Systematic protocol for assessment of the validity of BOLD MRI in a rabbit model of inflammatory arthritis at 1.5 tesla.

BACKGROUND: Blood-oxygen-level-dependent (BOLD) MRI has the potential to identify regions of early hypoxic and vascular joint changes in inflammatory arthritis. There is no standard protocol for analysis of BOLD MRI measurements in musculoskeletal disorders. OBJECTIVE: To optimize the following BOLD MRI reading parameters: (1) statistical threshold values (low, r > 0.01 versus high, r > 0.2); (2) summary measures of BOLD contrast (percentage of activated voxels [PT%] versus percentage signal difference between on-and-off signal intensities [diff_on_off]); and (3) direction of BOLD response (positive, negative and positive + negative). MATERIALS AND METHODS: Using BOLD MRI protocols at 1.5 T, arthritic (n = 21) and contralateral (n = 21) knees of 21 juvenile rabbits were imaged at baseline and on days 1, 14 and 28 after a unilateral intra-articular injection of carrageenan. Nine non-injected rabbits served as external control knees (n = 18). By comparing arthritic to contralateral knees, receiver operating characteristic curves were used to determine diagnostic accuracy. RESULTS: Using diff_on_off and positive + negative responses, a threshold of r > 0.01 was more accurate than r > 0.2 (P = 0.03 at day 28). Comparison of summary measures yielded no statistically significant difference (P > 0.05). Although positive + negative (AUC = 0.86 at day 28) and negative responses (AUC = 0.90 at day 28) for PT% were the most diagnostically accurate, positive + negative responses for diff_on_off (AUC = 0.78 at day 28) also had acceptable accuracy. CONCLUSIONS: The most clinically relevant reading parameters included a lower threshold of r > 0.01 and a positive + negative BOLD response. We propose that diff_on_off is a more clinically relevant summary measure of BOLD MRI, while PT% can be used as an ancillary measure.

Correlative BOLD MR imaging of stages of synovitis in a rabbit model of antigen-induced arthritis.

BACKGROUND: Because of the ability of blood-oxygen-level-dependent (BOLD) MRI to assess blood oxygenation changes within the microvasculature, this technique holds potential for evaluating early perisynovial changes in inflammatory arthritis. OBJECTIVE: To evaluate the feasibility of BOLD MRI to detect interval perisynovial changes in knees of rabbits with inflammatory arthritis. MATERIALS AND METHODS: Rabbit knees were injected with albumin (n=9) or saline (n=6) intra-articularly, or were not injected (control knees, n=9). Except for two rabbits (albumin-injected, n=2 knees; saline-injected, n=2 knees) that unexpectedly died on days 7 and 21 of the experiment, respectively, all other animals were scanned with BOLD MRI on days 0, 1, 7, 14, 21 and 28 after induction of arthritis. T2*-weighted gradient-echo MRI was performed during alternate 30 s of normoxia/hyperoxia. BOLD MRI measurements were compared with clinical, laboratory and histological markers. RESULTS: Percentage of activated voxels was significantly greater in albumin-injected knees than in contralateral saline-injected knees (P=0.04). For albumin-injected knees (P<0.05) and among different categories of knees (P=0.009), the percentage of activated BOLD voxels varied over time. A quadratic curve for on-and-off BOLD difference was delineated for albumin- and saline-injected knees over time (albumin-injected, P=0.047; saline-injected, P=0.009). A trend toward a significant difference in synovial histological scores between albumin-injected and saline-injected knees was noted only for acute scores (P=0.07). CONCLUSION: As a proof of concept, BOLD MRI can depict perisynovial changes during progression of experimental arthritis.

Imaging of SHOX-associated anomalies.

Human growth is a multifactorial trait influenced by environmental, hormonal, and genetic factors. Although it is clear that multiple factors contribute to an individual's final height and limb development, genetic factors play a crucial role. One such gene is the short stature homeobox ( SHOX) containing gene. Knowledge about the SHOX gene has rapidly increased since its discovery in 1997, and we now know that SHOX haploinsufficiency affects the development of the extremities and is an important cause of short stature. Currently, SHOX mutations occur with an estimated incidence of roughly 1 in 1000 newborns, making mutations of this gene one of the most common genetic defects associated with growth failure and skeletal deformities. Heterozygous mutations of SHOX have been implicated in patients with Madelung's deformity, Leri-Weill dyschondrosteosis (77%), Turner's syndrome (66%), and idiopathic short stature (3%), and homozygous mutations of SHOX gene have been identified in patients with Langer's mesomelic dysplasia (100%). Recognition of the early radiographic features encountered in SHOX haploinsufficiency maybe pivotal for the diagnosis. In this article, we summarize the genetic and clinical features of the various SHOX haploinsufficiency-associated disorders. We present the characteristic imaging features of these disorders and the results of growth hormone treatment trials.

Quantifying Complex Micro-Topography of Degenerated Articular Cartilage Surface by Contrast-Enhanced Micro-Computed Tomography and Parametric Analyses.

One of the earliest changes in osteoarthritis (OA) is a surface discontinuity of the articular cartilage (AC), and these surface changes become gradually more complex with OA progression. We recently developed a contrast enhanced micro-computed tomography (µCT) method for visualizing AC surface in detail. The present study aims to introduce a µCT analysis technique to parameterize these complex AC surface features and to demonstrate the feasibility of using these parameters to quantify degenerated AC surface. Osteochondral plugs (n = 35) extracted from 19 patients undergoing joint surgery were stained with phosphotungstic acid and imaged using µCT. The surface micro-topography of AC was analyzed with developed method. Standard root mean square roughness (Rq ) was calculated as a reference, and the Area Under Curve (AUC) for receiver operating characteristic analysis was used to compare the acquired quantitative parameters with semi-quantitative visual grading of µCT image stacks. The parameters quantifying the complex micro-topography of AC surface exhibited good sensitivity and specificity in identifying surface continuity (AUC: 0.93, [0.80 0.99]), fissures (AUC: 0.94, [0.83 0.99]) and fibrillation (AUC: 0.98, [0.88 1.0]). Standard Rq was significantly smaller compared with the complex roughness (CRq ) already with mild surface changes with all surface reference parameters - continuity, fibrillation, and fissure sum. Furthermore, only CRq showed a significant difference when comparing the intact surface with lowest fissure sum score. These results indicate that the presented method for evaluating complex AC surfaces exhibit potential to identify early OA changes in superficial AC and is dynamic throughout OA progression. © 2019 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. Society. 9999:1-12, 2019.

Effect of exercise on articular cartilage.

This review primarily focuses on how the macromolecular composition and architecture of articular cartilage and its unique biomechanical properties play a pivotal role in the ability of articular cartilage to withstand mechanical loads several magnitudes higher than the weight of the individual. Current findings on short-term and long-term effects of exercise on human articular cartilage are reviewed, and the importance of appropriate exercises for individuals with normal and diseased or aberrated cartilage is discussed.

Articular cartilage development: a molecular perspective.

In this article, development of articular cartilage and endochondral ossification is reviewed, from the perspective of both morphologic aspects of histogenesis and molecular biology, particularly with respect to key signaling molecules and extracellular matrix components most active in cartilage development. The current understanding of the roles of transforming growth factor ß and associated signaling molecules, bone morphogenic proteins, and molecules of the Wnt-ß catenin system in chondrogenesis are described. Articular cartilage development is a highly conserved complex biological process that is dynamic and robust in nature, which proceeds well without incident or failure in all joints of most young growing individuals.

Pulmonary thromboembolism in children.

Pulmonary thromboembolism (PTE) is uncommonly diagnosed in the pediatric patient, and indeed often only discovered on autopsy. The incidence of pediatric PTE depends upon the associated underlying disease, diagnostic tests used, and index of suspicion. Multiple risk factors can be found including: peripartum asphyxia, dyspnea, haemoptysis, chest pain, dehydration, septicemia, central venous lines (CVLs), trauma, surgery, ongoing hemolysis, vascular lesions, malignancy, renal disease, foreign bodies or, uncommonly, intracranial venous sinus thrombosis, burns, or nonbacterial thrombotic endocarditis. Other types of embolism can occur uncommonly in childhood and need to be recognized, as the required treatment will vary. These include pulmonary cytolytic thrombi, foreign bodies, tumor and septic emboli, and post-traumatic fat emboli. No single noninvasive test for pulmonary embolism is both sensitive and specific. A combination of diagnostic procedures must be used to identify suspect or confirmed cases of PTE. This article reviews the risk factors, clinical presentation and treatment of pulmonary embolism in children. It also highlights the current diagnostic tools and protocols used to evaluate pulmonary embolism in pediatric patients.

A cartilage derived novel compound DDP (2,6-dimethyldifuro-8-pyrone): isolation, purification, and identification.

OBJECTIVE: Fluorescent biomolecules within cartilage matrix can be used as specific markers of cartilage metabolism. While establishing the protocol to evaluate mature collagen crosslinks in articular cartilage (AC) associated with maturation, aging, and osteoarthritis, chromatographic analysis of the crosslinks also revealed an apparently novel fluorescent peak. Preliminary investigation of this compound (now abbreviated DDP) in various tissues from rabbits, calves, chickens, and humans showed that this compound is AC-specific. We aimed to isolate, purify, and identify this fluorescent compound. METHODS: Fully encapsulated, bovine metacarpophalangeal joints (n = 350, age < 2 years) were used as the source for AC. DDP was isolated and purified by reverse phase high pressure liquid chromatography, and its elution was monitored using a fluorescence detector at excitation lambda = 306 nm, and emission lambda = 395 nm. The liquid phase of DDP was characterized by mass spectrometry and nuclear magnetic resonance spectroscopy. DDP solution (5.7 microg/microl) was crystallized in 100% deuterated methanol and the DDP crystal was characterized by single crystal x-ray diffraction. RESULTS: From bulk preparations, 12 pg (58 nmol) per gram dried AC of the novel compound was isolated and purified. Analytical techniques to identify this AC-specific compound, 2,6-dimethyldifuro-8-pyrone, corroborate and confirm its molecular structure and atomic connectivity in both liquid and solid phase. DDP is a symmetrical aromatic compound with molecular weight 204, molecular forrmula C11H8O4, and a molar extinction coefficient 4,700 M(-1) at maximal UV absorption (lambda = 306 nm). CONCLUSION: 2,6-dimethyldifuro-8-pyrone (DDP) is a novel cartilage-specific compound that could have potential application as a unique biochemical marker in joint diseases involving articular cartilage degradation.

Novel fluorescent compound (DDP) in calf, rabbit, and human articular cartilage and synovial fluid.

OBJECTIVE: To investigate the presence of and quantify 2,6-dimethyldifuro-8-pyrone (DDP), a novel fluorescent compound identified as in various calf, rabbit, and human tissue/fluid samples, to determine the DDP level in articular cartilage (AC) laminae, and to investigate the changes in cartilage DDP content with cartilage maturation. METHODS: Samples were obtained from calf (< 2 years), rabbit (< 2 weeks to 2 years) or human AC and synovial fluid (SF) as well as other non-cartilaginous tissues. SF and tissue samples were hydrolyzed with 6 M HCl (24 hours at 110 degrees C), lyophilized, and dissolved in HPLC mobile phase. DDP and collagen crosslink peaks were measured using a fluorescence detector at excitation and emission wavelengths of 295 and 395 nm, respectively. RESULTS: DDP was detected from calf metacarpophalangeal joint AC (362 +/- 48 pmol/mg dry weight), SF (4.5 +/- 0.3 pmol/microl SF), and intervertebral disc (24 +/- 4 pmol/mg). DDP was not detected in calf ligament, tendon, bone, ocular lens, cornea, or elastic cartilage. The DDP amount was greater in mid-deep cartilage lamina (448 +/- 63 pmol/mg) than superficial-mid lamina (129 +/- 52 pmol/mg) (p = 0.008). DDP level decreased with maturation in rabbit knee joint AC from 185 +/- 40 (< 2 weeks) to 27 +/- 3 (2 years) pmol/mg dry weight. DDP was not detected in adult rabbit ligament, tendon, meniscus, or bone. DDP was detected in human knee joint AC and SF. The DDP level in osteoarthritic lesions was present in lower concentrations (range: 0 to 96 pmol/mg dried AC) compared to intact AC (range: 63 to 236 pmol/mg) of the same knee. CONCLUSION: DDP is a hyaline cartilage specific compound present in all articular cartilage samples from various articulating joints/animal species. DDP level increases with AC depth and decreases with cartilage maturation. DDP is a potential indicator of cartilage metabolism during normal growth, ageing, and cartilage disease.

Severe acute respiratory syndrome (SARS): chest radiographic features in children.

BACKGROUND: Severe acute respiratory syndrome (SARS) is a recently recognized condition of viral origin associated with substantial morbidity and mortality rates in adults. Little information is available on its radiologic manifestations in children. OBJECTIVE: The goal of this study was to characterize the radiographic presentation of children with SARS. MATERIALS AND METHODS: We abstracted data (n=62) on the radiologic appearance and course of SARS in pediatric patients with suspect (n=25) or probable (n=37) SARS, diagnosed in five hospital sites located in three cities: Toronto, Singapore, and Hong Kong. Available chest radiographs and thoracic CTs were reviewed for the presence of the following radiographic findings: airspace disease, air bronchograms, airways inflammation and peribronchial thickening, interstitial disease, pleural effusion, and hilar adenopathy. RESULTS: A total of 62 patients (suspect=25, probable=37) were evaluated for SARS. Patient ages ranged from 5.5 months to 17 years and 11.5 months (average, 6 years and 10 months) with a female-to-male ratio of 32:30. Forty-one patients (66.1%) were in close contact with other probable, suspect, or quarantined cases; 10 patients (16.1%) had recently traveled to WHO-designated affected areas within 10 days; and 7 patients (11.2%) were transferred from other hospitals that had SARS patients. Three patients, who did not have close/hospital contact or travel history to affected areas, were classified as SARS cases based on their clinical signs and symptoms and on the fact that they were living in an endemic area. The most prominent clinical presentations were fever, with a temperature over 38 degrees C (100%), cough (62.9%), rhinorrhea (22.6%), myalgia (17.7%), chills (14.5%), and headache (11.3%). Other findings included sore throat (9.7%), gastrointestinal symptoms (9.7%), rigor (8.1%), and lethargy (6.5%). In general, fever and cough were the most common clinical presentations amongst younger pediatric SARS cases (age<10 years), whereas, in addition to these symptoms, headache, myalgia, sore throat, chills, and/or rigor were common in older patients (age>/=10 years). The chest radiographs of 35.5% of patients were normal. The most prominent radiological findings that were observed in the remaining patients were areas of consolidation (45.2%), often peripheral with multifocal lesions in 22.6%. Peribronchial thickening was noted on chest radiographs of 14.5% of patients. Pleural effusion was observed only in one patient (age 17 years and 11.5 months), whereas interstitial disease was not observed in any patient. CONCLUSION: In pediatric cases, SARS manifests with nonspecific radiographic features making radiological differentiation difficult, especially from other commonly encountered childhood respiratory viral illnesses causing airspace disease. The radiographic presentation of suspected SARS cases ranged from normal to mild perihilar peribronchial thickening. The radiographic presentations, as expected, were relatively more pronounced in the SARS probable cases.