bluuebunny/crossref_metadata_2025_split huggingface dataset:
Progesterone Activates a Progesterone Receptor Membrane Component 1-Dependent Mechanism That Promotes Human Granulosa/Luteal Cell Survival But Not Progesterone Secretion
Authors: Peluso John J. , Liu Xiufang , Gawkowska Anna , Johnston-MacAnanny Erika 
Published: May 2009

Context: Progesterone (P4) promotes its own secretion and the survival of human granulosa/luteal (GL) cells.
Objective: The objective of these studies was to determine whether progesterone receptor membrane component-1 (PGRMC1) mediates P4’s actions.
Design: In vitro studies were conducted on GL cells from women undergoing in vitro fertilization and GL5 cells, which are derived from GL cells.
Setting and Patients: GL cells were obtained from women undergoing fertility treatment at a university-based clinic and used for in vitro studies.
Main Outcome Measures: PCR, Western blot, and immunocytochemistry were used to detect various progestin binding proteins. 3H-P4 binding kinetics were assessed on partially purified PGRMC1. Apoptosis was determined after culture by either TUNEL or DAPI staining. P4 was measured by an ELISA assay. PGRMC1 was depleted using small interfering RNA.
Results: GL and GL5 cells expressed several P4 binding proteins including the nuclear progesterone receptor (PGR), progestin/adipoQ receptors (PAQR 7, 8, and 5) and PGRMC1. Ligand binding studies revealed that both P4 and the progestin, R5020, bound PGRMC1 with an EC50 of approximately 10 nm. Interestingly, P4 inhibited apoptosis at concentrations in the 10 nm range, whereas R5020 stimulated P4 secretion at concentrations of at lease 16 μm. Depleting PGRMC1 attenuated P4’s antiapoptotic action but failed to influence R5020-induced P4 secretion.
Conclusions: These studies conclusively demonstrate that in human GL cells PGRMC1 functions as a receptor through which P4 activates a signal cascade that prevents apoptosis. In contrast, PGRMC1 does not mediate P4’s ability to acutely promote its own secretion.
Mutation Analysis of the Muscarinic Cholinergic Receptor Genes in Isolated Growth Hormone Deficiency Type IB
Authors: Mohamadi Ali , Martari Marco , Holladay Cindy D. , Phillips John A. , Mullis Primus E. , Salvatori Roberto 
Published: May 2009

Background: Isolated GH deficiency (IGHD) is familial in 5–30% of patients. The most frequent form (IGHD-IB) has autosomal recessive inheritance, and it is known that it can be caused by mutations in the GHRH receptor (GHRHR) gene or in the GH gene. However, most forms of IGHD-IB have an unknown genetic cause. In normal subjects, muscarinic cholinergic stimulation causes an increase in pituitary GH release, whereas its blockade has the opposite effect, suggesting that a muscarinic acetylcholine receptor (mAchR) is involved in stimulating GH secretion. Five types of mAchR (M1–M5) exist. A transgenic mouse in which the function of the M3 receptor was selectively ablated in the central nervous system has isolated GH deficiency similar to animals with defective GHRH or GHRHR gene.
Objective: We hypothesized that mAchR mutations may cause a subset of familial IGHD.
Patients/Methods: After confirming the expression of M1–M5 receptor mRNA in human hypothalamus, we analyzed the index cases of 39 families with IGHD-IB for mutations in the genes encoding for the five receptors. Coding sequences for each of the five mAchRs were subjected to direct sequencing.
Results: In one family, an affected member was homozygous for a M3 change in codon 65 that replaces valine with isoleucine (V65I). The V65I receptor was expressed in CHO cells where it had normal ability to transmit methacholine signaling.
Conclusion: mAchR mutations are absent or rare (less than 2.6%) in familial IGHD type IB.
Cross Sectional Survey of the Scottish General Public's Awareness of, Views on, and Attitudes Toward Nonmedical Prescribing
Authors: Stewart Derek C , George Johnson , Diack H Lesley , Bond Christine M , Mccaig Dorothy J , Cunningham It Scott , Munro Kim , Pfleger David 
Published: May 2009

Background Nonmedical (ie, nonphysician) prescribing is a key development in the UK that has brought about many changes in prescribing policy and practice. Systematic research into the views of the general public toward such developments is limited. Objective To determine the awareness of, views on, and attitudes of members of the Scottish general public toward nonmedical prescribing, with an emphasis on pharmacist prescribing. Methods A questionnaire was mailed in November 2006 to a random sample of 5000 members of the general public in Scotland aged 18 and over, obtained from the UK electoral roll. The questionnaire contained items on awareness of nonmedical prescribing, levels of comfort with specific health professionals, and attitudes toward pharmacist prescribing. Results Response rate was 37.1%. More than half of the individuals who responded were taking prescribed drugs. Nine hundred and seventy-eight (56.6%) were aware that trained health professionals could write prescriptions for medicines previously only prescribed by physicians. Awareness was associated with: increasing age (p < 0.001), having a health professional in their immediate family (p < 0.001), self-rated general health (p < 0.005), and a higher education level (p < 0.01). In logistic regression, all factors were retained as independent predictors of awareness (p < 0.001). Comfort levels for nonmedical prescribing were highest for pharmacists (median 4, IQR 3–5 [1 = low, 5 = high]), closely followed by nurses, and lowest for radiographers (median 2, IQR 1–4) (p <0.001). While more than half of the respondents supported pharmacists having a prescribing role, fewer felt that pharmacists should prescribe the same range of drugs as physicians. There were concerns about lack of privacy in a pharmacy, despite acknowledging its enhanced convenience. Conclusions Our results indicate that more than half of the respondents were aware of nonmedical prescribing. A higher proportion was more comfortable with prescribing by pharmacists and nurses than with other healthcare professionals. Several issues relating to aspects of clinical governance were highlighted, specifically education and data handling.
A Short Treatment With an Antibody to Sclerostin Can Inhibit Bone Loss in an Ongoing Model of Colitis
Authors: Eddleston Alison , Marenzana Massimo , Moore Adrian R , Stephens Paul , Muzylak Mariusz , Marshall Diane , Robinson Martyn K 
Published: May 2009

Abstract
Chronic inflammation leads to bone loss, and increased fracture rates have been reported in a number of human chronic inflammatory conditions. The study reported here investigates the skeletal effects of dosing a neutralizing antibody to the bone regulatory protein sclerostin in a mouse model of chronic colitis. When dosed prophylactically, an antibody to sclerostin (Scl-AbI) did not reduce the weight loss or histological changes associated with colitis but did prevent inflammation-induced bone loss. At the end of the experiment, Scl-AbI–treated animals had a significantly higher femoral BMD (+27%, p &lt; 0.05) than control antibody (Cntrl-Ab)-treated animals. In a second experiment, treatment with Scl-AbI was delayed until colitis had developed, by which time the mechanical properties of femurs in colitic animals were significantly worse than those of healthy age-matched control mice (maximum load, −26%, p &lt; 0.05; energy, −37%, p &lt; 0.05; ultimate strength, −33%, p &lt; 0.05; elastic modulus, −17%, p &lt; 0.05). A short treatment with Scl-AbI halted bone loss and reversed the decline of both intrinsic and extrinsic mechanical properties of the femur such that, after 19 days of treatment, the bone mechanical properties in the Scl-AbI–treated animals were not significantly different from those of noncolitic age-matched controls. Serum markers of bone formation and resorption suggested that the antibody to sclerostin stimulated osteoblast activity and inhibited osteoclast-mediated bone resorption.
Effects of hPTH(1-34) Infusion on Circulating Serum Phosphate, 1,25-Dihydroxyvitamin D, and FGF23 Levels in Healthy Men
Authors: Burnett-Bowie Sherri-Ann M , Henao Maria P , Dere Melissa E , Lee Hang , Leder Benjamin Z 
Published: May 2009

Abstract
Fibroblast growth factor 23 (FGF23) promotes phosphaturia and suppresses 1,25-dihydroxyvitamin D [1,25(OH)2D] production. PTH also promotes phosphaturia, but, in contrast, stimulates 1,25(OH)2D production. The relationship between FGF23 and PTH is unclear, and the acute effect of pharmacologically dosed PTH on FGF23 secretion is unknown. Twenty healthy men were infused with human PTH(1-34) [hPTH(1-34)] at 44 ng/kg/h for 24 h. Compared with baseline, FGF23, 1,25(OH)2D, ionized calcium (iCa), and serum N-telopeptide (NTX) increased significantly over the 18-h hPTH(1-34) infusion (p &lt; 0.0001), whereas serum phosphate (PO4) transiently increased and then returned to baseline. FGF23 increased from 35 ± 10 pg/ml at baseline to 53 ± 20 pg/ml at 18 h (p = 0.0002); 1,25(OH)2D increased from 36 ± 16 pg/ml at baseline to 80 ± 33 pg/ml at 18 h (p &lt; 0.0001); iCa increased from 1.23 ± 0.03 mM at baseline to 1.46 ± 0.05 mM at hour 18 (p &lt; 0.0001); and NTX increased from 17 ± 4 nM BCE at baseline to 28 ± 8 nM BCE at peak (p &lt; 0.0001). PO4 was 3.3 ± 0.6 mg/dl at baseline, transiently rose to 3.7 ± 0.4 mg/dl at hour 6 (p = 0.016), and then returned to 3.4 ± 0.5 mg/dl at hour 12 (p = 0.651). hPTH(1-34) infusion increases endogenous 1,25(OH)2D and FGF23 within 18 h in healthy men. Whereas it is possible that the rise in PO4 contributed to the observed increase in FGF23, the increase in 1,25(OH)2D was more substantial and longer sustained than the change in serum phosphate. Given prior data that suggest that neither PTH nor calcium stimulate FGF23 secretion, these data support the assertion that 1,25(OH)2D is a potent physiologic stimulator of FGF23 secretion.
Bilateral Fractures of the Femur Diaphysis in a Patient With Rheumatoid Arthritis on Long-Term Treatment With Alendronate: Clues to the Mechanism of Increased Bone Fragility
Authors: Somford Matthijs P , Draijer Frits W , Thomassen Bregje JW , Chavassieux Pascale M , Boivin Georges , Papapoulos Socrates E 
Published: May 2009

Abstract
Unusual fractures of the femur diaphysis have been reported in patients treated with alendronate and, although no causal relationship has been established, excessive suppression of bone turnover and length of treatment with alendronate have been implicated in their pathogenesis. We report here clinical, biochemical, and radiological findings of a patient with rheumatoid arthritis and multiple risk factors for fractures who was treated with alendronate for 8 yr and developed spontaneous bilateral subtrochanteric/diaphyseal fractures. Bone biopsies obtained form the iliac crest and the femur showed decreased bone formation with histomorphometric evidence of markedly increased bone resorption at the femur. These results show for the first time that an imbalance between bone resorption and bone formation at the affected bone is associated with the occurrence of these atypical femur fractures. The cause of this imbalance is currently unknown, and further studies of the epidemiology and pathogenesis of diaphyseal femur fractures are warranted.
Vps33a Mediates RANKL Storage in Secretory Lysosomes in Osteoblastic Cells
Authors: Kariya Yoshiaki , Honma Masashi , Aoki Shigeki , Chiba Atsushi , Suzuki Hiroshi 
Published: May 2009

Abstract
Previous studies have indicated that the amount of RANKL expressed on the cell surface of osteoblasts or bone marrow stromal cells (BMSCs) is considered an important factor determining the extent of osteoclast activation. However, subcellular trafficking of RANKL and its regulatory mechanisms in osteoblastic cells is still unclear. In this study, we showed that RANKL is predominantly localized in lysosomal organelles, but little is found on the cell surface of osteoblastic cells. We also showed that RANKL is relocated to the plasma membrane in response to stimulation with RANK-Fc–coated beads, indicating that the lysosomal organelles where RANKL is localized function as secretory lysosomes. In addition, using a protein pull-down method, we identified vacuolar protein sorting (Vps)33a as interacting with the cytoplasmic tail of RANKL. Furthermore, knockdown of Vps33a expression reduced the lysosomal storage of RANKL and caused the accumulation of newly synthesized RANKL in the Golgi apparatus, indicating that Vps33a is involved in transporting RANKL from the Golgi apparatus to secretory lysosomes. We also showed that suppression of Vps33a affects the cell surface expression level of RANKL and disrupts the regulated behavior of RANKL. These results suggest that RANKL storage in secretory lysosomes is important to control osteoclast activation and to maintain bone homeostasis.
LPS-Induced Inhibition of Osteogenesis Is TNF-α Dependent in a Murine Tooth Extraction Model
Authors: Tomomatsu Nobuyoshi , Aoki Kazuhiro , Alles Neil , Soysa Niroshani S , Hussain Anower , Nakachi Hiroyuki , Kita Souma , Shimokawa Hitoyata , Ohya Keiichi , Amagasa Teruo 
Published: May 2009

Abstract
TNF-α is a major etiologic factor of inflammatory bone diseases such as periodontitis and rheumatoid arthritis. In addition, patients with metabolic diseases such as chronic heart disease and diabetes have significantly increased plasma levels of TNF-α. Several lines of evidence show inhibition of osteoblastogenesis by TNF-α in vitro. Therefore, bone formation and osteogenesis in these patients might be inhibited because of TNF-α. However, little is known about the inhibitory role of TNF-α in bone formation/osteogenesis in vivo. The purpose of this study was to investigate the role of TNF-α in osteogenesis using a murine tooth extraction model. Lipopolysaccharide (LPS) was injected subcutaneously into the calvariae of either wildtype (WT) or TNF-α–deficient (KO) mice. The left incisor was extracted 4 days after LPS injection. The measuring area was established as the tooth socket under the mesial root of the first molar. A significant increase in serum TNF-α levels after LPS injection was observed in WT mice. The BMD of the tooth socket was significantly decreased by LPS injection 21 days after extraction in WT but not in KO mice. Histomorphometric analysis showed a significant decrease in the mineral apposition rate after LPS injection, which appeared at an early stage in WT but not in KO mice. Injection of a peptide that blocked the TNF-α signaling pathway by preventing transmission of the NF-κB signal recovered the inhibition of osteogenesis observed after LPS injection. In conclusion, TNF-α might play a major role in LPS-induced inhibition of osteogenesis under inflammatory conditions.
Effects of Repetitive Loading on Bone Mass and Geometry in Young Male Tennis Players: A Quantitative Study Using MRI
Authors: Ducher Gaele , Daly Robin M , Bass Shona L 
Published: May 2009

Abstract
Pre- and early puberty seem to be the most opportune times for exercise to improve bone strength in girls, but few studies have addressed this issue in boys. This study investigated the site-, surface-, and maturity-specific exercise-induced changes in bone mass and geometry in young boys. The osteogenic effects of loading were analyzed by comparing the playing and nonplaying humeri of 43 male pre-, peri-, and postpubertal competitive tennis players 10–19 yr of age. Total bone area, medullary area, and cortical area were determined at the mid (40–50%) and distal humerus (60–70%) of both arms using MRI. Humeral bone mass (BMC) was derived from a whole body DXA scan. In prepubertal boys, BMC was 17% greater in the playing compared with nonplaying arm (p &lt; 0.001), which was accompanied by a 12–21% greater cortical area, because of greater periosteal expansion than medullary expansion at the midhumerus and periosteal expansion associated with medullary contraction at the distal humerus. Compared with prepuberty, the side-to-side differences in BMC (27%) and cortical area (20–33%) were greater in peripuberty (p &lt; 0.01). No differences were found between peri- and postpuberty despite longer playing history in the postpubertal players. The osteogenic response to loading was greater in peri- compared with prepubertal boys, which is in contrast with our previous findings in girls and may be caused by differences in training history. This suggests that the window of opportunity to improve bone mass and size through exercise may be longer in boys than in girls.
Improvements in Vertebral Body Strength Under Teriparatide Treatment Assessed In Vivo by Finite Element Analysis: Results From the EUROFORS Study
Authors: Graeff Christian , Chevalier Yan , Charlebois Mathieu , Varga Peter , Pahr Dieter , Nickelsen Thomas N , Morlock Michael M , Glüer Claus C , Zysset Philippe K 
Published: May 2009

Abstract
Monitoring of osteoporosis therapy based solely on DXA is insufficient to assess antifracture efficacy. Estimating bone strength as a variable closely linked to fracture risk is therefore of importance. Finite element (FE) analysis–based strength measures were used to monitor a teriparatide therapy and the associated effects on whole bone and local fracture risk. In 44 postmenopausal women with established osteoporosis participating in the EUROFORS study, FE models based on high-resolution CT (HRCT) of T12 were evaluated after 0, 6, 12, and 24 mo of teriparatide treatment (20 μg/d). FE-based strength and stiffness calculations for three different load cases (compression, bending, and combined compression and bending) were compared with volumetric BMD (vBMD) and apparent bone volume fraction (app. BV/TV), as well as DXA-based areal BMD of the lumbar spine. Local damage of the bone tissue was also modeled. Highly significant improvements in all analyzed variables as early as 6 mo after starting teriparatide were found. After 24 mo, bone strength in compression was increased by 28.1 ± 4.7% (SE), in bending by 28.3 ± 4.9%, whereas app. BV/TV was increased by 54.7 ± 8.8%, vBMD by 19.1 ± 4.0%, and areal BMD of L1–L4 by 10.2 ± 1.2%. When comparing standardized increases, FE changes were significantly larger than those of densitometry and not significantly different from app. BV/TV. The size of regions at high risk for local failure was significantly reduced under teriparatide treatment. Treatment with teriparatide leads to bone strength increases for different loading conditions of close to 30%. FE is a suitable tool for monitoring bone anabolic treatment in groups or individual patients and offers additional information about local failure modes. FE variables showed a higher standardized response to changes than BMD measurements, but further studies are needed to show that the higher response represents a more accurate estimate of treatment-induced fracture risk reduction.
Bone, Muscle, and Physical Activity: Structural Equation Modeling of Relationships and Genetic Influence With Age
Authors: Lang Dean H , Conroy David E , Lionikas Arimantas , Mack Holly A , Larsson Lars , Vogler George P , Vandenbergh David J , Blizard David A , McClearn Gerald E , Sharkey Neil A 
Published: May 2009

Abstract
Correlations among bone strength, muscle mass, and physical activity suggest that these traits may be modulated by each other and/or by common genetic and/or environmental mechanisms. This study used structural equation modeling (SEM) to explore the extent to which select genetic loci manifest their pleiotropic effects through functional adaptations commonly referred to as Wolff's law. Quantitative trait locus (QTL) analysis was used to identify regions of chromosomes that simultaneously influenced skeletal mechanics, muscle mass, and/or activity-related behaviors in young and aged B6×D2 second-generation (F2) mice of both sexes. SEM was used to further study relationships among select QTLs, bone mechanics, muscle mass, and measures of activity. The SEM approach provided the means to numerically decouple the musculoskeletal effects of mechanical loading from the effects of other physiological processes involved in locomotion and physical activity. It was found that muscle mass was a better predictor of bone mechanics in young females, whereas mechanical loading was a better predictor of bone mechanics in older females. An activity-induced loading factor positively predicted the mechanical behavior of hindlimb bones in older males; contrarily, load-free locomotion (i.e., the remaining effects after removing the effects of loading) negatively predicted bone performance. QTLs on chromosomes 4, 7, and 9 seem to exert some of their influence on bone through actions consistent with Wolff's Law. Further exploration of these and other mechanisms through which genes function will aid in development of individualized interventions able to exploit the numerous complex pathways contributing to skeletal health.
Alteration of RANKL-Induced Osteoclastogenesis in Primary Cultured Osteoclasts From SERCA2+/− Mice
Authors: Yang Yu-Mi , Kim Min Seuk , Son Aran , Hong Jeong Hee , Kim Kyung-Ho , Seo Jeong Taeg , Lee Syng-Ill , Shin Dong Min 
Published: May 2009

Abstract
RANKL is essential for the terminal differentiation of monocytes/marcrophages into osteoclasts. RANKL induces long-lasting oscillations in the intracellular concentration of Ca2+ ([Ca2+]i) only after 24 h of stimulation. These Ca2+ oscillations play a switch-on role in NFATc1 expression and osteoclast differentiation. Which Ca2+ transporting pathway is induced by RANKL to evoke the Ca2+ oscillations and its specific role in RANKL-mediated osteoclast differentiation is not known. This study examined the effect of a partial loss of sarco/endoplasmic reticulum Ca2+ ATPase type2 (SERCA2) on osteoclast differentiation in SERCA2 heterozygote mice (SERCA2+/−). The BMD in the tibias of SERCA2+/− mice increased &gt;1.5-fold compared with wildtype mice (WT). RANKL-induced [Ca2+]i oscillations were generated 48 h after RANKL treatment in the WT mice but not in the SERCA2+/− bone marrow–derived macrophages (BMMs). Forty-eight hours after RANKL treatment, there was a lower level of NFATc1 protein expression and markedly reduced translocation of NFATc1 into the nucleus during osteoclastogenesis of the SERCA2+/− BMMs. In addition, RANKL treatment of SERCA2+/− BMMs incompletely induced formation of multinucleated cells, leading to reduced bone resorption activity. These results suggest that RANKL-mediated induction of SERCA2 plays a critical role in the RANKL-induced [Ca2+]i oscillations that are essential for osteoclastogenesis.