence staining. Cellular binding/uptake of the conjugate by DBTRG-05MG, H4, and C6 cells was 1452, 975, and 46 times higher, respectively, than that of nontargeted CNCs. The uptake mechanism was determined by preincubation of the cells with the uptake inhibitors chlorpromazine or genistein. DBTRG-05MG and C6 cells internalized the conjugate primarily via caveolae-mediated endocytosis, whereas H4 cells internalized the conjugate primarily via clathrin-mediated endocytosis.

Trends in use of total knee arthroplasty in Korea from 2001 to 2010.

BACKGROUND: The use of total knee arthroplasty (TKA) has increased substantially in most Western countries. However, the trends in TKA use and changes in demographic characteristics of patients having TKA in Korea remain unclear. QUESTIONS/PURPOSES: We documented the trends in TKA use and in the demographics of patients undergoing TKA in Korea over the past decade and determined whether current TKA use in Korea corresponds to worldwide trends. METHODS: Using the Health Insurance Review and Assessment Service of Korea database, we analyzed TKA records (n = 398,218) from 2001 to 2010 in Korea. Trends in TKA use and demographics, including numbers and rates of primary and revision TKA, growth rate and the revision burden, and age- and sex-specific rates, were estimated. They were compared with nationwide TKA registry reports from other countries, and a systematic review was performed. RESULTS: Over the past decade, the primary and revision TKA rates increased by 407% and 267%, respectively. However, the revision burden remained 2%. The highest proportion was observed in 65 to 74 years old and the greatest increase in 75 to 84 years old, but a decrease was observed in those 55 to 64 years old. Women consistently had a ninefold higher TKA rate. The primary TKA rate was comparable with that of other countries, but the revision burden remained lower. In addition, old and female patients comprised considerably higher proportions in Korea. CONCLUSIONS: During the past decade, TKA use in Korea has markedly increased and caught up with the use levels of most developed Western countries. Trends toward consistent growth in elderly patients and higher rates in females were observed. Appropriate healthcare strategies reflecting these trends in demographics are urgently needed in Korea.

Empirical relationship between TEM-derived myelin volume fraction and MRI-R2 values in aging ex vivo rat corpus callosum.

Ex vivo ratiometric measurements of short- and long-T2 components using the multiple spin echo sequence of MRI are often employed to evaluate alterations in myelin content in the white matter (WM) of the brain. However, the relationship between absolute MRI-T2 values (long-T2 component) and myelin volumetric information in aged ex vivo rodent WM appears to be influenced by factors such as animal species, field strength, and fixation durations/washing. Here, multiple spin echo sequence-based MRI-R2 (the reciprocal of T2) values were measured in the corpus callosum (CC) region in the post-mortem rat brains (n = 9) of different age groups with common fixation techniques without washing at 7 T. Transmission electron microscopy (TEM)-based quantification of myelin volume fraction (MVF) and corresponding Monte-Carlo simulation to estimate relaxation rates (R2,IE) due to diffusion in the presence of inhomogeneous magnetic field perturbation in intra- and extra-cellular (IE) spaces were respectively performed. To determine whether the short-T2 components originating from myelin water were mixed with long-T2 components from IE water or were undetectable, the MVF values obtained from TEM results were respectively compared with MRI-R2 and R2,IE values. A significant correlation (Pearson's correlation coefficient r = 0.8763; p < 0.01) of average MRI-R2 and MVF values was observed. Estimated R2,IE values from Monte-Carlo simulations in IE water signals were also positively correlated (r = 0.8281; p < 0.01) with MVF values. However, the magnitudes of R2,IE values were much smaller than those observed for MRI-R2 values, indicating that changes in R2 related MVF are likely dominated by myelin water components. Such comparisons between independent parameters from MRI, TEM, and simulations support the suggestion that myelin water signals were indistinguishably mixed to exhibit mono-exponential T2 relaxation, and multiple spin echo sequence-based MRI-R2 values in aging ex vivo rat CC without prolonged washing still reflect the volumetric information of myelin, likely due to enhanced water exchange across the myelin.

User-designed device with programmable release profile for localized treatment.

Three-dimensional printing enables precise and on-demand manufacture of customizable drug delivery systems to advance healthcare toward the goal of personalized medicine. However, major challenges remain in realizing personalized drug delivery that fits a patient-specific drug dosing schedule using local drug delivery systems. In this study, a user-designed device is developed as implantable therapeutics that can realize personalized drug release kinetics by programming the inner structural design on the microscale. The drug release kinetics required for various treatments, including dose-dense therapy and combination therapy, can be implemented by controlling the dosage and combination of drugs along with the rate, duration, initiation time, and time interval of drug release according to the device layer design. After implantation of the capsular device in mice, the in vitro-in vivo and pharmacokinetic evaluation of the device is performed, and the therapeutic effect of the developed device is achieved through the local release of doxorubicin. The developed user-designed device provides a novel platform for developing next-generation drug delivery systems for personalized and localized therapy.

Internal Carotid Artery Pseudoaneurysm Secondary to Skull Base Osteomyelitis: A Case Report.

We report a case of a pseudoaneurysm secondary to skull base osteomyelitis (SBO) in an 82-year-old female. The patient was hospitalized with an acute episode of bleeding from the right ear, which persisted despite packing placed in the ear. We suspected bleeding from the internal carotid artery (ICA) and performed angiography, which revealed a pseudoaneurysm that presumably developed secondary to invasion of the wall of the petrous segment of the right ICA, and the patient underwent emergency coil embolization. Bleeding from the ear recurred a week later, and we performed repeat angiography, followed by embolization and deployment of multiple stents at the site of the pseudoaneurysm, which controlled the bleeding. Clinicians should be mindful of a pseudoaneurysm as a rare complication of SBO, following the spread of infection to adjacent soft tissues or vessels. A pseudoaneurysm should be considered in the differential diagnosis in patients with recurrent epistaxis or bleeding from the ears in addition to cranial nerve symptoms, and this condition warrants urgent evaluation.

Adaptive cellular response of the substantia nigra dopaminergic neurons upon age-dependent iron accumulation.

Progressive iron accumulation in the substantia nigra in the aged human brain is a major risk factor for Parkinson's disease and other neurodegenerative diseases. Heavy metals, such as iron, produce reactive oxygen species and consequently oxidative stress in cells. It is unclear, however, how neurons in the substantia nigra are protected against the age-related, excessive accumulation of iron. In this study, we examined the cellular response of the substantia nigra against age-related iron accumulation in rats of different ages. Magnetic resonance imaging confirmed the presence of iron in 6-month-old rats; in 15-month-old rats, iron accumulation significantly increased, particularly in the midbrain. Transcriptome analysis of the region, in which iron deposition was observed, revealed an increase in stress response genes in older animals. To identify the genes related to the cellular response to iron, independent of neurodevelopment, we exposed the neuroblastoma cell line SH-SY5Y to a similar quantity of iron and then analyzed their transcriptomic responses. Among various stress response pathways altered by iron overloading in the rat brain and SH-SY5Y cells, the genes associated with topologically incorrect protein responses were significantly upregulated. Knockdown of HERPUD1 and CLU in this pathway increased susceptibility to iron-induced cellular stress, thus demonstrating their roles in preventing iron overload-induced toxicity. The current study details the neuronal response to excessive iron accumulation, which is associated with age-related neurodegenerative diseases.