Miracle-dz/UniFAR-FTUs huggingface dataset:
NF‐κB Has a Direct Role in Inhibiting Bmp‐ and Wnt‐Induced Matrix Protein Expression

The host response to pathogens through nuclear factor κB (NF‐κB) is an essential defense mechanism for eukaryotic organisms. NF‐κB‐mediated host responses inhibit bone and other connective tissue synthesis and are thought to affect the transcription of matrix proteins through multiple indirect pathways. We demonstrate that inhibiting NF‐κB in osteoblasts increases osteocalcin expression in vivo in mice with periodontal disease. Mutating NF‐κB binding sites on osteocalcin (OC) or bone sialoprotein (Bsp) promoters rescues the negative impact of NF‐κB on their transcription and that NF‐κB can inhibit Wnt‐ and Bmp‐induced OC and Bsp transcription, even when protein synthesis is inhibited, indicating a direct effect of NF‐κB. This inhibition depends on p65‐p50 NF‐κB heterodimer formation and deacetylation by HDAC1 but is not affected by the noncanonical NF‐κB pathway. Moreover, NF‐κB reduces Runx2 and β‐catenin binding to OC/Bsp promoters independently of their nuclear localization. Thus, inflammatory signals stimulate the direct interaction of NF‐κB with response elements to inhibit binding of β‐catenin and Runx2 binding to nearby consensus sites and reduce expression of matrix proteins. This direct mechanism provides a new explanation for the rapid decrease in new bone formation after inflammation‐related NF‐κB activation. © 2015 American Society for Bone and Mineral Research.
True Gold or Pyrite: A Review of Reference Point Indentation for Assessing Bone Mechanical Properties In Vivo

Although the gold standard for determining bones' mechanical integrity is the direct measure of mechanical properties, clinical evaluation has long relied on surrogates of mechanical properties for assessment of fracture risk. Nearly a decade ago, reference point indentation (RPI) emerged as an innovative way to potentially assess mechanical properties of bone in vivo. Beginning with the BioDent device, and then followed by the newer generation OsteoProbe, this RPI technology has been utilized in several publications. In this review we present an overview of the technology and some important details about the two devices. We also highlight select key studies, focused specifically on the in vivo application of these devices, as a way of synthesizing where the technology stands in 2015. The BioDent machine has been shown, in two clinical reports, to be able to differentiate fracture versus nonfracture patient populations and in preclinical studies to detect treatment effects that are consistent with those quantified using traditional mechanical tests. The OsteoProbe appears able to separate clinical cohorts yet there exists a lack of clarity regarding details of testing, which suggests more rigorous work needs to be undertaken with this machine. Taken together, RPI technology has shown promising results, yet much more work is needed to determine if its theoretical potential to assess mechanical properties in vivo can be realized. © 2015 American Society for Bone and Mineral Research.
Retraction: ‘Amelioration of Osteoporosis and Hypovitaminosis D by Sunlight Exposure in Hospitalized Elderly Women With Alzheimer's Disease: A Randomized Controlled Trial’

The above article, published online on 4 April 2005 in Wiley Online Library (wileyonlinelibrary.com), and in JBMR Volume 20, Issue 8, pages 1327–1333, together with a subsequent Expression of Concern published online in JBMR on 24 June 2015, has been retracted by agreement between the authors, the Journal Editor in Chief, Juliet Compston, and Wiley Periodicals, Inc. The retraction has been agreed due to duplication of text and concerns about the underlying data to which the authors have given no satisfactory response. Dr. Sato acknowledges that his co‐authors are named as such for honorary reasons and are not responsible for the content of the manuscript.
Low‐Level Cadmium Exposure Is Associated With Decreased Bone Mineral Density and Increased Risk of Incident Fractures in Elderly Men: The MrOS Sweden Study

One risk factor for osteoporosis that has attracted increasing attention in recent years is exposure to cadmium. The aim of this study was to examine the associations between low‐level cadmium exposure, from diet and smoking, and bone mineral density (BMD) and incident fractures in elderly men. The study population consisted of 936 men from the Swedish cohort of the Osteoporotic Fractures in Men (MrOS) study, aged 70 to 81 years at inclusion (years 2002 to 2004), with reliable data on cadmium in urine (U‐Cd) analyzed using inductively coupled plasma mass spectrometry in baseline samples. The participants also answered a questionnaire on lifestyle factors and medical history. BMD was measured at baseline using dual‐energy X‐ray absorptiometry (DXA) in the total body, hip, and lumbar spine. During the follow‐up period (until 2013), all new fractures were registered by date and type. Associations between BMD and U‐Cd were assessed using multiple linear regression, and associations between incident fractures and baseline U‐Cd were analyzed using Cox regression. In both cases, a number of potential confounders and other risk factors (eg, age, smoking, body mass index [BMI], and physical activity) were included in the models. We found significant negative associations between U‐Cd and BMD, with lower BMD (4% to 8%) for all sites in the fourth quartile of U‐Cd, using the first quartile as the reference. In addition, we found positive associations between U‐Cd and incident fractures, especially nonvertebral osteoporosis fractures in the fourth quartile of U‐Cd, with hazard ratios of 1.8 to 3.3 in the various models. U‐Cd as a continuous variable was significantly associated with nonvertebral osteoporosis fractures (adjusted hazard ratio 1.3 to 1.4 per μg Cd/g creatinine), also in never‐smokers, but not with the other fracture groups (all fractures, hip fractures, vertebral fractures, and other fractures). Our results indicate that even relatively low cadmium exposure through diet and smoking increases the risk of low BMD and osteoporosis‐related fractures in elderly men. © 2015 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).
Targeting of Mesenchymal Stromal Cells by Cre‐Recombinase Transgenes Commonly Used to Target Osteoblast Lineage Cells

The targeting specificity of tissue‐specific Cre‐recombinase transgenes is a key to interpreting phenotypes associated with their use. The Ocn‐Cre and Dmp1‐Cre transgenes are widely used to target osteoblasts and osteocytes, respectively. Here, we used high‐resolution microscopy of bone sections and flow cytometry to carefully define the targeting specificity of these transgenes. These transgenes were crossed with Cxcl12gfp mice to identify Cxcl12‐abundant reticular (CAR) cells, which are a perivascular mesenchymal stromal population implicated in hematopoietic stem/progenitor cell maintenance. We show that in addition to osteoblasts, Ocn‐Cre targets a majority of CAR cells and arteriolar pericytes. Surprisingly, Dmp1‐Cre also targets a subset of CAR cells, in which expression of osteoblast‐lineage genes is enriched. Finally, we introduce a new tissue‐specific Cre‐recombinase, Tagln‐Cre, which efficiently targets osteoblasts, a majority of CAR cells, and both venous sinusoidal and arteriolar pericytes. These data show that Ocn‐Cre and Dmp1‐Cre target broader stromal cell populations than previously appreciated and may aid in the design of future studies. Moreover, these data highlight the heterogeneity of mesenchymal stromal cells in the bone marrow and provide tools to interrogate this heterogeneity. © 2016 American Society for Bone and Mineral Research.
Serum 25‐hydroxyvitamin D level and acute‐phase reaction following initial intravenous bisphosphonate

Children often will complain of severe musculoskeletal pain and will develop fever with a first course of intravenous bisphosphonates. Acute-phase reaction (APR) can be severe enough for the child to refuse further therapy. The mechanism underlying the APR from intravenous bisphosphonates is not known. However in a double-blind, randomized, crossover, placebo-controlled study in 12 children, treatment with Atorvastatin did not alleviate the APR. Recently, Bertoldo and colleagues reported an association between serum 25hydroxyvitamin D [25(OH)D] level and APR after bisphosphonate infusion. In essence, lower levels of vitamin D were associated more frequently with APR, and vice versa. We report the results of reanalysis of our data in order to evaluate a possible association between serum 25(OH)D level and APR following initial intravenous bisphosphonate treatment in children. In our bone andmineral disorder clinic, intravenous infusion of bisphosphonates is given on two consecutive days, referred to as a cycle. In our published study, children received two cycles given 3 to 4 months apart. Children completed the visual analogue pain scale (0 to 100mm) at baseline before the infusion (pain scale 1). Pain scale 2 was completed on day 1 late in the evening, pain scale 3 on day 2 in the morning prior to the second infusion, pain scale 4 was completed on day 2 late in the evening after the infusion, and pain scale 5 in the morning of day 3. The children’s families also recorded whether they needed medications to alleviate their pain or fever as either ‘‘Yes’’ or ‘‘No.’’ For musculoskeletal pain, children were given oxycodone, considered not to interfere with the inflammatory markers that were being evaluated. For fever ( 398C), if tepid sponging did not bring the temperature down, patients were instructed to take acetaminophen. APR was categorized as presence of fever needing acetaminophen and/or musculoskeletal pain requiring oxycodone. Nonparametric Spearman correlation between serum 25(OH)D level and pain scales and multivariate regression modeling with backward elimination were performed using SPSS 18.0. A p value less than . 05 was considered significant. The mean age of 12 children (10 girls and 2 boys) was 12.1 4.2 years. In the first cycle, 7 children (58.3%) developed APR. There was no significant correlation between serum 25(OH)D level (Mayo Medical Laboratories, Rochester, MN, USA) and pain scale prior to bisphosphonate infusion. In contrast, following bisphosphonate infusion, an inverse correlation was found between pain scale and serum 25(OH)D (Table 1 and Fig. 1). These findings remained true for the second cycle (2 children developed APR) and for the two cycles combined together (data not shown). The two cycles then were combined for multivariate analysis. The correlation between serum 25(OH)D level and sum of pain scales after infusion remained significant even after adjusting for confounding variables such as treatment arms (placebo versus Atorvastatin), body mass index (BMI), parathyrLETTER TO THE EDITOR JBMR
Activation of Wnt Signaling by Mechanical Loading Is Impaired in the Bone of Old Mice

Aging diminishes bone formation engendered by mechanical loads, but the mechanism for this impairment remains unclear. Because Wnt signaling is required for optimal loading‐induced bone formation, we hypothesized that aging impairs the load‐induced activation of Wnt signaling. We analyzed dynamic histomorphometry of 5‐month‐old, 12‐month‐old, and 22‐month‐old C57Bl/6JN mice subjected to multiple days of tibial compression and corroborated an age‐related decline in the periosteal loading response on day 5. Similarly, 1 day of loading increased periosteal and endocortical bone formation in young‐adult (5‐month‐old) mice, but old (22‐month‐old) mice were unresponsive. These findings corroborated mRNA expression of genes related to bone formation and the Wnt pathway in tibias after loading. Multiple bouts (3 to 5 days) of loading upregulated bone formation–related genes, e.g., Osx and Col1a1, but older mice were significantly less responsive. Expression of Wnt negative regulators, Sost and Dkk1, was suppressed with a single day of loading in all mice, but suppression was sustained only in young‐adult mice. Moreover, multiple days of loading repeatedly suppressed Sost and Dkk1 in young‐adult, but not in old tibias. The age‐dependent response to loading was further assessed by osteocyte staining for Sclerostin and LacZ in tibia of TOPGAL mice. After 1 day of loading, fewer osteocytes were Sclerostin‐positive and, corroboratively, more osteocytes were LacZ‐positive (Wnt active) in both 5‐month‐old and 12‐month‐old mice. However, although these changes were sustained after multiple days of loading in 5‐month‐old mice, they were not sustained in 12‐month‐old mice. Last, Wnt1 and Wnt7b were the most load‐responsive of the 19 Wnt ligands. However, 4 hours after a single bout of loading, although their expression was upregulated threefold to 10‐fold in young‐adult mice, it was not altered in old mice. In conclusion, the reduced bone formation response of aged mice to loading may be due to failure to sustain Wnt activity with repeated loading. © 2016 American Society for Bone and Mineral Research.
Skeletal Fluorosis Due To Inhalation Abuse of a Difluoroethane‐Containing Computer Cleaner

Skeletal fluorosis (SF) is endemic in many countries and millions of people are affected worldwide, whereas in the United States SF is rare with occasional descriptions of unique cases. We report a 28‐year‐old American man who was healthy until 2 years earlier when he gradually experienced difficulty walking and an abnormal gait, left hip pain, loss of mobility in his right wrist and forearm, and progressive deformities including enlargement of the digits of both hands. Dual‐energy X‐ray absorptiometry (DXA) of his lumbar spine, femoral neck, total hip, and the one‐third forearm revealed bone mineral density (BMD) Z‐scores of +6.2, +4.8, +3.0, and –0.2, respectively. Serum, urine, and bone fluoride levels were all elevated and ultimately explained by chronic sniffing abuse of a computer cleaner containing 1,1‐difluoroethane. Our findings reflect SF due to the unusual cause of inhalation abuse of difluoroethane. Because this practice seems widespread, particularly in the young, there may be many more such cases. © 2016 American Society for Bone and Mineral Research.
Calcium Pyrophosphate Deposition Pseudoabscess.

C alcium pyrophosphate deposition (CPPD) disease is a common rheumatic arthropathy caused by the deposition of calcium pyrophosphate (CPP) crystals in and around joints, especially in knee, wrist, and hip joints. We report a case of CPPD disease presenting with polyarthritis and an aseptic inflammatory reaction of left obturator externus muscle, which mimicked an infectious process. To our knowledge, this is the third reported CPPD case of aseptic pyomyositis mimicking an abscess. A 60-year-old male athlete presented to our hospital with arthralgia of multiple joints. About 1 week prior to admission, he developed arthralgia of the wrists, knees, and ankles. In addition, he had dull pain over bilateral inguinal areas with nondermatomal radiation to gluteal regions. The pain was precipitated by movement and mostly relieved by rest. His pains persisted, and the involved joints became swollen. He took some nonsteroidal anti-inflammatory drugs, but there was lack of improvement. He was febrile on admission. Initial laboratory examinations revealed leukocytosis, elevated C-reactive protein, and erythrocyte sedimentation rate. Complete fever workup was performed, but infection was excluded. Joint aspiration was performed for his ankles, knees, and wrists. Joint fluid analysis showed inflammatory arthritis with typical CPP crystals. Metabolic
Vitamin D Levels and Associations With Disease Activity in Chinese Han Patients With Early Rheumatoid Arthritis.

To the Editor: W e have read with interest the article by Raczkiewicz et al describing low vitamin D levels in patients with rheumatoid arthritis (RA). We report that low levels are also seen even in early RA. The identification of immunomodulatory effects of vitamin D has led to recent speculation that it may play a role in RA. Vitamin D deficiency has been suggested as an environmental risk factor, based on vitamin D levels in patients with RA as well as studies of animal models of arthritis. Several studies reported contradictory results regarding correlation between disease activity and vitamin D metabolites levels. The aim of this study was to assess the levels of vitamin D in patients with RA and estimate the relationship between vitamin D level and disease activity in a well-characterized group of Chinese Han with recent-onset RA.
Irreversible Deterioration of Cortical and Trabecular Microstructure Associated With Breastfeeding

Estrogen deficiency associated with menopause is accompanied by an increase in the rate of bone remodeling and the appearance of a remodeling imbalance; each of the greater number of remodeling transactions deposits less bone than was resorbed, resulting in microstructural deterioration. The newly deposited bone is also less completely mineralized than the older bone resorbed. We examined whether breastfeeding, an estrogen‐deficient state, compromises bone microstructure and matrix mineral density. Distal tibial and distal radial microarchitecture were quantified using high‐resolution peripheral quantitative computed tomography in 58 women before, during, and after breastfeeding and in 48 controls during follow‐up of 1 to 5 years. Five months of exclusive breastfeeding increased cortical porosity by 0.6% (95% confidence interval [CI] 0.3–0.9), reduced matrix mineralization density by 0.26% (95% CI 0.12–0.41) (both p < 0.01), reduced trabecular number by 0.22 per mm (95% CI 0.15–0.28), and increased trabecular separation by 0.07 mm (95% CI 0.05–0.08) (all p < 0.001). Relative to prebreastfeeding, at a median of 2.6 years (range 1 to 4.8) after cessation of breastfeeding, cortical porosity remained 0.58 SD (95% CI 0.48–0.68) higher, matrix mineralization density remained 1.28 SD (95% CI 1.07–1.49) lower, and trabeculae were 1.33 SD (95% CI 1.15–1.50) fewer and 1.06 SD (95% CI 0.91–1.22) more greatly separated (all p < 0.001). All deficits were greater than in controls. The results were similar at distal radius. Bone microstructure may be irreversibly deteriorated after cessation of breastfeeding at appendicular sites. Studies are needed to establish whether this deterioration compromises bone strength and increases fracture risk later in life. © 2016 American Society for Bone and Mineral Research.
Effect of an Educational Intervention for Surgeons on Osteoporosis Management at 2-Year Follow-up in Patients With Fragility Fracture.

The numbers of fractures in the first phase and third phase were reported before hospitalization. These data were collected by medical history of patients. All patients in the first phase and third phase were followed up for 2 years after discharge, and the numbers of second fractures were reported. F ragility fractures affect millions of individuals leading to decreased quality of life and increased mortality rates and put a considerable burden on every health care system. Aging of human populations, regardless of whether in developed or developing countries, results in an increasing burden of fragility fractures. Therefore, it is critical that the physicians remain acutely aware of the likelihood of osteoporosis underlying the fragility fracture and treat the patients who are at risk in order to reduce the risk of future fractures. A study performed in a developing country reported that more than 90% of the orthopedic surgeons did not include bone mass densitometry (BMD) when evaluating patients with fragility fractures, and only a third of these patients received proper dosage of treatment. Furthermore, the study of Mehrpour et al showed that only 10.5% of the patients had been informed by their orthopedic surgeon that they had osteoporosis. Appropriate pharmacological intervention significantly decreases the risk of second fracture. As a result, the medical systems should be prompted to capture patients who merit postfracture assessment and evaluate them for secondary prevention of fractures. A 3-phase prospective observational study was designed to evaluate the effectiveness of education of orthopedic surgeons on the management of osteoporotic diseases in patients with fragility fractures and to see how the t score of the patients changes if they receive correct medical management from April 2011 to July 2014. This study was approved by our institutional review board. A written informed consent of all participants was obtained before the study. Patients from the academic tertiary care, level I trauma hospitals, with at least a fracture of the femoral neck, intertrochanteric, vertebral, distal radius, ramus of pubic, and/or shoulder (proximal of humerus) were eligible to be studied. Among the 764 fractures identified, 515 (67%) met the eligibility criteria. Of these, 367 women and 148
A cooled water-irrigated intraesophageal balloon to prevent thermal injury during cardiac ablation: experimental study based on an agar phantom

A great deal of current research is directed to finding a way to minimize thermal injury in the esophagus during radiofrequency catheter ablation of the atrium. A recent clinical study employing a cooling intraesophageal balloon reported a reduction of the temperature in the esophageal lumen. However, it could not be determined whether the deeper muscular layer of the esophagus was cooled enough to prevent injury. We built a model based on an agar phantom in order to experimentally study the thermal behavior of this balloon by measuring the temperature not only on the balloon, but also at a hypothetical point between the esophageal lumen and myocardium (2 mm distant). Controlled temperature (55 °C) ablations were conducted for 120 s. The results showed that (1) the cooling balloon provides a reduction in the final temperature reached, both on the balloon surface and at a distance of 2 mm; (2) coolant temperature has a significant effect on the temperature measured at 2 mm from the esophageal lumen (it has a less effect on the temperature measured on the balloon surface) and (3) the pre-cooling period has a significant effect on the temperature measured on the balloon surface (the effect on the temperature measured 2 mm away is small). The results were in good agreement with those obtained in a previous clinical study. The study suggests that the cooling balloon gives thermal protection to the esophagus when a minimum pre-cooling period of 2 min is programmed at a coolant temperature of 5 °C or less.