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1.
Arthroscopy ; 40(4): 1044-1055, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37716627

ABSTRACT

PURPOSE: To develop a machine learning model capable of identifying subscapularis tears before surgery based on imaging and physical examination findings. METHODS: Between 2010 and 2020, 202 consecutive shoulders underwent arthroscopic rotator cuff repair by a single surgeon. Patient demographics, physical examination findings (including range of motion, weakness with internal rotation, lift/push-off test, belly press test, and bear hug test), and imaging (including direct and indirect signs of tearing, biceps status, fatty atrophy, cystic changes, and other similar findings) were included for model creation. RESULTS: Sixty percent of the shoulders had partial or full thickness tears of the subscapularis verified during surgery (83% of these were upper third). Using only preoperative imaging-related parameters, the XGBoost model demonstrated excellent performance at predicting subscapularis tears (c-statistic, 0.84; accuracy, 0.85; F1 score, 0.87). The top 5 features included direct signs related to the presence of tearing as evidenced on magnetic resonance imaging (MRI) (changes in tendon morphology and signal), as well as the quality of the MRI and biceps pathology. CONCLUSIONS: In this study, machine learning was successful in predicting subscapularis tears by MRI alone in 85% of patients, and this accuracy did not decrease by isolating the model to the top features. The top five features included direct signs related to the presence of tearing as evidenced on MRI (changes in tendon morphology and signal), as well as the quality of the MRI and biceps pathology. Last, in advanced modeling, the addition of physical examination or patient characteristics did not make a significant difference in the predictive ability of this model. LEVEL OF EVIDENCE: Level III, diagnostic case-control study.


Subject(s)
Lacerations , Rotator Cuff Injuries , Humans , Rotator Cuff/diagnostic imaging , Rotator Cuff/surgery , Rotator Cuff Injuries/diagnostic imaging , Rotator Cuff Injuries/surgery , Case-Control Studies , Physical Examination/methods , Shoulder/surgery , Rupture , Arthroscopy/methods , Magnetic Resonance Imaging
2.
Skeletal Radiol ; 52(2): 175-181, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36006463

ABSTRACT

OBJECTIVE: The purpose of this study is to evaluate the accuracy of MR arthrography in detecting isolated posterior glenoid labral injuries using arthroscopy as the reference standard. METHODS: MR arthrograms of 97 patients with isolated posterior glenoid labral tears by arthroscopy and those of 96 age and gender-matched controls with intact posterior labra were reviewed by two blinded radiologists for the presence and location of posterior labral abnormalities. The sensitivity and specificity of detection of posterior labral tears were calculated as well as the prevalence of associated pathologies. Medical records were reviewed for demographics, history and direction of shoulder instability, and prior surgery. RESULTS: Posterior labral pathology was detected by MR arthrography with sensitivities of 76% and 84% for readers 1 and 2, and a specificity of 88% for both readers. Kappa value for interreader agreement was 0.91. Twenty-two of twenty-three (96%) tears isolated to the posteroinferior quadrant on arthroscopy were correctly identified on MRI. Commonly associated pathologies included paralabral cyst (38%), humeral fracture (7%), and glenoid fracture (2%). Fifteen of ninety-seven (16%) patients with posterior tears on both arthroscopy and MRI had glenoid rim deficiency on imaging versus no patients with intact posterior labra (p < 0.001). Forty of ninety-seven (41%) patients with posterior tears on arthroscopy had a history of posterior instability versus none without posterior tears. There was no significant difference in tear length on MRI between those with a history of instability and those without (p = 0.56). CONCLUSION: MR arthrography is accurate in detecting posterior glenoid labroligamentous injuries.


Subject(s)
Joint Instability , Shoulder Injuries , Shoulder Joint , Humans , Arthrography/methods , Shoulder Joint/surgery , Shoulder , Joint Instability/diagnostic imaging , Joint Instability/surgery , Shoulder Injuries/diagnostic imaging , Shoulder Injuries/pathology , Magnetic Resonance Imaging/methods , Arthroscopy , Sensitivity and Specificity , Retrospective Studies
3.
AJR Am J Roentgenol ; 216(4): 1022-1030, 2021 04.
Article in English | MEDLINE | ID: mdl-32755207

ABSTRACT

BACKGROUND. CT attenuation thresholds that accurately distinguish enostoses from untreated osteoblastic metastases have been published. In the Mayo Clinic practices, these thresholds have been applied more broadly to distinguish benign sclerotic bone lesions other than enostoses from osteoblastic metastases. OBJECTIVE. The purpose of this article is to determine if CT attenuation thresholds allow the distinguishing of benign sclerotic bone lesions from osteoblastic metastases in patients undergoing bone biopsy. METHODS. A retrospective search was conducted to identify sclerotic lesions described on CT between October 7, 1998, and July 15, 2018, that underwent subsequent biopsy. Two musculoskeletal radiologists recorded lesions' maximum and mean attenuation. Using previously published attenuation thresholds, sensitivity and specificity for differentiating benign sclerotic lesions from osteoblastic metastases were calculated. ROC curve analysis was performed to determine if more appropriate attenuation thresholds exist. Intraclass correlation coefficients (ICCs) were computed. RESULTS. A total of 280 patients met inclusion criteria. Of those, 162 had malignant biopsy results and 118 had benign biopsy results. Of the 162 malignant lesions, 81 had received prior treatment. Maximum and mean attenuation were not significantly different between benign and malignant lesions for either reader (all p > .05). For reader 1, to distinguish benign from malignant lesions, a maximum attenuation threshold of more than 1060 HU resulted in sensitivity of 23.7%, specificity of 87.0%, and accuracy of 60.6%. A mean attenuation threshold of greater than 885 HU resulted in sensitivity of 19.5%, specificity of 90.7%, and accuracy 60.7%. ROC curve analysis showed AUCs for mean and maximum attenuation thresholds of 51.8% and 54.6%, respectively. Subgroup analyses of benign versus malignant and treated versus untreated lesions had similar results. Similar findings were obtained for reader 2. The two readers' ICC was 0.946 for maximum attenuation and 0.918 for mean attenuation. CONCLUSION. Published attenuation thresholds for distinguishing enostoses from osteoblastic metastases had slightly decreased specificity and markedly decreased sensitivity when applied to the differentiation of benign sclerotic lesions from osteoblastic metastases in our sample of biopsy-proven lesions. ROC analysis showed no high-performing attenuation threshold alternative. CLINICAL IMPACT. Published CT attenuation thresholds intended for distinguishing enostoses from osteoblastic metastases should not be used more broadly. More accurate alternative thresholds could not be derived.


Subject(s)
Bone Neoplasms/pathology , Bone and Bones/pathology , Tomography, X-Ray Computed , Aged , Biopsy , Bone Neoplasms/diagnostic imaging , Bone and Bones/diagnostic imaging , Female , Humans , Male , Middle Aged , Retrospective Studies , Sclerosis , Sensitivity and Specificity , Tomography, X-Ray Computed/methods
4.
Skeletal Radiol ; 50(7): 1419-1425, 2021 Jul.
Article in English | MEDLINE | ID: mdl-33404669

ABSTRACT

OBJECTIVE: To characterize the extent of retention and biodistribution of gadolinium (Gd) following intra-articular (IA) injection of linear and macrocyclic gadolinium-based contrast agents (GBCAs) into the knee joint of a rat model. MATERIALS AND METHODS: Fifteen Wistar rats were divided into five groups and underwent fluoroscopically-guided injections of both knee joints of (1) clinical 1:200 dilution (low dose, LD) gadodiamide (linear GBCA), (2) LD gadobutrol (macrocyclic GBCA), (3) undiluted (high dose, HD) gadodiamide, (4) HD gadobutrol, and (5) saline. Gd concentrations were quantified by inductively coupled plasma mass spectrometry in (1) blood and urine samples obtained over a 72 h period and (2) knee joint tissues, brain, kidney, and bone marrow at 3 days post-injection. RESULTS: Both HD and LD gadodiamide and gadobutrol were rapidly absorbed from the joint with peak serum and urine concentration at 1 h post-injection, with relatively faster clearance of gadobutrol. All GBCA-exposed groups had detectable levels of Gd in the joint tissues, bone marrow, and/or kidneys (median tissue gadolinium range: 0.1-71 µg Gd/g tissue), with higher amounts observed with gadodiamide versus gadobutrol. Retention within brain tissues was only detected following HD gadodiamide administration but not LD gadodiamide nor HD or LD gadobutrol. CONCLUSION: There was rapid systemic absorption, redistribution, and widespread multi-organ retention of Gd following IA injection of both linear and macrocyclic GBCAs, despite substantial amounts of urinary excretion. Higher concentrations of Gd were observed with administration of gadodiamide compared to gadobutrol in most tissues and biofluids.


Subject(s)
Gadolinium , Organometallic Compounds , Animals , Contrast Media , Gadolinium DTPA , Magnetic Resonance Imaging , Rats , Rats, Wistar , Tissue Distribution
5.
J Inherit Metab Dis ; 43(4): 737-747, 2020 07.
Article in English | MEDLINE | ID: mdl-31609457

ABSTRACT

The clinical effects of alkaptonuria (AKU) are delayed and ageing influences disease progression. Morbidity of AKU is secondary to high circulating homogentisic acid (HGA) and ochronosis. It is not known whether HGA is produced by or processed in the kidney in AKU. Data from AKU patients from four studies were merged to form a single AKU group. A control group of non-AKU subjects was generated by merging data from two non-AKU studies. Data were used to derive renal clearance and fractional excretion (FE) ratios for creatinine, HGA, phenylalanine (PHE) and tyrosine (TYR) using standard calculations, for comparison between the AKU and the control groups. There were 225 AKU patients in the AKU group and 52 in the non-AKU control group. Circulating HGA increased with age (P < 0.001), and was significantly associated with decreased HGA clearance (CLHGA ) (P < 0.001) and FEHGA (P < 0.001). CLHGA and FEHGA were increased beyond the theoretical maximum renal plasma flow, confirming renal production and emphasising the greater contribution of net tubular secretion than glomerular filtration to renal elimination of HGA. The kidneys are crucial to elimination of HGA. Elimination of HGA is impaired with age resulting in worsening disease over time. The kidney is an important site for production of HGA. Tubular secretion of HGA contributes more to elimination of HGA in AKU than glomerular filtration.


Subject(s)
Alkaptonuria/metabolism , Glomerular Filtration Rate , Homogentisic Acid/metabolism , Kidney/metabolism , Ochronosis/etiology , Adult , Alkaptonuria/physiopathology , Case-Control Studies , Creatinine/metabolism , Female , Humans , Linear Models , Male , Middle Aged , Ochronosis/physiopathology , Phenylalanine/metabolism , Sex Factors , Tyrosine/metabolism
6.
Skeletal Radiol ; 48(10): 1591-1597, 2019 Oct.
Article in English | MEDLINE | ID: mdl-31069468

ABSTRACT

OBJECTIVE: To provide microdissection and histological confirmation of normal Pacinian corpuscles prospectively identified using MRI in a cadaver model. METHODS: 3-T MRI of a cadaveric hand specimen was performed with fiduciary markers on the skin. Based on previous descriptions, subcutaneous nodules representing presumed Pacinian corpuscles were localized with respect to the skin markers, and their sizes and depths were recorded. Focused ultrasound was performed to attempt to visualize the corpuscles. Subsequent microdissection was then performed and the presence and location of Pacinian corpuscles were recorded and compared with the findings on MRI. Histological evaluation for each identified corpuscle was performed. RESULTS: The MRI demonstrated 11 T2-hyperintense palmar subcutaneous nodules around the second through fifth metacarpophalangeal joints. None was visible sonographically. The first eight were dissected and proved to be normal Pacinian corpuscles histologically. In sites devoid of subcutaneous nodules on MRI, subsequent dissection failed to reveal any corpuscles. CONCLUSION: On MRI, normal Pacinian corpuscles appear as round or oval, T2-hyperintense subcutaneous nodules in the palms, clustered around the metacarpophalangeal joints, and should not be mistaken for pathological conditions.


Subject(s)
Hand/diagnostic imaging , Hand/pathology , Magnetic Resonance Imaging/methods , Pacinian Corpuscles/diagnostic imaging , Pacinian Corpuscles/pathology , Cadaver , Humans , Prospective Studies
7.
Skeletal Radiol ; 48(10): 1541-1554, 2019 Oct.
Article in English | MEDLINE | ID: mdl-30919024

ABSTRACT

Ulnar nerve compression at the elbow, specifically the cubital tunnel, is the second most common upper extremity compression neuropathy. Many patients presenting with compression symptoms will subsequently undergo surgical intervention. We review the open surgical treatment of cubital tunnel syndrome and review the expected postoperative imaging appearance of those treatments on magnetic resonance imaging (MR), including: simple or in situ decompression, medial epicondylectomy, and anterior transposition, including subcutaneous, intramuscular, and submuscular variants. We discuss the relevant anatomy of the presurgical cubital tunnel and common sites and causes of ulnar nerve compression at and about the cubital tunnel. The imaging appearance of the preoperative and postoperative ulnar nerve and postoperative complications are reviewed.


Subject(s)
Cubital Tunnel Syndrome/diagnostic imaging , Cubital Tunnel Syndrome/surgery , Decompression, Surgical/methods , Magnetic Resonance Imaging/methods , Postoperative Complications/diagnostic imaging , Humans , Ulnar Nerve/diagnostic imaging , Ulnar Nerve/surgery
10.
Skeletal Radiol ; 47(11): 1553-1558, 2018 Nov.
Article in English | MEDLINE | ID: mdl-29632963

ABSTRACT

Pacinian corpuscles, the main touch receptors to pressure and vibration, are ubiquitous in the deep dermis and hypodermis of the fingers and palms. Nevertheless, their existence is largely unknown to most radiologists. We frequently noted hyperintense nodules in the palms of patients on water-sensitive MRI sequences, but were unable to explain their etiology. We recently encountered two patients who had Pacinian corpuscles identified at surgical exploration and pathological analysis. Pre-operative MRI examinations in these patients showed T2 hyperintense subcutaneous palmar nodules corresponding to these corpuscles in a pattern identical to those seen incidentally in other patients. Descriptions from the dermatopathological and orthopedic literature closely correspond to our MRI observations. Based on these data, we hypothesize that the MRI finding that we previously noted represents normal Pacinian corpuscles.


Subject(s)
Hand/diagnostic imaging , Incidental Findings , Pacinian Corpuscles/diagnostic imaging , Aged , Female , Fingers/diagnostic imaging , Hand/innervation , Humans , Magnetic Resonance Imaging , Male , Neurofibroma/diagnostic imaging , Retrospective Studies
11.
Skeletal Radiol ; 47(11): 1475-1481, 2018 Nov.
Article in English | MEDLINE | ID: mdl-29754193

ABSTRACT

OBJECTIVE: The purpose of this study is to describe the MR arthrogram appearance of the postoperative glenoid labrum and to describe the features consistent with recurrent tear. MATERIALS AND METHODS: We identified 30 patients who had undergone glenoid labral repair, had a subsequent MR arthrogram of his or her shoulder, and went on to repeat shoulder arthroscopy. Each MR arthrogram was reviewed blindly, and the glenoid labrum was described as normal, irregular, or torn. Additional findings recorded included the presence or absence of a paralabral cyst and suture anchors in the glenoid. The operative report was also reviewed for each patient to determine the status of the labrum at arthroscopy. RESULTS: Following consensus review, 18/30 MRIs were felt to demonstrate recurrent glenoid labral tear, 11/30 showed an irregular labrum, and 1/30 was called normal. The radiology impression regarding the presence or absence of a recurrent glenoid labral tear agreed with the operative report in 24/30 (80%) cases, and was discrepant in six. This equals 83.3% sensitivity and 81.8% specificity of MR arthrogram in the diagnosis of recurrent labral tear in this study. A paralabral cyst was present in 3/30 (10%) cases, all three of which were torn. CONCLUSIONS: MR arthrogram findings of signal equal to gadolinium or fluid within or underlying the glenoid labrum and markedly diminutive or absent labrum were the most useful features to diagnose recurrent tear. Some signal underlying the labrum, which is confined to the anterosuperior quadrant, may be normal. The secondary finding of a paralabral cyst was also highly sensitive for recurrent tear.


Subject(s)
Magnetic Resonance Imaging/methods , Postoperative Complications/diagnostic imaging , Rotator Cuff Injuries/diagnostic imaging , Rotator Cuff Injuries/surgery , Adolescent , Adult , Aged , Contrast Media , Female , Humans , Male , Middle Aged , Recurrence , Retrospective Studies , Sensitivity and Specificity , Treatment Outcome
12.
Calcif Tissue Int ; 100(1): 95-106, 2017 01.
Article in English | MEDLINE | ID: mdl-27796463

ABSTRACT

Accelerating the integration of a joint replacement or the healing of a bone fracture, particularly a complicated non-union fracture, would improve patient welfare and decrease healthcare costs. Currently, an autologous bone graft is the gold standard method for the treatment of complicated non-union fractures, but it is not always possible to harvest such a graft. A proactive highly inductive so-called smart material approach is pertinent in these cases. In this study, the surface chemistry of a previously approved material with desirable bulk material properties was modified to investigate its potential as an economical and effective alternative. The objective was to create stable synthetic chemical coatings that could guide cells along the osteogenic lineage required to generate mineralised tissue that would induce and accelerate bone healing. Primary human osteoblast-like cells were cultured in vitro for 7, 14 and 28 days on amine-terminated (chain length in the range 3-11) silane-modified glass surfaces with controlled nanotopography, to determine how surface chemistry and nanotopography change osteoblast function. The materials were characterised using atomic force microscopy (AFM), scanning electron microscopy (SEM), water contact angle (WCA) and a novel ninhydrin assay. The cells were analysed using qRT-PCR, von Kossa tinctural staining for mineralisation, and visualised using both transmitted white light and electron microscopy. Bone-like nodules, quantified using microscopy, only formed on the short-chain (chain length 3 and 4) amines after 7 days, as did the up-regulation of sclerostin, suggestive of a more mature osteoblast phenotype. In this paper, we report more rapid nodule formation than has previously been observed, without the addition of exogenous factors in the culture medium. This suggests that the coating would improve the integration of implants with bone or be the basis of a smart biomaterial that would accelerate the bone regeneration process.


Subject(s)
Cell Differentiation/physiology , Osteoblasts/cytology , Osteocytes/cytology , Bone Regeneration/physiology , Bone and Bones/cytology , Calcification, Physiologic/physiology , Cell Culture Techniques/methods , Cells, Cultured , Humans , Microscopy, Atomic Force/methods , Osteogenesis/physiology , Surface Properties
15.
Biophys J ; 108(5): 1199-212, 2015 Mar 10.
Article in English | MEDLINE | ID: mdl-25762331

ABSTRACT

Although the magnitude of a protein's net charge (Z) can control its rate of self-assembly into amyloid, and its interactions with cellular membranes, the net charge of a protein is not viewed as a druggable parameter. This article demonstrates that aspirin (the quintessential acylating pharmacon) can inhibit the amyloidogenesis of superoxide dismutase (SOD1) by increasing the intrinsic net negative charge of the polypeptide, i.e., by acetylation (neutralization) of multiple lysines. The protective effects of acetylation were diminished (but not abolished) in 100 mM NaCl and were statistically significant: a total of 432 thioflavin-T amyloid assays were performed for all studied proteins. The acetylation of as few as three lysines by aspirin in A4V apo-SOD1-a variant that causes familial amyotrophic lateral sclerosis (ALS)-delayed amyloid nucleation by 38% and slowed amyloid propagation by twofold. Lysines in wild-type- and ALS-variant apo-SOD1 could also be peracetylated with aspirin after fibrillization, resulting in supercharged fibrils, with increases in formal net charge of ∼2 million units. Peracetylated SOD1 amyloid defibrillized at temperatures below unacetylated fibrils, and below the melting temperature of native Cu2,Zn2-SOD1 (e.g., fibril Tm = 84.49°C for acetylated D90A apo-SOD1 fibrils). Targeting the net charge of native or misfolded proteins with small molecules-analogous to how an enzyme's Km or Vmax are medicinally targeted-holds promise as a strategy in the design of therapies for diseases linked to protein self-assembly.


Subject(s)
Amyloid/chemistry , Aspirin/pharmacology , Static Electricity , Superoxide Dismutase/chemistry , Acetylation , Amino Acid Sequence , Amyloid/drug effects , Amyotrophic Lateral Sclerosis/genetics , Humans , Molecular Sequence Data , Mutation, Missense , Superoxide Dismutase/genetics , Superoxide Dismutase/metabolism , Superoxide Dismutase-1 , Transition Temperature
16.
Front Radiol ; 4: 1330399, 2024.
Article in English | MEDLINE | ID: mdl-38440382

ABSTRACT

Introduction: Dual-energy CT (DECT) is a non-invasive way to determine the presence of monosodium urate (MSU) crystals in the workup of gout. Color-coding distinguishes MSU from calcium following material decomposition and post-processing. Manually identifying these foci (most commonly labeled green) is tedious, and an automated detection system could streamline the process. This study aims to evaluate the impact of a deep-learning (DL) algorithm developed for detecting green pixelations on DECT on reader time, accuracy, and confidence. Methods: We collected a sample of positive and negative DECTs, reviewed twice-once with and once without the DL tool-with a 2-week washout period. An attending musculoskeletal radiologist and a fellow separately reviewed the cases, simulating clinical workflow. Metrics such as time taken, confidence in diagnosis, and the tool's helpfulness were recorded and statistically analyzed. Results: We included thirty DECTs from different patients. The DL tool significantly reduced the reading time for the trainee radiologist (p = 0.02), but not for the attending radiologist (p = 0.15). Diagnostic confidence remained unchanged for both (p = 0.45). However, the DL model identified tiny MSU deposits that led to a change in diagnosis in two cases for the in-training radiologist and one case for the attending radiologist. In 3/3 of these cases, the diagnosis was correct when using DL. Conclusions: The implementation of the developed DL model slightly reduced reading time for our less experienced reader and led to improved diagnostic accuracy. There was no statistically significant difference in diagnostic confidence when studies were interpreted without and with the DL model.

17.
Neuroscience ; 546: 178-187, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38518925

ABSTRACT

Automatic abnormality identification of brachial plexus (BP) from normal magnetic resonance imaging to localize and identify a neurologic injury in clinical practice (MRI) is still a novel topic in brachial plexopathy. This study developed and evaluated an approach to differentiate abnormal BP with artificial intelligence (AI) over three commonly used MRI sequences, i.e. T1, FLUID sensitive and post-gadolinium sequences. A BP dataset was collected by radiological experts and a semi-supervised artificial intelligence method was used to segment the BP (based on nnU-net). Hereafter, a radiomics method was utilized to extract 107 shape and texture features from these ROIs. From various machine learning methods, we selected six widely recognized classifiers for training our Brachial plexus (BP) models and assessing their efficacy. To optimize these models, we introduced a dynamic feature selection approach aimed at discarding redundant and less informative features. Our experimental findings demonstrated that, in the context of identifying abnormal BP cases, shape features displayed heightened sensitivity compared to texture features. Notably, both the Logistic classifier and Bagging classifier outperformed other methods in our study. These evaluations illuminated the exceptional performance of our model trained on FLUID-sensitive sequences, which notably exceeded the results of both T1 and post-gadolinium sequences. Crucially, our analysis highlighted that both its classification accuracies and AUC score (area under the curve of receiver operating characteristics) over FLUID-sensitive sequence exceeded 90%. This outcome served as a robust experimental validation, affirming the substantial potential and strong feasibility of integrating AI into clinical practice.


Subject(s)
Artificial Intelligence , Brachial Plexus , Magnetic Resonance Imaging , Humans , Magnetic Resonance Imaging/methods , Brachial Plexus/diagnostic imaging , Brachial Plexus Neuropathies/diagnostic imaging , Machine Learning , Female , Male , Adult
18.
Interv Neuroradiol ; : 15910199231221857, 2024 Jan 05.
Article in English | MEDLINE | ID: mdl-38179603

ABSTRACT

Epidural steroid injections are commonly performed using fluoroscopic or CT guidance. With both modalities, the injection of contrast material is necessary before steroid administration to ensure adequate epidural flow and exclude non-epidural flow. While fluoroscopic guidance is conventional, CT is utilized at some centers and can be particularly helpful in the setting of challenging or postoperative anatomy. It is important for proceduralists to be adept at evaluating contrast media flow patterns under both modalities. The goal of this review article is to describe and provide examples of epidural and non-epidural flow patterns on both conventional fluoroscopy and CT. Specific non-epidural patterns discussed include intrathecal flow, intradural/subdural flow, vascular uptake, flow into the retrodural space of Okada, inadvertent facet joint flow, and intradiscal flow.

19.
J Am Chem Soc ; 135(42): 15897-908, 2013 Oct 23.
Article in English | MEDLINE | ID: mdl-24066782

ABSTRACT

The reactivity of asparagine residues in Cu, Zn superoxide dismutase (SOD1) to deamidate to aspartate remains uncharacterized; its occurrence in SOD1 has not been investigated, and the biophysical effects of deamidation on SOD1 are unknown. Deamidation is, nonetheless, chemically equivalent to Asn-to-Asp missense mutations in SOD1 that cause amyotrophic lateral sclerosis (ALS). This study utilized computational methods to identify three asparagine residues in wild-type (WT) SOD1 (i.e., N26, N131, and N139) that are predicted to undergo significant deamidation (i.e., to >20%) on time scales comparable to the long lifetime (>1 year) of SOD1 in large motor neurons. Site-directed mutagenesis was used to successively substitute these asparagines with aspartate (to mimic deamidation) according to their predicted deamidation rate, yielding: N26D, N26D/N131D, and N26D/N131D/N139D SOD1. Differential scanning calorimetry demonstrated that the thermostability of N26D/N131D/N139D SOD1 is lower than WT SOD1 by ~2-8 °C (depending upon the state of metalation) and <3 °C lower than the ALS mutant N139D SOD1. The triply deamidated analog also aggregated into amyloid fibrils faster than WT SOD1 by ~2-fold (p < 0.008**) and at a rate identical to ALS mutant N139D SOD1 (p > 0.2). A total of 534 separate amyloid assays were performed to generate statistically significant comparisons of aggregation rates among WT and N/D SOD1 proteins. Capillary electrophoresis and mass spectrometry demonstrated that ~23% of N26 is deamidated to aspartate (iso-aspartate was undetectable) in a preparation of WT human SOD1 (isolated from erythrocytes) that has been used for decades by researchers as an analytical standard. The deamidation of asparagine--an analytically elusive, sub-Dalton modification--represents a plausible and overlooked mechanism by which WT SOD1 is converted to a neurotoxic isoform that has a similar structure, instability, and aggregation propensity as ALS mutant N139D SOD1.


Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , Asparagine/metabolism , Aspartic Acid/metabolism , Superoxide Dismutase/metabolism , Amyotrophic Lateral Sclerosis/genetics , Asparagine/blood , Asparagine/chemistry , Aspartic Acid/blood , Aspartic Acid/chemistry , Humans , Models, Molecular , Molecular Structure , Mutation, Missense , Protein Stability , Superoxide Dismutase/chemistry , Superoxide Dismutase/genetics , Superoxide Dismutase-1 , Temperature
20.
AJR Am J Roentgenol ; 200(4): 872-8, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23521463

ABSTRACT

OBJECTIVE: The Enterprise stent is the first closed-cell stent designed to treat wide-necked intracranial aneurysms. Advantages of the design can include improvement in keeping coils within an aneurysm and the ability of the stent to be recaptured. We compared the technical and clinical complications of the Enterprise stent with the open-cell Neuroform stent, its primary alternative. SUBJECTS AND METHODS: Patients undergoing Enterprise and Neuroform stent-assisted aneurysm coiling were enrolled in prospective registries starting in March 2007 and February 2003, respectively. All consecutive patients through December 2011 were included. Deployment success and difficulty, stent movement and misplacement, and procedural complications were compared. RESULTS: Enterprise deployment success was high (108 of 115 attempts, 93.9%) with 102 aneurysms receiving a stent compared with Neuroform (173 of 214 attempts, 80.8%, p = 0.001) with 163 aneurysms. Enterprise was easier to deploy (1.7% vs 15.9% difficult deployment, p < 0.0001). There were no significant differences in the rates of stent movement, misplacement, or symptomatic hemorrhage. Symptomatic thromboembolic events, however, were more frequent with the Enterprise stent (8.7% vs 1.4%, p = 0.0021). The Enterprise stent enabled treatment of 10 additional aneurysms that could not be treated with Neuroform and had a higher rate of immediate aneurysm occlusion (87.3% vs 73.0%, p = 0.0058). CONCLUSION: Enterprise was easier to deploy and enabled treatment of additional aneurysms; however, there were more thromboembolic complications. On the basis of these findings, we prefer to use the Neuroform stent first and rely on the Enterprise stent as an easy-to-deliver backup for stent-assisted coiling.


Subject(s)
Embolization, Therapeutic/instrumentation , Intracranial Aneurysm/therapy , Stents , Adult , Aged , Aged, 80 and over , Cerebral Angiography , Embolization, Therapeutic/adverse effects , Female , Humans , Intracranial Aneurysm/diagnostic imaging , Male , Middle Aged , Prospective Studies , Registries , Stents/adverse effects , Treatment Outcome
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