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To compare the inter-observer variability of apparent diffusion coefficient (ADC) values of prostate lesions measured by 2D-region of interest (ROI) with and without specific measurement instruction. Forty lesions in 40 patients who underwent prostate MR followed by targeted prostate biopsy were evaluated. A multi-reader study (10 readers) was performed to assess the agreement of ADC values between 2D-ROI without specific instruction and 2D-ROI with specific instruction to place a 9-pixel size 2D-ROI covering the lowest ADC area. The computer script generated multiple overlapping 9-pixel 2D-ROIs within a 3D-ROI encompassing the entire lesion placed by a single reader. The lowest mean ADC values from each 2D-small-ROI were used as reference values. Inter-observer agreement was assessed using the Bland-Altman plot. Intraclass correlation coefficient (ICC) was assessed between ADC values measured by 10 readers and the computer-calculated reference values. Ten lesions were benign, 6 were Gleason score 6 prostate carcinoma (PCa), and 24 were clinically significant PCa. The mean±SD ADC reference value by 9-pixel-ROI was 733 ± 186 (10-6 mm2/s). The 95% limits of agreement of ADC values among readers were better with specific instruction (±112) than those without (±205). ICC between reader-measured ADC values and computer-calculated reference values ranged from 0.736-0.949 with specific instruction and 0.349-0.919 without specific instruction. Interobserver agreement of ADC values can be improved by indicating a measurement method (use of a specific ROI size covering the lowest ADC area).

There is evidence that mast cells contribute to skeletal response to injury, but it is less clear whether these immune cells directly influence normal bone growth and turnover. Mature mast cells are common in the bone marrow of humans and rats, but have not been convincingly demonstrated to be present in the bone marrow of healthy mice, potentially limiting the mouse as a model for characterizing the full range of mast cell/bone cell interactions. An initial goal of this investigation was to comprehensively screen seven strains of mice for mature mast cells in bone marrow. Finding none, we then investigated three approaches to home these cells to the marrow of mice unable to generate mast cells: (1) administration of soluble kit ligand to membrane kit ligand-deficient mice, (2) adoptive transfer of wild-type hematopoietic stem cells to kit receptor-deficient mice, and (3) adoptive transfer of wild-type mouse bone marrow-derived mast cells generated in vitro and delivered intravenously to mice. Only the third approach was successful. Using this method, we then evaluated the impact of bone marrow-derived mast cells on bone mass, architecture, turnover, and gene expression. The adoptive transfer of mast cells resulted in alterations in cancellous bone microarchitecture and cell populations in the vertebra, and in differential expression of genes associated with bone metabolism in the tibia. Taken together, our results support the concept that bone marrow mast cells influence bone metabolism and suggest that homing mast cells to the bone marrow of mice is a useful model to understand the role of these cells in skeletal health and disease.

Leptin-deficient (ob/ob) and leptin receptor (Lepr)-deficient db/db mice develop a mild form of osteoclast-rich osteopetrosis, most evident in long bone epiphyses, implying leptin is important for normal replacement of cartilage during skeletal maturation. However, it is unclear whether leptin acts as a permissive or regulatory factor and whether its actions are mediated via peripheral pathways. Here we show the osteopetrotic phenotype is not evident in ob/+ or db/+ mice, suggesting that leptin acts as a critical but permissive factor for skeletal maturation. The importance of leptin is further supported by our results showing that interventions known to increase bone resorption (mild cold stress, simulated microgravity, or particle-induced inflammation) did not advance skeletal maturation in ob/ob mice whereas long-duration hypothalamic leptin gene therapy was effective. Additionally, administration of leptin by subcutaneously implanted osmotic pumps (400 ng/h) for 2 weeks accelerated skeletal maturation in ob/ob mice. Because leptin has the potential to act on the skeleton through peripheral pathways, we interrogated osteoclast-lineage cells for the presence of Lepr and evaluated skeletal response to the introduction of bone marrow Lepr+ cells into db/db mice. We identified Lepr on marrow MCSFR+CD11b+ osteoclast precursors and on osteoclasts generated in vitro. We then adoptively transferred Lepr+ marrow cells from GFP mice or wildtype (WT) mice into Lepr- db/db mice. Following engraftment, most MCSFR+ CD11b+ cells in marrow expressed GFP. Whereas db/db→db/db had minimal influence on epiphyseal cartilage, WT→db/db decreased cartilage. These findings suggest peripheral leptin signaling is required for normal osteoclast-dependent replacement of cartilage by bone during skeletal maturation.

Breast cancer metastasizes to bone in the majority of patients with advanced disease. We investigated the effects of inadequate dietary calcium (Ca) on bone turnover, tumor growth, and bone response to tumor in tibia inoculated with 4T1 mammary carcinoma cells. Nine-month-old female Balb/c mice were placed on an adequate Ca (5 g/kg diet, n = 30) or low Ca (80 mg/kg diet, n = 31) diet for 14 days, then injected intratibially with 1,000 4T1 cells (transfected with luciferase for bioluminescence imaging), and sacrificed at 5, 10, or 21 days post-inoculation (n = 7-10 mice/group). Control mice (n = 6/group) were injected with carrier and sacrificed at 10 days post-inoculation. Tibiae with muscle intact were excised and evaluated by microcomputed tomography and histology. In vivo bioluminescent imaging revealed that 4T1 cells metastasized to lung. Therefore, lungs were removed for quantification of tumor. Mice fed low Ca exhibited higher bone turnover and higher tibial lesion scores than mice fed adequate Ca. Lesion severity, manifested as cortical osteolysis and periosteal woven bone formation, and tumor cell infiltration to muscle, increased with time, irrespective of diet. However, for most skeletal endpoints the rates of increase were greater in mice consuming low Ca compared to mice consuming adequate Ca. Infiltration of tumor cells into adjacent muscle, but not metastasis to lung, was also greater in mice consuming low Ca diet. The findings suggest that high bone turnover due to Ca insufficiency results in greater local mammary tumor cell growth, cortical osteolysis, woven bone formation, and invasion to muscle in mice.

To describe outcomes of patients with giant prolactinoma (≥4 cm) and identify predictors of therapeutic response. In this retrospective study, complete biochemical and structural response were defined as prolactin (PRL) ≤25 ng/mL and no visible tumor at follow-up, respectively. Giant prolactinoma (median size, 4.8 cm [range, 4 to 9.8 cm]; median PRL, 5,927 ng/mL [range, 120 to 100,000 ng/mL]) was diagnosed in 71 patients. Treatments included: dopamine agonists (DAs) (n = 70, 99%), surgery (n = 30, 42%), radiation (n = 10, 14%), and somatostatin analogs (n = 2, 3%). Patients treated with DA monotherapy were older compared with those who received subsequent therapies (47 years vs. 28 years; = .003) but had similar initial PRL and tumor size. Surgically managed patients were younger compared with the nonsurgical group (35 years vs. 46 years; = .02) and had lower initial PRL (3,121 ng/mL vs. 6,920 ng/mL; = .02), yet they had similar tumor response. Hypopituitarism was more common following surgery compared to medical management: adrenal insufficiency (69% vs. 27%; <.001), hypothyroidism (67% vs. 38%; = .02), growth hormone deficiency (24% vs. 6%; = .04), and diabetes insipidus (17% vs. 3%; = .04). Therapeutic response did not correlate with sex, age, initial PRL, tumor size, or first-line therapy mode. At median follow-up of 4.8 years, the median PRL was 18.3 ng/mL (range, 0.6 to 12,680 ng/mL), and final volume was 0.9 cm (range, 0 to 43.0 cm ). In those with available data, 36/65 (55%) patients achieved PRL normalization, and 16/61 (26%) had no visible tumor at follow-up. Most patients with giant prolactinoma have excellent response to DA. Sex, age, initial PRL, and tumor size do not predict therapeutic response. = bromocriptine; = cabergoline; = cerebrospinal fluid; = dopamine agonist; = magnetic resonance imaging; = prolactin.

Zinc (Zn) deficiency impairs bone growth. However, the precise skeletal effects of varying levels of Zn deficiency and response to subsequent Zn repletion on the growing skeleton are incompletely understood. To address this gap in knowledge, we investigated the effects of dietary Zn ((severe deficiency (< 0.5 mg Zn/kg diet) and short-term Zn repletion (30 mg/kg diet), marginal deficiency (6 mg Zn/kg diet)) on bone mass, density, and cortical and cancellous bone microarchitecture in growing male Sprague Dawley rats. Marginal Zn intake for 42 days had no effect on bone mass or cortical and cancellous bone microarchitecture. Twenty-one days of severe Zn deficiency lowered serum osteocalcin and C terminal telopeptide of type I collagen (CTX-1), decreased tibial bone mineral content and density, and lowered cross-sectional volume, cortical volume, and cortical thickness in tibial diaphysis as compared to both Zn-adequate (30 mg/kg diet) and pair-fed controls. Severe Zn deficiency similarly lowered cancellous bone volume in proximal tibial metaphysis. Zn repletion (10 days) accelerated weight gain, indicative of catch-up growth, normalized CTX-1 and osteocalcin, but did not normalize bone mass (unadjusted and adjusted for body weight) or cortical and cancellous bone microarchitecture. In summary, severe but not marginal Zn deficiency in rapidly growing rats impaired acquisition of cortical and cancellous bone, resulting in abnormalities in bone microarchitecture. Zn repletion accelerated weight gain compared to Zn-adequate controls but absence of a compensatory increase in serum osteocalcin or bone mass suggests Zn repletion may be insufficient to fully counteract the detrimental effects of prior Zn deficiency on skeletal growth.

BackgroundNational guidelines recommend that waist circumference (WC) be measured in patients with a body mass index (BMI) 27–35 kg/m2. Unfortunately, perhaps due to logistical reasons, WC is seldom measured in clinical settings. Herein, we describe the performance of a self-operated waist measurement device (SOWMD) as a potential means to overcome barriers to measuring WC.Materials and methodsTen volunteers underwent WC measures by professionals and SOWMD on 5 separate days to assess the reproducibility and accuracy. We then compared SOWMD measures with CT-derived fat content by recruiting 81 patients scheduled for a diagnostic abdominal CT scan.ResultsThere was no difference between professionally measured and SOWMD-measured WC; the intraindividual coefficient of variation over the 5 days was between 0.4% and 2.2%. The WC measured manually, by SOWMD and CT scan were highly correlated (r=0.90–0.92, all p<0.001). The minimal WC measured by SOWMD was a better predictor (r=0.81 for all patients, r=0.87 for men, both p<0.001) of CT-measured visceral adipose tissue volume than other approaches. The minimal WC measured by SOWMD was correlated with fasting plasma glucose (r=0.40, p<0.05), triglyceride (r=0.41, p<0.01) and high-density cholesterol (r=−0.49, p<0.001) concentrations.ConclusionSOWMD is a reproducible, accurate and convenient way to measure WC that can provide added value for health care providers when combined with BMI information.

Particles generated from wear of prosthesis joint bearing surfaces induce inflammation-mediated periprosthetic bone resorption (osteolysis). Morbidly obese leptin-deficient ob/ob mice are resistant to polyethylene particle-induced bone loss, suggesting that leptin, a hormone produced by adipocytes that circulates in concentrations proportional to total body adiposity, increases osteolysis. To confirm that particles induce less osteolysis in leptin-deficient mice after controlling for cold stress (room temperature)-induced bone loss, ob/ob mice on a C57BL/6 (B6) background and colony B6 wildtype (WT) mice housed at thermoneutral temperature were randomized to control or particle treatment groups (N = 5/group). Polyethylene particles were implanted over calvaria and mice sacrificed 2 weeks later. Compared to particle-treated WT mice, particle-treated ob/ob mice had lower osteolysis score, less infiltration of immune cells, and less woven bone formation. To determine the role of leptin in particle-induced osteolysis, ob/ob mice were randomized into one of 4 groups (n = 6–8/group): (1) control, (2) particles, (3) particles + continuous leptin (osmotic pump, 6 μg/d), or (4) particles + intermittent leptin (daily injection, 40 μg/d). Leptin treatment increased particle-induced osteolysis in ob/ob mice, providing evidence that the adpiokine may play a role in inflammation-driven bone loss. Additional research is required to determine whether altering leptin levels within the physiological range results in corresponding changes in polyethylene-particle-induced osteolysis.

Particles generated from wear of prosthesis joint bearing surfaces induce inflammation-mediated periprosthetic bone resorption (osteolysis). Morbidly obese leptin-deficient ob/ob mice are resistant to polyethylene particle-induced bone loss, suggesting that leptin, a hormone produced by adipocytes that circulates in concentrations proportional to total body adiposity, increases osteolysis. To confirm that particles induce less osteolysis in leptin-deficient mice after controlling for cold stress (room temperature)-induced bone loss, ob/ob mice on a C57BL/6 (B6) background and colony B6 wildtype (WT) mice housed at thermoneutral temperature were randomized to control or particle treatment groups (N = 5/group). Polyethylene particles were implanted over calvaria and mice sacrificed 2 weeks later. Compared to particle-treated WT mice, particle-treated ob/ob mice had lower osteolysis score, less infiltration of immune cells, and less woven bone formation. To determine the role of leptin in particle-induced osteolysis, ob/ob mice were randomized into one of 4 groups (n = 6–8/group): (1) control, (2) particles, (3) particles + continuous leptin (osmotic pump, 6 μg/d), or (4) particles + intermittent leptin (daily injection, 40 μg/d). Leptin treatment increased particle-induced osteolysis in ob/ob mice, providing evidence that the adpiokine may play a role in inflammation-driven bone loss. Additional research is required to determine whether altering leptin levels within the physiological range results in corresponding changes in polyethylene-particle-induced osteolysis.

Deep-learning algorithms typically fall within the domain of supervised artificial intelligence and are designed to “learn” from annotated data. Deep-learning models require large, diverse training datasets for optimal model convergence. The effort to curate these datasets is widely regarded as a barrier to the development of deep-learning systems. We developed RIL-Contour to accelerate medical image annotation for and with deep-learning. A major goal driving the development of the software was to create an environment which enables clinically oriented users to utilize deep-learning models to rapidly annotate medical imaging. RIL-Contour supports using fully automated deep-learning methods, semi-automated methods, and manual methods to annotate medical imaging with voxel and/or text annotations. To reduce annotation error, RIL-Contour promotes the standardization of image annotations across a dataset. RIL-Contour accelerates medical imaging annotation through the process of annotation by iterative deep learning (AID). The underlying concept of AID is to iteratively annotate, train, and utilize deep-learning models during the process of dataset annotation and model development. To enable this, RIL-Contour supports workflows in which multiple-image analysts annotate medical images, radiologists approve the annotations, and data scientists utilize these annotations to train deep-learning models. To automate the feedback loop between data scientists and image analysts, RIL-Contour provides mechanisms to enable data scientists to push deep newly trained deep-learning models to other users of the software. RIL-Contour and the AID methodology accelerate dataset annotation and model development by facilitating rapid collaboration between analysts, radiologists, and engineers.