Distinctive Features of Orbital Adipose Tissue (OAT) in Graves' Orbitopathy.

Depot specific expansion of orbital-adipose-tissue (OAT) in Graves' Orbitopathy (GO) is associated with lipid metabolism signaling defects. We hypothesize that the unique adipocyte biology of OAT facilitates its expansion in GO. A comprehensive comparison of OAT and white-adipose-tissue (WAT) was performed by light/electron-microscopy, lipidomic and transcriptional analysis using ex vivo WAT, healthy OAT (OAT-H) and OAT from GO (OAT-GO). OAT-H/OAT-GO have a single lipid-vacuole and low mitochondrial number. Lower lipolytic activity and smaller adipocytes of OAT-H/OAT-GO, accompanied by similar essential linoleic fatty acid (FA) and (low) FA synthesis to WAT, revealed a hyperplastic OAT expansion through external FA-uptake via abundant SLC27A6 (FA-transporter) expression. Mitochondrial dysfunction of OAT in GO was apparent, as evidenced by the increased mRNA expression of uncoupling protein 1 (UCP1) and mitofusin-2 (MFN2) in OAT-GO compared to OAT-H. Transcriptional profiles of OAT-H revealed high expression of Iroquois homeobox-family (IRX-3&5), and low expression in HOX-family/TBX5 (essential for WAT/BAT (brown-adipose-tissue)/BRITE (BRown-in-whITE) development). We demonstrated unique features of OAT not presented in either WAT or BAT/BRITE. This study reveals that the pathologically enhanced FA-uptake driven hyperplastic expansion of OAT in GO is associated with a depot specific mechanism (the SLC27A6 FA-transporter) and mitochondrial dysfunction. We uncovered that OAT functions as a distinctive fat depot, providing novel insights into adipocyte biology and the pathological development of OAT expansion in GO.

Retinal Vascular Changes in Response to Hypoxia: A High-Altitude Expedition Study.

Westwood, Jessica, India Mayhook-Walker, Ciaran Simpkins, Andrew Darby-Smith, Dan Morris, and Eduardo Normando. Retinal vascular changes in response to hypoxia: a high-altitude expedition study. High Alt Med Biol. 25:49-59, 2024. Background: Increased tortuosity and engorgement of retinal vasculature are recognized physiological responses to hypoxia. This can lead to high-altitude retinopathy (HAR), but incidence reports are highly variable, and our understanding of the etiological mechanisms remains incomplete. This study quantitatively evaluated retinal vascular changes during an expedition to 4,167 m. Methods: Ten healthy participants summited Mount Toubkal, Morocco. Fundus images were taken predeparture, daily throughout the expedition, and 1 month postreturn. Diameter and tortuosity of four vessels were assessed, in addition to vessel density and features of HAR. Results: Significant (p ≤ 0.05) increases in tortuosity and diameter were observed in several vessels on high-altitude exposure days. There was a strong correlation between altitude and supratemporal retinal artery diameter on days 2, 3, and 6 of the expedition (r = 0.7707, 0.7951, 0.7401, respectively; p < 0.05). There was a significant increase in median vessel density from 6.7% at baseline to 10.0% on summit day. Notably there were no incidences of HAR. Conclusion: Physiological but not pathological changes were seen in this cohort, which gives insight into the state of the cerebral vasculature throughout this expedition. These results are likely attributable to relatively low altitude exposure, a conservative ascent profile, and the cohort's demographic. Future study must include daily retinal images at higher altitudes and take steps to mitigate environmental confounders. This study is relevant to altitude tourists, patients with diabetic retinopathy or retinal vein occlusion, and critically ill patients.

Precision-controlled ultrafast electron microscope platforms. A case study: Multiple-order coherent phonon dynamics in 1T-TaSe2 probed at 50 fs-10 fm scales.

We report on the first detailed beam tests attesting the fundamental principle behind the development of high-current-efficiency ultrafast electron microscope systems where a radio frequency (RF) cavity is incorporated as a condenser lens in the beam delivery system. To allow for the experiment to be carried out with a sufficient resolution to probe the performance at the emittance floor, a new cascade loop RF controller system is developed to reduce the RF noise floor. Temporal resolution at 50 fs in full-width-at-half-maximum and detection sensitivity better than 1% are demonstrated on exfoliated 1T-TaSe2 system under a moderate repetition rate. To benchmark the performance, multi-terahertz edge-mode coherent phonon excitation is employed as the standard candle. The high temporal resolution and the significant visibility to very low dynamical contrast in diffraction signals via high-precision phase-space manipulation give strong support to the working principle for the new high-brightness femtosecond electron microscope systems.

A labeled data set of underwater images of fish and crab species from five mesohabitats in Puget Sound WA USA.

The sustainable management of fisheries and aquaculture requires an understanding of how these activities interact with natural fish populations. GoPro cameras were used to collect an underwater video data set on and around shellfish aquaculture farms in an estuary in the NE Pacific from June to August 2017 and June to August 2018 to better understand habitat use by the local fish and crab communities. Images extracted from these videos were labeled to produce a data set that is suitable for use in training computer vision models. The labeled data set contains 77,739 images sampled from the collected video; 67,990 objects (fishes and crustaceans) have been annotated in 30,384 images (the remainder have been annotated as "empty"). The metadata of the data set also indicates whether a physical magenta filter was used during video collection to counteract reduced visibility. These data have the potential to help researchers address system-level and in-depth regional shellfish aquaculture questions related to ecosystem services and shellfish aquaculture interactions.

Thymosin ß4 promotes the recovery of peripheral neuropathy in type II diabetic mice.

Peripheral neuropathy is one of the most common complications of diabetes mellitus. Using a mouse model of diabetic peripheral neuropathy, we tested the hypothesis that thymosin ß4 (Tß4) ameliorates diabetes-induced neurovascular dysfunction in the sciatic nerve and promotes recovery of neurological function from diabetic peripheral neuropathy. Tß4 treatment of diabetic mice increased functional vascular density and regional blood flow in the sciatic nerve, and improved nerve function. Tß4 upregulated angiopoietin-1 (Ang1) expression, but suppressed Ang2 expression in endothelial and Schwann cells in the diabetic sciatic nerve. In vitro, incubation of Human Umbilical Vein Endothelial Cells (HUVECs) with Tß4 under high glucose condition completely abolished high glucose-downregulated Ang1 expression and high glucose-reduced capillary-like tube formation. Moreover, incubation of HUVECs under high glucose with conditioned medium collected from Human Schwann Cells (HSCs) treated with Tß4 significantly reversed high glucose-decreased capillary-like tube formation. PI3K/Akt signaling pathway is involved in Tß4-regulated Ang1 expression on endothelial and Schwann cells. These data indicate that Tß4 likely acts on endothelial cells and Schwann cells to preserve and/or restore vascular function in the sciatic nerve which facilitates improvement of peripheral nerve function under diabetic neuropathy. Thus, Tß4 has potential for the treatment of diabetic peripheral neuropathy.

A Comparison of Wearable Tonometry, Photoplethysmography, and Electrocardiography for Cuffless Measurement of Blood Pressure in an Ambulatory Setting.

OBJECTIVE: While non-invasive, cuffless blood pressure (BP) measurement has demonstrated relevancy in controlled environments, ambulatory measurement is important for hypertension diagnosis and control. We present both in-lab and ambulatory BP estimation results from a diverse cohort of participants. METHODS: Participants (N=1125, aged 21-85, 49.2% female, multiple hypertensive categories) had BP measured in-lab over a 24-hour period with a subset also receiving ambulatory measurements. Radial tonometry, photoplethysmography (PPG), electrocardiography (ECG), and accelerometry signals were collected simultaneously with auscultatory or oscillometric references for systolic (SBP) and diastolic blood pressure (DBP). Predictive models to estimate BP using a variety of sensor-based feature groups were evaluated against challenging baselines. RESULTS: Despite limited availability, tonometry-derived features showed superior performance compared to other feature groups and baselines, yieldingprediction errors of 0.32 ±9.8 mmHg SBP and 0.54 ±7.7 mmHg DBP in-lab, and 0.86 ±8.7 mmHg SBP and 0.75 ±5.9 mmHg DBP for 24-hour averages. SBP error standard deviation (SD) was reduced in normotensive (in-lab: 8.1 mmHg, 24-hr: 7.2 mmHg) and younger (in-lab: 7.8 mmHg, 24-hr: 6.7 mmHg) subpopulations. SBP SD was further reduced 15-20% when constrained to the calibration posture alone. CONCLUSION: Performance for normotensive and younger participants was superior to the general population across all feature groups. Reference type, posture relative to calibration, and controlled vs. ambulatory setting all impacted BP errors. SIGNIFICANCE: Results highlight the need for demographically diverse populations and challenging evaluation settings for BP estimation studies. We present the first public dataset of ambulatory tonometry and cuffless BP over a 24-hour period to aid in future cardiovascular research.

Combination treatment with VELCADE and low-dose tissue plasminogen activator provides potent neuroprotection in aged rats after embolic focal ischemia.

BACKGROUND AND PURPOSE: Treatment with a selective proteasome inhibitor, VELCADE, in combination with tissue plasminogen activator (tPA) extended the therapeutic window to 6 hours in young rats after stroke. However, stroke is a major cause of death and disability in the elderly. The present study investigated the effect of VELCADE in combination with a low-dose tPA on aged rats after embolic stroke. METHODS: Male Wistar rats at the age of 18 to 20 months were treated with VELCADE (0.2 mg/kg) alone, a low-dose tPA (5 mg/kg) alone, combination of VELCADE and tPA, or saline 2 hours after embolic middle cerebral artery occlusion. To test the contribution of endothelial nitric oxide synthase to VELCADE-mediated neuroprotection, endothelial nitric oxide synthase knockout and wild-type mice were treated with VELCADE (0.5 mg/kg) 2 hours after embolic stroke. RESULTS: Treatment with VELCADE significantly reduced infarct volume, whereas tPA alone did not reduce infarct volume and aggravated blood-brain barrier disruption in aged rats compared with saline-treated rats. However, the combination treatment significantly enhanced the reduction of infarct volume, which was associated with an increase in endothelial nitric oxide synthase activity compared with saline-treated rats. Additionally, the combination treatment promoted thrombolysis and did not increase the incidence of hemorrhage transformation. VELCADE significantly reduced lesion volume in wild-type mice but failed to significantly reduce lesion volume in endothelial nitric oxide synthase knockout mice. CONCLUSIONS: Treatment with VELCADE exerts a neuroprotective effect in aged rats after stroke. The combination of VELCADE with the low-dose tPA further amplifies the neuroprotective effect. Endothelial nitric oxide synthase at least partly contributes to VELCADE-mediated neuroprotection after stroke.

Coupling of angiogenesis and neurogenesis in cultured endothelial cells and neural progenitor cells after stroke.

Angiogenesis and neurogenesis are coupled processes. Using a coculture system, we tested the hypothesis that cerebral endothelial cells activated by ischemia enhance neural progenitor cell proliferation and differentiation, while neural progenitor cells isolated from the ischemic subventricular zone promote angiogenesis. Coculture of neural progenitor cells isolated from the subventricular zone of the adult normal rat with cerebral endothelial cells isolated from the stroke boundary substantially increased neural progenitor cell proliferation and neuronal differentiation and reduced astrocytic differentiation. Conditioned medium harvested from the stroke neural progenitor cells promoted capillary tube formation of normal cerebral endothelial cells. Blockage of vascular endothelial growth factor receptor 2 suppressed the effect of the endothelial cells activated by stroke on neurogenesis as well as the effect of the supernatant obtained from stroke neural progenitor cells on angiogenesis. These data suggest that angiogenesis couples to neurogenesis after stroke and vascular endothelial growth factor likely mediates this coupling.

Automatic preparation, calibration, and simulation of deformable objects.

Many simulation environments - particularly those intended for medical simulation - require solid objects to deform at interactive rates, with deformation properties that correspond to real materials. Furthermore, new objects may be created frequently (for example, each time a new patient's data is processed), prohibiting manual intervention in the model preparation process. This paper provides a pipeline for rapid preparation of deformable objects with no manual intervention, specifically focusing on mesh generation (preparing solid meshes from surface models), automated calibration of models to finite element reference analyses (including a novel approach to reducing the complexity of calibrating nonhomogeneous objects), and automated skinning of meshes for interactive simulation.

Providing metrics and performance feedback in a surgical simulator.

One of the most important advantages of computer simulators for surgical training is the opportunity they afford for independent learning. However, if the simulator does not provide useful instructional feedback to the user, this advantage is significantly blunted by the need for an instructor to supervise and tutor the trainee while using the simulator. Thus, the incorporation of relevant, intuitive metrics is essential to the development of efficient simulators. Equally as important is the presentation of such metrics to the user in such a way so as to provide constructive feedback that facilitates independent learning and improvement. This paper presents a number of novel metrics for the automated evaluation of surgical technique. The general approach was to take criteria that are intuitive to surgeons and develop ways to quantify them in a simulator. Although many of the concepts behind these metrics have wide application throughout surgery, they have been implemented specifically in the context of a simulation of mastoidectomy. First, the visuohaptic simulator itself is described, followed by the details of a wide variety of metrics designed to assess the user's performance. We present mechanisms for presenting visualizations and other feedback based on these metrics during a virtual procedure. We further describe a novel performance evaluation console that displays metric-based information during an automated debriefing session. Finally, the results of several user studies are reported, providing some preliminary validation of the simulator, the metrics, and the feedback mechanisms. Several machine learning algorithms, including Hidden Markov Models and a Naïve Bayes Classifier, are applied to our simulator data to automatically differentiate users' expertise levels.

Evaluating drilling and suctioning technique in a mastoidectomy simulator.

This paper presents several new metrics related to bone removal and suctioning technique in the context of a mastoidectomy simulator. The expertise with which decisions as to which regions of bone to remove and which to leave intact is evaluated by building a Naïve Bayes classifier using training data from known experts and novices. Since the bone voxel mesh is very large, and many voxels are always either removed or not removed regardless of expertise, the mutual information was calculated for each voxel and only the most informative voxels used for the classifier. Leave-out-one cross validation showed a high correlation of calculated expert probabilities with scores assigned by instructors. Additional metrics described in this paper include those for assessing smoothness of drill strokes, proper drill burr selection, sufficiency of suctioning, two-handed tool coordination, and application of appropriate force and velocity magnitudes as functions of distance from critical structures.

Validating metrics for a mastoidectomy simulator.

One of the primary barriers to the acceptance of surgical simulators is that most simulators still require a significant amount of an instructing surgeon's time to evaluate and provide feedback to the students using them. Thus, an important area of research in this field is the development of metrics that can enable a simulator to be an essentially self-contained teaching tool, capable of identifying and explaining the user's weaknesses. However, it is essential that these metrics be validated in able to ensure that the evaluations provided by the "virtual instructor" match those that the real instructor would provide were he/she present. We have previously proposed a number of algorithms for providing automated feedback in the context of a mastoidectomy simulator. In this paper, we present the results of a user study in which we attempted to establish construct validity (with inter-rater reliability) for our simulator itself and to validate our metrics. Fifteen subjects (8 experts, 7 novices) were asked to perform two virtual mastoidectomies. Each virtual procedure was recorded, and two experienced instructing surgeons assigned global scores that were correlated with subjects' experience levels. We then validated our metrics by correlating the scores generated by our algorithms with the instructors' global ratings, as well as with metric-specific sub-scores assigned by one of the instructors.

Multitargeted effects of statin-enhanced thrombolytic therapy for stroke with recombinant human tissue-type plasminogen activator in the rat.

BACKGROUND: Microvascular dysfunction posttreatment of stroke with recombinant human tissue-type plasminogen activator (rht-PA) constrains the therapeutic window to 3 hours. Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) promote vascular thrombolysis and reduce the inflammation response. We therefore investigated the neuroprotective effects of a combination of atorvastatin and delayed rht-PA treatment in a rat model of embolic stroke. METHODS AND RESULTS: Rats subjected to embolic middle cerebral artery occlusion were treated with atorvastatin in combination with rht-PA 4 hours after stroke. Magnetic resonance imaging measurements revealed that combination treatment with atorvastatin and rht-PA blocked the expansion of the ischemic lesion, which improved neurological function compared with saline-treated rats. Real-time reverse transcription-polymerase chain reaction analysis of single endothelial cells isolated by laser-capture microdissection from brain tissue and immunostaining showed that combination treatment downregulated expression of tissue factor, von Willebrand factor, protease-activated receptor-1, intercellular adhesion molecule-1, and matrix metalloproteinase-9, which concomitantly reduced cerebral microvascular thrombosis and enhanced microvascular integrity. Combination treatment did not increase cerebrovascular endothelial nitric oxide synthase (eNOS) levels or eNOS activity, and inhibition of NOS activity with N-nitro-L-arginine methyl ester did not block the beneficial effects of combination treatment on stroke. Furthermore, combination treatment compared with thrombolytic monotherapy increased cerebral blood flow and reduced infarct volume in eNOS-null mice. CONCLUSIONS: These data demonstrate that combination treatment with atorvastatin and rht-PA exerts a neuroprotective effect when administered 4 hours after stroke and that the therapeutic benefits are likely attributed to its multitargeted effects on cerebrovascular patency and integrity.

Virtual 3D planning and guidance of mandibular distraction osteogenesis.

We present a system for 3D planning and pre-operative rehearsal of mandibular distraction osteogenesis procedures. Two primary architectural components are described: a planning system that allows geometric bone manipulation to rapidly explore various modifications and configurations, and a visuohaptic simulator that allows both general-purpose training and preoperative, patient-specific procedure rehearsal. We provide relevant clinical background, then describe the underlying simulation algorithms and their application to craniofacial procedures.

Achieving proper exposure in surgical simulation.

One important technique common throughout surgery is achieving proper exposure of critical anatomic structures so that their shapes, which may vary somewhat among patients, can be confidently established and avoided. In this paper, we present an algorithm for determining which regions of selected structures are properly exposed in the context of a mastoidectomy simulation. Furthermore, our algorithm then finds and displays all other points along the surface of the structure that lie along a sufficiently short and straight path from an exposed portion such that their locations can be safely inferred. Finally, we present an algorithm for providing realistic visual cues about underlying structures with view-dependent shading of the bone.

Signs of Insufficiency Fractures Overlooked in a Patient Receiving Chronic Bisphosphonate Therapy.

Chronic bisphosphonate therapy is associated with atypical fractures of the subtrochanteric and proximal femoral diaphyseal regions. Various radiologic imaging signs can identify bisphosphonate-associated stress fractures before they progress to complete fractures. Identifying patients who are at risk and modifying treatment can prevent these fractures from occurring. We present a case study of a patient taking bisphosphonate with 2 years of chronic pain, and characteristic clinical signs of bisphosphonate-associated incomplete stress fractures that went untreated until the patient suffered from a right subtrochanteric complete fracture. Our goal is to make physicians aware of the signs of insufficiency fractures associated with chronic bisphosphonate therapy such that appropriate clinical decisions are made to optimize the quality of patient care.

In vivo evaluation of a novel, wrist-mounted arterial pressure sensing device versus the traditional hand-held tonometer.

Although hemodynamic parameters can be assessed non-invasively, state-of-the-art non-invasive systems generally require an expert operator and are not applicable for ambulatory measurements. These limitations have restricted our understanding of the continuous behavior of hemodynamic parameters. In this manuscript, we introduce a novel wrist-mounted device that incorporates an array of pressure sensors which can be used to extract arterial waveforms and relevant pulse wave analysis biomarkers. In vivo evaluation is performed with Bland-Altman analysis to compare the novel sensor to a gold-standard hand-held tonometer by assessing their reproducibility and agreement in peripheral augmentation index (AIx) estimation at the radial artery. Arterial waves from 28 randomly selected participants were recorded in a controlled environment. Initially we assess the reproducibility of AIx results for both devices. The intra-class correlation coefficient (ICC) and mean difference ± SD were [0.913, 0.033±0.048] and [0.859, 0.039±0.076] for the hand-held and the wrist-mounted tonometer respectively. We then show that the AIx values derived from the novel tonometer have good agreement, accuracy, and precision when compared against the AIx values derived from the reference hand-held tonometer (ICC 0.927, mean difference 0.026±0.049). In conclusion, we have presented evidence that the new wrist-mounted arterial pressure sensor records arterial waveforms that can be processed to yield AIx values that are in good agreement with its traditional hand-held counterpart.

Development of a circulating miRNA assay to monitor tumor burden: From mouse to man.

Circulating miRNA stability suggests potential utility of miRNA based biomarkers to monitor tumor burden and/or progression, particularly in cancer types where serial biopsy is impractical. Assessment of miRNA specificity and sensitivity is challenging within the clinical setting. To address this, circulating miRNAs were examined in mice bearing human SCLC tumor xenografts and SCLC patient derived circulating tumor cell explant models (CDX). We identified 49 miRNAs using human TaqMan Low Density Arrays readily detectable in 10 µl tail vein plasma from mice carrying H526 SCLC xenografts that were low or undetectable in non-tumor bearing controls. Circulating miR-95 measured serially in mice bearing CDX was detected with tumor volumes as low as 10 mm(3) and faithfully reported subsequent tumor growth. Having established assay sensitivity in mouse models, we identified 26 miRNAs that were elevated in a stage dependent manner in a pilot study of plasma from SCLC patients (n = 16) compared to healthy controls (n = 11) that were also elevated in the mouse models. We selected a smaller panel of 10 previously reported miRNAs (miRs 95, 141, 200a, 200b, 200c, 210, 335#, 375, 429) that were consistently elevated in SCLC, some of which are reported to be elevated in other cancer types. Using a multiplex qPCR assay, elevated levels of miRNAs across the panel were also observed in a further 66 patients with non-small cell lung, colorectal or pancreatic cancers. The utility of this circulating miRNA panel as an early warning of tumor progression across several tumor types merits further evaluation in larger studies.

An interactive simulation environment for craniofacial surgical procedures.

Recent advances in medical imaging and surgical techniques have made possible the correction of severe facial deformities and fractures. Surgical correction techniques often involve the direct manipulation - both relocation and surgical fracture - of the underlying facial bone. The work presented here introduces an environment for interactive, visuohaptic simulation of craniofacial surgical procedures, with an emphasis on both mandibular distraction procedures and traditional orthognathic surgeries. The simulator is intended both for instruction and for procedure-specific rehearsal, and can thus load canonical training cases or patient-specific image data into the interactive environment. A network module allows remote demonstration of procedure technique, a form of 'haptic tutoring'. This paper discusses the simulation, haptic feedback, and graphic rendering techniques used to drive the environment. Particular emphasis is placed on techniques for fracture and subsequent rigid manipulation of bone structures, a key component of the relevant procedures.

Quantifying risky behavior in surgical simulation.

Evaluating a trainee's performance on a simulated procedure involves determining whether a specified objective was met while avoiding certain "injurious" actions that damage vulnerable structures. However, it is also important to teach the stylistic behaviors that minimize overall risk to the patient, even though these criteria may be more difficult to explicitly specify and detect. In this paper, we address the development of metrics that evaluate the risk in a trainee's behavior while performing a simulated mastoidectomy. Specifically, we measure the trainee's ability to maintain an appropriate field of view so as to avoid drilling bone that is hidden from view, as well as to consistently apply appropriate forces and velocities. Models of the maximum safe force and velocity magnitudes as functions of distances from key vulnerable structures are learned from model procedures performed by an expert surgeon on the simulator. In addition to quantitatively scoring the trainee's performance, these metrics allow for interactive 3D visualization of the performance by distinctive coloring of regions in which excessive forces or velocities were applied or insufficient visibility was maintained, enabling the trainee to pinpoint his/her mistakes and how to correct them. Although these risky behaviors relate to a mastoidectomy simulator, the objectives of maintaining visibility and applying safe forces and velocities are common in surgery, so it may be possible to extend much of this methodology to other procedures.