bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiac Safety Analysis of Doxorubicin and Cyclophosphamide Followed by Paclitaxel With or Without Trastuzumab in the North Central Cancer Treatment Group N9831 Adjuvant Breast Cancer Trial
Authors: Perez Edith A. , Suman Vera J. , Davidson Nancy E. , Sledge George W. , Kaufman Peter A. , Hudis Clifford A. , Martino Silvana , Gralow Julie R. , Dakhil Shaker R. , Ingle James N. , Winer Eric P. , Gelmon Karen A. , Gersh Bernard J. , Jaffe Allan S. , Rodeheffer Richard J.
Published: February 2008

Purpose

To assess cardiac safety and potential cardiac risk factors associated with trastuzumab in the NCCTG N9831 Intergroup adjuvant breast cancer trial.

Patients and Methods

Patients with HER2-positive operable breast cancer were randomly assigned to doxorubicin plus cyclophosphamide (AC) followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab then trastuzumab alone (arm C). Left ventricular ejection fraction (LVEF) was evaluated at registration and 3, 6, 9, and 18 to 21 months.

Results

Of 2,992 patients completing AC, 5.0% had LVEF decreases disallowing trastuzumab (decrease below normal: 2.4%, decrease > 15%: 2.6%). There were 1,944 patients with satisfactory or no LVEF evaluation who proceeded to post-AC therapy. Cardiac events (congestive heart failure [CHF] or cardiac death [CD]): arm A, n = 3 (2 CHF, 1 CD); arm B, n = 19 (18 CHF, 1 CD); arm C, n = 19 (all CHF); 3-year cumulative incidence: 0.3%, 2.8%, and 3.3%, respectively. Cardiac function improved in most CHF cases following trastuzumab discontinuation and cardiac medication. Factors associated with increased risk of a cardiac event in arms B and C: older age (P < .003), prior/current antihypertensive agents (P = .005), and lower registration LVEF (P = .033). Incidence of asymptomatic LVEF decreases requiring holding trastuzumab was 8% to 10%; LVEF recovered and trastuzumab was restarted in approximately 50%.

Conclusion

The cumulative incidence of post-AC cardiac events at 3 years was higher in the trastuzumab-containing arms versus the control arm, but by less than 4%. Older age, lower registration LVEF, and antihypertensive medications are associated with increased risk of cardiac dysfunction in patients receiving trastuzumab following AC.
Making the Case for School-Based Health: Where Do We Stand?
Authors: Silberberg Mina , Cantor Joel C.
Published: February 2008

School-based health centers (SBHCs) have proliferated rapidly nation-wide and remain politically popular. This article explores the disconnect between the evidence and the discourse on SBHCs, drawing upon the authors' evaluation of SBHCs in Newark, New Jersey, and a critical assessment of the evaluative literature and public discourse on school clinics to argue that a number of important issues are being overlooked by both research and advocacy. These issues include variations in the health needs and health care resources of different communities and the questions of whether and how SBHCs can best integrate with existing resources to fill unmet local needs. Furthermore, despite the cautions of experts that third-party reimbursement (via traditional fee-for-service insurance or participation in health maintenance organizations) cannot cover clinic expenses and is difficult to obtain, pursuit of reimbursement continues to be a goal of some SBHC sponsors, helping to promote a clinic model that in some communities is very likely not to be the best way to address student needs or to build on clinic strengths. Discussion around SBHCs should focus on diagnosing specific community needs, identifying the best approach to meeting those needs, and seeking funding sources that match the work that needs to be done.
The Unintended Consequences of New Zealand's Primary Health Care Reforms
Authors: Gauld Robin
Published: February 2008

In 2001, the New Zealand government commenced a program to reform the organization of publicly funded primary care services. While there have been several positive results of this reform, including the reduction of patient co-payments and the extension of the range of primary care services, the government's program was a hastily implemented attempt to place primary care, the delivery of which is dominated by private doctors, under firm state control. It was also an attempt to override preexisting arrangements. As such, the government succeeded in its goal of establishing new primary health organizations (PHOs), but there were also significant unintended consequences. As detailed in this article, these consequences include (1) the creation of a labyrinthine funding and organizational system with a variable capacity to deliver on the government's reform objectives, (2) an increase in the power and scope of preexisting doctor organizations combined with a government unable to wrest control over the setting of patient co-payment levels, and (3) an emerging lack of clarity about future directions for the primary health care sector.
Black Markets: The Supply and Demand of Body Parts
Authors: Bard Jennifer S.
Published: February 2008

Black Markets: The Supply and Demand of Body Parts is an important contribution to the body of scholarship and policy analysis about one of the most difficult problems facing contemporary health policy, public health, and bioethics: the fact that the demand for donor organs far outstrips supply. In this book, Michelle Goodwin systematically reviews the general ways in which the United States' current organ-donation and transplantation system negatively affects potential donors and recipients, particularly African Americans. She proposes solving these problems by changing the current system that prohibits payment for organs to one that allows it. However, I argue that the entire discussion of a market-based solution to the problem of a shortage in supply in donor organs suffers from a flaw far greater than the inability to predict how such a market would work, because of a lack of reliable evidence that an offer of compensation would be effective in changing the minds of people who currently decline to donate the organs of their loved ones.
Modulation of Cystathionine β-Synthase Activity by Altering Heme Environment
Authors: Ozaki Shin-ichi , Doi Masafumi , Migita Catharina T
Published: February 2008

Human cystathionine β-synthase (CBS) is unique in bearing not only a catalytically important pyridoxal-5′-phosphate (PLP) but also heme. We have observed the alternation of heme environment under the alkaline condition causes the inactivation of CBS. On the basis of crystal structure, we propose that the change in the axial ligation of heme would modulate CBS activity through the interaction with Arg-266.
Electrochemical Codeposition of Mg–Li Alloys from a Molten KCl–LiCl–MgCl2 System
Authors: Yan Yongde , Zhang Milin , Han Wei , Xue Yun , Cao Dianxue , Yuan Yi
Published: February 2008

This work presents a novel study on electrochemical codeposition of Mg–Li alloys on molybdenum in KCl–LiCl (50:50 wt %) melts containing different concentrations MgCl2 at 943 K. Cyclic voltammograms showed that the underpotential deposition (UPD) of lithium on pre-deposited magnesium leads to the formation of liquid Mg–Li alloys. The codepositon of Mg and Li happens when the current intensity exceeds 0.59 A cm−2 in KCl–LiCl melts containing 5 wt % MgCl2. α, α + β, and β phases Mg–Li alloys with different lithium contents were obtained by galvanostatic electrolysis from KCl–LiCl melts with different concentrations MgCl2.
Understanding speaker attitudes from prosody by adults with Parkinson's disease
Authors: Monetta Laura. , Cheang Henry S. , Pell Marc D.
Published: February 2008

The ability to interpret vocal (prosodic) cues during social interactions can be disrupted by Parkinson's disease, with notable effects on how emotions are understood from speech. This study investigated whether PD patients who have emotional prosody deficits exhibit further difficulties decoding the attitude of a speaker from prosody. Vocally inflected but semantically nonsensical ‘pseudo‐utterances’ were presented to listener groups with and without PD in two separate rating tasks. Task 1 required participants to rate how confident a speaker sounded from their voice and Task 2 required listeners to rate how polite the speaker sounded for a comparable set of pseudo‐utterances. The results showed that PD patients were significantly less able than HC participants to use prosodic cues to differentiate intended levels of speaker confidence in speech, although the patients could accurately detect the polite/impolite attitude of the speaker from prosody in most cases. Our data suggest that many PD patients fail to use vocal cues to effectively infer a speaker's emotions as well as certain attitudes in speech such as confidence, consistent with the idea that the basal ganglia play a role in the meaningful processing of prosodic sequences in spoken language (Pell & Leonard, 2003).
Neurocognitive and functional outcomes in persons recovering from West Nile virus illness
Authors: Sejvar James J. , Curns Aaron T. , Welburg Leonie. , Jones James F. , Lundgren Louisa M. , Capuron Lucile. , Pape John. , Reeves William C. , Campbell Grant L.
Published: February 2008

Long‐term neurocognitive and functional impairments following West Nile virus (WNV) disease are poorly understood. We assessed quality‐of‐life indices and neurocognitive performance in a cohort of 54 persons recovering from one of three WNV disease syndromes (fever [WNF], meningitis [WNM], or encephalitis [WNE]) approximately 1.5 years following acute illness. We compared findings between the three syndromic groups; the study cohort and a demographically similar group of 55 controls from a study of chronic fatigue syndrome (CFS); and the study cohort and a ‘normative’ control population based on cognitive test data. Persistent symptoms, diminished quality of life, and functional impairment were reported by 50% of WNF patients, and 75% each of WNM and WNE patients. Overall, objective neurocognitive performance did not differ significantly between the three syndromic groups, or between the study cohort and the CFS controls or the normative controls. In some neurocognitive subtests, the study cohort scored below the 15th percentile when compared with normative control data. Most persons who returned to independent living following hospitalization for WNV illness had persistent subjective complaints, but had normal cognitive function. However, a minority displayed subtle neurocognitive deficits more than 18 months following acute disease.
Contralateral visual search deficits following TMS
Authors: Schindler I. , Ellison A. , Milner A. D.
Published: February 2008

Transcranial magnetic stimulation of posterior parietal vs. superior temporal sites cause differential effects on conventional conjunction vs. feature search tasks, respectively. We now report that when a decision has to be made on the target's left/right location, different lateralized deficits emerge in these two cases. With full‐field arrays, we found a specific PPC search deficit for contralateral space. With smaller, structured arrays presented in left or right hemispace, we found a specific STG deficit for contralateral parts of the array.
When the whole is more than the sum of the parts: Evidence from visuospatial neglect
Authors: Gallace A. , Imbornone E. , Vallar G.
Published: February 2008

One possible pathological mechanism underlying the rightward bisection error of right‐brain‐damaged patients with left spatial neglect is a leftward relaxation of the spatial representational medium. This view was originally based on the finding that patients with left neglect, required to extend horizontal segments, in order to double their original length, may exhibit a relative left overextension of the drawn lines (Bisiachet al., 1994). We investigated this putative distortion of representational space using a 16 cm ‘line segmentation’ task (Experiment 1). Were the representation of space relaxed contralesionally, a progressive increase from right to left of the size of the drawn segments would be expected. Right‐brain‐damaged patients with left unilateral neglect (N=12) performed the segmentation task with no left versus right differences, as right‐brain‐damaged patients without neglect (N=8), and neurologically unimpaired control subjects (N=10), did. Experiments 2 and 3 explored the effects of sample length (1, 2, 4, and 8 cm), by which the 16 cm lines had to be segmented. Neglect patients produced longer left‐sided segments only for the 8 cm sample (i.e. half of the length of the segment). This set of experiments suggests an impairment in the segmentation task only with the larger (8 cm) sample, when a more global level of processing may be involved. Experiment 4 assessed this hypothesis by a ‘part/whole’ bisection task, using 8 cm lines, presented either embedded in a longer 16 cm line or in isolation. Neglect patients made a larger rightward bisection error when the segment was not embedded. The suggestion is made that the lateral distortion of the representation of space in neglect patients (i.e. a leftward relaxation of the spatial medium) concerns tasks where a more ‘global’ representation of the visual stimulus has to be set up. The different demands of the segmentation and bisection tasks are discussed.
Face processing in different brain areas, and critical band masking
Authors: Rolls Edmund T.
Published: February 2008

Neurophysiological evidence is described showing that some neurons in the macaque inferior temporal visual cortex have responses that are invariant with respect to the position, size, view, and spatial frequency of faces and objects, and that these neurons show rapid processing and rapid learning. Critical band spatial frequency masking is shown to be a property of these face‐selective neurons and of the human visual perception of faces. Which face or object is present is encoded using a distributed representation in which each neuron conveys independent information in its firing rate, with little information evident in the relative time of firing of different neurons. This ensemble encoding has the advantages of maximizing the information in the representation useful for discrimination between stimuli using a simple weighted sum of the neuronal firing by the receiving neurons, generalization, and graceful degradation. These invariant representations are ideally suited to provide the inputs to brain regions such as the orbitofrontal cortex and amygdala that learn the reinforcement associations of an individual's face, for then the learning, and the appropriate social and emotional responses generalize to other views of the same face. A theory is described of how such invariant representations may be produced by self‐organizing learning in a hierarchically organized set of visual cortical areas with convergent connectivity. The theory utilizes either temporal or spatial continuity with an associative synaptic modification rule. Another population of neurons in the cortex in the superior temporal sulcus encodes other aspects of faces such as face expression, eye‐gaze, face view, and whether the head is moving. These neurons thus provide important additional inputs to parts of the brain such as the orbitofrontal cortex and amygdala that are involved in social communication and emotional behaviour.

Outputs of these systems reach the amygdala, in which face‐selective neurons are found, and also the orbitofrontal cortex, in which some neurons are tuned to face identity and others to face expression. In humans, activation of the orbitofrontal cortex is found when a change of face expression acts as a social signal that behaviour should change; and damage to the human orbitofrontal and pregenual cingulate cortex can impair face and voice expression identification, and also the reversal of emotional behaviour that normally occurs when reinforcers are reversed.
Asperger syndrome: How does it relate to non‐verbal learning disability?
Authors: Ryburn B. , Anderson V. , Wales R.
Published: February 2008

The syndrome of non‐verbal learning disabilities (NLD) is associated with prominent non‐verbal deficits such as reduced perceptual and spatial abilities, against a background of relatively intact verbal abilities. Asperger syndrome is one of the several developmental disorders for which Byron Rourke has claimed that almost all the signs and symptoms of NLD are present. This study investigated the claim utilizing a battery of neuropsychological tests that were found to be sensitive to NLD in the original learning disordered populations used to describe the syndrome. Children aged between 8 and 14 were recruited to form two groups: (1) children with Asperger syndrome (N=14) and (2) normal healthy schoolchildren (N=20). By contrast to the main principle outlined in the NLD model, children with Asperger syndrome did not display a relative difficulty with spatial‐ or problem‐solving tasks; indeed, they displayed significantly higher performance on some non‐verbal tasks in comparison with verbal tasks. It was only in relation to their high levels of psychosocial and interpersonal difficulties, which are also predicted on the basis of their psychiatric diagnosis, that the children with Asperger syndrome were clearly consistent with the NLD model in this study. These results raise questions about the relevance of the syndrome of NLD for children with Asperger syndrome.
Bone Formation During Distraction Osteogenesis Is Dependent on Both VEGFR1 and VEGFR2 Signaling
Authors: Jacobsen Kimberly A , Al-Aql Zainab S , Wan Chao , Fitch Jennifer L , Stapleton Stephanie N , Mason Zachary D , Cole Robert M , Gilbert Shawn R , Clemens Thomas L , Morgan Elise F , Einhorn Thomas A , Gerstenfeld Louis C
Published: February 2008

Introduction: Distraction osteogenesis (DO) is characterized by the induction of highly vascularized new bone formation through an intramembranous process largely devoid of the formation of cartilage.

Materials and Methods: To test the hypothesis that DO is strictly dependent on vascualrization, we inhibited vascular endothelial growth factor (VEGF) activity by antibody blockade of both receptors VEGFR1 (Flt-1) and VEGFR2 (Flk-1) or only VEGFR2 (Flk-1) in a previously developed murine tibia DO model. During normal DO, VEGFR1 (Flt-1), VEGFR2 (Flk-1), VEGFR3 (Flt4) and all four VEGF ligand (A, B, C, and D) mRNAs are induced.

Results: The expression of mRNA for the receptors generally paralleled those of the ligands during the period of active distraction. Bone formation, as assessed by μCT, showed a significant decrease with the double antibody treatment and a smaller decrease with single antibody treatment. Vessel volume, number, and connectivity showed progressive and significant inhibition in all of these of parameters between the single and double antibody blockade. Molecular analysis showed significant inhibition in skeletal cell development with the single and double antibody blockade of both VEGFR1 and 2. Interestingly, the single antibody treatment led to selective early development of chondrogenesis, whereas the double antibody treatment led to a failure of both osteogenesis and chondrogenesis.

Conclusions: Both VEGFR1 and VEGFR2 are functionally essential in blood vessel and bone formation during DO and are needed to promote osteogenic over chondrogenic lineage progression.
Bone Mass Is Preserved and Cancellous Architecture Altered Due to Cyclic Loading of the Mouse Tibia After Orchidectomy
Authors: Fritton J Christopher , Myers Elizabeth R , Wright Timothy M , van der Meulen Marjolein CH
Published: February 2008

Introduction: The study of adaptation to mechanical loading under osteopenic conditions is relevant to the development of osteoporotic fracture prevention strategies. We previously showed that loading increased cancellous bone volume fraction and trabecular thickness in normal male mice. In this study, we tested the hypothesis that cyclic mechanical loading of the mouse tibia inhibits orchidectomy (ORX)-associated cancellous bone loss.

Materials and Methods: Ten-week-old male C57BL/6 mice had in vivo cyclic axial compressive loads applied to one tibia every day, 5 d/wk, for 6 wk after ORX or sham operation. Adaptation of proximal cancellous and diaphyseal cortical bone was characterized by μCT and dynamic histomorphometry. Comparisons were made between loaded and nonloaded contralateral limbs and between the limbs of ORX (n = 10), sham (n = 11), and basal (n = 12) groups and tested by two-factor ANOVA with interaction.

Results: Cyclic loading inhibited bone loss after ORX, maintaining absolute bone mass at age-matched sham levels. Relative to sham, ORX resulted in significant loss of cancellous bone volume fraction (−78%) and trabecular number (−35%), increased trabecular separation (67%), no change in trabecular thickness, and smaller loss of diaphyseal cortical properties, consistent with other studies. Proximal cancellous bone volume fraction was greater with loading (ORX: 290%, sham: 68%) than in contralateral nonloaded tibias. Furthermore, trabeculae thickened with loading (ORX: 108%, sham: 48%). Dynamic cancellous bone histomorphometry indicated that loading was associated with greater mineral apposition rates (ORX: 32%, sham: 12%) and smaller percent mineralizing surfaces (ORX: −47%, sham: −39%) in the final week. Loading resulted in greater BMC (ORX: 21%, sham: 15%) and maximum moment of inertia (ORX: 39%, sham: 24%) at the cortical midshaft.

Conclusions: This study shows that cancellous bone mass loss can be prevented by mechanical loading after hormonal compromise and supports further exploration of nonpharmacologic measures to prevent rapid-onset osteopenia and associated fractures.
In Vivo Genome-Wide Expression Study on Human Circulating B Cells Suggests a NovelESR1andMAPK3Network for Postmenopausal Osteoporosis
Authors: Xiao Peng , Chen Yuan , Jiang Hui , Liu Yao-Zhong , Pan Feng , Yang Tie-Lin , Tang Zi-Hui , Larsen Jennifer A , Lappe Joan M , Recker Robert R , Deng Hong-Wen
Published: February 2008

Introduction: Osteoporosis is characterized by low BMD. Studies have shown that B cells may participate in osteoclastogenesis through expression of osteoclast-related factors, such as RANKL, transforming growth factor β (TGFB), and osteoprotegerin (OPG). However, the in vivo significance of B cells in human bone metabolism and osteoporosis is still largely unknown, particularly at the systematic gene expression level.

Materials and Methods: In this study, Affymetrix HG-U133A GeneChip arrays were used to identify genes differentially expressed in B cells between 10 low and 10 high BMD postmenopausal women. Significance of differential expression was tested by t-test and adjusted for multiple testing with the Benjamini and Hochberg (BH) procedure (adjusted p ≤ 0.05).

Results: Twenty-nine genes were downregulated in the low versus high BMD group. These genes were further analyzed using Ingenuity Pathways Analysis (Ingenuity Systems). A network involving estrogen receptor 1 (ESR1) and mitogen activated protein kinase 3 (MAPK3) was identified. Real-time RT-PCR confirmed differential expression of eight genes, including ESR1, MAPK3, methyl CpG binding protein 2 (MECP2), proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1), Scr-like-adaptor (SLA), serine/threonine kinase 11 (STK11), WNK lysine-deficient protein kinase 1 (WNK1), and zinc finger protein 446 (ZNF446).

Conclusions: This is the first in vivo genome-wide expression study on human B cells in relation to osteoporosis. Our results highlight the significance of B cells in the etiology of osteoporosis and suggest a novel mechanism for postmenopausal osteoporosis (i.e., that downregulation of ESR1 and MAPK3 in B cells regulates secretion of factors, leading to increased osteoclastogenesis or decreased osteoblastogenesis).
Doubly Truncated FosB Isoform (Δ2ΔFosB) Induces Osteosclerosis in Transgenic Mice and Modulates Expression and Phosphorylation of Smads in Osteoblasts Independent of Intrinsic AP-1 Activity
Authors: Sabatakos George , Rowe Glenn C , Kveiborg Marie , Wu Meilin , Neff Lynn , Chiusaroli Riccardo , Philbrick William M , Baron Roland
Published: February 2008

Introduction: Activator protein (AP)-1 family members play important roles in the development and maintenance of the adult skeleton. Transgenic mice that overexpress the naturally occurring ΔFosB splice variant of FosB develop severe osteosclerosis. Translation of Δfosb mRNA produces both ΔFosB and a further truncated isoform (Δ2ΔFosB) that lacks known transactivation domains but, like ΔFosB, induces increased expression of osteoblast marker genes.

Materials and Methods: To test Δ2ΔFosB's ability to induce bone formation in vivo, we generated transgenic mice that overexpress only Δ2ΔFosB using the enolase 2 (ENO2) promoter-driven bitransgenic Tet-Off system.

Results: Despite Δ2ΔFosB's failure to induce transcription of an AP-1 reporter gene, the transgenic mice exhibited both the bone and the fat phenotypes seen in the ENO2-ΔFosB mice. Both ΔFosB and Δ2ΔFosB activated the BMP-responsive Xvent-luc reporter gene and increased Smad1 expression. Δ2ΔFosB enhanced BMP-induced Smad1 phosphorylation and the translocation of phospho-Smad1 (pSmad1) to the nucleus more efficiently than ΔFosB and showed a reduced induction of inhibitory Smad6 expression.

Conclusions: ΔFosB's AP-1 transactivating function is not needed to induce increased bone formation, and Δ2ΔFosB may act, at least in part, by increasing Smad1 expression, phosphorylation, and translocation to the nucleus.
OPG and sRANKL Serum Concentrations in Osteopenic, Postmenopausal Women After 2-Year Genistein Administration
Authors: Marini Herbert , Minutoli Letteria , Polito Francesca , Bitto Alessandra , Altavilla Domenica , Atteritano Marco , Gaudio Agostino , Mazzaferro Susanna , Frisina Alessia , Frisina Nicola , Lubrano Carla , Bonaiuto Michele , D'Anna Rosario , Cannata Maria Letizia , Corrado Francesco , Cancellieri Francesco , Faraci Marianna , Marini Rolando , Adamo Elena Bianca , Wilson Steven , Squadrito Francesco
Published: February 2008

Introduction: RANKL and its decoy receptor osteoprotegerin (OPG) constitute a complex physiological mediator system involved in the regulation of bone resorption and may be responsible for the homeostatic mechanism of normal bone remodeling. Genistein, an isoflavone representing 1–5% of total phytoestrogen content in soybean products, may positively regulate cellular bone metabolism, but its mechanism of action on bone is not yet fully understood.

Materials and Methods: We studied the serum levels of both soluble RANKL (sRANKL) and OPG and the sRANKL/OPG ratio in 389 postmenopausal women (age, 49–67 yr) with a femoral neck BMD <0.795 g/cm2 and no significant comorbid conditions after 24-mo therapy with genistein, (n = 198; 54 mg/d) or placebo (n = 191). Both intervention and placebo contained calcium and vitamin D3. All patients received dietary instruction in an isocaloric fat-reduced diet.

Results: In comparison with placebo, sRANKL level was lower (p < 0.001 versus placebo) and OPG higher in genistein recipients (p < 0.001 versus placebo) at 1 and 2 yr, respectively. Moreover, at the end of 24 mo, genistein produced a significant reduction in the sRANKL/OPG ratio compared with placebo (genistein = −0.021, 95% CI, −0.020 to −0.022; placebo = +0.004, 95% CI, 0.003–0.005; difference = −0.020, 95% CI, −0.015 to −0.025, p < 0.001).

Conclusions: Our findings suggest that genistein plus calcium and vitamin D3 as part of a healthy diet is able to positively modulate bone turnover in a cohort of osteopenic, postmenopausal women and improve sRANKL-OPG balance after 24 mo of treatment.
Cortical Bone Loss in Androgen-Deficient Aged Male Rats Is Mainly Caused by Increased Endocortical Bone Remodeling
Authors: Reim Natascha S , Breig Bianca , Stahr Kerstin , Eberle Johannes , Hoeflich Andreas , Wolf Eckhard , Erben Reinhold G
Published: February 2008

Introduction: Hypogonadism is considered to be one of the major risk factors for osteoporosis in men. Here, we sequentially studied the effects of androgen deficiency on cortical bone in aged orchiectomy (ORX) rats.

Materials and Methods: One hundred seventy 13-mo-old male Fischer-344 rats were either ORX or sham-operated. After in vivo fluorochrome labeling, groups of 8–15 SHAM and ORX rats each were killed at 2 wk and 1, 2, 3, 4, 6, and 9 mo after surgery. To examine the effects of testosterone replacement therapy, 9-mo-old ORX rats were supplemented with testosterone undecanoate at a weekly dose of 6 mg/kg for 4 mo. Cortical bone changes in the tibial shaft were monitored by pQCT analysis and by bone histomorphometry.

Results: SHAM rats did not show age-related bone loss at the tibial diaphysis. pQCT analysis and bone histomorphometry showed cortical bone osteopenia in ORX rats, beginning from 2 mo after surgery until the end of the study. Androgen deficiency induced a sustained decrease in periosteal bone formation during the first 4 mo after ORX. However, although periosteal expansion of the tibial shaft tended to be slower in ORX rats compared with SHAM controls, the reduction in total cross-sectional area in ORX animals reached statistical significance only at 4 mo after surgery. The major mechanism for cortical bone loss in aged ORX rats was a progressive expansion of the marrow cavity, which was associated with an initial increase in endocortical eroded perimeter at 1 and 2 mo after surgery, followed by a sustained increase in endocortical bone formation until the end of the study. All these changes were prevented in aged ORX rats receiving testosterone supplementation in an insulin-like growth factor system–independent fashion.

Conclusions: We conclude that androgen deficiency–induced cortical bone loss in aged, nongrowing rats is mainly caused by augmented endocortical bone remodeling.
Interleukin-4 and Interleukin-13 Stimulate the Osteoclast Inhibitor Osteoprotegerin by Human Endothelial Cells Through the STAT6 Pathway
Authors: Stein Nicola C , Kreutzmann Carmen , Zimmermann Sara-Pia , Niebergall Ute , Hellmeyer Lars , Goettsch Claudia , Schoppet Michael , Hofbauer Lorenz C
Published: February 2008

Introduction: Endothelial cells of the bone vasculature modulate development, remodeling, and repair of bone by secreting osteotropic cytokines and hormones, which can act on osteoblastic and osteoclastic lineage cells. RANKL is the essential factor for differentiation, activation, and survival of osteoclasts, whereas osteoprotegerin (OPG) is a soluble decoy receptor and inhibitor for RANKL.

Materials and Methods: In this study, we analyzed the regulation of OPG by T helper 2 (Th2) cytokines interleukin (IL)-4 and the closely related IL-13 in human umbilical vein endothelial cells (HUVECs), the underlying signaling pathway, and its functional relevance on osteoclastic resorption.

Results: IL-4 and IL-13 induced OPG mRNA levels and protein secretion in HUVEC by up to 4-fold in a dose- and time-dependent fashion (maximum effect after 48 h and at 10 ng/ml). Activation of the transcription factor STAT6 preceded IL-4–induced OPG expression, and blockade of IL-4–induced STAT6 activation by the phospholipase C–specific inhibitor D609 decreased OPG expression. Soluble IL-4 receptor (sIL-4R) dose-dependently abolished both IL-4–induced STAT6 phosphorylation and OPG expression. RANKL stimulated the activity of osteoclasts, which was antagonized by HUVEC-derived supernatant containing OPG. The inhibitory effect on osteoclastogenesis was completely and specifically abrogated by a neutralizing OPG antibody in unstimulated HUVEC supernatant and partially in IL-4–stimulated HUVEC supernatant.

Conclusions: In summary, IL-4 and IL-13 induced OPG expression through activation of STAT6 in endothelial cells, and HUVEC-derived OPG is an IL-4/IL-13–induced inhibitor of osteoclastic resorption. These data underline the impact of Th2 cytokines on bone resorption through modulation of endothelial cell–derived cytokines.
Frequency and Risk Factors Associated With Osteonecrosis of the Jaw in Cancer Patients Treated With Intravenous Bisphosphonates
Authors: Hoff Ana O , Toth Béla B , Altundag Kadri , Johnson Marcella M , Warneke Carla L , Hu Mimi , Nooka Ajay , Sayegh Gilbert , Guarneri Valentina , Desrouleaux Kimberly , Cui Jeffrey , Adamus Andrea , Gagel Robert F , Hortobagyi Gabriel N
Published: February 2008

Introduction: Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates. The incidence and risk factors associated with this disorder have not been clearly defined.

Materials and Methods: We conducted a retrospective analysis of 4019 patients treated with intravenous bisphosphonates between 1996 and 2004. Our goals were to estimate the frequency, understand the clinical presentation, and identify risk factors associated with ONJ development.

Results: Sixteen of 1338 patients with breast cancer (1.2%) and 13 of 548 patients with multiple myeloma (2.4%) developed ONJ. The median dose and duration of treatment with pamidronate or zoledronic acid were significantly higher in patients with ONJ (p < 0.0001). Multivariate Cox proportional hazards regression analysis identified treatment with zoledronic acid (hazards ratio [HR], 15.01; 95% CI: 2.41–93.48; p = 0.0037), treatment with pamidronate followed by zoledronic acid (HR, 4.00; 95% CI: 0.86–18.70; p = 0.078), and dental extractions (HR, 53.19; 95% CI: 18.20–155.46; p < 0.0001) as significant risks for ONJ in breast cancer. In multiple myeloma, dental extractions (HR, 9.78; 95% CI: 3.07–31.14; p = 0.0001) and osteoporosis (HR, 6.11; 95% CI: 1.56–23.98; p = 0.0095) were significant risk factors while controlling for bisphosphonate therapy. Thirteen of 29 patients were followed for a median of 17.1 mo (range, 7–67 mo); lesions healed in 3 patients during this period.

Conclusions: ONJ is an uncommon but long-lasting disorder that occurs mainly in breast cancer and multiple myeloma patients treated with intravenous bisphosphonates. High cumulative doses of bisphosphonates, poor oral health, and dental extractions may be significant risk factors for ONJ development. ONJ resolved in 23% of patients with conservative therapy.
Apoptotic Bodies Convey Activity Capable of Initiating Osteoclastogenesis and Localized Bone Destruction
Authors: Kogianni Giolanta , Mann Val , Noble Brendon S
Published: February 2008

Introduction: Osteocyte apoptosis co-localizes with sites of osteoclastic bone resorption in vivo, but to date, no causal molecular or signaling link has been identified between these two processes.

Materials and Methods: Osteocyte apoptotic bodies (OABs) derived from the MLO-Y4 osteocyte-like cell line and primary murine osteocytes and apoptotic bodies (ABs) derived from primary murine osteoblasts were introduced onto the right parietal bone of murine calvariae, and osteoclastic bone resorption was examined 5 days after treatment. In addition, the ability of primary murine and cell line–derived OABs to support osteoclastogenesis was examined in vitro in co-culture with murine bone marrow hematopoietic progenitors in the absence of RANKL or macrophage-colony stimulating factor.

Results: For the first time, we show that OABs are capable of initiating de novo osteoclastic bone resorption on quiescent bone surfaces in vivo. Furthermore, the addition of OABs to mononuclear osteoclast precursors (OPs) in vitro resulted in the maintenance of OP cell numbers and an increase in the proportion and activity of TRACP+ cells. In contrast, application of ABs from osteoblasts showed no osteoclastogenic activity either in vivo or in vitro. The osteoclastogenic capacity of OABs was shown to be independent of the known osteoclastogenic factor RANKL but dependent on the induction of TNF-α production by OP.

Conclusions: These data point to a mechanism by which dying osteocytes might target bone destruction through the distribution of OAB-associated signals and give further physiological meaning to the apoptotic process in bone.
Identification of Quantitative Trait Loci Affecting Murine Long Bone Length in a Two-Generation Intercross of LG/J and SM/J Mice
Authors: Norgard Elizabeth A , Roseman Charles C , Fawcett Gloria L , Pavličev Mihaela , Morgan Clinton D , Pletscher L Susan , Wang Bing , Cheverud James M
Published: February 2008

Introduction: Study of mutations with large phenotypic effects has allowed the identification of key players in skeletal development. However, the molecular nature of variation in large, phenotypically normal populations tends to be characterized by smaller phenotypic effects that remain undefined.

Materials and Methods: We use interval mapping and quantitative trait locus (QTL) mapping techniques in the combined F2-F3 populations (n = 2111) of an LG/J × SM/J mouse intercross to detect QTLs associated with the lengths of the humerus, ulna, femur, and tibia.

Results: Seventy individual trait QTLs affecting long bone lengths were detected, with several chromosomes harboring multiple QTLs. The genetic architecture suggests mainly small, additive effects on long bone length, with roughly one third of the QTLs displaying dominance. Sex interactions were common, and four sex-specific QTLs were observed. Pleiotropy could not be rejected for most of the QTLs identified. Thirty-one epistatic interactions were detected, almost all affecting regions including or immediately adjacent to QTLs.

Conclusions: A complex regulatory network with many gene interactions modulates bone growth, possibly with integrated skeletal modules that allow fine-tuning of developmental processes present. Candidate genes in the QTL CIs include many genes known to affect endochondral bone growth and genes that have not yet been associated with bone growth or body size but have a strong potential to influence these traits.
JNK/c-Jun Signaling Mediates an Anti-Apoptotic Effect of RANKL in Osteoclasts
Authors: Ikeda Fumiyo , Matsubara Takuma , Tsurukai Taro , Hata Kenji , Nishimura Riko , Yoneda Toshiyuki
Published: February 2008

Introduction: RANKL is known to be important not only for differentiation and activation of osteoclasts but also for their survival. Experimentally, apoptosis of osteoclasts is rapidly induced by the deprivation of RANKL. RANKL activates Elk-related tyrosine kinase (ERK), p38, c-Jun N-terminal kinase (JNK), and NF-κB pathways through TRAF6 in osteoclasts and the precursor cells. It has been shown that ERK is critical for regulation of osteoclast survival. However, an involvement of other RANKL signaling pathways such as JNK signaling in survival of osteoclasts has not been fully understood yet.

Materials and Methods: Osteoclasts derived from primary mouse bone marrow cells by soluble RANKL (sRANKL) were treated with a JNK inhibitor, SP600125, or infected with adenovirus carrying dominant-negative (DN)-c-jun, DN-c-fos, mitogen-activated protein kinase kinase 1 (MEKK1), I-κBα mutant, or NF-κB components, p50 and p65. Osteoclasts were cultured with or without sRANKL, and apoptotic phenotype was determined by TUNEL assay, DAPI staining, and expression of cleaved caspase 3 followed by TRACP staining.

Results: Overexpression of TRAF6 activated JNK and NF-κB signaling pathways and clearly prevented osteoclasts from apoptosis caused by abrogation of sRANKL. An anti-apoptotic effect of RANKL/RANK/TRAF6 signaling on osteoclast was inhibited by JNK-specific inhibitor SP600125 and by overexpression of dominant-negative JNK1, c-jun, and c-fos. Also, overexpression of MEKK1 inhibited apoptosis of osteoclasts even in the absence of sRANKL along with activation of JNK/c-jun signaling. On the other hand, blockade of NF-κB signaling by I-κBα mutant or overexpression of NF-κB components showed a marginal effect on apoptosis of osteoclasts.

Conclusions: An important role of RANKL-induced activation of MEKK1/JNK/c-jun signaling in the regulation of apoptosis in osteoclasts was shown. Our study suggests that c-fos plays a role as a partner of activator protein-1 factor, c-jun, during the regulation of apoptosis in osteoclasts.
Impact of Systematic Implementation of a Clinical Case Finding Strategy on Diagnosis and Therapy of Postmenopausal Osteoporosis
Authors: Geusens Piet , Dumitrescu Bianca , van Geel Tineke , van Helden Sven , Vanhoof Johan , Dinant Geert Jan
Published: February 2008

Introduction: Case finding for osteoporosis in postmenopausal women is advocated in guidelines of osteoporosis, but implementation is unsatisfactory. We studied, in daily practice, the impact of systematic implementation of a previously validated clinical decision rule and fracture history on referral for bone densitometry (DXA) and drug prescription for osteoporosis.

Materials and Methods: Before-after impact analysis in 41,478 consecutive consulting postmenopausal women, included by 1080 general practitioners (GPs) during 2 mo, using the osteoporosis self-assessment (OST) index (based on age and weight, indicating women at low [LR], moderate [MR], and high risk [HR] for having osteoporosis [T-score < −2.5 in spine and/or hip]) and fracture history. Relative risks (RRs) and 95% CIs were calculated between referrals before (n = 6580) and after intervention (n = 10,379) and between risk subgroups.

Results: Post-intervention RR for referral for DXA was 1.9 (95% CI, 1.8–2.0). Compared with LR women with prior DXA, the RR was 6.3 (95% CI, 6.0–6.6) in MR and 10.7 (95% CI, 10.0–11.4) in HR women without fracture, but similar in MR and HR women with fracture (11.4 and 11.6, respectively). New cases of osteoporosis were diagnosed in 3811 women, 96% of whom were prescribed drug treatment. Of HR women, 79% were referred for DXA. The sensitivity of a low OST index to predict osteoporosis was 92% and specificity was 16%.

Conclusions: The impact of temporary systematic implementation of this case finding strategy on GP practice was high: it nearly tripled referrals for DXA, and 96% of patients found to have osteoporosis had treatment. The impact depended on OST index and fracture history. Only 79% of HR women were referred for DXA. Specificity of a low OST index to predict osteoporosis was low. This indicates the need in the GP population for case finding strategies with fewer barriers for referral for DXA and with higher accuracy for predicting osteoporosis.
Caloric Restriction Decreases Cortical Bone Mass but Spares Trabecular Bone in the Mouse Skeleton: Implications for the Regulation of Bone Mass by Body Weight
Authors: Hamrick Mark W , Ding Ke-Hong , Ponnala Sumant , Ferrari Serge L , Isales Carlos M
Published: February 2008

Introduction: Body weight is positively correlated with bone mass and density, and both muscle mass and body fat are thought to play a role in regulating bone metabolism. We examined bone metabolism in calorically restricted mice to determine how alterations in soft tissue mass affect bone mass, density, and strength.

Materials and Methods: Caloric restriction (CR) was initiated in male mice at 14 wk of age at 10% restriction, increased to 25% restriction at 15 wk, and then increased to 40% restriction at 16 wk, where it was maintained until 24 wk of age when the study was terminated. Control mice were fed ad libitum (AL). Body composition, BMD, and BMC were measured by DXA, BMD and BMC in the femoral metaphysis were measured by pQCT, femora were tested in three-point bending, serum leptin and IGF-1 were measured using immunoassay, and osteoblast and osteoclast numbers were determined using histomorphometry.

Results: Body weight, lean mass, fat mass, percent body fat, serum leptin, and serum IGF-1 were all significantly lower in CR mice than AL mice. Whole body BMC and BMD did not differ significantly between the two groups. Femur BMC, BMD, cortical thickness, and fracture strength decreased significantly in CR mice, but trabecular bone volume fraction in the femur did not change with food restriction. Vertebral cortical thickness also decreased with caloric restriction, whereas spine BMC, BMD, and trabecular bone volume fraction were significantly increased with caloric restriction.

Conclusions: Caloric restriction and its related weight reduction are associated with marked decreases in lean mass, fat mass, serum leptin and IGF-1, and cortical bone mass. Consistent with the opposite effects of leptin on cortical and cancellous bone, trabecular bone mass is spared during food restriction.
The Changing Role of the Embryo in Evolutionary Thought: Roots of Evo–DevoR. Amundson (2005). Cambridge, United Kingdom: Cambridge University Press
Authors: Molenaar Peter C. M.
Published: February 2008

Evolutionary developmental biology (evo–devo) has become an established field of research, especially since the spectacular results obtained in the 1990s regarding cross-species molecular homologies of (Hox) genes acting early during embryogenesis in insects, vertebrates, and beyond. Amundson summarizes some of these results, which justify a central assertion of evo–devo, namely that one must understand how bodies are built in order to understand how the process of building bodies can be changed, that is, how evolution can occur. But Amundson's book is not about these discoveries, but about the history of evo–devo.
Sex Differences in the Heritability of Resilience
Authors: Boardman Jason D. , Blalock Casey L. , Button Tanya M. M.
Published: February 2008

We examine the heritability of psychological resilience among US adults aged 25 to 74 years. Using monozygotic and same sex dizygotic twin pairs from the National Survey of Mid-Life Development in the United States (MIDUS) we show that positive affect is equally heritable among men (h2= .60) and women (h2= .59). We then estimate the heritability of positive affect after controlling for an exhaustive list of social and inter-personal stressors, and we operationalize the residual for positive affect as resilience. According to this specification, the heritability of resilience is higher among men (h2= .52) compared to women (h2= .38). We show that self-acceptance is one of the most important aspects of psychological functioning that accounts for the heritability of resilience among both men and women. However, compared to women, men appear to derive additional benefits from environmental mastery that may enable otherwise sex-neutral resilient tendencies to manifest.
A Study of Diabetes Mellitus Within a Large Sample of Australian Twins
Authors: Condon Julianne , Shaw Joanne E. , Luciano Michelle , Kyvik Kirsten O. , Martin Nicholas G. , Duffy David L.
Published: February 2008

Twin studies of diabetes mellitus can help elucidate genetic and environmental factors in etiology and can provide valuable biological samples for testing functional hypotheses, for example using expression and methylation studies of discordant pairs. We searched the volunteer Australian Twin Registry (19,387 pairs) for twins with diabetes using disease checklists from nine different surveys conducted from 1980–2000. After follow-up questionnaires to the twins and their doctors to confirm diagnoses, we eventually identified 46 pairs where one or both had type 1 diabetes (T1D), 113 pairs with type 2 diabetes (T2D), 41 female pairs with gestational diabetes (GD), 5 pairs with impaired glucose tolerance (IGT) and one pair with MODY. Heritabilities of T1D, T2D and GD were all high, but our samples did not have the power to detect effects of shared environment unless they were very large. Weight differences between affected and unaffected cotwins from monozygotic (MZ) discordant pairs were large for T2D and GD, but much larger again for discordant dizygotic (DZ) pairs. The bivariate genetic analysis (under the multifactorial threshold model) estimated the genetic correlation between body mass index (BMI) and T2D to be 0.46, and the environmental correlation at only 0.06.