bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of thyroid dysfunction on N-terminal pro-B-type natriuretic peptide concentrations
Authors: Manuchehri Alireza M , Jayagopal Vijay , Kilpatrick Eric S , Atkin Stephen L
Published: April 2006

Background: B-type natriuretic peptides and N-terminal pro-B-type natriuretic peptides (NT-proBNP) have been suggested as being useful for the diagnosis of congestive heart failure. We have shown previously that changes in thyroid function are associated with changes in concentrations of other low molecular weight molecules. Therefore, the aim of this study was to assess whether similar changes occurred with NT-proBNP concentrations following treatment of thyroid dysfunction.

Methods: Seventeen patients (12 female, 5 male, age range 24-77 years) with newly diagnosed hypothyroidism and 21 patients (16 female, 5 male, age range 21-66 years) with newly diagnosed hyperthyroidism had NT-proBNP measured at baseline and when they subsequently became euthyroid.

Results: NT-proBNP levels were not significantly different in the hyperthyroid group from the hypothyroid, either before ( P = 0.706) or after treatment to euthyroidism ( P = 0.170). The hypothyroid group showed a rise in NT-proBNP after treatment ( P < 0.001). There was a marginally significant fall in the NT-proBNP levels in the hyperthyroid group ( P = 0.05). However, these changes were within the expected wide range of biological variability of NT-proBNP shown in earlier studies.

Conclusions: Hypothyroidism alters NT-proBNP concentrations, but the magnitude of this effect may be lost in the wide biological variability of natriuretic peptides and this statistically significant finding is not likely to be of clinical relevance.
Investigation into possible causes of interference in serum testosterone measurement in women
Authors: Heald A H , Butterworth A , Kane J W , Borzomato J , Taylor N F , Layton T , Kilpatrick E S , Rudenski A
Published: April 2006

Background: Direct (non-extracted) testosterone immunoassays may give spuriously high results in women. The presumed interferents may be removed if testosterone is extracted into an organic phase before being measured. We aimed to clarify possible causes and effects of interference in testosterone measurement in women.

Methods: Women who had a blood sample referred to Hope Hospital Clinical Biochemistry laboratory for measurement of serum testosterone concentration over a six-month period were studied. Clinical and treatment data were recorded. A difference (direct-minus-extracted testosterone) of less than 1.0 nmol/L was used to define a group with low interference. A difference of 2.5 nmol/L or more was used to define a group with significant interference.

Results: The distribution of interference in 1271 serum samples from female patients was unimodal. There were no group differences in clinical presentation or treatment. The median degree of interference was 1.4 nmol/L. In 42 female patients with varying degrees of interference, identified on routine assay, regression analysis showed strong association between dehydroepiandrosterone sulphate (DHEA-S) and interference (direct-minus-extracted testosterone) ( r = 0.77, P<0.001).

Conclusions: Given that DHEA-S is present in very variable amounts in blood, it is possible that even with a low cross reactivity, DHEA-S or one of its metabolites significantly interferes in the testosterone assay when at higher concentrations.
Potentially clinically toxic concentrations of whole blood manganese in a patient fed enterally with a high tea consumption
Authors: Ross Colleen , O'Reilly Dennis St J , McKee Ruth
Published: April 2006

This report describes a 37-year-old female patient who after seven years on intermittent overnight enteral feeding supplementation was noted to have an increased whole blood manganese concentration. Manganese toxicity is well documented after pathological absorption through inhalation via the lungs, or after intravenous administration to patients on long-term total parenteral nutrition. A dietary history revealed high tea consumption. The association between high blood manganese concentrations and enteral/oral nutrition does not appear to have previously been described.
Exonic deletions as a cause of erythropoietic protoporphyria
Authors: Wood Lisa H , Whatley Sharon D , McKenna Kevin , Badminton Michael N
Published: April 2006

Erythropoietic protoporphyria (EPP) is an inherited disorder that results from partial deficiency of ferrochelatase (FECH), the terminal enzyme of haem biosynthesis. Current methods that examine the exons and their flanking regions of the FECH gene fail to identify mutations in about one in seven of families with EPP. The presence in some families of intragenic deletions that are not identifiable by current methods for sequencing the FECH gene may partly explain the low sensitivity of mutation detection in EPP. Here we describe the identification by gene dosage analysis of a deletion of exons 3 and 4 in a family with EPP in whom a mutation had not been found by sequencing-based methods.
The LH/FSH ratio has little use in diagnosing polycystic ovarian syndrome
Authors: Cho Li Wei , Jayagopal Vijay , Kilpatrick Eric S , Holding Stephen , Atkin Stephen L
Published: April 2006

Background: The luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio is often requested to help diagnose polycystic ovarian syndrome (PCOS) despite a recent consensus recommending against its use. This study aimed to compare the variability of the LH/FSH ratio in PCOS with that of normal menstruating women over a full cycle in order to establish the diagnostic utility, or otherwise, of the test.

Methods: Twelve women with PCOS and 11 matched controls had blood collected at four-day intervals on 10 consecutive occasions over a complete menstrual cycle.

Results: The median LH/FSH ratio for individual subjects did not differ significantly between the PCOS and the non-affected group (1.6 versus 1.2, P=0.14). Only 7.6% of samples from PCOS patients had an LH/FSH ratio above three, compared with 15.6% of samples from normal subjects.

Conclusion: This study confirms that measurement of the LH/FSH ratio is of limited use in the diagnosis of PCOS.
Clinical expression of C282Y homozygous HFE haemochromatosis at 14 years of age
Authors: Rossi Enrico , Wallace Daniel F , Subramaniam V Nathan , St Pierre Timothy G , Mews Catherine , Jeffrey Gary P
Published: April 2006

A 14-year-old boy who presented with debilitating lethargy was shown to have an elevated serum ferritin of 572 μg/L and a C282Y homozygous HFE genotype. Liver iron concentration was measured non-invasively by magnetic resonance imaging, which revealed a liver iron concentration of 59 μmol/g dry weight (children's reference range <14). The early phenotypic expression was further investigated by screening genomic DNA for the presence of co-inherited mutations in genes responsible for non- HFE haemochromatosis. Coding regions and splice sites in genes encoding hepcidin and haemojuvelin were sequenced and previously described mutations in ferroportin 1 and transferrin receptor 2 genes were screened. Although no mutations were found, the most likely cause for the early expression is the presence of novel mutations or gene(s).
HLA class II DRB1 polymorphism in Argentinians undergoing chronic Trypanosoma cruzi infection
Authors: García Borrás Silvia , Diez Cristina , Cotorruelo Carlos , Pellizon Oscar , Biondi Claudia , Beloscar Juan , Bottasso Oscar , Racca Amelia
Published: April 2006

DNA typing of human lymphocyte antigen ( HLA)-dicloro-1-[beta]-D-ribofuranosyl-benzimidazole 1 ( DRB1) alleles in 35 individuals serologically positive for T. cruzi and in 41 healthy controls was performed. DRB1* 0409 allele was significantly more prevalent in seropositive individuals, with a trend being also observed for the DRB1* 0701 and DRB1* 1503 alleles. Although statistically insignificant, the latter was found more frequent in cases with cardiomyopathy.
Medication Safety: Occurrence and Impact of Unanticipated Variation in Intravenous Methotrexate Dosing
Authors: Parshuram Christopher S , Dupuis L Lee , To Teresa , Weitzman Sheila S , Koren Gideon , Laupacis Andreas
Published: April 2006

Background:

Studies using direct measurement suggest that the doses of up to 65% of drug infusions are outside industry standards. These preparation-associated errors occur despite routine safety procedures. As of April 5, 2006, the clinical impact of these errors had not been evaluated.

Objective:

To measure the occurrence and associated clinical outcomes of variations in intravenous methotrexate dosing.

Methods:

A prospective observational study was performed on 47 methotrexate infusions of 800 mg/m2 that were administered to 19 children with acute lymphoblastic leukemia. Serum methotrexate concentrations were measured at the end of the infusions, which were administered over 24 hours. The total methotrexate dose was determined by direct measurement of the concentration and the volume of each infusion.

Results:

Dosing errors greater than or equal to 10% occurred in 11 (23%) infusions and ranged from –61% to 55% of the ideal dose. Repeated measures regression analysis found the measured total methotrexate dose was not significantly associated with the serum methotrexate concentration (p = 0.58) or with clinical toxicities. The methotrexate dose administered over the last hours of infusion (p = 0.006) and the serum creatinine level at diagnosis (p = 0.05) were the most significant predictors of the methotrexate concentration. High methotrexate concentrations were significantly associated with increased hepatic aminotransferase levels; however, the degree of elevation was of limited clinical relevance.

Conclusions:

While unexpected errors in drug dosing are more common than is suggested by other methods, the clinical impact observed in this model of methotrexate infusion was not demonstrably greater than medication errors described by other methods. Subsequent studies in this model of dosing error will require larger sample sizes, and other drugs should be evaluated.
Patient Safety and Quality Improvement Act of 2005
Authors: Fassett William E
Published: April 2006

Objective:

To review Public Law (PL) 109-41—the Patient Safety and Quality Improvement Act of 2005 (PSQIA)—and summarize key medication error research that contributed to congressional recognition of the need for this legislation.

Data Sources:

Relevant publications related to medication error research, patient safety programs, and the legislative history of and commentary on PL 109-41, published in English, were identified by MEDLINE, PREMEDLINE, Thomas (Library of Congress), and Internet search engine–assisted searches using the terms healthcare quality, medication error, patient safety, PL 109-41, and quality improvement. Additional citations were identified from references cited in related publications.

Study Selection and Data Extraction:

All relevant publications were reviewed. Summarization of the PSQIA was carried out by legal textual analysis.

Data Synthesis:

PL 109-41 provides privilege and confidentiality for patient safety work product (PSWP) developed for reporting to patient safety organizations (PSOs). It does not establish federal mandatory reporting of significant errors; rather, it relies on existing state reporting systems. The Act does not preempt stronger state protections for PSWP. The Agency for Healthcare Research and Quality is directed to certify PSOs and promote the establishment of a national network of patient safety databases. Whistleblower protection and penalties for unauthorized disclosure of PSWP are among its enforcement mechanisms.

Conclusions:

The Act protects clinicians who report minor errors to PSOs and protects the information from disclosure, but providers must increasingly embrace a culture of interdisciplinary concern for patient safety if this protection is to have real impact on patient care.
Generating inferences from written and spoken language: A comparison of children with visual impairment and children with sight
Authors: Edmonds Caroline J. , Pring Linda
Published: April 2006

The two experiments reported here investigated the ability of sighted children and children with visual impairment to comprehend text and, in particular, to draw inferences both while reading and while listening. Children were assigned into ‘comprehension skill’ groups, depending on the degree to which their reading comprehension skill was in line with that predicted by their decoding skill. They then read (either print or Braille) and listened to a series of novel short stories. These were followed by a series of questions, which required either the generation of inferences, or an answer that could be taken literally from the text. The results suggest that children with and without sight are comparable in their ability to draw inferences, and that children with visual impairment show an advantage for literal questions under auditory presentation.
The role of experience and discourse in children's developing understanding of pretend play actions
Authors: Rakoczy Hannes , Tomasello Michael , Striano Tricia
Published: April 2006

The present work investigated the development of an explicit understanding of pretend play actions. Study 1 revealed a long décalage between earlier implicit understanding of pretence as an intentional activity and a later more explicit understanding. Study 2 was a training study. It tested for two factors – systematic pretence experience and explicit pretence discourse – that may be important in development from early implicit to later explicit pretence understanding. Two training groups of 3.5‐year‐old children received the same pretence experiences involving systematic contrasts between pretending, really performing and trying to perform actions. In the ‘explicit’ group, these experiences were talked about with explicit ‘pretend to’ and ‘pretend that’ language. In the ‘implicit’ group no such discourse was used, but only implicit discourse in talking about pretence versus real actions. The two training groups were compared with a control group that received functional play experience. After training, only the explicit group showed improvement in their explicit pretence understanding. In none of the groups was there any transfer to tasks tapping mental state understanding, false belief (FB) and appearance‐reality, (A‐R). The findings are discussed in the context of current theories about the developmental relations between pretence, discourse, and mental state understanding.
Imitation and representational development in young children with Down syndrome
Authors: Wright Ingram , Lewis Vicky , Collis Glyn M.
Published: April 2006

Competence in object search and pretend play are argued to reflect young children's representational abilities and appear delayed in children with Down syndrome relative to social and imitative skills. This paper explores the effects on object search and play of this social strength in children with Down syndrome. Three experiments compared performance on traditional tasks with modified tasks designed to assess the role of imitation in object search and pretend play. Children with Down syndrome, relative to typically‐developing children, were able and willing to imitate hiding actions when no object was hidden (Experiment 1). When imitation was prevented in object search, children with Down syndrome searched less effectively than typically‐developing children (Experiment 2). In play, children with Down syndrome expressed more willingness to imitate a counter‐functional action, modelled by the experimenter, despite apparent competence in spontaneous functional play (Experiment 3). These findings indicate that object search and play behaviours of children with Down syndrome rely more heavily on imitation than is the case for typically‐developing children. The implications for the development of children with Down syndrome and models of representational development are discussed.
Intermittent Ibandronate Preserves Bone Quality and Bone Strength in the Lumbar Spine After 16 Months of Treatment in the Ovariectomized Cynomolgus Monkey
Authors: Müller Ralph , Hannan Mary , Smith Susan Y , Bauss Frieder
Published: April 2006

The dose-dependent effect of ibandronate treatment on bone mass and architecture was assessed in a large animal study of OVX monkeys using μCT for quantitative bone morphometry and biomechanical testing for measures of bone strength. The study showed that intermittent ibandronate preserved lumbar spine bone quality and strength in these animals after 16 months of treatment.

Introduction: Ibandronate is a bisphosphonate, which is a class of compounds that, in pharmacologically active doses, not only suppresses bone resorption and turnover but also prevents loss of bone mass and strength in the ovariectomized (OVX) rat.

Materials and Methods: We evaluated the effects of ibandronate on bone mass and architecture in the OVX cynomolgus macaque. Sixty-one adult female macaques were divided into five groups (N = 11–15): sham control, OVX control, and OVX low- (10 μg/kg), medium- (30 μg/kg), and high- (150 μg/kg) dose ibandronate. Treatment was administered by intravenous bolus injection every 30 days for 16 months starting at ovariectomy. This dosing schedule is equivalent to a 3-monthly dosing regimen in human subjects over 4 years. Animals were killed at the conclusion of the study, and excised bone specimens of the first lumbar vertebra (L1) were evaluated for quantitative bone densitometry, morphometry, and mechanical properties. Architectural parameters were assessed by μCT including direct 3D bone morphometry. A measure of specimen strength was obtained using destructive compression testing.

Results and Conclusions: A significant loss of bone mass and related changes in bone architecture after ovariectomy resulted in a reduction of whole bone strength as expressed by high correlations between architectural and mechanical properties. In this analysis, BMC was the best single predictor of whole bone strength (r2 = 67%). Nevertheless, including architectural indices in a multiple linear regression analysis increased that prediction to 88%. With respect to the treatment, the medium- and high-dose groups were not significantly different from the sham group for all bone mineral and structural parameters. Additionally, significant differences were seen for all measured parameters between the high-dose group and the OVX group, and for some parameters, between the medium-dose group and the OVX group. Intermittent ibandronate treatment effectively and dose-dependently prevented bone loss, architectural deterioration, and strength reduction in the lumbar spine of OVX monkeys.
Neridronate Prevents Bone Loss in Patients Receiving Androgen Deprivation Therapy for Prostate Cancer
Authors: Morabito Nancy , Gaudio Agostino , Lasco Antonino , Catalano Antonino , Atteritano Marco , Trifiletti Aldo , Anastasi Giuseppina , Melloni Darwin , Frisina Nicola
Published: April 2006

Today, androgen deprivation therapy is a cornerstone of treatment for advanced prostate cancer, although it presents important complications such as osteoporosis. Neridronate, a relatively new bisphosphonate, is able to prevent bone loss in patients with prostate cancer during androgen ablation.

Introduction: Androgen-deprivation therapy (ADT) is a cornerstone of treatment for advanced prostate cancer. This therapy has iatrogenic complications, such as osteoporosis. The aim of our study was to evaluate the efficacy of neridronate, a relatively new bisphosphonate, to prevent bone loss during androgen ablation.

Materials and Methods: Forty-eight osteoporotic patients with prostate cancer, treated with 3-month depot triptorelina, were enrolled and randomly assigned to two different treatment groups: group A (n = 24) was treated with a daily calcium and cholecalciferol supplement (500 mg of elemental calcium and 400 IU cholecalciferol), and group B (n = 24) received in addition to the same daily calcium and cholecalciferol supplement, 25 mg of neridronate given intramuscularly every month. All patients also received bicalutamide for 4 weeks. Lumbar and femoral BMD was evaluated by DXA at baseline and after 1 year of therapy; moreover, deoxypyridinoline (DPD) and bone alkaline phosphatase (BALP) were determined at the beginning, midway through, and at the end of the study.

Results: After 6 and 12 months, whereas patients treated only with calcium and cholecalciferol (group A) showed a marked bone loss, with increased levels of DPD and BALP compared with baseline values, patients treated also with neridronate (group B) had substantially unchanged levels of these markers. After 1 year of treatment, lumbar and total hip BMD decreased significantly in patients treated only with calcium and cholecalciferol (group A), whereas it did not change significantly at any skeletal site in patients treated also with neridronate (group B). No relevant side effects were recorded during our study.

Conclusions: Neridronate is an effective treatment in preventing bone loss in the hip and lumbar spine in men receiving ADT for prostate cancer.
Association Between Exercise and Pubertal BMD Is Modulated by Estrogen Receptor α Genotype
Authors: Suuriniemi Miia , Mahonen Anitta , Kovanen Vuokko , Alén Markku , Lyytikäinen Arja , Wang Qingju , Kröger Heikki , Cheng Sulin
Published: April 2006

Genetic and environmental factors contribute to bone mass, but the ways they interact remain poorly understood. This study of 245 pre- and early pubertal girls found that the PvuII polymorphism in the ER-α gene modulates the effect of exercise on BMD at loaded bone sites.

Introduction: Impaired achievement of bone mass at puberty is an important risk factor for the development of osteoporosis in later life. Genetic, as well as environmental, factors contribute to bone mass, but the ways they interact with each other remain poorly understood.

Materials and Methods: We investigated the interaction between a PvuII polymorphism at the ER-α gene and physical activity (PA) on the modulation of bone mass and geometry in 245 10- to 13-year-old pre- and early pubertal Finnish girls. Level of PA was assessed using a questionnaire. Bone properties were measured using DXA and pQCT. The analyses were controlled for the effects of Tanner stage and body size index.

Results: Girls with heterozygote ER-α genotype (Pp) and high PA had significantly higher bone mass and BMD, as well as thicker cortex, at loaded bone sites than their low-PA counterparts. No differences were found in bone properties of the distal radius, which is not a weight-bearing bone. Bone properties did not differ in either homozygote groups (PP and pp) regardless of the PA level.

Conclusions: These findings suggest that the PvuII polymorphism in the ER-α gene may modulate the effect of exercise on BMD at loaded bone sites. The heterozygotes may benefit most from the effect of exercise, whereas neither of the homozygote groups received any significant improvement from high PA. Furthermore, high PA may hide the genetic influence on bone. Indeed, it seems that one may compensate one's less favorable Pp genotype by increasing leisure PA at early puberty.
Anti-Hip Fracture Efficacy of Bisphosphonates: A Bayesian Analysis of Clinical Trials
Authors: Nguyen Nguyen D , Eisman John A , Nguyen Tuan V
Published: April 2006

In postmenopausal women, the efficacy of bisphosphonates on hip fracture risk is not clear. This Bayesian meta-analysis quantitatively reviewed data from 12 randomized clinical trials with 18,667 patients and found that bisphosphonate treatment was associated with a reduced risk for hip fracture by 42%.

Introduction: The efficacy of antiresorptive bisphosphonates therapy on reducing hip fracture is not clear, because evidence from randomized clinical trials (RCTs) is inconclusive. This study was undertaken to quantitatively assess the effect of bisphosphonates on hip fracture using literature review and meta-analysis.

Materials and Methods: Bayesian methods of meta-analysis were applied to synthesize data from 12 RCTs available between 1990 and 2004. The trials involved 18,667 postmenopausal women with low BMD or osteoporosis who have been followed or treated for between 1 and 4 years. The medications used were etidronate (two trials) alendronate (six trials), risedronate (three trials), and clodronate (one trial). The primary endpoint was the incidence of hip fracture.

Results: When data from all 12 studies were pooled, treatment with bisphosphonates was associated with a reduced risk for hip fracture by 42% (relative risk {RR}, 0.58; 95% credible interval {CrI}, 0.42-0.80). The absolute rate reduction was 52 hip fractures per 10,000 women (95% CrI, 4–110) for a period of 3-year treatment. The probability that bisphosphonates are better than placebo (in reducing hip fracture risk by at least 30%) was 0.90.

Conclusions: In postmenopausal women with osteoporosis or low BMD, bisphosphonate treatment is associated with reduced risk of hip fracture.
Immune Regulation of 25-Hydroxyvitamin-D3-1α-Hydroxylase in Human Monocytes
Authors: Stoffels Katinka , Overbergh Lut , Giulietti Annapaula , Verlinden Lieve , Bouillon Roger , Mathieu Chantal
Published: April 2006

Monocytes express 1α-hydroxylase, the enzyme responsible for final hydroxylation of vitamin D3, in response to IFNγ and CD14/TLR4 activation. Cross-talk between the JAK-STAT, the NF-κB, and the p38 MAPK pathways is necessary, and direct binding of C/EBPβ to its recognition sites in the promoter of the 1α-hydroxylase gene is a prerequisite.

Introduction: The activated form of vitamin D3, 1,25(OH)2D3, known for its action in bone and mineral homeostasis, has important immunomodulatory effects. 1,25(OH)2D3 modulates the immune system through specific nuclear receptors, whereas macrophages produce 1,25(OH)2D3. In monocytes, the expression of 1α-hydroxylase, the enzyme responsible for final hydroxylation of vitamin D3, is regulated by immune stimuli. The aim of this study was to elucidate the intracellular pathways through which interferon (IFN)γ and Toll-like receptor (TLR) modulation regulate expression of 1α-hydroxylase in monocytes/macrophages.

Materials and Methods: Monocytes were isolated from peripheral blood mononuclear cells (PBMCs) and stimulated with IFNγ (12.5 U/ml) and/or lipopolysaccharide (LPS; 100 ng/ml) for 48 h. The following inhibitors were used: janus kinase (JAK) inhibitor AG490 (50 μM), NF-κB inhibitor sulfasalazine (0.25 mM), p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 (5 μM). 1α-hydroxylase mRNA expression was monitored by qRT-PCR. Phosphorylation of transcription factors was studied by Western blotting. Transfection of mutated or deletion promoter constructs, cloned in the pGL3-luciferase reporter plasmid, were performed in the RAW264.7 cell line. Cells were stimulated with IFNγ (100 U/ml) and LPS (100 μg/ml), and promoter activity was studied. Binding of signal transducer and activator of transcription (STAT)1α, NF-κB, and C/EBPβ to their respective binding sites in the promoter was analyzed by gel shift assays.

Results: 1α-hydroxylase mRNA expression in monocytes is synergistically induced by IFNγ and CD14/TLR4 ligation and paralleled by 1,25(OH)2D3 production. This induction requires the JAK-STAT, NF-κB, and p38 MAPK pathways. Each of them is essential, because blocking individual pathways is sufficient to block 1α-hydroxylase expression (JAK inhibitor, 60% inhibition, p < 0.01; NF-κB inhibitor, 70% inhibition, p < 0.05; p38 MAPK inhibitor, 95% inhibition, p < 0.005). In addition, we show the involvement of the p38 MAPK pathway in phosphorylation of C/EBPβ. Direct binding of C/EBPβ to its recognition sites in the 1α-hydroxylase promoter is necessary to enable its immune-stimulated upregulation.

Conclusion: IFNγ and CD14/TLR4 binding regulate expression of 1α-hydroxylase in monocytes in a synergistic way. Combined activation of the JAK-STAT, p38 MAPK, and NF-κB pathways is necessary, with C/EBPβ most probably being the essential transcription factor controlling immune-mediated transcription.
Incidence of Primary Hyperparathyroidism in Rochester, Minnesota, 1993–2001: An Update on the Changing Epidemiology of the Disease
Authors: Wermers Robert A , Khosla Sundeep , Atkinson Elizabeth J , Achenbach Sara J , Oberg Ann L , Grant Clive S , Melton L Joseph
Published: April 2006

We updated the incidence of primary hyperparathyroidism in Rochester, Minnesota. The lower rates previously noted persisted, whereas parathyroidectomies at our institution remained high. These data suggest an etiologic factor may be responsible for the peak incidence in the 1970s.

Introduction: Automated serum calcium measurements were associated with a dramatic rise in primary hyperparathyroidism in the early 1970s, but a progressive decline in the incidence thereafter was unexpected and suggested a fundamental change in the epidemiology of the disease. Our objective was to evaluate trends in the incidence of primary hyperparathyroidism since 1992.

Materials and Methods: In this population-based descriptive study, Rochester, MN, residents who met defined diagnostic criteria for primary hyperparathyroidism from January 1993 through December 2001 were identified through the medical record linkage system of the Rochester Epidemiology Project and the Mayo Clinic Laboratory Information System. Changes in incidence were evaluated by Poisson regression.

Results: Altogether, 136 Rochester residents (94 women and 42 men) were newly identified with primary hyperparathyroidism in 1993–2001. Their mean age was 56 years, and 93% had definite disease. The overall age- and sex-adjusted (to 2000 U.S. whites) rate during this period was 21.6 per 100,000 person-years, which was less than the annual rate of 29.1 per 100,000 observed in 1983–1992 and 82.5 per 100,000 in July 1974–1982. Although community incidence declined, the number of parathyroidectomies performed at our institution increased during the same period. Serum calcium was deleted from the automated chemistry panel in June 1996, but most subjects remained asymptomatic at diagnosis (95%) with mild hypercalcemia. The majority of subjects were observed without parathyroid surgery (75%), and there was minimal impact on patient management from the 1990 NIH consensus conference on asymptomatic primary hyperparathyroidism.

Conclusions: The lower incidence of primary hyperparathyroidism noted through 1992 has persisted in our community through 2001, whereas parathyroidectomies at our institution remained high. These data suggest that some underlying etiologic factor, in addition to the introduction of automated serum calcium testing, may have been responsible for the peak incidence in the 1970s.
Initial Characterization of PTH-Related Protein Gene-Driven lacZ Expression in the Mouse
Authors: Chen Xuesong , Macica Carolyn M , Dreyer Barbara E , Hammond Vicki E , Hens Julie R , Philbrick William M , Broadus Arthur E
Published: April 2006

The PTHrP gene generates low-abundance mRNA and protein products that are not easily localized by in situ hybridization histochemistry or immunohistochemistry. We report here a PTHrP-lacZ knockin mouse in which β-gal activity seems to provide a simple and sensitive read-out of PTHrP gene expression.

Introduction: PTH-related protein (PTHrP) is widely expressed in fetal and adult tissues, typically as low-abundance mRNA and protein products that maybe difficult to localize by conventional methods. We created a PTHrP-lacZ knockin mouse as a means of surveying PTHrP gene expression in general and of identifying previously unrecognized sites of PTHrP expression.

Materials and Methods: We created a lacZ reporter construct under the control of endogenous PTHrP gene regulatory sequences. The AU-rich instability sequences in the PTHrP 3′ untranslated region (UTR) were replaced with SV40 sequences, generating products with lacZ/β gal kinetics rather than those of PTHrP. A nuclear localization sequence was not present in the construct.

Results: We characterized β-galactosidase (β-gal) activity in embryonic whole mounts and in the skeleton in young and adult animals. In embryos, we confirmed widespread PTHrP expression in many known sites and in several novel epidermal appendages (nail beds and footpads). In costal cartilage, β-gal activity localized to the perichondrium but not the underlying chondrocytes. In the cartilaginous molds of forming long bones, β-gal activity was first evident at the proximal and distal ends. Shortly after birth, the developing secondary ossification center formed in the center of this PTHrP-rich chondrocyte population. As the secondary ossification center developed, it segregated this population into two distinct PTHrP β-gal+ subpopulations: a subarticular subpopulation immediately subjacent to articular chondrocytes and a proliferative chondrocyte subpopulation proximal to the chondrocyte columns in the growth plate. These discrete populations remained into adulthood. β-gal activity was not identified in osteoblasts but was present in many periosteal sites. These included simple periosteum as well as fibrous tendon insertion sites of the so-called bony and periosteal types; the β-gal-expressing cells in these sites were in the outer fibrous layer of the periosteum or its apparent equivalents at tendon insertion sites. Homozygous PTHrP-lacZ knockin mice had the expected chondrodysplastic phenotype and a much expanded region of proximal β-gal activity in long bones, which appeared to reflect in large part the effects of feedback signaling by Indian hedgehog on proximal cell proliferation and PTHrP gene expression.

Conclusions: The PTHrP-lacZ mouse seems to provide a sensitive reporter system that may prove useful as a means of studying PTHrP gene expression.
Effect of Age-Related Chronic Immobility on Markers of Bone Turnover
Authors: Chen Jian Sheng , Cameron Ian D , Cumming Robert G , Lord Stephen R , March Lyn M , Sambrook Philip N , Simpson Judy M , Seibel Markus J
Published: April 2006

The effects of acute immobilization on bone turnover are well known, but the effects of chronic hypomobility with aging have not been studied. In a cohort of 1064 frail elderly subjects, immobility was significantly associated with serum PINP but not serum CTx after adjusting for confounders. The effect of immobility may be more marked on bone formation than on bone resorption.

Introduction: Accelerated bone turnover and rapid bone loss caused by acute immobilization is well recognized, but the effects of age-related chronic reduction in mobility on bone turnover have been less well studied. We assessed the associations between bone turnover and measures of mobility in a cohort of elderly subjects.

Materials and Methods: We measured serum levels of the aminoterminal propeptide of type I collagen (PINP), a marker of bone formation, and serum concentrations of the carboxyterminal telopeptide of type I collagen (CTx), a marker of bone resorption, as well as serum intact PTH, serum 25 hydroxyvitamin D (25OHD), mobility, and static balance in a well-characterized sample of 1064 elderly men and women living in residential aged care facilities. Serum creatinine, phosphate, albumin, and calcium were measured in a randomly selected subgroup of 447 subjects.

Results: The subjects were elderly and frail; their mean age was 86.0 years (range, 65–101 years); 69% used a walking aid; and 77% were vitamin D deficient (serum 25OHD level < 39 nM). Both serum PINP and CTx increased with age in both sexes. Elevated PINP or CTx was significantly correlated with high PTH, creatinine, and albumin in both genders, except for albumin in women. Age- and gender-adjusted serum CTx and PINP were significantly higher in those with poorer mobility and those with worse static balance. In multivariate analyses, higher serum PINP but not CTx was associated with poorer mobility and worse static balance.

Conclusions: Our findings suggest that poor mobility contributes to the state of accelerated bone turnover usually seen in the elderly. The effect of chronic relative immobility may be more marked on bone formation than bone resorption.
Pretreatment Levels of Bone Turnover and the Antifracture Efficacy of Alendronate: The Fracture Intervention Trial
Authors: Bauer Douglas C , Garnero Patrick , Hochberg Marc C , Santora Art , Delmas Pierre , Ewing Susan K , Black Dennis M
Published: April 2006

The influence of pretreatment bone turnover on alendronate efficacy is not known. In the FIT, we examined the effect of pretreatment bone turnover on the antifracture efficacy of daily alendronate given to postmenopausal women. The nonspine fracture efficacy of alendronate was significantly greater among both osteoporotic and nonosteoporotic women with higher baseline levels of the bone formation marker PINP.

Introduction: Previous trials have shown that high bone turnover is associated with greater increases in BMD among bisphosphonate-treated women. The influence of pretreatment bone turnover levels on antifracture efficacy has not been well studied.

Materials and Methods: We randomized women 55–80 years of age with femoral neck BMD T scores ≤ −1.6 to alendronate (ALN), 5–10 mg/day (n = 3105), or placebo (PBO; n = 3081). At baseline, 3495 women were osteoporotic (femoral neck BMD T score ≤ −2.5 or prevalent vertebral fracture), and 2689 were not osteoporotic (BMD T score > −2.5 and no prevalent vertebral fracture). Pretreatment levels of bone-specific alkaline phosphatase (BSALP), N-terminal propeptide of type 1 collagen (PINP), and C-terminal cross-linked telopeptide of type 1 collagen (sCTx) were measured in all participants using archived serum (20% fasting). The risk of incident spine and nonspine fracture was compared in ALN- and PBO-treated subjects stratified into tertiles of baseline bone marker level.

Results and Conclusions: During a mean follow-up of 3.2 years, 492 nonspine and 294 morphometric vertebral fractures were documented. Compared with placebo, the reduction in nonspine fractures with ALN treatment differed significantly among those with low, intermediate, and high pretreatment levels of PINP levels (p = 0.03 for trend). For example, among osteoporotic women in the lowest tertile of pretreatment PINP (<41.6 ng/ml), the ALN versus PBO relative hazard for nonspine fracture was 0.88 (95% CI: 0.65, 1.21) compared with a relative hazard of 0.54 (95% CI: 0.39, 0.74) among those in the highest tertile of PINP (>56.8 ng/ml). Results were similar among women without osteoporosis at baseline. Although they did not reach statistical significance, similar trends were observed with baseline levels of BSALP. Conversely, spine fracture treatment efficacy among osteoporotic women did not differ significantly according to pretreatment marker levels. Spine fracture treatment efficacy among nonosteoporotic women was related to baseline BSALP (p = 0.05 for trend). In summary, alendronate nonspine fracture efficacy is greater among both osteoporotic and nonosteoporotic women with high pretreatment PINP. If confirmed in other studies, these findings suggest that bisphosphonate treatment may be most effective in women with elevated bone turnover.
Human Osteoblast Precursors Produce Extracellular Adenosine, Which Modulates Their Secretion of IL-6 and Osteoprotegerin
Authors: Evans Bronwen AJ , Elford Carole , Pexa Annette , Francis Karen , Hughes Alis C , Deussen Andreas , Ham Jack
Published: April 2006

We showed that human osteoprogenitor cells produced adenosine and expressed ecto-5′-nucleotidase and all four adenosine receptor subtypes. Adenosine stimulated IL-6 but inhibited osteoprotegerin secretion, suggesting that adenosine is a newly described regulator of progenitor cell function.

Introduction: Maintaining skeletal homeostasis relies on there being a balance between bone formation and resorption; an imbalance between these processes can lead to diseases such as osteoporosis and rheumatoid arthritis. Recent reports showed that locally produced ATP, acting through P2 receptors, has pronounced effects on bone formation. However, ATP can be enzymatically cleaved to adenosine that has little or no activity at P2 receptors but mediates its action through the P1 family of receptors. We studied whether adenosine may also have an important role in controlling bone cell differentiation and function.

Materials and Methods: Extracellular adenosine levels were analyzed by high-performance liquid chromatography in HCC1 and bone marrow stromal (BMS) cells. Ecto-5′-nucleotidase (CD73) expression and activity was determined by RT-PCR, immunocytochemistry, and the cleavage of etheno-AMP to ethenoadenosine. Adenosine receptor expression and activity were determined by RT-PCR and cAMP measurements. The effects of adenosine receptor agonists on IL-6, osteoprotegerin (OPG), and RANKL expression were determined by ELISA and QRT-PCR.

Results: HCC1 and BMS cells produce adenosine and express CD73 and all four adenosine receptor subtypes. The A2b receptor was shown to be functionally dominant in HCC1 cells, as determined by cAMP production and in its stimulation of IL-6 secretion. Adenosine receptor agonism also inhibited OPG secretion and OPG but not RANKL mRNA expression.

Conclusions: Our findings show that HCC1 and primary BMS cells produce adenosine, express CD73 and all four adenosine receptor subtypes. In HCC1 cells, adenosine has a potent stimulatory action on IL-6 secretion but an inhibitory action on OPG expression. These data show for the first time that adenosine may be an important regulator of progenitor cell differentiation and hence an important local contributor to the regulation of bone formation and resorption.
Polymorphisms in the Aromatase Gene Predict Areal BMD as a Result of Affected Cortical Bone Size: The GOOD Study
Authors: Lorentzon Mattias , Swanson Charlotte , Eriksson Anna-Lena , Mellström Dan , Ohlsson Claes
Published: April 2006

The association between aromatase gene polymorphisms, bone parameters, and sex steroid levels was studied in 1068 men (18.9 ± 0.6 years of age). Several aromatase gene polymorphisms were found to be associated with serum testosterone levels and cortical bone size but not with trabecular volumetric BMD.

Introduction: Both testosterone and estrogens are important for the male skeleton. Aromatase, the product of the CYP19 gene, is the key enzyme in the conversion of testosterone to estradiol. A functional aromatase enzyme has been shown to be crucial for the normal development of the male skeleton. The role of genetic polymorphisms in the aromatase gene for trabecular volumetric BMD (vBMD) and cortical bone size has not previously been studied in men.

Materials and Methods: The Gothenburg Osteoporosis and Obesity Determinants (GOOD) study consists of 1068 men (18.9 ± 0.6 years of age). The TTTA repeat polymorphism (TTTAn) and three single nucleotide polymorphisms (SNPs), including the Val80 SNP, in the CYP19 gene, were analyzed. Serum levels of testosterone and estradiol were measured. Areal BMD (aBMD) was measured by DXA, whereas cortical and trabecular vBMD and cortical bone size were measured by pQCT.

Results: The TTTAn and the Val80 genotypes were independent predictors of aBMD of the radius, lumbar spine, total body, and cortical bone size (cortical cross-sectional area and thickness) of both the radius and tibia. In contrast, trabecular vBMD was not associated with CYP19 polymorphisms. Homozygosity for the long allele (>9 repeats) of the TTTAn and for the G allele of the Val80 SNP was associated with the highest aBMD and testosterone levels as well as with the greatest cortical bone size. Regression analyses indicated that the association with aBMD was mediated through affected cortical bone size.

Conclusions: We showed, in a large well-characterized cohort of men at the age of peak bone mass, that several common aromatase polymorphisms are associated with cortical bone size but not with trabecular vBMD. One may speculate that affected CYP19 activity, resulting in altered testosterone levels during pubertal development, might contribute to the association between CYP19 polymorphisms and cortical bone size.
Glucocorticoid-Treated Mice Have Localized Changes in Trabecular Bone Material Properties and Osteocyte Lacunar Size That Are Not Observed in Placebo-Treated or Estrogen-Deficient Mice
Authors: Lane Nancy E , Yao Wei , Balooch Mehdi , Nalla Ravi K , Balooch Guive , Habelitz Stefan , Kinney John H , Bonewald Lynda F
Published: April 2006

This study compares changes in bone microstructure in 6-month-old male GC-treated and female ovariectomized mice to their respective controls. In addition to a reduction in trabecular bone volume, GC treatment reduced bone mineral and elastic modulus of bone adjacent to osteocytes that was not observed in control mice nor estrogen-deficient mice. These microstructural changes in combination with the macrostructural changes could amplify the bone fragility in this metabolic bone disease.

Introduction: Patients with glucocorticoid (GC)-induced secondary osteoporosis tend to fracture at higher bone mineral densities than patients with postmenopausal osteoporosis. This suggests that GCs may alter bone material properties in addition to BMD and bone macrostructure.

Materials and Methods: Changes in trabecular bone structure, elastic modulus, and mineral to matrix ratio of the fifth lumbar vertebrae was assessed in prednisolone-treated mice and placebo-treated controls for comparison with estrogen-deficient mice and sham-operated controls. Compression testing of the third lumbar vertebrae was performed to assess whole bone strength.

Results: Significant reductions in trabecular bone volume and whole bone strength occurred in both prednisolone-treated and estrogen-deficient mice compared with controls after 21 days (p < 0.05). The average elastic modulus over the entire surface of each trabecula was similar in all the experimental groups. However, localized changes within the trabeculae in areas surrounding the osteocyte lacunae were observed only in the prednisolone-treated mice. The size of the osteocyte lacunae was increased, reduced elastic modulus around the lacunae was observed, and a “halo” of hypomineralized bone surrounding the lacunae was observed. This was associated with reduced (nearly 40%) mineral to matrix ratio determined by Raman microspectroscopy. These localized changes in elastic modulus and bone mineral to matrix ratio were not observed in the other three experimental groups.

Conclusions: Based on these results, it seems that GCs may have direct effects on osteocytes, resulting in a modification of their microenvironment. These changes, including an enlargement of their lacunar space and the generation of a surrounding sphere of hypomineralized bone, seem to produce highly localized changes in bone material properties that may influence fracture risk.