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Leydig cells are crucial to the production of testosterone in males. It is unknown if the cancer chemotherapeutic drug, 6-mercaptopurine (6 MP), produces Leydig cell failure among adult survivors of childhood acute lymphoblastic leukemia. Moreover, it is not known whether Leydig cell failure is due to either a loss of cells or an impairment in their function. Herein, we show, in a subset of childhood cancer survivors, that Leydig cell failure is related to the dose of 6 MP. This was extended, in a murine model, to demonstrate that 6 MP exposure induced caspase 3 activation, and the loss of Leydig cells was independent of Bak and Bax activation. The death of these non-proliferating cells was triggered by 6 MP metabolism, requiring formation of both cytosolic reactive oxygen species and thiopurine nucleotide triphosphates. The thiopurine nucleotide triphosphates (with physiological amounts of dATP) uniquely activated the apoptosome. An ABC transporter (Abcc4/Mrp4) reduced the amount of thiopurines, thereby providing protection for Leydig cells. The studies reported here demonstrate that the apoptosome is uniquely activated by thiopurine nucleotides and suggest that 6 MP induced Leydig cell death is likely a cause of Leydig cell failure in some survivors of childhood cancer.

ObjectiveTo determine the diagnostic performance of standing computerized tomography (SCT) of the knee for osteophytes and subchondral cysts compared with fixed-flexion radiography, using MRI as the reference standard.MethodsTwenty participants were recruited from the Multicenter Osteoarthritis Study. Participants' knees were imaged with SCT while standing in a knee-positioning frame, and with postero-anterior fixed-flexion radiography and 1T MRI. Medial and lateral marginal osteophytes and subchondral cysts were scored on bilateral radiographs and coronal SCT images using the OARSI grading system and on coronal MRI using Whole Organ MRI Scoring. Imaging modalities were read separately with images in random order. Sensitivity, specificity and accuracy for the detection of lesions were calculated and differences between modalities were tested using McNemar's test.ResultsParticipants' mean age was 66.8 years, body mass index was 29.6 kg/m(2) and 50% were women. Of the 160 surfaces (medial and lateral femur and tibia for 40 knees), MRI revealed 84 osteophytes and 10 subchondral cysts. In comparison with osteophytes and subchondral cysts detected by MRI, SCT was significantly more sensitive (93 and 100%; p < 0.004) and accurate (95 and 99%; p < 0.001 for osteophytes) than plain radiographs (sensitivity 60 and 10% and accuracy 79 and 94%, respectively). For osteophytes, differences in sensitivity and accuracy were greatest at the medial femur (p = 0.002).ConclusionsIn comparison with MRI, SCT imaging was more sensitive and accurate for detection of osteophytes and subchondral cysts than conventional fixed-flexion radiography. Additional study is warranted to assess diagnostic performance of SCT measures of joint space width, progression of OA features and the patellofemoral joint.

ObjectiveTo evaluate whether T2 relaxation time measurements obtained at 3 T MRI predict the onset of radiographic knee osteoarthritis (OA).Materials and methodsWe performed a nested case-control study of incident radiographic knee OA in the Osteoarthritis Initiative cohort. Cases were 50 knees with baseline Kellgren-Lawrence (KL) grade of 0 that developed KL grade of 2 or more over a 4-year period. Controls were 80 knees with KL grade of 0 after 4 years of follow-up. Baseline T2 relaxation time measurements and laminar analysis of T2 in deep and superficial layers were performed in all knee compartments. The association of T2 values with incident OA was assessed with logistic regression and differences in T2 values by case-control status with linear regression, adjusting for age, sex, body mass index (BMI) and other covariates.ResultsBaseline T2 values in all compartments except the medial tibia were significantly higher in knees that developed OA compared with controls and were particularly elevated in the superficial cartilage layers in all compartments. There was an increased likelihood of incident knee OA associated with higher baseline T2 values, particularly in the patella, adjusted OR per 1 SD increase in T2 (3.37 (95% CI 1.72 to 6.62)), but also in the medial femur (1.90 (1.07 to 3.39)), lateral femur (2.17 (1.11 to 4.25)) and lateral tibia (2.23 (1.16 to 4.31)).ConclusionsThese findings suggest that T2 values assessed when radiographic changes are not yet apparent may be useful in predicting the development of radiological tibiofemoral OA.

BackgroundTo develop a semi-quantitative MR-based hip osteoarthritis (OA) evaluation system (Scoring hip osteoarthritis with MRI, SHOMRI), and to test its reproducibility and face validity.MethodsThe study involved 98 subjects with informed consent. Three-Tesla MR imaging of hip was performed in three planes with intermediate-weighted fat saturated FSE sequences. Two radiologists assessed cartilage loss, bone marrow edema pattern, subchondral cyst in 10 subregions, and assessed labrum in 4 subregions. In addition, presence or absence of ligamentum teres integrity, paralabral cysts, intra-articular body, and effusion in the hip joint were analyzed using the SHOMRI system. The reproducibility was assessed with intra-class correlation coefficient (ICC), Cohen's Kappa values and percent agreement. SHOMRI scores were correlated with radiographic Kellgren-Lawrence (KL) and OARSI atlas gradings, and clinical parameters, the hip osteoarthritis outcome score (HOOS) and hip range of motion (ROM), using Spearman's rank correlation and ordinal logistic regression.ResultsICC values were in the excellent range, 0.91 to 0.97. Cohen's Kappa values and percent agreement ranged from 0.55 to 0.79 and 66 to 99%, respectively. SHOMRI demonstrated significant correlations with KL and OARSI gradings as well as with clinical parameters, HOOS and ROM (P < 0.05). Among the SHOMRI features, subchondral cyst and bone marrow edema pattern showed the highest correlation with HOOS and ROM.ConclusionSHOMRI demonstrated moderate to excellent reproducibility and significant correlation with radiographic gradings and clinical parameters.

PurposeTo assess whether changes in knee cartilage MR-based T2 relaxation times are associated with weight loss in individuals with risk factors for knee osteoarthritis (OA) compared with controls with stable weight.Materials and methodsOne hundred twenty-seven individuals with risk factors for knee OA were studied: 62 subjects had a body mass index (BMI) decrease≥10% over 48 months and 65 controls had a BMI change

This paper summarizes the content and results of a workshop about the teaching of evolution presented to public middle school and high school science teachers by individuals involved both in university education and the professional development of teachers. The goals of the workshop were to: (1) provide teachers with knowledge and resources to more effectively teach evolutionary theory, (2) increase teacher awareness of legal and cognitive issues associated with the teaching and learning of evolution, (3) address teacher misconceptions about evolutionary theory, (4) assess teachers' acceptance of evolutionary theory, and (5) make inferences about the preparedness of Arizona's public school students for a rigorous university life science curriculum that includes evolutionary biology. Participating teachers created concept maps about evolutionary theory, completed the Measure of Acceptance of the Theory of Evolution (MATE) survey at the beginning and end of the workshop, and responded to a survey the week following the workshop. The results of these measures indicate that some Arizona science teachers have misconceptions about evolutionary theory that may be passed on to their students, and these misconceptions, if not corrected, must be addressed in introductory-level science courses at the university level. Based on feedback from the follow-up survey, different teachers with varying levels of acceptance of evolution are all keen to learn from university educators and attend professional development workshops. Such workshops--and engagement between secondary and tertiary educators - can clearly have an effect on the conceptions of both teachers and students, and thus on the acceptance of evolution generally. We therefore strongly encourage the involvement of university educators in science education outreach that addresses evolutionary theory.

Gastrointestinal illnesses are a significant health burden for the US population, with 40 million office visits each year for gastrointestinal complaints and nearly 250,000 deaths. Acute and chronic inflammations are a common element of many gastrointestinal diseases. Inflammatory processes may be initiated by a chemical injury (acid reflux in the esophagus), an infectious agent (Helicobacter pylori infection in the stomach), autoimmune processes (graft versus host disease after bone marrow transplantation), or idiopathic (as in the case of inflammatory bowel diseases). Inflammation in these settings can contribute to acute complaints (pain, bleeding, obstruction, and diarrhea) as well as chronic sequelae including strictures and cancer. Research into the pathophysiology of these conditions has been limited by the availability of primary human tissues or appropriate animal models that attempt to physiologically model the human disease. With the many recent advances in tissue engineering and primary human cell culture systems, it is conceivable that these approaches can be adapted to develop novel human ex vivo systems that incorporate many human cell types to recapitulate in vivo growth and differentiation in inflammatory microphysiological environments. Such an advance in technology would improve our understanding of human disease progression and enhance our ability to test for disease prevention strategies and novel therapeutics. We will review current models for the inflammatory and immunological aspects of Barrett's esophagus, acute graft versus host disease, and inflammatory bowel disease and explore recent advances in culture methodologies that make these novel microphysiological research systems possible.

PurposeTo describe a scoring system for quantification of cartilage lesions (Cartilage Lesion Score [CaLS]), to determine its reproducibility, to examine the association of CaLS-detected longitudinal change with known risk factors for osteoarthritis (OA) progression by comparing a group of subjects with OA risk factors with a group of subjects without OA risk factors, and to compare the CaLS system with the established semiquantitative Whole-Organ Magnetic Resonance Imaging Score (WORMS) and Boston-Leeds Osteoarthritis Knee Score (BLOKS) systems in terms of detection of cartilage defect progression.Materials and methodsAll subjects provided written informed consent, and the local institutional review board approved this HIPAA-compliant study. Fifty-two subjects with and 25 subjects without risk factors for knee OA were randomly selected from the Osteoarthritis Initiative. Inclusion criteria were age of 45-60 years, body mass index of 19-27 kg/m(2), and no knee pain or OA on radiographs at baseline. Baseline and 24-month follow-up right knee 3-T magnetic resonance images were analyzed with WORMS, BLOKS, and CaLS systems. Progression of cartilage lesions with each scoring system was compared by using multilevel mixed-effects linear-regression models. κ values were calculated to determine reliability.ResultsIntraclass coefficient values for inter- and intraobserver reliability of the CaLS system were 0.86 and 0.91, respectively. Interobserver κ value range for individual features was 0.81-0.94. The CaLS system enabled significantly higher detection of cartilage lesion progression than did WORMS or BLOKS systems (P < .001); 51.8% (56 of 108), 17.6% (19 of 108), and 13.0% (14 of 108) of the lesions progressed when analyzed with the CaLS, WORMS, and BLOKS systems, respectively. With the CaLS system, subjects with OA risk factors had significantly higher odds of progression than did subjects without risk factors (odds ratio, 2.78; P = .005).ConclusionThe CaLS system is a reproducible scoring system for cartilage lesions that yields an improved detection rate for monitoring progression when compared with detection rates of semiquantitative WORMS and BLOKS systems.

ObjectiveTo examine the cross-sectional association of whole-knee synovitis assessed by contrast-enhanced magnetic resonance imaging (CEMRI) with radiographic tibiofemoral osteoarthritis (OA), non-CEMRI-assessed cartilage damage, and meniscal status.MethodsMulticenter Osteoarthritis Study (MOST) is a cohort study of people with or at high risk of knee OA. Subjects are a subset of MOST who volunteered for both CEMRI and non-CEMRI. Using CEMRI, synovitis was assessed at 11 sites and graded 0-2 at each site. Presence of "whole-knee synovitis" was defined as the synovitis score of ≥ 1 at any site from each knee. Cartilage and meniscal damage was evaluated using non-CEMRI based on the Whole Organ MRI Score. Logistic regression was used to assess associations of synovitis with radiographic OA (Kellgren-Lawrence grade ≥ 2), widespread cartilage damage, and meniscal damage, adjusting for age, sex, and body mass index (BMI). Additional analyses were performed excluding subjects who had chondrocalcinosis on radiography and those taking antiinflammatory medications.ResultsFour hundred four subjects were included (mean age 58.8 ± 7.0 yrs, BMI 29.6 ± 4.9 kg/m(2), 45.5% women). On CEMRI, the maximum synovitis score across 11 sites in each knee was 0 in 106 knees (26.2%), 1 in 135 (33.4%), and 2 in 163 (40.4%). Synovitis was associated with radiographic OA [adjusted OR (aOR) 3.25, 95% CI 1.98-5.35] and widespread cartilage damage (aOR 1.91, 95% CI 1.24-2.92). Severe meniscal damage showed a borderline significant association with synovitis (aOR 1.74, 95% CI 0.99-3.04). Additional analyses as described did not notably change the results.ConclusionCEMRI-detected synovitis is strongly associated with tibiofemoral radiographic OA and MRI-detected widespread cartilage damage.

ObjectiveTo investigate hip shape by active shape modeling (ASM) as a potential predictor of incident radiographic hip osteoarthritis (RHOA) and symptomatic hip osteoarthritis (SRHOA).MethodsAll hips developing RHOA from baseline (Kellgren/Lawrence [K/L] grade 0/1) to mean 6-year followup (K/L grade ≥2, 190 hips) and 1:1 control hips (K/L grade 0/1 at both times, 192 hips) were included. Proximal femur shape was defined on baseline anteroposterior pelvis radiographs and submitted to ASM, producing a mean shape and continuous variables representing independent modes of shape variation. Mode scores (n = 14, explaining 95% of shape variance) were simultaneously included in logistic regression models with incident RHOA and SRHOA as dependent variables, adjusted for intraperson correlations, sex, race, body mass index (BMI), baseline K/L grade, and/or symptoms.ResultsWe evaluated 382 hips from 342 individuals: 61% women and 83% white, with mean age 62 years and mean BMI 29 kg/m(2) . Several modes differed by sex and race, but no modes were associated with incident RHOA overall. Among men only, modes 1 and 2 were significantly associated (for a 1-SD decrease in mode 1 score: odds ratio [OR] 1.7 [95% confidence interval (95% CI) 1.1-2.5] and for a 1-SD increase in mode 2 score: OR 1.5 [95% CI 1.0-2.2]) with incident RHOA. A 1-SD decrease in mode 2 or 3 score increased the odds of SRHOA by 50%.ConclusionThis study confirms other reports that variations in proximal femur shape have a modest association with incident hip OA. The observation of proximal femur shape associations with hip symptoms requires further investigation.

Children who have 'early contact' with youth justice (YJ) are a group of significant policy interest. Understanding circumstances which precede or co-occur with YJ contact can support the development of preventive investments and inform debates about systemic reform, such as 'raise the age'. Using whole-of-population administrative data from the SA Better Evidence Better Outcomes Linked Data (BEBOLD) platform, we examine differences between children who have early (i.e. between the ages of 10 and 13 years) versus late (i.e. at age 14 or older) YJ contact, relative to the general population. Children born 1991–2022 were followed from birth to age 18 (N = 249,995). Compared to the late-contact group, children with early contact experienced more serious YJ contact (91% versus 59% experienced custody); were more disadvantaged at birth (e.g. 66% versus 45% born into jobless families); had more serious child protection contact by age 10 (26% versus 12% experienced out-of-home care); and experienced mental health-related hospitalisations from ages 12–18 (43% versus 34%). Relative to the general population, both groups were characterised by significant social and economic disadvantage, child protection contact and mental health challenges. The need for investment in early prevention to divert children from the justice system is clear. [ABSTRACT FROM AUTHOR]

Objective Developing targeted, culturally competent educational materials is critical for participant understanding of engagement in a large genomic study that uses computational pipelines to produce genome-informed risk assessments. Materials and Methods Guided by the Smerecnik framework that theorizes understanding of multifactorial genetic disease through 3 knowledge types, we developed English and Spanish infographics for individuals enrolled in the Electronic Medical Records and Genomics Network. Infographics were developed to explain concepts in lay language and visualizations. We conducted iterative sessions using a modified "think-aloud" process with 10 participants (6 English, 4 Spanish-speaking) to explore comprehension of and attitudes towards the infographics. Results We found that all but one participant had "awareness knowledge" of genetic disease risk factors upon viewing the infographics. Many participants had difficulty with "how-to" knowledge of applying genetic risk factors to specific monogenic and polygenic risks. Participant attitudes towards the iteratively-refined infographics indicated that design saturation was reached. Discussion There were several elements that contributed to the participants' comprehension (or misunderstanding) of the infographics. Visualization and iconography techniques best resonated with those who could draw on prior experiences or knowledge and were absent in those without. Limited graphicacy interfered with the understanding of absolute and relative risks when presented in graph format. Notably, narrative and storytelling theory that informed the creation of a vignette infographic was most accessible to all participants. Conclusion Engagement with the intended audience who can identify strengths and points for improvement of the intervention is necessary to the development of effective infographics. [ABSTRACT FROM AUTHOR]