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With integrated curricula and multidisciplinary assessments becoming more prevalent in medical education, there is a continued need for educational research to explore the advantages, consequences, and challenges of integration practices. This retrospective analysis investigated the number of items needed to reliably assess anatomical knowledge in the context of gross anatomy and histology. A generalizability analysis was conducted on gross anatomy and histology written and practical examination items that were administered in a discipline-based format at Indiana University School of Medicine and in an integrated fashion at the University of Alabama School of Medicine and Rush University Medical College. Examination items were analyzed using a partially nested design s×(i:o) in which items were nested within occasions (i:o) and crossed with students (s). A reliability standard of 0.80 was used to determine the minimum number of items needed across examinations (occasions) to make reliable and informed decisions about students' competence in anatomical knowledge. Decision study plots are presented to demonstrate how the number of items per examination influences the reliability of each administered assessment. Using the example of a curriculum that assesses gross anatomy knowledge over five summative written and practical examinations, the results of the decision study estimated that 30 and 25 items would be needed on each written and practical examination to reach a reliability of 0.80, respectively. This study is particularly relevant to educators who may question whether the amount of anatomy content assessed in multidisciplinary evaluations is sufficient for making judgments about the anatomical aptitude of students. Anat Sci Educ 10: 109-119. © 2016 American Association of Anatomists.

Introduction The human cranial vault possesses an incredible, complex anatomical intricacy. Bridging the divide between 2-dimensional (2D) learning resources and the 3-dimensional (3D) world in which the anatomy becomes clinically relevant poses an intellectual challenge. Advances in computer graphics and modelling technologies have allowed increasingly accurate and representative resources to supplement cadaveric dissection specimens. Objective To create accurate virtual models of all cranial bones to augment education, research, and clinical endeavours. Methods Through a careful analysis of osteological specimens and high-resolution radiographic studies, a highly accurate virtual model of the human skull was created and annotated with relevant anatomical landmarks. Results The skull was divided into 6 major segments including frontal, ethmoid, sphenoid, temporal, parietal, and occipital bones. These bones were thoroughly annotated to demonstrate the intricate anatomical features. Conclusion This virtual model has the potential to serve as a valuable resource for educational, research, and clinical endeavours, and demonstrates the significance of advances in computer modelling that can contribute to our understanding of neurosurgical anatomical substrates.

The use of quick response (QR) codes within undergraduate university courses is on the rise, yet literature concerning their use in medical education is scant. This study examined student perceptions on the usefulness of QR codes as learning aids in a medical gross anatomy course, statistically analyzed whether this learning aid impacted student performance, and evaluated whether performance could be explained by the frequency of QR code usage. Question prompts and QR codes tagged on cadaveric specimens and models were available for four weeks as learning aids to medical (n = 155) and doctor of physical therapy (n = 39) students. Each QR code provided answers to posed questions in the form of embedded text or hyperlinked web pages. Students' perceptions were gathered using a formative questionnaire and practical examination scores were used to assess potential gains in student achievement. Overall, students responded positively to the use of QR codes in the gross anatomy laboratory as 89% (57/64) agreed the codes augmented their learning of anatomy. The users' most noticeable objection to using QR codes was the reluctance to bring their smartphones into the gross anatomy laboratory. A comparison between the performance of QR code users and non-users was found to be nonsignificant (P = 0.113), and no significant gains in performance (P = 0.302) were observed after the intervention. Learners welcomed the implementation of QR code technology in the gross anatomy laboratory, yet this intervention had no apparent effect on practical examination performance. Anat Sci Educ 8: 421–428. © 2014 American Association of Anatomists.

This qualitative case study examined the experiences and perceptions of repeating first year medical students in two different gross anatomy laboratory formats at the Indiana University School of Medicine—Indianapolis campus. In the fall of 2010, the students experienced the anatomy laboratory as an open laboratory. In the fall of 2011, peer teaching was implemented in the laboratory. This study sought to better understand how each format affected student-learning processes. Individual interviews, focus group discussion, and qualitative data analysis identified four major themes in repeating student perspectives in the gross anatomy laboratory: the loss and reclaiming of confidence; the intensification of accountability towards fellow students and future patients; the struggle for, and equalization of power; and the metamorphosis of "anatomy as parts" into "anatomy as body". The results highlight the complex, multifaceted learning experiences medical students have while dissecting, and in particular, while teaching their peers. Participants' experiences encompassed the intellectual aspects of learning anatomy but also transcended it to provide important perspectives on the educational, intrapersonal, and interpersonal dynamics present in the laboratory.

Chronic kidney disease–mineral bone disorder (CKD-MBD) is a systemic disorder that describes the complex bone and mineral abnormalities that occur in CKD. To understand the pathophysiology of CKD-MBD and determine whether the early use of phosphate binders would alter this physiology, we used a naturally occurring, slowly progressive model of CKD-MBD, the Cy/+ rat. Male Cy/+ rats were compared with their normal littermates at 20 weeks of age after 1 week of no phosphate binder, calcium carbonate, or sevelamer carbonate. The Cy/+ rat had renal function that was 50% of that of normal littermates, elevated parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), decreased 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels, but normal calcium and phosphorus levels. There was a significant positive correlation of blood FGF23 and phosphorus levels and blood FGF23 and urine phosphorus levels. There was an inverse correlation between FGF23 and calcium levels. mRNA from the kidney demonstrated 50% reduction in klotho and Npt2a expression but no difference in CYP27B1. In the intestine, CKD animals had reduced active phosphate absorption in the jejunum using modified Ussing chambers and a reduction in Npt2b expression throughout the small intestine compared with normal littermates. In bone, mRNA expression of FGF23 was reduced (driven by lowering with phosphate binders), and TRAP expression was increased in CKD. By histology, there was increased osteoclast activity and number, and there were reductions in some measures of femoral neck mechanical strength. One week of phosphate binders reduced intestinal phosphate flux, serum phosphorus levels, and urinary phosphate excretion. These results demonstrate marked abnormalities in kidney, intestine, and bone in early CKD-MBD. While phosphate binders were effective in lowering urine phosphorus, they had little effect on end organs after 1 week of administration. © 2011 American Society for Bone and Mineral Research

The role of diet in health and diseases related to muscle and bone has been an area of active study. Recently, endocannabinoids (EC), endogenous derivatives of arachidonic acid, an omega-6 (n-6) polyunsaturated fatty acid (PUFA), have been discovered to play regulatory roles in bone mass and muscle energy metabolism. This signaling system consists of the G-protein coupled cannabinoid receptors, CB1 and CB2, expressed in central and peripheral tissues and cells, which are variably activated by the production and on demand release of endogenous and synthetic agonists and antagonists. We propose that the balance between omega-6 and omega-3 (n-3) PUFA is an important modifier for the activation and suppression of endocannabinoid receptors and therefore, downstream signaling actions in cells. The potential of dietary PUFA to regulate this signaling system to influence the metabolic and physiological outcomes favorable to musculoskeletal health is the purpose of this review. The important role of n-3 PUFA in metabolic and physiological processes that attenuate muscle and bone loss under conditions of disease and stress is one aspect described herein. In this review, we first introduce the EC agonists (ligands) and their receptors (CB1 and CB2) and the general actions of EC signaling in various organs and systems. Second, we describe EC signaling in bone and muscle and how dietary PUFA influence the levels of endogenous agonists. Third, we discuss the potential implications of how dietary PUFA impact this system to minimize muscle atrophy and osteopenia and support healthy muscle development and bone modeling.

A common, but paradoxic, feature among osteopetrotic human infants is the presence of rickets. This disorder of mineralization is manifested radiographically and histologically by increased growth plate cartilage and hypertrophic cell zone thickness and excess metaphyseal osteoid and biochemically by decreased serum calcium and phosphorus concentrations. Rickets has also been reported in two osteopetrotic animal mutations, the osteosclerotic (oc) mouse and the toothless (tl) rat. Although the phenotypic expression of the rachitic lesion in the oc mouse closely resembles that in affected humans, the results of the present study show that the lesion in the tl rat does not. Compared with normal littermates, histologic and morphometric analyses of tibial growth plate cartilage in tl rats up to 5 weeks of age showed age-related increases in thickness of the proliferative cell zone and decreases in thickness of the hypertrophic cell zone that were most apparent within the central, but not lateral, regions of the growth plate and areas of acellularity and failure of chondrocytes to transform synchronously from proliferative cell to hypertrophic cell phenotypes. Femoral ash content, composition, and accretion rates did not differ from those in normal rats during the first 5 weeks of life. These findings do not support the rachitic nature of the cartilage lesion in the tl rat. Rather, a chondrodysplastic disorder is suggested, which more closely resembles the cartilage defect present in this mutation.

In polycystic kidney disease (PKD), genetic mutations in polycystin 1 and 2 lead to defective intracellular trafficking of calcium, thereby decreasing intracellular calcium and altering cAMP signaling to favor proliferation. We hypothesized that calcimimetics, allosteric modulators of the calcium-sensing receptor, would reduce cyst growth by increasing intracellular calcium. We randomly assigned 20-wk-old male rats with a form of autosomal dominant PKD (heterozygote Cy/+) to one of four groups for 14 to 18 wk of treatment: (group 1) no treatment; (group 2) calcimimetic R-568 formulated in the diet; (group 3) R-568 plus calcium-supplemented drinking water (R-568 plus Ca); or (group 4) Ca-supplemented drinking water with a normal diet (Ca). Severity of PKD did not progress in any of the three treatment groups between 34 and 38 wk. Compared with no treatment, cyst growth was unaffected at 34 wk by all treatments, but cyst volume and fibrosis were lower at 38 wk, with both R-568-treated groups demonstrating a greater reduction than calcium alone. Between 34 and 38 wk, the total kidney weight increased by 78% in the control group (P < 0.001) and by 19% in the Ca group (P < 0.01), but did not increase in the R-568 or R-568 plus Ca groups, suggesting inhibition of disease progression despite equivalent suppression of parathyroid hormone. In summary, treatment of hyperparathyroidism halts late-stage progression of rodent cystic kidney disease. The benefit of R-568 alone suggests calcium-sensing receptor modulation may have additional inhibitory effects on late-stage cyst growth resulting from a direct modulation of intracellular calcium.

Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD) is a newly defined syndrome encompassing patients with chronic kidney disease that have a triad of biochemical alterations in calcium, phosphorus and parathyroid hormone, vascular calcification, and bone abnormalities. Here we describe a novel Cy/+ rat model of slowly progressive kidney disease spontaneously developing the three components of CKD-MBD when fed a normal phosphorus diet. Since the renal disorder progressed 'naturally' we studied the effect of dietary manipulation during the course of the disease. Animals with early, but established, chronic kidney disease were fed a casein-based or a grain-based protein diet both of which had equivalent total phosphorus contents. The two different sources of dietary protein had profound effects on the progression of CKD-MBD, likely due to differences in intestinal bioavailability of phosphorus. Although both dietary treatments resulted in the same serum phosphorous levels, the casein-fed animals had increased urinary phosphorus excretion and elevated serum FGF23 compared to the grain-fed rats. This model should help identify early changes in the course of chronic kidney disease that may lead to CKD-MBD.

With integrated curricula and multidisciplinary assessments becoming more prevalent in medical education, there is a continued need for educational research to explore the advantages, consequences, and challenges of integration practices. This retrospective analysis investigated the number of items needed to reliably assess anatomical knowledge in the context of gross anatomy and histology. A generalizability analysis was conducted on gross anatomy and histology written and practical examination items that were administered in a discipline-based format at Indiana University School of Medicine and in an integrated fashion at the University of Alabama School of Medicine and Rush University Medical College. Examination items were analyzed using a partially nested design s×(i:o) in which items were nested within occasions (i:o) and crossed with students (s). A reliability standard of 0.80 was used to determine the minimum number of items needed across examinations (occasions) to make reliable and informed decisions about students' competence in anatomical knowledge. Decision study plots are presented to demonstrate how the number of items per examination influences the reliability of each administered assessment. Using the example of a curriculum that assesses gross anatomy knowledge over five summative written and practical examinations, the results of the decision study estimated that 30 and 25 items would be needed on each written and practical examination to reach a reliability of 0.80, respectively. This study is particularly relevant to educators who may question whether the amount of anatomy content assessed in multidisciplinary evaluations is sufficient for making judgments about the anatomical aptitude of students. Anat Sci Educ 10: 109-119. © 2016 American Association of Anatomists.

Ovariectomy (OVX) in female rats precipitates a marked reduction in endogenous estrogen concentrations and induces bone remodeling abnormalities that augment bone loss and increase the risk of developing osteopenia. This research examined the combined effects of two levels of soy isoflavones (IFs), trace (-IF) and high (+IF) (0.03 and 3.43 mg/g protein, respectively), and two levels of n-3 polyunsaturated fatty acids (PUFAs) on bone conservation in 2-month-old sexually mature OVX Sprague-Dawley rats. All dietary treatments provided 110.4 g/kg of fat from either safflower oil (N6) or a blend of safflower oil and menhaden oil (N3). OVX rats were randomly assigned to the N6-IF, N6+IF, N3-IF and N3+IF groups. The OVX and sham rats were euthanized after 12 weeks of feeding. Data for sequential femoral and tibial in vivo bone mineral density and bone mineral content (BMC) measurements were determined every 4 weeks. The hindlimb mineral data indicated a trend toward a positive bone mineral-sparing effect related to +IF. Among the OVX rats, those fed the N3+IF diet had a significantly higher value for tibial BMC. The concentration of serum pyridinoline cross-links was significantly lower in the N3+IF group. These findings indicate a complementary action of soy IFs and n-3 PUFAs for attenuating bone mineral reduction in OVX rats.

The “story” of the trigeminal nerve complex is a rich and multifaceted one. It involves details of the peripheral distribution and functionality of its three divisions, how their fibers originate and/or are connected to and conveyed within central pathways of the brain, and the common lesions and disorders associated with this nerve. It is also a story that has intersected over the years with advances in surgical, clinical, and imaging technologies, unlocking mysteries of the disorders of this nerve, leading to advances in treatments and outcomes. This chapter reviews the relevant literature on all these fronts to provide a contemporary understanding of the clinical anatomy of this important, complex cranial nerve.

The use of quick response (QR) codes within undergraduate university courses is on the rise, yet literature concerning their use in medical education is scant. This study examined student perceptions on the usefulness of QR codes as learning aids in a medical gross anatomy course, statistically analyzed whether this learning aid impacted student performance, and evaluated whether performance could be explained by the frequency of QR code usage. Question prompts and QR codes tagged on cadaveric specimens and models were available for four weeks as learning aids to medical (n = 155) and doctor of physical therapy (n = 39) students. Each QR code provided answers to posed questions in the form of embedded text or hyperlinked web pages. Students' perceptions were gathered using a formative questionnaire and practical examination scores were used to assess potential gains in student achievement. Overall, students responded positively to the use of QR codes in the gross anatomy laboratory as 89% (57/64) agreed the codes augmented their learning of anatomy. The users' most noticeable objection to using QR codes was the reluctance to bring their smartphones into the gross anatomy laboratory. A comparison between the performance of QR code users and non-users was found to be nonsignificant (P = 0.113), and no significant gains in performance (P = 0.302) were observed after the intervention. Learners welcomed the implementation of QR code technology in the gross anatomy laboratory, yet this intervention had no apparent effect on practical examination performance.

This minireview on skeletal biology describes the actions of prostaglandins and cytokines involved in the local regulation of bone metabolism, it documents the role of lipids in bone biology, and it presents relationships between fatty acids and other factors that impact skeletal metabolism. The data presented herein show consistent and reproducible beneficial effects of omega-3 (n-3) fatty acids on bone metabolism and bone/joint diseases. Polyunsaturated fatty acids modulate eicosanoid biosynthesis in numerous tissues and cell types, alter signal transduction, and influence gene expression. These effects have not been explored in the skeletal system. Future research on n-3 fatty acids in bone biology should focus on the following two aspects. First, the further elucidation of how n-3 fatty acids alter biochemical and molecular processes involved in bone modeling and bone cell differentiation, and second, the evaluation of the potential pharmaceutical applications of these nutraceutical fatty acids in maintaining bone mineral status and controlling inflammatory bone/joint diseases.

Bone is a unique tissue providing support, movement, and mineral balance for the body. Bone growth is achieved in the young by a process called modeling, and maintained during adulthood by a process termed remodeling. Three types of cells are responsible for the formation of cartilage and bone; the chondrocyte, osteoblast, and osteoclast. These cells are under the influence of a plethora of regulatory molecules, which govern their action to provide an individual optimal bone mass. Interruption of this homeostatic machinery, especially in the elderly, often results in a loss of bone mass (osteoporosis) or cartilage damage (rheumatoid arthritis). Many pharmacological agents have been made available in an effort to prevent or alleviate these pathologies, however, one vector often overlooked is the diet. This review focuses on the relationship between dietary polyunsaturated fatty acids and bone biology, both in vivo and in vitro.

Bone remodelling processes are regulated by systemic hormones and a multitude of local and systemic factors, including prostaglandins, cytokines, and growth factors. Dietary fatty acids and their derivatives (eicosanoids) have been a recent focus of investigation on bone and cartilage metabolism. Specific fatty acids are recognized modulators of eicosanoid biosynthesis, signal transduction, and gene expression. The actions of polyunsaturated fatty acids have not been extensively examined in the skeletal system. Promising research on fatty acids and bone remodelling should evaluate the potential effects on pathways for osteoclastogenesis and osteoblastogenesis.

The effect of red palm olein on bone metabolism was investigated in growing rats. Fifty weanling male Sprague-Dawley rats were randomly assigned to five groups and fed ad libitum the following diets: Reference diet, 70 g soybean oil/kg diet; Red-35, 35 g red palm olein + 35 g soybean oil/kg diet; Red-50, 50 g red palm olein + 20 g soybean oil/kg diet; RPO-35, 35 g refined palm oil + 35 g soybean oil/kg diet; RPO-50, 50 g refined palm oil + 20 g soybean oil/kg diet. Rat growth was not affected by the dietary lipid treatments after 42 d of feeding. Rats demonstrated significant differences in tissue fatty acid composition that reflected the dietary lipid treatments. The concentrations of saturated fatty acids and monounsaturated fatty acids were higher but polyunsaturated fatty acids (PUFA) lower in tibia marrow of rats given the palm oil treatments compared with those given soybean oil. The reduction in total n-6 PUFA concentration in bone of rats given palm oil was associated with higher bone specific alkaline phosphatase activity and endosteal mineral apposition rate and bone formation rate in tibia. No difference was found in ex vivo PGE 2 production in femur from rats. The histomorphometric analyses indicated that red palm olein might support bone formation and bone modeling in growing rats. Palm oil or palm antioxidants may play a role in bone formation.

The effects of dietary polyunsaturated fatty acids (PUFA) on ex vivo bone prostaglandin E(2) (PGE(2)) production and bone formation rate were evaluated in rats. Weanling male Sprague-Dawley rats were fed AIN-93G diet containing 70 g/kg of added fat for 42 d. The dietary lipid treatments were formulated with safflower oil and menhaden oil to provide the following ratios of (n-6)/(n-3) fatty acids: 23.8 (SMI), 9.8 (SMII), 2.6 (SMIII), and 1.2 (SMIV). Ex vivo PGE(2) production in liver homogenates and bone organ cultures (right femur and tibia) were significantly lower in rats fed diets with a lower dietary ratio of (n-6)/(n-3) fatty acids than in those fed diets with a higher dietary ratio. Regression analysis revealed a significant positive correlation between bone PGE(2) and the ratio of arachidonic acid (AA)/eicosapentaenoic acid (EPA), but significant negative correlations between bone formation rate and either the ratio of AA/EPA or PGE(2) in bone. Activities of serum alkaline phosphatase isoenzymes, including the bone-specific isoenzyme (BALP), were greater in rats fed a diet high in (n-3) or a low ratio of (n-6)/(n-3), further supporting the positive action of (n-3) fatty acids on bone formation. These results demonstrated that the dietary ratio of (n-6)/(n-3) modulates bone PGE(2) production and the activity of serum BALP in growing rats.

The osteopetrotic rat mutation toothless (tl) is characterized by little or no bone resorption, few osteoclasts and macrophages, and chondrodysplasia at the growth plates. Short-term treatment of tl rats with colony-stimulating factor-1 (CSF-1) has been shown to increase the number of osteoclasts and macrophages, producing dramatic resolution of skeletal sclerosis at some, but not all, sites. Defects in production of vitamin D-binding protein-macrophage activating factor (DBP-MAF) have been identified in two other independent osteopetrotic mutations of the rat (op and ia), and two in the mouse (op and mi), in which macrophages and osteoclasts can be activated by the administration of exogenous DBP-MAF. The present studies were undertaken to examine the histology and residual growth defects in tl rats following longer CSF-1 treatments, to investigate the possibility that exogenous DBP-MAF might act synergistically with CSF-1 to improve the tl phenotype, and to assess the integrity of the endogenous DBP-MAF pathway in this mutation. CSF-1 treatment-with or without DBP-MAF-induced resorption of metaphyseal bone to the growth plate on the marrow side, improved slightly but did not normalize long bone growth, and caused no improvement in the abnormal histology of the growth plate. Injections of lysophosphatidylcholine (lyso-Pc) to prime macrophage activation via the DBP-MAF pathway raised superoxide production to similar levels in peritoneal macrophages from both normal and mutant animals, indicating no defect in the DBP-MAF pathway in tl rats. Interestingly, pretreatments with CSF-1 alone also increased superoxide production, although the mechanism for this remains unknown. In summary, we find that, unlike other osteopetrotic mutations investigated to date, the DBP-MAF pathway does not appear to be defective in the tl rat; that additional DBP-MAF does not augment the beneficial skeletal effects seen with CSF-1 alone; and that the growth plate chondrodystrophy seen in this mutation is unaffected by either molecule. Thus, the tl mutation intercepts the function of a gene required for both normal endochondral ossification and bone resorption, thereby uncoupling the coordination of skeletal metabolism required for normal long bone growth.

We report on an in vivo model of human myeloma producing bone disease in irradiated severe combined immunodeficiency disease mice using the human myeloma cell line JJN-3 and its subline JJN-3 T1. The cell lines are not Epstein-Barr virus transformed and produce large amounts of hepatocyte growth factor (HGF). Mice had radiological signs of osteolysis and mild hypercalcemia. Xenografted cells were predominantly found in bone marrow and brown adipose tissue, but also in meninges and liver. Take was documented by histopathological examination, immunophenotyping of cultured bone marrow, and radiography. HGF was detected in serum and bone marrow plasma. Disease generally occurred within 45 days of intravenous inoculation and was signaled by paraparesis or signs of intracranial neoplasia. More than 90% of the mice had take of xenografts. The subline JJN-3 T1 gave more reproducible bone marrow take than the native cell line. Bone histomorphometric examination revealed a 99% reduction in osteoblast counts and a 33% reduction in osteoclast counts in areas of tumor growth. Bone formation rates were reduced by 53%. The results suggest that osteoblastopenia and reduced bone formation is of importance for the occurrence of osteolytic lesions in this model.

The osteopetrotic (op/op) rat mutation is a lethal mutation in which decreased osteoclast function (bone resorption) coexists with markedly elevated serum levels of 1,25-dihydroxyvitamin D3[1,25(OH)2D3]. Increased circulating levels of 1,25(OH)2D3 have been reported in other osteopetrotic animal mutations and in some osteopetrotic children. This study examined the effects of 1,25(OH)2D3 infusions on serum and skeletal parameters in normal and mutant rats of op stock. We also examined vitamin D receptor expression and binding in bone cells from op normal and mutant animals. Four-week-old normal and mutant rats were infused either with propylene glycol (used as controls) or with 12.5–125 ng of 1,25(OH)2D3/d using osmotic minipumps implanted subcutaneously for 1 wk. Sera were analyzed for calcium, phosphorus, and 1,25(OH)2D3 levels. Histomorphometric analyses of proximal tibiae from treated normal (50 ng/d) and op mutant (125 ng/d) rats and their vehicle-infused controls were performed. Normal animals infused with 1,25(OH)2D3 exhibited a dose-dependent increase in serum calcium levels. Histomorphometric analyses of metaphyseal bone within the primary spongiosae region showed that 1,25(OH)2D3 increased osteoclast number with a reduction in osteoblast surface associated with a decrease in growth plate cartilage thickness. However, similar analyses on secondary spongiosae showed a decrease in osteoclast number and surface associated with an anabolic response. Op mutants infused with 1,25(OH)2D3 did not exhibit any change in serum calcium levels or histomorphometric parameters related to growth plate cartilage and metaphyseal bone compared with mutant controls. Vitamin D mRNA and protein levels were increased two- to threefold in op mutants compared to age-matched normal rats. However, binding affinity of 1,25(OH)2D3 to its receptor was similar between op mutant and normal animals. High dose calcitriol therapy, under the conditions and period of treatment used in this study, failed to stimulate bone turnover in op rats, suggesting that they are resistant to the skeletal effects of 1,25(OH)2D3. The failure of osteoclast activation in response to 1,25(OH)2D3 treatment may be associated with osteoblast incompetence in this mutation.

Recent investigations and clinical studies suggest that dietary lipids and antioxidant nutrients influence bone formation and cartilage biology. In animals, bone modeling appears to be optimal when (n-3) fatty acids are supplied in the diet to moderate the metabolic and physiologic effects of (n-6) fatty acids. In osteoporosis, greater osteoclastic activity results in excessive mineral loss and bone destruction. New evidence supports the idea that dietary fatty acids and antioxidants can attenuate osteoclastic activity to reduce the severity of osteolytic diseases of the bone and joint. Moreover, (n-6) fatty acids may aggravate the deficiency of antioxidant enzyme protective systems in epiphyseal cartilage of long bones. For example, vitamin E was reported to increase in vivo trabecular bone formation rate and to restore collagen synthesis in chondrocytes enriched with linoleic acid. This review presents new information that documents a role for dietary lipids and antioxidants in supporting bone formation and cartilage function for optimal health. © 1997 Elsevier Science Inc.

This study examined the effects of dietary fat on the fatty acid composition of liver and bone, and on the concentration of insulin-like growth factor-I (IGF-I) in liver and bone, as well as the relationship of these factors to bone metabolism. Day-old male broiler chicks were given a semipurified diet containing one of four lipid sources: soybean oil (SBO), butter+corn oil (BC), margarine+corn oil (MAC), or menhaden oil+corn oil (MEC) at 70 g/kg of the diet. At 21 and 42 d of age, chicks fed MEC had the highest concentration of (n-3) fatty acids [20:5(n-3), 22:5(n-3) and 22:6(n-3)] in polar and neutral lipids of cortical bone but the lowest amount of 20:4(n-6) in polar lipids. Diets containing t-18:1 fatty acids (MAC and BC) resulted in t18:1 accumulation in bone and liver. Bone IGF-I concentration increased from 21 to 42 d in chicks given the SBO and BC diets. Tibial periosteal bone formation rate (BFR) was higher in chicks given BC compared with those consuming SBO and MEC at 21 d. The higher BFR and concentrations of hexosamine in serum and IGF-I in cartilage, but lower 20:4(n-6) content in bone polar lipids in chicks given BC compared with those given SBO suggest that BC optimized bone formation by altering the production of bone growth factors. A second study confirmed that dietary butter fat lowered ex vivo prostaglandin E2 production and increased trabecular BFR in chick tibia. These studies showed that dietary fat altered BFR perhaps by controlling the production of local regulatory factors in bone.

A rarely recognized extra-wide sternum was demonstrated by Tc-99m methylene diphosphonate bone scans in two adult patients. One patient was a 53-year-old man with prostate cancer who had no sternal symptoms or known sternal deformity. The second patient was a 41-year-old man with carcinoma of the lung whose extra-wide sternum was associated with a pectus excavatum deformity involving the lower half of the mesosternum (corpus sternum). A proper name for this developmental abnormality, "eurysternum" (eury-Greek word meaning broad; wide), is suggested. Two other patients, one with another type of wide sternum and another with a mesosternal foramen (fenestra sternii) deformity are also described. Related embryology and developmental anatomy of the sternum are reviewed.

Osteopetrosis is a metabolic bone disease characterized by a systemic increase in skeletal mass. It results from a defect in the production or function of osteoclasts and is inherited in nine genetically distinct osteopetrotic animal mutations and man. Studies of these mutations have revealed that osteopetrosis is a complex, heterogeneous disorder in its expression, etiology, and response to treatment by bone marrow transplantation or by hormone/growth factor therapy. These animal mutations have been valuable tools for probing the pathogenesis and treatment of osteopetrosis, and information obtained from these studies has been used clinically for the treatment of humans with osteopetrosis. In addition, studies of these mutations have contributed significantly to understanding normal bone cell biology, including the origin of the osteoclast and the significance of colony-stimulating factor-1 in osteoclast development. The resistance of some of these mutations to cure by stem cell transplantation and hormone therapy, coupled with similar observations and experiences in the human condition, indicates that these animal mutations will continue to serve important roles in the development of alternative therapies to treat resistant forms of the disease. These studies are bound to improve the understanding of normal bone biology by providing additional insights into the regulation of osteoclasts by osteoblasts and their products or by other elements of the skeletal microenvironment.

The present study was conducted to determine whether provision of preformed dietary docosapentaenoic acid (DPAn-6) can replace DHA for normal long bone growth as assessed by dual-energy X-ray absorptiometry for mineral content (BMC). A newly modified artificial rearing method was employed to generate n-3 fatty acid-deficient rats. Except the dam-reared (DR; 3·1 % α-linolenic acid) group, newborn pups were separated from their mothers at age 2 d and given artificial rat milk containing linoleic acid (LA), or LA supplemented with 1 % DHA (22 : 6n-3; DHA), 1 % DPAn-6 (DPA), or 1 % DHA plus 0·4 % DPAn-6 (DHA/DPA). The rats were later weaned onto similar pelleted diets. At adulthood, the rats were euthanised and bones (femur, tibia, and lumbar vertebrae) collected for tissue fatty acid analysis and bone mineral density (BMD) determination. The analyses showed that long bones such as femur and tibia in DPAn-6-treated rats contained higher DPAn-6 content and generally had the lowest BMC and BMD values. Hence, DPAn-6 did not replace DHA for normal bone growth and maximal BMC in femur, indicating an indispensible role of DHA in bone health. In conclusion, DHA accumulates in the osteoblast-rich and nerve-abundant periosteum of femur; DHA but not EPA appears to be a vital constituent of marrow and periosteum of healthy modelling bone; and both DHA and total n-3 PUFA strongly correlate to BMC.

Background Chronic kidney disease-mineral bone disorder (CKD-MBD), a newly defined disorder in patients with CKD, describes the interacting triad of (1) biochemical abnormalities of calcium, phosphorus and parathyroid hormone (PTH), (2) extraskeletal calcification and (3) abnormal bone. Methods We studied the effects of the calcimimetic R-568, R-568 with calcium (R-568 + Ca) or calcium (Ca) alone compared with control CKD rats on this triad in the Cy/+ male rat, a model of progressive CKD that spontaneously develops CKD-MBD on a normal phosphorus diet. Animals were treated for either 14 or 18 weeks beginning at 20 weeks of age (34-week and 38-week animals, respectively). Results The results demonstrated similar efficacy of R-568, R-568 + Ca and Ca in lowering PTH levels. R-568 alone lowered plasma calcium compared to control over time, but increased phosphorus compared to control early in the course of the disease, but not at 38 weeks. Animals treated with Ca alone or R-568 + Ca had lower phosphorus levels; the Ca alone group had elevated Ca levels. Bone volume improved in the calcium-treated groups. In contrast, arterial and cardiac calcification worsened by most assessments in the R-568 + Ca and Ca alone treated animals compared with R-568 alone whereas R-568 alone treatment showed beneficial effects on most sites of extraskeletal calcification. Conclusion Thus, R-568, with or without Ca, improved the biochemical abnormalities of hyperparathyroidism but with higher and lower calcium levels, respectively, compared with controls. However, R-568 + Ca had more dramatic improvement in bone volume, but more extraskeletal calcification than R-568 alone. This complexity demonstrates that treatment of one component of CKD-MBD may lead to undesirable effects on other components.

The primary macrophage growth factor, colony-stimulating factor-1 (CSF-1), is homodimeric and exists in 3 biologically active isoforms: a membrane-spanning, cell-surface glycoprotein (csCSF-1) and secreted glycoprotein (sgCSF-1) and proteoglycan (spCSF-1) isoforms. To investigate the in vivo role of the chondroitin sulfate glycosaminoglycan (GAG) chain of spCSF-1, we created mice that exclusively express, in a normal tissue-specific and developmental manner, either the secreted precursor of spCSF-1 or the corresponding precursor in which the GAG addition site was mutated. The reproductive, hematopoietic tooth eruption and tissue macrophage defects of CSF-1-deficient, osteopetrotic Csf1op/Csf1op mice were corrected by transgenic expression of the precursors of either sgCSF-1 or spCSF-1. Furthermore, in contrast to the transgene encoding csCSF-1, both failed to completely correct growth retardation, suggesting a role for csCSF-1 in the regulation of body weight. However, spCSF-1, in contrast to sgCSF-1, completely resolved the osteopetrotic phenotype. Furthermore, in transgenic lines expressing different concentrations of sgCSF-1 or spCSF-1, spCSF-1 more efficiently corrected Csf1op/Csf1op defects of tooth eruption, eyelid opening, macrophage morphology, and B-cell deficiency than sgCSF-1. These results indicate an important role of the CSF-1 chondroitin sulfate proteoglycan in in vivo signaling by secreted CSF-1. (Blood. 2006;107:786-795)

Hypoestrogenic states escalate bone loss in animals and humans. This study evaluated the effects of the amount and ratio of dietary n-6 and n-3 polyunsaturated fatty acids (PUFAs) on bone mineral in 3-month-old sexually mature ovariectomized (OVX) Sprague-Dawley rats. For 12 weeks, the rats were fed either a high-PUFA (HP) or a low-PUFA (LP) diet with a ratio of n-6/n-3 PUFAs of 5:1 (HP5 and LP5) or 10:1 (HP10 and LP10). All diets (modified AIN-93G) provided 110.4 g/kg of fat from safflower oil and/or high-oleate safflower oil blended with n-3 PUFAs (DHASCO oil) as a source of docosahexaenoic acid (DHA). Fatty acid analyses confirmed that the dietary ratio of 5:1 significantly elevated the amount of DHA in the periosteum, marrow and cortical and trabecular bones of the femur. Dual-energy X-ray absorptiometry measurements for femur and tibia bone mineral content (BMC) and bone mineral density showed that the DHA-rich diets (HP5 and LP5) resulted in a significantly lower bone loss among the OVX rats at 12 weeks. Rats fed the LP diets displayed the lowest overall serum concentrations of the bone resorption biomarkers pyridinoline (Pyd) and deoxypyridinoline, whereas the bone formation marker osteocalcin was lowest in the HP groups. Regardless of the dietary PUFA content, DHA in the 5:1 diets (HP5 and LP5) preserved rat femur BMC in the absence of estrogen. This study indicates that the dietary ratio of n-6/n-3 PUFAs (LP5 and HP5) and bone tissue concentration of total long-chain n-3 PUFAs (DHA) minimize femur bone loss as evidenced by a higher BMC in OVX rats. These findings show that dietary DHA lowers the ratio of 18:2n-6 (linoleic acid)/n-3 in bone compartments and that this ratio in tissue correlates with reduced Pyd but higher bone alkaline phosphatase activity and BMC values that favor bone conservation in OVX rats.

The philosopher William of Ockham is recognized for the maxim that an assumption introduced to explain a phenomenon must not be multiplied beyond necessity, or that the simplest explanation is probably the correct explanation. The general truth is that conjugated linoleic acids (CLAs) are nutrients. However, the demonstration that these isomers of octadecadienoic acid protect against cancers in rodents stimulated curiosity that directed significant resources to characterize the biological functions of these fatty acids in cell and animal models. The benefits to human subjects given supplements of CLA were at best modest. The disappointing results in humans should be taken as an opportunity to critically evaluate all findings of CLA use and to consolidate the common actions of this nutrient so that future investigations focus on specific isomers and the most reasonable mechanisms. As such, the principal and consistently reported benefits of CLA have been in improving cancer outcomes, reducing body fat in growing animals, and modulating cell functions. Recognizing where related actions of CLA converge in specific disease conditions and physiologic states is how research efforts should be directed to minimize the pursuit of superfluous theories. Here, we briefly review the current biological effects of CLA and attempt to integrate their potential effect on the physiology and health of the skeletal system. Thus, the purpose of this review is to advance the science of CLA and to identify areas of research in which these nutrients affect bone metabolism and skeletal health.

Several systemic hormones and localized growth factors coordinate events of bone formation and resorption to support bone growth in the young and maintain bone mineral content in the adult. Some of the more important factors produced in the bone microenvironment that impact skeletal biology include prostaglandins, cytokines, and insulin-like growth factors. Dietary fat sources that exert potent biological effects on the skeletal tissues belong to the omega-6 and omega-3 families of essential fatty acids. Specific long-chain polyunsaturated fatty acids (PUFA) belonging to these families are substrates for prostanoids that influence the differentiation and activity of cells in bone and cartilage tissues. These PUFA appear to alter prostanoid formation, cell-to-cell signaling processes, and impact transcription factors in vivo. Hence, these biologically active PUFA can be called nutraceutical fatty acids. This review highlights the role of nutraceutical fatty acids on bone metabolism and joint disease. The recent discovery of transcription factors controlling osteoblast function, and soluble proteins directing osteoclastogenesis and osteoblastogenesis offer new research opportunities for studying nutraceutical fatty acids in skeletal biology.

Osteoporosis, osteoarthritis and inflammatory joint disease afflict millions of people worldwide. Inflammatory cytokines inhibit chondrocyte proliferation and induce cartilage degradation for which part of the response is mediated by PGE2. Excess production of PGE2 is linked to osteoporosis and arthritis and is associated with bone and proteoglycan loss. PGE2 also influences the IGF-I/IGFBP axis to facilitate bone and cartilage formation. Recent investigations with growing rats given butter fat and supplements of CLA demonstrated an increased rate of bone formation and reduced ex vivo bone PGE2 production, respectively. Furthermore, the supplements of CLA isomers resulted in their enrichment in lipids of various bone compartments of animals. The effects of CLA on bone biology in rats (IGF action and cytokines) appear to be dependent on the level of n-6 and n-3 fatty acids in the diet; however, these studies generally showed that CLA decreased ex vivo bone PGE2 production and in osteoblast-like cultures. Anti-inflammatory diets, including nutraceutical applications of CLA, may be beneficial in moderating cyclooygenase 2 (COX-2) activity or expression (influencing PGE2 biosynthesis) and might help to reduce rheumatoid arthritis (secondary osteoporosis). This review summarizes findings of CLA on bone modeling in rats and effects on cellular functions of osteoblasts and chondrocytes. These experiments indicate that CLA isomers possess anti-inflammatory activity in bone by moderating prostanoid formation.

A study was designed to examine the effects of dietary conjugated linoleic acid (CLA) on serum concentrations of insulin-like growth factor-I (IGF-I) and IGF binding proteins (IGFBP) and the relationship of these factors to bone metabolism. Weanling male rats were fed AIN-93G diet containing 70 g/kg of added fat for 42 days. Treatments included 0 g/kg or 10 g/kg of CLA and soybean oil (SBO) or menhaden oil + safflower oil (MSO) following a 2 x 2 factorial design. Serum IGFBP was influenced by dietary polyunsaturated fatty acid (PUFA) type ((n-6) and (n-3)) and CLA (p = 0.01 for 38-43 kDa bands corresponding to IGFBP-3). CLA increased IGFBP level in rats fed SBO (p = 0.05) but reduced it in those fed MSO (p = 0.01). Rats fed MSO had the highest serum IGFBP-3 level. Both (n-3) fatty acids and CLA lowered ex vivo prostaglandin E2 production in bone organ culture. In tibia, rats given CLA had reduced mineral apposition rate (3.69 vs. 2.79 microm/day) and bone formation rate (BFR) (0.96 vs. 0.65 microm3/microm2/day); however, the BFR tended to be higher with MSO. Dietary lipid treatments did not affect serum intact osteocalcin or bone mineral content. These results showed that dietary PUFA type and CLA modulate local factors that regulate bone metabolism.

This study examined the effects of dietary (n-6) and (n-3) polyunsaturated fatty acids (PUFA) and acetylsalicylic acid (ASA) on bone ash content, morphometry, fatty acid composition, ex vivo PGE2 biosynthesis, tissue IGF-I concentration, and serum alkaline phosphatase (ALPase) activity in chicks. Newly hatched chicks were fed a semipurified diet containing soybean oil (S) or menhaden oil / safflower oil (M) at 90 g/kg. At 4 days of age, chicks were divided into four equal treatment groups receiving 0 mg [symbol: see text] or 500 mg [symbol: see text] of ASA/kg of diet: S[symbol: see text]ASA, M[symbol: see text]ASA, S[symbol: see text]ASA, and M[symbol: see text]ASA. Lipid and ASA treatments did not affect bone length, bone ash, or bone mineral content in chicks. Chicks fed M had increased fractional labeled trabecular surface and tissue level bone formation rates, independent of ASA treatment, compared with those given S. A significant fat x ASA interaction effect was found for trabecular bone volume, thickness, separation, and number. Chicks fed S had higher 20:4(n-6) but lower 20:5(n-3) concentrations in liver and bone compared with those given M. Ex vivo PGE2 biosynthesis was higher in liver homogenates and bone organ cultures of chicks fed S compared with the values for those given M at 17 days. ASA treatment decreased ex vivo PGE2 production in liver homogenates and bone organ cultures of chicks, independent of the dietary lipids. Chicks fed ASA had a lower concentration of IGF-I in tibiotarsal bone compared with those not given ASA at 19 days. Serum ALPase activity was higher in chicks given M compared with those fed S, but the values were reversed with ASA feeding. This study demonstrated that both dietary fat and ASA modulated bone PGE2 biosynthesis, and that (n-3) PUFA and fat x ASA interactions altered bone morphometry.

The coexistence of osteopetrosis and rickets (osteopetrorickets) in humans has been described frequently. The osteosclerotic mouse is a unique, lethal osteopetrotic mutation that also has rickets. Attempts to cure this mutation by bone marrow transplantation have been largely unsuccessful, and its resistance to cure presumably is attributable to hypomineralized skeletal tissue that does not support osteoclast neogenesis, differentiation, and function. Current opinion regarding the clinical treatment of patients with osteopetrorickets involves first, the resolution of the rickets, followed by bone marrow transplantation to resolve the osteopetrosis, although this has not been successfully performed in humans. Attempts were made in the current study to reverse the rachitic lesion in the osteosclerotic mouse by feeding female breeders a high calcium (2.0%) diet throughout pregnancy and lactation. Mutant offspring (2 to 3 weeks of age) from such mothers remained hypocalcemic and hypophosphatemic, showed no decrease in growth plate cartilage thickness, and did not have enhanced cartilage or skeletal mineralization. For this unique mutation, efforts should be continued toward developing the appropriate therapies for reversal of its rachitic and skeletal defects ; such therapies may yield insights into the clinical care of human infants with osteopetrorickets.

The American Association of Clinical Anatomists (AACA) is a diverse group that includes practicing clinicians, some of whom work outside the academic realm, and other clinicians and basic scientists whose primary responsibility is to patient care, publication, and teaching. This essay pointedly examines why our professional activities often do not lend themselves to the personal and professional realizations for promotion, tenure, and prestige enjoyed by most research-oriented colleagues. Thus the issue of how we can thrive as a distinct group of academic professionals warrants sincere dialogue. Most of the scholarship contributed over the past 2 years to Clinical Anatomy has come from investigators outside the AACA, and only 11% of the AACA membership have published in Clinical Anatomy during this time. A self-examination and analysis of the issues that may bear on these findings are discussed in the hope that they may prompt introspection and encourage development of individual and association strategies that promote increased membership support of the AACA and its journal. Clin. Anat. 10:208–209, 1997. © 1997 Wiley-Liss, Inc.