Asymmetric Implant Design for Posterolateral Overhang of the Femoral Component in Total Knee Arthroplasty: A Retrospective Computed Tomography-Based Study.

Introduction During total knee arthroplasty (TKA), also referred to as total knee replacement (TKR), patients may experience pain in the posterolateral knee. One possible cause is the impingement between the popliteus tendon and the femoral components. The purpose of this study was to analyze the posterolateral overhang of the femoral component using 3D template software. Methods Preoperative CT scan images of 50 knees (11 males and 39 females) with osteoarthritis of grade 2 or lower according to the Kellgren-Lawrence classification were analyzed. The mean age of the subjects was 73.8±7.6 years (range 52-84 years). The Athena (Soft Cube Co., Ltd., Osaka, Japan) knee 3D image-matching software was used for the analysis. The positions of the two femoral components (symmetrical and asymmetrical) were simulated. In the coronal plane, the component overhang was measured between the resected lateral part of the posterior femur and its corresponding component size, and the two designs were compared in three zones (proximal, central, and distal). Results In the simulated femoral component, the asymmetric design had a significantly lower component overhang than the symmetric design in the proximal zone of the lateral posterior condyle (0.2±1.9 mm vs. 3.5±1.6 mm, p<0.01). In the proximal zone, significant overhang (>3 mm) was observed in 30 knees (60.0%) with the symmetric design, but only three knees (6.0%) had asymmetric designs (p<0.01). Conclusions The posterolateral overhang of the lateral posterior condyle occurs when a symmetrical prosthesis is used. The use of an asymmetric implant with a small, rounded proximal portion of the lateral posterior condyle improves this overhang and is expected to decrease problems such as impingement of the popliteus tendon and improve patient satisfaction.

Exploring the extension quantities of a medial collateral ligament pie-crusting model using a finite element method.

Medial collateral ligament (MCL) pie-crusting can balance the soft tissue during total knee arthroplasty but requires more studies with the finite element method (FEM). We have developed three models of MCL pie-crusting utilizing FEM, treating the MCL in the following ways: (1) as a singular elastic body with both ends attached to the bone (model A), (2) as 19 bundled elastic bodies, each attached to both ends of the bone (model B), and (3) as 19 bundled elastic bodies with an adhesive component in the gap, attached to both ends of the bone (model C). The pie-crusting model was created by adding a cut around the center of each model. The left side of the model was fixed and forces of 80 and 120 N in the positive direction of the x-axis were applied. Model A was extended by 0.0068 and 0.010 mm for approximately 10 punctures. Model B-2 was extended by 1.34 and 2.01 mm, approximately twice as much as model B-1. Model C was extended by 0.34 and 0.50 mm for every 10 punctures added. These findings clarify that the model composed of aggregates of fibers with adhesive parts (model C) is suitable for MCL pie-crusting analysis.

Rare Co-occurrence of Spinal Cord Hemorrhage from Radiation-induced Cavernous Hemangioma and Classical Hodgkin Lymphoma Post-transplant Lymphoproliferative Disorder.

Post-transplant lymphoproliferative disorders (PTLDs) are lymphoproliferative diseases that occur after solid organ transplantation or hematopoietic stem cell transplantation (HSCT). The development of PTLD is often associated with reactivation of Epstein-Barr virus (EBV). A 26-year-old woman with a history of HSCT and total-body irradiation developed spinal cord hemorrhage from a radiation-induced cavernous hemangioma (RICH) shortly after the development of classical Hodgkin lymphoma PTLD with EBV reactivation. Although little is known about the factors leading to hemorrhagic events from spinal cord RICH, we suspect that EBV reactivation may have been a factor contributing to the hemorrhage in the present case.

UBL3 Interaction with α-Synuclein Is Downregulated by Silencing MGST3.

Ubiquitin-like 3 (UBL3) is a membrane-anchored protein that plays a crucial role in sorting proteins into small extracellular vesicles. Aggregations of alpha-synuclein (α-syn) are associated with the pathology of neurodegenerative diseases such as Parkinson's disease. Recently, the interaction between UBL3 and α-syn was discovered, with potential implications in clearing excess α-syn from neurons and its role in disease spread. However, the regulator that can mediate the interaction between UBL3 and α-syn remains unclear. In this study, using the split gaussian luciferase complementation assay and RNA interference technology, we identified that QSOX2, HTATIP2, UBE3C, MGST3, NSF, HECTD1, SAE1, and ATG3 were involved in downregulating the interaction between UBL3 and α-syn. Notably, silencing MGST3 had the most significant impact. Immunocytochemistry staining confirmed the impact of MGST3 silencing on the co-localization of UBL3 and α-syn in cells. MGST3 is a part of the antioxidant system, and silencing MGST3 is believed to contribute to oxidative stress. We induced oxidative stress with hydrogen peroxide, observing its effect on the UBL3-α-syn interaction, and showing that 800 µM of H2O2 downregulated this interaction. In conclusion, silencing MGST3 downregulates the interaction between UBL3 and α-syn.

UBL3 Interacts with Alpha-Synuclein in Cells and the Interaction Is Downregulated by the EGFR Pathway Inhibitor Osimertinib.

Ubiquitin-like 3 (UBL3) acts as a post-translational modification (PTM) factor and regulates protein sorting into small extracellular vesicles (sEVs). sEVs have been reported as vectors for the pathology propagation of neurodegenerative diseases, such as α-synucleinopathies. Alpha-synuclein (α-syn) has been widely studied for its involvement in α-synucleinopathies. However, it is still unknown whether UBL3 interacts with α-syn, and is influenced by drugs or compounds. In this study, we investigated the interaction between UBL3 and α-syn, and any ensuing possible functional and pathological implications. We found that UBL3 can interact with α-syn by the Gaussia princeps based split luciferase complementation assay in cells and immunoprecipitation, while cysteine residues at its C-terminal, which are considered important as PTM factors for UBL3, were not essential for the interaction. The interaction was upregulated by 1-methyl-4-phenylpyridinium exposure. In drug screen results, the interaction was significantly downregulated by the treatment of osimertinib. These results suggest that UBL3 interacts with α-syn in cells and is significantly downregulated by epidermal growth factor receptor (EGFR) pathway inhibitor osimertinib. Therefore, the UBL3 pathway may be a new therapeutic target for α-synucleinopathies in the future.

Endocannabinoid 2-Arachidonoylglycerol Levels in the Anterior Cingulate Cortex, Caudate Putamen, Nucleus Accumbens, and Piriform Cortex Were Upregulated by Chronic Restraint Stress.

Endocannabinoid 2-arachidonoylglycerol (2-AG) has been implicated in habituation to stress, and its augmentation reduces stress-induced anxiety-like behavior. Chronic restraint stress (CRS) changes the 2-AG levels in some gross brain areas, such as the forebrain. However, the detailed spatial distribution of 2-AG and its changes by CRS in stress processing-related anatomical structures such as the anterior cingulate cortex (ACC), caudate putamen (CP), nucleus accumbens (NAc), and piriform cortex (PIR) are still unclear. In this study, mice were restrained for 30 min in a 50 mL-centrifuge tube for eight consecutive days, followed by imaging of the coronal brain sections of control and stressed mice using desorption electrospray ionization mass spectrometry imaging (DESI-MSI). The results showed that from the forebrain to the cerebellum, 2-AG levels were highest in the hypothalamus and lowest in the hippocampal region. 2-AG levels were significantly (p < 0.05) upregulated and 2-AG precursors levels were significantly (p < 0.05) downregulated in the ACC, CP, NAc, and PIR of stressed mice compared with control mice. This study provided direct evidence of 2-AG expression and changes, suggesting that 2-AG levels are increased in the ACC CP, NAc, and PIR when individuals are under chronic stress.

Heat-Treated Osteochondral Allograft and Autologous Chondrocyte Implantation for a Large Osteochondral Defect: A Case Report.

CASE: A 21-year-old man presented with knee pain secondary to tibial plateau malunion and an osteochondral defect 1 year after open reduction and initial fixation. Two-stage reconstruction with transplantation of a bulk heat-treated osteochondral allograft and an autologous chondrocyte implantation was performed. CONCLUSION: This technique may be a good choice for large defects in the articular cartilage in cases of tibial plateau malunion. It may be a viable alternative for defect reconstruction, resulting in favorable early clinical, functional, and radiological outcomes.

Coenzyme Q10 in the eye isomerizes by sunlight irradiation.

Photoisomerization of lipids has been well studied. As for the eyes, photoisomerization from 11-cis isomer to all-trans-retinal is well-known as the first step of the visual transduction in the photoreceptors. In addition to that, there would be other ocular lipids that undergo photoisomerization, which may be involved in ocular health and function. To explore any photoisomerizable lipids in the eyes, the nonirradiated and sunlight-irradiated eyeball extracts were subjected to liquid chromatography-mass spectrometry analysis, followed by the identification of the decreased lipid species in the irradiated extracts. Surprisingly, more than nine hundred lipid species were decreased in the irradiated extracts. Three lipid species, coenzyme Q10 (CoQ10), triglyceride(58:4), and coenzyme Q9, were decreased both significantly (p < 0.05) and by more than two-fold, where CoQ10 showed the most significant decrease. Later, photoisomerization was identified as the prominent cause underlying the decrease of CoQ10. Interestingly, CoQ10 in the sunlight-irradiated fresh eyeballs was also isomerized. Both the visible light and ultraviolet radiation were capable of producing CoQ10 isomer, while the latter showed rapid action. This study is believed to enhance our understanding of the biochemistry and photodamage of the eye and can potentially contribute to the advancement of opto-lipidomics.

Cerebellar Ataxia as a Common Clinical Presentation Associated with DNMT1 p.Y511H and a Review of the Literature.

The phenotypes of patients with disease-associated variants in DNMT1 have been classified into two syndromes: hereditary sensory and autonomic neuropathy type 1E (HSAN1E, MIM614116, https://www.omim.org/ ) and autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN, MIM604121). The amino acid codon 511 is a hotspot, and p.Y511C is the most frequently observed disease-associated variant among those in HSAN1E patients, whereas there have been only a few reports on patients with p.Y511H. In this study, we report on the cases of a kindred carrying the DNMT1 variant NM_001130823.2:c.1531 T > C (p.Y511H) presenting with the ADCA-DN phenotype. The review of the literature further revealed that later ages at onset and the presence of cerebellar ataxia are the main characteristics of patients carrying the DNMT1 p.Y511H as compared with those carrying DNMT1 p.Y511C. Although HSAN1E and ADCA-DN are proposed to be called DNMT1-complex disorders owing to their overlapping symptoms, this finding suggests a distinct genotype-phenotype correlation regarding the DNMT1 p.Y511H and p.Y511C variants.

Clinical Characteristics of Neuronal Intranuclear Inclusion Disease-Related Retinopathy With CGG Repeat Expansions in the NOTCH2NLC Gene.

Purpose: To report the ocular characteristics of neuronal intranuclear inclusion disease (NIID)-related retinopathy with expansion of the CGG repeats in the NOTCH2NLC gene. Methods: Seven patients from six families (aged 66-81 years) diagnosed with adult-onset NIID were studied. Ophthalmologic examinations, including the best-corrected visual acuity (BCVA), Goldmann perimetry, fundus photography, fundus autofluorescence (FAF) imaging, optical coherence tomography (OCT), and full-field electroretinography (ERGs), were performed. The expansion of the CGG repeats in the NOTCH2NLC gene was determined. Results: All patients had an expansion of the CGG repeats (length approximately from 330-520 bp) in the NOTCH2NLC gene. The most common symptoms of the five symptomatic cases were reduced BCVA and night blindness. The other two cases did not have any ocular symptoms. The decimal BCVA varied from 0.15 to 1.2. Goldmann perimetry was constricted in all four cases tested; physiological blind spot was enlarged in two of the cases. The FAF images showed an absence of autofluorescence (AF) around the optic disc in all cases and also showed mild hypo-AF or extinguished AF in the midperiphery. In all cases, the OCT images showed an absence of the ellipsoid zone of the photoreceptors in the peripapillary region, and hyperreflective dots were also present between the retinal ganglion cell layer and outer nuclear layer. The macular region was involved in the late stage of the retinopathy. The full-field ERGs showed rod-cone dysfunction. Conclusions: Patients with adult-onset NIID with CGG repeats expansions in the NOTCH2NLC gene had similar ophthalmologic features, including rod-cone dysfunction with progressive retinal degeneration in the peripapillary and midperipheral regions. The primary site is most likely the photoreceptors. Because the ocular symptoms are often overlooked due to dementia and occasionally precede the onset of dementia, detailed ophthalmological examinations are important for the early diagnosis of NIID-related retinopathy.

Enhanced spectral resolution for broadband coherent anti-Stokes Raman spectroscopy.

The spectral resolution of broadband Fourier-transform coherent anti-Stokes Raman spectroscopy is limited by the maximum optical path length difference that can be scanned within a short time in an interferometer. However, alternatives to the Fourier transform exist which can bypass this limitation with certain assumptions. We apply one such approach to broadband coherent Raman spectroscopy using interferometers with a short delay line (low Fourier spectral resolution) and large delay line (high Fourier spectral resolution). With this method, we demonstrate that broadband coherent Raman spectroscopy of closely spaced vibrational bands is possible using a short delay line interferometer with comparable spectral resolution to the longer delay line instrument. We discuss how this approach may be particularly useful for more complex Raman spectra, such as those measured from biological samples.

Quantifying normal and parkinsonian gait features from home movies: Practical application of a deep learning-based 2D pose estimator.

OBJECTIVE: Gait movies recorded in daily clinical practice are usually not filmed with specific devices, which prevents neurologists benefitting from leveraging gait analysis technologies. Here we propose a novel unsupervised approach to quantifying gait features and to extract cadence from normal and parkinsonian gait movies recorded with a home video camera by applying OpenPose, a deep learning-based 2D-pose estimator that can obtain joint coordinates from pictures or videos recorded with a monocular camera. METHODS: Our proposed method consisted of two distinct phases: obtaining sequential gait features from movies by extracting body joint coordinates with OpenPose; and estimating cadence of periodic gait steps from the sequential gait features using the short-time pitch detection approach. RESULTS: The cadence estimation of gait in its coronal plane (frontally viewed gait) as is frequently filmed in the daily clinical setting was successfully conducted in normal gait movies using the short-time autocorrelation function (ST-ACF). In cases of parkinsonian gait with prominent freezing of gait and involuntary oscillations, using ACF-based statistical distance metrics, we quantified the periodicity of each gait sequence; this metric clearly corresponded with the subjects' baseline disease statuses. CONCLUSION: The proposed method allows us to analyze gait movies that have been underutilized to date in a completely data-driven manner, and might broaden the range of movies for which gait analyses can be conducted.

Molecular contrast on phase-contrast microscope.

An optical microscope enables image-based findings and diagnosis on microscopic targets, which is indispensable in many scientific, industrial and medical settings. A standard benchtop microscope platform, equipped with e.g., bright-field and phase-contrast modes, is of importance and convenience for various users because the wide-field and label-free properties allow for morphological imaging without the need for specific sample preparation. However, these microscopes never have capability of acquiring molecular contrast in a label-free manner. Here, we develop a simple add-on optical unit, comprising of an amplitude-modulated mid-infrared semiconductor laser, that is attached to a standard microscope platform to deliver the additional molecular contrast of the specimen on top of its conventional microscopic image, based on the principle of photothermal effect. We attach this unit, termed molecular-contrast unit, to a standard phase-contrast microscope, and demonstrate high-speed label-free molecular-contrast phase-contrast imaging of silica-polystyrene microbeads mixture and molecular-vibrational spectroscopic imaging of HeLa cells. Our simple molecular-contrast unit can empower existing standard microscopes and deliver a convenient accessibility to the molecular world.

Estimating acceleration time point of respiratory decline in ALS patients: A novel metric.

OBJECTIVE: We aimed to derive and assess a novel metric for respiratory decline: the timing of acceleration of respiratory functional decline during the course of the disease in patients with amyotrophic lateral sclerosis (ALS). METHODS: In this single-center retrospective study, we reviewed consecutive definite/probable ALS patients, diagnosed and followed up at our hospital. We recorded serial slow vital capacity (percentage of predicted slow vital capacity; %VC) since diagnosis for all patients. These serial %VC data were fitted with logistic function of the time since diagnosis, and 'acceleration point' was calculated as the week in which the second derivative of the fitted logistic function had the minimum value. RESULTS: We included 62 patients with ALS, whose serial %VC data had been recorded for a median of 8 times over a median of 94.3 weeks. The calculated acceleration time-point was the time-point at which the %VC is becoming 0.789 times of maximum %VC, and had a strong association with the period since diagnosis to the administration of nutritional/respiratory support (p < 0.001). Bulbar-type ALS or lower Body Mass Index at diagnosis, both are well-known ALS prognostic factors, were also associated with more rapid arrival of the acceleration time-point. CONCLUSIONS: We introduced the time-point of acceleration in the vital capacity decline during disease progression as a novel metric for ALS respiratory decline. Although we could not build a practically-available clinical model that directly predicts acceleration time-point due to the limited sample size, our metric may be used as one of the helpful indicators in the management during earlier disease course of ALS, such as to be careful for the potentially approaching acceleration time-point when the %VC is decreasing to approximately 0.789 times of initial %VC.

Quantitative Analysis of Surface Electromyography for Pediatric Neuromuscular Disorders.

INTRODUCTION: Needle electromyography (EMG) has been an important diagnostic tool, although discomfort may limit its use in some children. We investigated the diagnostic utility of the clustering index (CI) method, a quantitative analysis for surface EMG (SEMG), in children. METHODS: SEMG was recorded from the tibialis anterior muscle. Discriminant analysis between patients with neurogenic disorders and patients with myopathy was performed for whole epochs by using the CI and area values. RESULTS: Forty-five children (29 with myopathy, 16 with neurogenic disorders; age 9 ± 3.9 years) were enrolled. The mean discriminant function value of the neurogenic group was 0.58 ± 0.88 (-0.48-2.30), whereas that of the myopathic group was -0.55 ± 0.70 (-2.38-0.68). When the cutoff value was set at the limit of the other group, 17 of 29 children with myopathy and 7 of 16 children with neurogenic disorders were correctly classified. DISCUSSION: The CI method can be a useful noninvasive diagnostic tool in children with neuromuscular disorders. Muscle Nerve 58:824-827, 2018.

Polyurethane Foam Wound Dressing Technique for Areola Skin Graft Stabilization and Nipple Protection After Nipple-Areola Reconstruction.

We describe a new wound management technique using a soft dressing material to stabilize the areola skin graft and protect the nipple after nipple-areola reconstruction at the final stage of breast reconstruction. We introduced a center-fenestrated multilayered hydrocellular polyurethane foam dressing material that provides adequate pressure and retains a moist environment for a smooth skin graft "take." Moreover, the reconstructed nipple can be monitored at any time through the fenestrated window for adequate blood circulation. Altogether, this simple and inexpensive wound dressing technique improves the clinical outcome. Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Clinicopathologic features of myositis patients with CD8-MHC-1 complex pathology.

OBJECTIVE: To determine the clinical features of myositis patients with the histopathologic finding of CD8-positive T cells invading non-necrotic muscle fibers expressing major histocompatibility complex class 1 (CD8-MHC-1 complex), which is shared by polymyositis (PM) and inclusion body myositis (IBM), in relation to the p62 immunostaining pattern of muscle fibers. METHODS: All 93 myositis patients with CD8-MHC-1 complex who were referred to our hospital from 1993 to 2015 were classified on the basis of the European Neuromuscular Center (ENMC) diagnostic criteria for IBM (Rose, 2013) or PM (Hoogendijk, 2004) and analyzed. RESULTS: The 93 patients included were 17 patients with PM, 70 patients with IBM, and 6 patients who neither met the criteria for PM nor IBM in terms of muscle weakness distribution (unclassifiable group). For these PM, IBM, and unclassifiable patients, their mean ages at diagnosis were 63, 70, and 64 years; autoimmune disease was present in 7 (41%), 13 (19%), and 4 (67%); hepatitis C virus infection was detected in 0%, 13 (20%), and 2 (33%); and p62 was immunopositive in 0%, 66 (94%), and 2 (33%), respectively. Of the treated patients, 11 of 16 PM patients and 4 of 6 p62-immunonegative patients in the unclassifiable group showed responses to immunotherapy, whereas all 44 patients with IBM and 2 p62-immunopositive patients in the unclassifiable group were unresponsive to immunotherapy. CONCLUSIONS: CD8-MHC-1 complex is present in patients with PM, IBM, or unclassifiable group. The data may serve as an argument for a trial of immunosuppressive treatment in p62-immunonegative patients with unclassifiable myositis.

Identification and segmentation of myelinated nerve fibers in a cross-sectional optical microscopic image using a deep learning model.

BACKGROUND: The morphometric analysis of myelinated nerve fibers of peripheral nerves in cross-sectional optical microscopic images is valuable. Several automated methods for nerve fiber identification and segmentation have been reported. This paper presents a new method that uses a deep learning model of a convolutional neural network (CNN). We tested it for human sural nerve biopsy images. METHODS: The method comprises four steps: normalization, clustering segmentation, myelinated nerve fiber identification, and clump splitting. A normalized sample image was separated into individual objects with clustering segmentation. Each object was applied to a CNN deep learning model that labeled myelinated nerve fibers as positive and other structures as negative. Only positives proceeded to the next step. For pretraining the model, 70,000 positive and negative data each from 39 samples were used. The accuracy of the proposed algorithm was evaluated using 10 samples that were not part of the training set. A P-value of <0.05 was considered statistically significant. RESULTS: The total true-positive rate (TPR) for the detection of myelinated fibers was 0.982, and the total false-positive rate was 0.016. The defined total area similarity (AS) and area overlap error of segmented myelin sheaths were 0.967 and 0.068, respectively. In all but one sample, there were no significant differences in estimated morphometric parameters obtained from our method and manual segmentation. COMPARISON WITH EXISTING METHODS: The TPR and AS were higher than those obtained using previous methods. CONCLUSIONS: High-performance automated identification and segmentation of myelinated nerve fibers were achieved using a deep learning model.

Atypical parkinsonism caused by Pro105Leu mutation of prion protein: A broad clinical spectrum.

OBJECTIVE: To delineate molecular and clinical characteristics of 3 families with PRNP P105L mutation, a variant of Gerstmann-Sträussler-Scheinker syndrome whose main motor symptoms were parkinsonism and/or involuntary movements. METHODS: The causative mutation was first determined in the affected patients of family 1 using whole-exome sequencing, and then mutational analysis was extended to families 2 and 3. The clinical features of the patients of these 3 families were summarized. Haplotype analysis was performed using high-density single nucleotide polymorphism array. RESULTS: The whole-exome sequencing revealed that the heterozygous mutation c.314C>T (p.P105L) in PRNP was the only known pathogenic mutation shared by the 3 patients of the family with autosomal dominant parkinsonism. We further identified the same mutation in patients of the other 2 families with autosomal dominant parkinsonism and/or involuntary movements. The clinical features of our patients with PRNP P105L mutation included various motor symptoms such as parkinsonism and involuntary movements in addition to progressive dementia. The clinical features in part overlapped with those of other forms of inherited prion diseases, such as fatal familial insomnia and Huntington disease-like type 1. The patients with PRNP P105L mutation shared a haplotype spanning 7.1 Mb around PRNP, raising the possibility that the mutations in the patients originated from a common founder. CONCLUSION: Most of the patients presented with parkinsonism in addition to progressive dementia. Although spastic paraparesis has been emphasized as the main clinical feature, the clinical spectrum of patients with PRNP P105L is broader than expected.