Pediatric Cardiology Fellowship Standards for Training in Exercise Medicine and Curriculum Outline.

Over the past 2 decades, fundamentals of exercise medicine, including clinical exercise testing, assessment and promotion of physical activity, exercise prescription, and supervised exercise training/rehabilitation programming have demonstrated considerable clinical value in the management of children and adolescents with congenital and acquired heart disease. Although the principles of exercise medicine have become an integral component in pediatric cardiology, there are no standardized training recommendations for exercise physiology during pediatric cardiology fellowship at this time. Thus, the Pediatric Cardiology Exercise Medicine Curriculum Committee (PCEMCC) was formed to establish core and advanced exercise physiology training recommendations for pediatric cardiology trainees. The PCEMCC includes a diverse group of pediatric cardiologists, exercise physiologists, and fellowship program directors. The expert consensus training recommendations are by no means a mandate and are summarized herein, including suggestions for achieving the minimum knowledge and training needed for general pediatric cardiology practice.

Cardiopulmonary Exercise Performance in the Pediatric and Young Adult Population Before and During the COVID-19 Pandemic.

Physical activity (PA) decreased and sedentary behavior (SB) increased in the pediatric population during the Coronavirus Disease 2019 (COVID-19) pandemic. We examined the effects of PA and SB on cardiopulmonary exercise performance in children, adolescents and young adults both with and without underling cardiac disease, and hypothesized that there will be a change in aerobic and physical working capacity during the pandemic. This was a single-center retrospective longitudinal cohort study in patients age 6-22 years who underwent serial maximal cardiopulmonary exercise stress testing before and during the COVID-19 pandemic. Metabolic variables were obtained; PA and SB data were extracted from clinic notes. A total of 122 patients (60% male) underwent serial exercise testing with a median age of 14 years at the first CPET. Predicted peak aerobic capacity significantly decreased among both females and males during the pandemic, even after adjusting for changes in somatic growth. There was no significant change in physical working capacity during the pandemic. Patients who were more aerobically fit experienced a greater decrease in aerobic capacity during the pandemic compared to those less fit. In conclusion, cardiopulmonary exercise performance, notably aerobic activity, decreased during the COVID-19 pandemic in children, adolescents and young adults compared to pre-pandemic values. This decline was most notable in those with the highest pre-pandemic aerobic capacity values and was independent of somatic growth or changes in BMI. This study has public health implications and demonstrates the importance of PA on overall cardiovascular health.

The influence of mechanical Circulatory support on post-transplant outcomes in pediatric patients: A multicenter study from the International Society for Heart and Lung Transplantation (ISHLT) Registry.

BACKGROUND: Mechanical circulatory support (MCS) is increasingly being used as a bridge to transplant in pediatric patients. We compare outcomes in pediatric patients bridged to transplant with MCS from an international cohort. METHODS: This retrospective cohort study of heart-transplant patients reported to the International Society for Heart and Lung Transplantation (ISHLT) registry from 2005-2017 includes 5,095 patients <18 years. Pretransplant MCS exposure and anatomic diagnosis were derived. Outcomes included mortality, renal failure, and stroke. RESULTS: 26% of patients received MCS prior to transplant: 240 (4.7%) on extracorporeal membrane oxygenation (ECMO), 1,030 (20.2%) on ventricular assist device (VAD), and 54 (1%) both. 29% of patients were <1 year, and 43.8% had congenital heart disease (CHD). After adjusting for clinical characteristics, compared to no-MCS and VAD, ECMO had higher mortality during their transplant hospitalization [OR 3.97 & 2.55; 95% CI 2.43-6.49 & 1.42-4.60] while VAD mortality was similar [OR 1.55; CI 0.99-2.45]. Outcomes of ECMO+VAD were similar to ECMO alone, including increased mortality during transplant hospitalization compared to no-MCS [OR 4.74; CI 1.81-12.36]. Patients with CHD on ECMO had increased 1 year, and 10 year mortality [HR 2.36; CI 1.65-3.39], [HR 1.82; CI 1.33-2.49]; there was no difference in survival in dilated cardiomyopathy (DCM) patients based on pretransplant MCS status. CONCLUSION: Survival in CHD and DCM is similar in patients with no MCS or VAD prior to transplant, while pretransplant ECMO use is strongly associated with mortality after transplant particularly in children with CHD. In children with DCM, long term survival was equivalent regardless of MCS status.

Change in knee osteoarthritis cartilage detected by delayed gadolinium enhanced magnetic resonance imaging following treatment with collagen hydrolysate: a pilot randomized controlled trial.

OBJECTIVE: To determine whether either of two magnetic resonance imaging approaches - delayed gadolinium enhanced magnetic resonance imaging of cartilage (dGEMRIC), or T2 mapping - can detect short-term changes in knee hyaline cartilage among individuals taking a formulation of collagen hydrolysate. DESIGN: Single center, prospective, randomized, placebo-controlled, double-blind, pilot trial of collagen hydrolysate for mild knee osteoarthritis (OA). Participants were allowed to continue the prior analgesic use. The primary outcome was change in dGEMRIC T1 relaxation time in the cartilage regions of interest at the 24-week timepoint. Secondary endpoints included the change in dGEMRIC T1 relaxation time between baseline and 48 weeks, the change in T2 relaxation time at 0, 24 and 48 weeks, the symptom and functional measures obtained at each of the visits, and overall analgesic use. RESULTS: Among a sample of 30 randomized subjects the dGEMRIC score increased in the medial and lateral tibial regions of interest (median increase of 29 and 41 ms respectively) in participants assigned to collagen hydrolysate but decreased (median decline 37 and 36 ms respectively) in the placebo arm with the changes between the two groups at 24 weeks reaching significance. No other significant changes between the two groups were seen in the other four regions, or in any of the T2 values or in the clinical outcomes. CONCLUSIONS: These preliminary results suggest that the dGEMRIC technique may be able to detect change in proteoglycan content in knee cartilage among individuals taking collagen hydrolysate after 24 weeks.

"Why aren't we there yet?" Re-examining standard paradigms in imaging of OA: summary of the 2nd annual workshop on imaging based measures of osteoarthritis.

OBJECTIVE: This white paper constitutes an overview of presentations and discussions from the 2nd annual osteoarthritis (OA) imaging workshop. DESIGN: This workshop brought together the communities of basic OA researchers, orthopedists and rheumatologists, imaging scientists, instrument manufacturers, and pharmaceutical and regulatory representatives to try to identify those factors that have limited imaging [focusing mostly on magnetic resonance imaging (MRI)] from making larger inroads into understanding and treating OA ("why aren't we there yet"), and to delineate future directions for success. RESULTS: The meeting was successful in raising awareness and questions about how we may proceed in this process. There was a general consensus that a change in direction is needed for OA imaging research to succeed in yielding a better understanding of OA and development of preventive and therapeutic procedures. CONCLUSIONS: Our current paradigms are limiting the potential for MRI, by limiting how trials are designed and interpreted. Many basic questions remain in biology, pathophysiology, pain, and biomechanics; these questions need to be identified and specific imaging protocols need to be developed to address them. The OA research communities need to work alongside the regulatory, pharmaceutical, and MRI industries to support the new ideas and engage in the positive reinforcement of resources to further the new studies.

Feasibility of immunocytochemical detection of tumor markers (XIAP, phosphohistone H1 and p63) in FNA cellblock samples from head and neck squamous cell carcinoma.

One of the major handicaps in contemporary clinical oncology is the inability to predict the responsiveness of any individual's malignancy to specific therapies. The purpose of this study was to test the feasibility of immunocytochemically detecting markers that may be affected by therapy or are predictive of therapeutic responsiveness, including phosphohistone H1 (anti-p-H1 MoAb 12D11) and X-linked inhibitor of apoptosis (XIAP) in small samples obtained via fine-needle aspiration (FNA) biopsy procedure, thus improving therapeutic monitoring. p63, a squamous stem cell regulatory protein, was also examined. These three markers were studied in FNA cell block samples of head and neck squamous cell carcinoma (HNSCC). Twenty-eight alcohol-fixed formalin-postfixed paraffin-embedded cell-block samples from FNAs of patients with HNSCC were subjected to antigen retrieval and then incubated with anti-XIAP, anti-p-H1, and anti-p63, and developed using EnVision-Plus reagents and diaminobenzidine as chromagen; Granular or heterogeneous cytoplasmic staining for XIAP and nuclear staining for p63 and p-H1 were considered positive. Among the 28 cases studied, the overall positive rates for XIAP, p-H1, and p63 were 60.7%, 96.4%, and 92.8%, respectively. The staining intensity for XIAP: + 70.6%, ++ 23.5%, +++ 0%, and ++++ 5.9%; for p-H1: + 48.1%, ++ 11.1%, +++37.0%, and ++++ 3.7%; and for p63: + 11.5%, ++ 23.1%, +++ 53.9%, and ++++ 11.5%. The expression of p-H1 and p63 appeared to be higher and stronger than that of XIAP in HNSCC. This study demonstrated the feasibility of monitoring expression of three tumor markers using FNA samples. p-H1 and XIAP may be useful for monitoring actions of cyclin-dependent kinase inhibitors, XIAP-lowering, and/or apoptosis-inducing drugs, respectively. Future studies will focus on the impact of therapies upon these staining profiles.

Precision of 3.0 Tesla quantitative magnetic resonance imaging of cartilage morphology in a multicentre clinical trial.

OBJECTIVE: Quantitative MRI (qMRI) of cartilage morphology is a promising tool for disease-modifying osteoarthritis drug (DMOAD) development. Recent studies at single sites have indicated that measurements at 3.0 Tesla (T) are more reproducible (precise) than those at 1.5 T. Precision errors and stability in multicentre studies with imaging equipment from various vendors have, however, not yet been evaluated. METHODS: A total of 158 female participants (97 Kellgren and Lawrence grade (KLG) 0, 31 KLG 2 and 30 KLG 3) were imaged at 7 clinical centres using Siemens Magnetom Trio and GE Signa Excite magnets. Double oblique coronal acquisitions were obtained at baseline and at 3 months, using water excitation spoiled gradient echo sequences (1.0x0.31x0.31 mm3 resolution). Segmentation of femorotibial cartilage morphology was performed using proprietary software (Chondrometrics GmbH, Ainring, Germany). RESULTS: The precision error (root mean square coefficient of variation (RMS CV)%) for cartilage thickness/volume measurements ranged from 2.1%/2.4% (medial tibia) to 2.9%/3.3% (lateral weight-bearing femoral condyle) across all participants. No significant differences in precision errors were observed between KLGs, imaging sites, or scanner manufacturers/types. Mean differences between baseline and 3 months ranged from <0.1% (non-significant) in the medial to 0.94% (p<0.01) in the lateral femorotibial compartment, and were 0.33% (p<0.02) for the total femorotibial subchondral bone area. CONCLUSIONS: qMRI performed at 3.0 T provides highly reproducible measurements of cartilage morphology in multicentre clinical trials with equipment from different vendors. The technology thus appears sufficiently robust to be recommended for large-scale multicentre trials.

GLUT1 and p63 expression in endometrial intraepithelial and uterine serous papillary carcinoma.

AIMS: To analyse the expression patterns of GLUT1, p63 and p53 and the possible correlation between these markers in uterine serous papillary carcinoma (USPC) and endometrial intraepithelial carcinoma (EIC). METHODS AND RESULTS: Fourteen cases of USPC, 12 of which also showed EIC, were examined for GLUT1, p63 and p53 immunoreactivity. Four-micrometre sections from formalin-fixed paraffin-embedded tissue were immunostained using commercially available primary antibodies and Dako Envision Plus reagents for visualization. Membranous GLUT1 immunoreactivity was observed in all cases, including all 14 invasive tumours (100%) and 11 of 12 associated EICs (92%), and was confined to neoplastic cells. In USPC, staining tended to be strongest in superficial antistromal regions. p63 positivity was found in 8/14 (57%) USPCs and 9/12 (75%) associated EICs. In 11 cases p53 was overexpressed in both invasive USPC (11/14; 79%) and EIC (11/12; 92%). p53+ USPCs tended to be positive for p63, whereas p53- USPCs were also negative for p63. CONCLUSIONS: GLUT1 is expressed in the vast majority of USPC and EIC, suggesting a biological role during the early steps of carcinogenesis in endometrial serous neoplasms. GLUT1 expression may be induced by hypoxia-related as well as other mechanisms.

dGEMRIC as a function of BMI.

OBJECTIVE: Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) reflects cartilage glycosaminoglycan (GAG) distribution. The technique assumes that the plasma levels of the contrast agent Gd-DTPA(2-) are the same across individuals after intravenous (IV) injection, when dosing by weight. However, adipose tissue has lower extracellular water (ECW) than lean tissue. The aims of this study were to measure (1) plasma Gd-DTPA(2-) levels vs body mass index (BMI), and (2) dGEMRIC vs BMI after correcting for the dose-BMI effect. METHOD: (1) Plasma Gd-DTPA(2-) levels were analyzed at 3-90 min after IV injection per body weight in 24 individuals with BMI between 21.5 and 46.5. (2) dGEMRIC was compared with BMI in 19 asymptomatic volunteers and 23 with osteoarthritis (OA). RESULTS: (1) Plasma Gd-DTPA(2-) kinetics were similar in obese and non-obese groups, however, overall concentration was higher in the obese group. A very obese subject (BMI 45) would have 1.4 times higher Gd-DTPA(2-) concentration than a lean subject (BMI 20), which translates into a bias in dGEMRIC of up to 20%. (2) With dose bias taken into account, dGEMRIC showed no correlation with BMI in asymptomatic knees. In OA knees, unnarrowed femoral compartments demonstrated a negative correlation between dGEMRIC and BMI (R=0.57, P=0.004). No correlation was seen in radiographically narrowed compartments. CONCLUSION: BMI can be a source of dosing bias in dGEMRIC and a correction factor should be considered in cross-sectional studies with a large range of BMI. There is no correlation between dGEMRIC and BMI in asymptomatic knees, but a negative correlation in OA knees.

Immunohistochemical detection of GLUT1, p63 and phosphorylated histone H1 in head and neck squamous intraepithelial neoplasia: evidence for aberrations in hypoxia-related, cell cycle- and stem-cell-regulatory pathways.

AIM: Most epithelial malignancies are characterized by multistep progression from preinvasive/intraepithelial neoplasia to invasive malignancy. Detection and grading of early squamous intraepithelial neoplasia may at times be problematic. The aim of this study was to examine the ability of immunomarkers GLUT1, phospho-histone H1 and p63 to detect such early lesions. METHODS: Sections of formalin-fixed paraffin-embedded tissue from 27 cases of squamous intraepithelial neoplasia, 26 associated with invasive carcinoma, were immunostained with anti-p63 (4A4; Santa Cruz), anti-GLUT1 (Chemicon) and anti-phospho-histone H1 (monoclonal 12D11) and compared with normal, hyperplastic and immature squamous metaplastic epithelium. RESULTS: Normal epithelium displayed phospho-histone H1 in scattered parabasal cells; p63 in the basal one-quarter to one-half of epithelium; and GLUT1 negativity or weak/equivocal mid-epithelial GLUT1+ foci. In hyperplasia phospho-histone H1+ cells were also limited to the parabasal layer; p63 positivity was essentially identical to that in normal epithelium; GLUT1 characteristically stained basal cells in rete-like areas. p63 staining in squamous intraepithelial neoplasia (grade 1) was indistinguishable from normal epithelial staining; in contrast, squamous intraepithelial neoplasia (grade 3) was readily apparent, with up to full-thickness p63 positivity. Squamous intraepithelial neoplasia (grade 1) was readily distinguishable from normal epithelium with both phospho-histone H1 and GLUT1 immunostaining; both markers were detected in cell layers above the parabasal layer. With both, progressively higher cell layers stained in proportion to the severity of the intraepithelial neoplasia, up to full thickness positivity in grade 3 squamous intraepithelial neoplasia. Squamous metaplasia and grade 3 squamous intraepithelial neoplasia were not distinguishable with p63 (both showed full-thickness staining) but were readily distinguishable with GLUT1 and phospho-histone H1 stains. GLUT1 appeared to be the most sensitive marker for all grades of intraepithelial neoplasia. CONCLUSION: Altered expression of all three markers was a common finding in squamous intraepithelial neoplasia, hence, dysregulation of cell cycle-promoting cyclin-dependent kinases (phospho-histone H1), altered stem cell regulatory pathways (p63) and enhancement of hypoxia-sensing pathways (GLUT1) are all early alterations in the progression of squamous malignancy of head and neck origin. A panel of all three may be a useful means of detecting squamous intraepithelial neoplasia.

Immunodetection of GLUT1, p63 and phospho-histone H1 in invasive head and neck squamous carcinoma: correlation of immunohistochemical staining patterns with keratinization.

Immunodetection of GLUT1, p63 and phospho-histone H1 in invasive head and neck squamous carcinoma: correlation of immunohistochemical staining patterns with keratinizationAims : To examine invasive head and neck squamous carcinomas for expression of GLUT1, a glucose transporter and marker of increased glucose uptake, glycolytic metabolism and response to tissue hypoxia; p63, a p53 homologue that is a marker of the undifferentiated proliferative basaloid phenotype; and phospho-histone H1, a marker of activation of the cell cycle-promoting cyclin-dependent kinases 1 and 2. Methods : Routinely processed slides from 34 invasive squamous carcinomas, including 25 with intraepithelial components, were immunostained with anti-GLUT1 (Chemicon), anti-p63 (4A4, Santa Cruz), and antiphospho-histone H1 (monoclonal 12D11). Results : In keratinizing carcinomas, all three markers were most commonly immunodetected peripherally, with loss of expression in central keratinized zones. In contrast, in non-keratinizing carcinomas, p63 and phospho-histone H1 expression was most commonly observed throughout tumour nests and anti-GLUT1 stained in a pattern suggestive of hypoxia-induced expression ('antistromal' staining), in which cells at the tumour-stromal interface were GLUT1- and cells in central, perinecrotic zones showed progressive induction of GLUT1. Intraepithelial components also displayed basal and 'antibasal' GLUT1 staining patterns, homologous to the pro- and antistromal patterns in invasive carcinoma; basal patterns in intraepithelial lesions appeared to be more predictive of keratinizing invasive carcinoma and antibasal intraepithelial staining more predictive of non-keratinizing poorly differentiated carcinomas. Conclusions : Keratinizing and non-keratinizing squamous carcinomas differ in expression patterns of GLUT1, p63 and phospho-histone H1. In the former, all three markers were typically suppressed in conjunction with keratinization; in the latter, GLUT1 expression was more likely to occur in a hypoxia-inducible pattern and expression of p63 and phospho-histone H1 was unsuppressed. GLUT1 expression patterns in intraepithelial lesions may be predictive of the differentiation status of the associated invasive carcinoma.

Proposal for a nomenclature for magnetic resonance imaging based measures of articular cartilage in osteoarthritis.

OBJECTIVE: Magnetic resonance imaging (MRI) of articular cartilage has evolved to be an important tool in research on cartilage (patho)physiology and osteoarthritis (OA). MRI provides a wealth of novel and quantitative information, but there exists no commonly accepted terminology for reporting these metrics. The objective of this initiative was to propose a nomenclature for definitions and names to be used in scientific communications and to give recommendations as to which minimal methodological information should be provided when reporting MRI-based measures of articular cartilage in OA. METHODS: An international group of experts with direct experience in MRI measurement of cartilage morphology or composition reviewed the existing literature. Through an iterative process that included a meeting with a larger group of scientists and clinicians (December 2nd, 2004, Chicago, IL, USA), they discussed, refined, and proposed a nomenclature for MRI-based measures of articular cartilage in OA. RESULTS: The group proposes a nomenclature that describes: (1) the anatomical location and (2) the structural feature being measured, each name consisting of a metric variable combined with a tissue label. In addition, the group recommends minimal methodological information that should be described. CONCLUSIONS: Utilization of this nomenclature should facilitate communication within the scientific community. Further, the uniform adoption of comprehensive nomenclature to describe quantitative MRI- features of articular cartilage should strengthen epidemiological, clinical, and pharmacological studies in OA.

Segmentation of intestinal gland images with iterative region growing.

A region growing algorithm for segmentation of human intestinal gland images is presented. The initial seeding regions are identified based on the large vacant regions (lumen) inside the intestinal glands by fitting with a very large moving window. The seeding regions are then expanded by repetitive application of a morphological dilate operation with a much smaller round window structure set. False gland regions (nongland regions initially misclassified as gland regions) are removed based on either their excessive ages of active growth or inadequate thickness of dams formed by the strings of goblet cell nuclei sitting immediately outside the grown regions. The goblet cell nuclei are then identified and retained in the image. The gland contours are detected by applying a large moving round window fitting to the enormous empty exterior of the goblet cell nucleus chains in the image. The assumptions based on real intestinal gland images include the closed chain structured goblet cell nuclei that sit side-by-side with only small gaps between the neighbouring nuclei and that the lumens enclosed by the goblet cell nucleus chains are most vacant with only occasional run-away nuclei. The method performs well for most normal and abnormal intestinal gland images although it is less applicable to cancer cases. The experimental results show that the segmentations of the real microscopic intestinal gland images are satisfactorily accurate based on the visual evaluations.

Can MTR be used to assess cartilage in the presence of Gd-DTPA2-?

Magnetization transfer (MT) and T(1) and T(2) relaxation of normal, trypsinized, and interleukin-1beta (IL-1beta)-treated cartilage were measured in the absence and presence of Gd-DTPA(2-). Without the addition of Gd-DTPA(2-), neither T(1) nor T(2) showed any significant change with cartilage damage. However, with Gd-DTPA(2-), trypsinized cartilage exhibited substantially shorter T(1) than normal cartilage, as expected due to the glycosaminoglycan (GAG) loss in these samples, and associated increased Gd-DTPA(2-) concentration. The T(2) results were similar, but less dramatic. The MT pseudo first-order exchange rate, RM(0B), did not depend on the contrast agent concentration, as expected, and was significantly faster for trypsinized and slower for IL-1beta-treated cartilage. In both cases, the MT fraction of the macromolecular pool M(0B) decreased while only trypsinized cartilage showed an increase in MT exchange rate R. The MT ratio (MTR) decreased with increasing Gd-DTPA(2-) concentration. However, interpretation of the MTR results in the presence of Gd-DTPA(2-) was complicated due to competing effects of increased longitudinal relaxivity and MT exchange. Therefore, in a cartilage sample with an unknown degree of GAG depletion and some collagen damage, a full MT analysis might be used to probe the molecular state of cartilage, but it would not be possible to use a simple MTR measurement after the administration of Gd-DTPA(2-) to differentially determine the amount of cartilage degradation in the sample.

Magnetic resonance imaging of relative glycosaminoglycan distribution in patients with autologous chondrocyte transplants.

RATIONALE AND OBJECTIVES: Autologous chondrocyte transplantation (ACT) is a potential treatment for full-thickness chondral lesions in the knee. Delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) has recently been developed as a sensitive and specific measure of cartilage glycosaminoglycans (GAGs). Under the conditions of dGEMRIC, T1 is directly related to the GAG concentration. Our aim for this study was to demonstrate the potential of dGEMRIC to evaluate ACT implants. METHODS: Eleven ACT implants were studied 2 to 24 months postoperatively by dGEMRIC. T1 values from three regions of interest were obtained to examine GAG content (1) in the implant, (2) in native cartilage adjacent to the implant, and (3) in native cartilage further removed from the implant (as "control"). RESULTS: One implant failed and therefore was not included. Four of the implants were studied between 2 and 6 months postoperatively and showed low T1 (GAG), less than 80% of the control native cartilage. Five of the six implants studied between 12 and 24 months postoperativley showed T1 (GAG) comparable to (>80%) of control. One 18-month graft showed low T1 comparable to the surrounding native cartilage, with normal GAG seen in cartilage far from the graft site. The GAG index (T1 values of the graft normalized to control) from the group of implants 6 months or less was 59% +/- 5% of control, whereas those at 12 to 24 months were 91% +/- 18% of control. The two groups were statistically different with a P value of 0.005. CONCLUSIONS: The GAG level in grafts that were implanted for less than 12 months appeared to be lower than that in the remote cartilage. At 12 months or greater, the grafts in this study had GAG levels that were comparable to both the adjacent and remote cartilage. This preliminary study of ACT implants has shown that it is feasible to apply the dGEMRIC technique in patients with ACT as a way to obtain information related to the composition of grafts. These results provide motivation and the pilot data with which to design further clinical studies.

Biochemical (and functional) imaging of articular cartilage.

Over the coming decades nondestructive biochemical imaging by magnetic resonance imaging (MRI) will provide an adjunct or surrogate for the destructive histologic and biochemical assays used today. A number of MRI methods demonstrate image contrast that, although influenced by the biochemical composition, is not normally specific to a particular measure of the biochemical state. The most widely used of these is T2-weighted imaging, which variably reveals collagen ultrastructure, hydration (or collagen content), and, to a lesser extent, glycosaminoglycan (GAG) concentration (each of these biochemical metrics is an important determinant of the functional integrity of cartilage). The lack of specificity of this technique (and others discussed herein) confounds efforts to improve strategies for evaluating cartilage. However, three methods permit a very specific measure of the cartilage biochemical state. Each of these three methods, explored in detail in this article, is rooted in a biophysical theory that relates the image signal intensity to a specific biochemical feature. Proton-density imaging directly measures water content (hydration), a parameter that might increase approximately 5% with significant degeneration. Magic-angle imaging, in which the angle dependence of T2 is measured, can provide a specific measure of collagen (or macromolecular) ultrastructure. The difficulty in getting the angle dependence presently precludes its use clinically. Delayed gadolinium-enhanced MRI of cartilage provides a specific measure of the distribution of GAGs. This method measures the distribution of a charged contrast agent, which in turn reflects the distribution of charge associated with GAG. This technique can be used in a clinical setting, and ongoing studies will explore its utility in monitoring therapeutic efficacy and disease progression. Although none of these techniques are presently in routine clinical use, emerging data provide promise that the future will see patient-specific biochemical analysis of cartilage, an outcome almost unimaginable 20 years ago.

Magnetic resonance imaging of articular cartilage.

Magnetic resonance imaging is the optimal modality for assessing articular cartilage because of superior soft tissue contrast, direct visualization of articular cartilage, and multiplanar capability. Despite these advantages, there has been disagreement as to the efficacy of magnetic resonance imaging of articular cartilage. The reason for this controversy is multifactorial but in part is attributable to the lack of the use of optimized pulse sequences for articular cartilage. The current authors will review the current state of the art of magnetic resonance imaging of articular cartilage and cartilage repair procedures, discuss future new directions in imaging strategies and methods being developed to measure cartilage thickness and volume measurements, and propose a magnetic resonance imaging protocol to evaluate cartilage that is achievable on most magnetic resonance scanners, vendor independent, practical (time and cost efficient), and accepted and used by a majority of musculoskeletal radiologists.