bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic variation in innate immunity and inflammation pathways associated with lung cancer risk
Authors: Shiels Meredith S. , Engels Eric A. , Shi Jianxin , Landi Maria Teresa , Albanes Demetrius , Chatterjee Nilanjan , Chanock Stephen J. , Caporaso Neil E. , Chaturvedi Anil K.
Published: October 2012

BACKGROUND:

Pulmonary inflammation may contribute to lung cancer etiology. The authors conducted a broad evaluation of the association of single nucleotide polymorphisms (SNPs) in innate immunity and inflammation pathways with lung cancer risk and conducted comparisons with a lung cancer genome‐wide association study (GWAS).

METHODS:

In total, 378 patients with lung cancer (cases) and a group of 450 controls from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial were included. A proprietary oligonucleotide pool assay was used to genotype 1429 SNPs. Odds ratios and 95% confidence intervals were estimated for each SNP, and P values for trend (Ptrend) were calculated. For statistically significant SNPs (Ptrend < .05), the results were replicated with genotyped or imputed SNPs in the GWAS, and P values were adjusted for multiple testing.

RESULTS:

In the PLCO analysis, a significant association was observed between lung cancer and 81 SNPs located in 44 genes (Ptrend < .05). Of these 81 SNPS, there was evidence for confirmation in the GWAS for 10 SNPs. However, after adjusting for multiple comparisons, the only SNP that retained a significant association with lung cancer in the replication phase was reference SNP rs4648127 (nuclear factor of kappa light polypeptide gene enhancer of B‐cells 1 [NFKB1]) (multiple testing‐adjusted Ptrend = .02). The cytosine‐thymine (CT)/TT genotype of NFKB1 was associated with reduced odds of lung cancer in the PLCO study (odds ratio, 0.56; 95% confidence interval, 0.37‐0.86) and the in the GWAS (odds ratio, 0.79; 95% confidence interval, 0.69‐0.90).

CONCLUSIONS:

A significant association was observed between a variant in the NFKB1 gene and the risk of lung cancer. The current findings add to evidence implicating inflammation and immunity in lung cancer etiology. Cancer 2012. Published 2012 by the American Cancer Society.
Loss of Gsx1 and Gsx2 function rescues distinct phenotypes in Dlx1/2 mutants
Authors: Wang Bei , Long Jason E. , Flandin Pierre , Pla Ramon , Waclaw Ronald R. , Campbell Kenneth , Rubenstein John L.R.
Published: October 2012

Mice lacking the Dlx1 and Dlx2 homeobox genes (Dlx1/2 mutants) have severe deficits in subpallial differentiation, including overexpression of the Gsx1 and Gsx2 homeobox genes. To investigate whether Gsx overexpression contributes to the Dlx1/2 mutant phenotypes, we made compound loss‐of‐function mutants. Eliminating Gsx2 function from the Dlx1/2 mutants rescued the increased expression of Ascl1 and Hes5 (Notch signaling mediators) and Olig2 (oligodendrogenesis mediator). In addition, Dlx1/2;Gsx2 mutants, like Dlx1/2;Ascl1 mutants, exacerbated the Gsx2 and Dlx1/2 patterning and differentiation phenotypes, particularly in the lateral ganglionic eminence (LGE) caudal ganglionic eminence (CGE), and septum, including loss of GAD1 expression. On the other hand, eliminating Gsx1 function from the Dlx1/2 mutants (Dlx1/2;Gsx1 mutants) did not severely exacerbate their phenotype; on the contrary, it resulted in a partial rescue of medial ganglionic eminence (MGE) properties, including interneuron migration to the cortex. Thus, despite their redundant properties, Gsx1 and ‐2 have distinct interactions with Dlx1 and ‐2. Gsx2 interaction is strongest in the LGE, CGE, and septum, whereas the Gsx1 interaction is strongest in the MGE. From these studies, and earlier studies, we present a model of the transcriptional network that regulates early steps of subcortical development. J. Comp. Neurol. 521:1561–1584, 2013. © 2012 Wiley Periodicals, Inc.
ON cone bipolar cell axonal synapses in the OFF inner plexiform layer of the rabbit retina
Authors: Lauritzen J. Scott , Anderson James R. , Jones Bryan W. , Watt Carl B. , Mohammed Shoeb , Hoang John V. , Marc Robert E.
Published: October 2012

Analysis of the rabbit retinal connectome RC1 reveals that the division between the ON and the OFF inner plexiform layer (IPL) is not structurally absolute. ON cone bipolar cells make noncanonical axonal synapses onto specific targets and receive amacrine cell synapses in the nominal OFF layer, creating novel motifs, including inhibitory crossover networks. Automated transmission electron microscopic imaging, molecular tagging, tracing, and rendering of ∼400 bipolar cells reveals axonal ribbons in 36% of ON cone bipolar cells, throughout the OFF IPL. The targets include γ‐aminobutyrate (GABA)‐positive amacrine cells (γACs), glycine‐positive amacrine cells (GACs), and ganglion cells. Most ON cone bipolar cell axonal contacts target GACs driven by OFF cone bipolar cells, forming new architectures for generating ON–OFF amacrine cells. Many of these ON–OFF GACs target ON cone bipolar cell axons, ON γACs, and/or ON–OFF ganglion cells, representing widespread mechanisms for OFF to ON crossover inhibition. Other targets include OFF γACs presynaptic to OFF bipolar cells, forming γAC‐mediated crossover motifs. ON cone bipolar cell axonal ribbons drive bistratified ON–OFF ganglion cells in the OFF layer and provide ON drive to polarity‐appropriate targets such as bistratified diving ganglion cells (bsdGCs). The targeting precision of ON cone bipolar cell axonal synapses shows that this drive incidence is necessarily a joint distribution of cone bipolar cell axonal frequency and target cell trajectories through a given volume of the OFF layer. Such joint distribution sampling is likely common when targets are sparser than sources and when sources are coupled, as are ON cone bipolar cells. J. Comp. Neurol. 521:977–1000, 2013. © 2012 Wiley Periodicals, Inc.
Basophil modulation by cytokine instruction
Authors: Voehringer David
Published: October 2012

Basophils have recently been recognized as critical effector cells in allergic reactions and protective immunity against helminths. Precise characterization of basophil biology could help to develop specific therapies that interfere with differentiation, tissue recruitment, or induction of effector functions and thereby ameliorate allergic disorders. The development, homeostasis, and effector functions of basophils are tightly regulated by extrinsic signals and in particular by cytokines. IL‐3, GM‐CSF, and thymic stromal lymphopoietin activate the STAT5 pathway that promotes proliferation, activation, and cytokine secretion but also induces a negative feedback loop via Pim‐1 and SOCS proteins. Basophils further express receptors for IL‐18 and IL‐33, which are associated with the signaling adaptor MyD88 and activate the NF‐κB and MAP kinase pathways. This review focuses on positive and negative regulation of basophils by these cytokines.
Syntaxin 11 is required for NK and CD8+ T‐cell cytotoxicity and neutrophil degranulation
Authors: D'Orlando Orietta , Zhao Fang , Kasper Brigitte , Orinska Zane , Müller Jürgen , Hermans‐Borgmeyer Irm , Griffiths Gillian M. , Zur Stadt Udo , Bulfone‐Paus Silvia
Published: October 2012

Syntaxin 11 (STX11) controls vesicular trafficking and is a key player in exocytosis. Since Stx11 mutations are causally associated with a familial hemophagocytic lymphohistio‐cytosis, we wanted to clarify whether STX11 is functionally important for key immune cell populations. This was studied in primary cells obtained from newly generated Stx11−/− mice. Our data revealed that STX11 is not only widely expressed in different immune cells, but also induced upon LPS or IFN‐γ treatment. However, Stx11 deficiency does not affect macrophage phagocytic function and cytokine secretion, mast cell activation, or antigen presentation by DCs. Instead, STX11 selectively controls lymphocyte cytotoxicity in NK and activated CD8+ T cells and degranulation in neutrophils. Stx11−/− NK cells and CTLs show impaired degranulation, despite a comparable activation, maturation and expression of the complex‐forming partners MUNC18–2 and VTI1B. In addition, Stx11−/− CTLs and NK cells produce abnormal levels of IFN‐γ. Since functional reconstitution rescues the defective phenotype of Stx11−/− CTLs, we suggest a direct, specific and key role of STX11 in controlling lymphocyte cytotoxicity, cytokine production and secretion. Finally, we show that these mice are a very useful tool for dissecting the role of STX11 in vesicular trafficking and secretion.
Etching Silicon with HF–HNO3–H2SO4/H2O Mixtures – Unprecedented Formation of Trifluorosilane, Hexafluorodisiloxane, and Si–F Surface Groups
Authors: Lippold Marcus , Böhme Uwe , Gondek Christoph , Kronstein Martin , Patzig‐Klein Sebastian , Weser Martin , Kroke Edwin
Published: October 2012

The etching behaviour of sulfuric‐acid‐containing HF–HNO3 solutions towards crystalline silicon surfaces has been studied over a wide range of H2SO4 concentrations. For mixtures with low sulfuric acid concentration, NO2/N2O4, N2O3, NO and N2O have been detected by means of FTIR spectroscopy. Increasing concentrations of nitric acid lead to high etching rates and to an enhanced formation of NO2/N2O4. Different products were observed for the etching of silicon with sulfuric‐acid‐rich mixtures [c(H2SO4) > 13 mol L–1]. Trifluorosilane and hexafluorodisiloxane were identified by FTIR spectroscopy as additional reaction products. In contrast to the commonly accepted wet chemical etching mechanism, the formation of trifluorosilane is not accompanied by the formation of molecular hydrogen (according to Raman spectroscopy). Thermodynamic calculations and direct reactions of F3SiH with the etching solution support an intermediate oxidation of trifluorosilane and the formation of hexafluorodisiloxane. The etched silicon surfaces were investigated by diffuse reflection FTIR and X‐ray photoelectron spectroscopy (XPS). Surprisingly, no SiH terminations were observed after etching in sulfuric‐acid‐rich mixtures. Instead, a fluorine‐terminated surface was found.
Synthesis of Biotinylated Multipodal Glycoclusters on a Solid Support
Authors: Karskela Marika , von Usedom Miriam , Virta Pasi , Lönnberg Harri
Published: October 2012

Trivalent glycoconjugates, each bearing a biotin side arm in addition to three different sugar ligands, have been synthesized on a solid support. The conjugates were assembled on an orthogonally protected pentaerythrityl tetramine core that was anchored to the support through a backbone amide linker. Peptide coupling chemistry was applied to elongate three of the branches with β‐alanine and a fully acylated glycosylacetic acid. The fourth branch was levulinoylated and oximated with aminooxy‐derivatized D‐biotin, followed by acidolytic release into solution. The acyl protecting groups were removed by methoxide‐catalyzed transesterification in methanol.
Consecutive SNH and Suzuki–Miyaura Cross‐Coupling Reactions – an Efficient Synthetic Strategy to Pyrimidines Bearing Pyrrole and Indole Fragments
Authors: Verbitskiy Egor V. , Rusinov Gennady L. , Charushin Valery N. , Chupakhin Oleg N. , Cheprakova Ekaterina M. , Slepukhin Pavel A. , Pervova Marina G. , Ezhikova Marina A. , Kodess Mikhail I.
Published: October 2012

The combination of the Suzuki–Miyaura cross‐coupling and nucleophilic aromatic substitution of hydrogen reactions is a versatile tool for the syntheses of 4‐(1R‐pyrrol‐2‐yl)‐ and 4‐(1R‐indol‐3‐yl)‐5‐(hetero)aryl‐substituted pyrimidines from commercially available 5‐bromopyrimidine. The SNH [AE, (addition–elimination)] and SNH [AO, (addition–oxidation)] reactions of 5‐bromopyrimidine with pyrroles and indoles were studied by gas chromatography–mass spectrometry. The structures of the intermediate σH adducts as well as the pyrrole‐(hetero)arylpyrimidine and indole‐(hetero)arylpyrimidine dyads were established for the first time by X‐ray crystal structure analysis.
Leucojum aestivum plants propagated in in vitro bioreactor culture and on solid media containing cytokinins
Authors: Ptak Agata , Simlat Magdalena , Kwiecień Michał , Laurain‐Mattar Dominique
Published: October 2012

Cytokinins are growth regulators that stimulate cell division and control morphogenesis in plants, however their role in regulating secondary metabolism is not well studied. The influence of various cytokinins (benzyladenine, zeatin, kinetin, meta‐topolin, thidiazuron) and culture systems (solid and temporary immersion RITA® system) on the quality Leucojum aestivum plant regenerated from somatic embryos was investigated. The largest number of regenerated plants (181.6 and 168.8) was obtained from the embryos cultivated on media enriched with meta‐topolin and benzyladenine. Thidiazuron and meta‐topolin led to the highest number of normally developed plants (94.8 and 90.6). The random amplified polymorphic DNA analysis of in vitro and in vivo plants showed four clusters of similarity. The highest biomass (growth index: 2.49) was obtained with the temporary immersion RITA® system. Alkaloid extracts were analyzed by LC‐MS, leading to the quantification of galanthamine and lycorine both in plant materials and in liquid media. The highest contents of galanthamine (0.05% dry weight) were observed in plants cultivated in the presence of thidiazuron in bioreactor system. Galanthamine was accumulated (highest content 0.05% dry weight) in plants cultivated in the presence of thidiazuron in bioreactor system whereas lycorine was synthetized mainly in plants cultivated on solid media.
Large ice‐contact slope movements: glacial buttressing, deformation and erosion
Authors: McColl Samuel T. , Davies Timothy R. H.
Published: October 2012

Glaciers and slope movements may act simultaneously to erode and modify glaciated slopes. Undercutting by glaciers can destabilize slopes but the extent to which slope failure may progress prior to subsequent glacier withdrawal has not hitherto been considered. The traditional view has been that the buttressing effect of ice prevents slope movement. The problem with this view is that ice is one‐third the density of rock and flows under low applied stress. Consequently, failed slopes may move into the glacier if they exert a stress in excess of the resistance provided by the glacier. Slope movement rate depends on ice rheology and other factors influencing driving and resisting stresses. Simple viscous equations are used to investigate these variables. The equations predict that small (<125 000 m3) ice‐contact rockslides can deform ice at several mm/year, increasing to several m/year for very large (>108 m3) rockslides. To test these estimates, field evidence is presented of slope movements in glaciated valleys of New Zealand; narrowing or squeezing of glaciers adjacent to unstable rock slopes is demonstrated and considered to be the result of slope movement. For one site, geomorphic mapping and slope movement monitoring data show that movement rates are of similar order of magnitude to those predicted by the viscous equations; closer agreement could be achieved with the application of modelling techniques that can more realistically model the complex slope geometries and stability factors encountered, or by obtaining additional empirical data to calibrate the models. This research implies that, while the concept of glacial debuttressing – the reduction of slope support from withdrawal of glaciers – is valid, complete debuttressing is not a prerequisite for the movement of ice‐contact rock slopes. These slope movements may contribute to the erosional processes of glaciers and the evolution of glaciated slopes in a previously unrecognized way. Copyright © 2012 John Wiley & Sons, Ltd.
Threshold of erosion of submarine bedrock landscapes by tidal currents
Authors: Mitchell Neil C. , Huthnance John M. , Schmitt Thierry , Todd Brian
Published: October 2012

Since sea level stabilized 7000 yr bp, shelf seas experiencing semi‐diurnal tides will have been affected by streaming four times per day. If tidal erosion of bedrock were even only marginally efficient, the ~10 million streamings since then should have left geomorphological imprints. We examine high‐resolution multibeam sonar data from three areas with extreme tidal currents. The Minas Passage (Bay of Fundy) experiencing 8‐knot surface tidal currents was surveyed in 2007 with a multibeam sonar. In an area near to transverse dunes, which are evidence for bedload transport, the data show local overhanging surfaces near to the sediment‐rock contact, potentially created by abrasion by saltating particles. However, they are uncommon. In the Straits of Messina, where surface currents reach 10 knots, surveying revealed ridges lying oblique to the flow that are not obviously broken into separate outcrops by erosion. In the Bristol Channel, UK, sonar data collected where currents reach 3·4 knots at 1·5 m above the bed reveal outcrops of limestone with superimposed sand dunes, but only minor rounding of blocks.

Holocene tidal currents have apparently been generally ineffective at eroding bedrock. We examine this issue further by compiling extreme tidal streams around the UK and from them estimate shear stresses, representing a macro‐tidal environment where peak surface currents reach 9·7 knots. Those data are compared with shear stresses in mountainous rivers where long‐term rates of erosion are comparable with tectonic uplift rates and are thus geomorphologically significant. Whereas river stresses reach 102–103 Pa, the largest tidal stresses are generally 101 and only rarely approach 102 Pa, too small for quarrying to operate generally. However, the vertical faces in the Minas Passage may represent the onset of abrasion. Given this limited evidence for abrasion, we explore conditions in the geological past for tides that may have locally eroded bedrock. Copyright © 2012 John Wiley & Sons, Ltd.
Auf der Spur von Multitalenten
Authors: Blume Alfred , Kreßler Jörg
Published: October 2012

Zwischen Brücke und Barriere: Zellmembranen haben einen äußerst komplexen Aufbau. Ihre grundlegenden Eigenschaften lassen sich oft jedoch besser anhand von Modellmembranen mit geringerer Komplexität entschlüsseln. Dies hat nicht zuletzt hohe biomedizinische Relevanz.
mTOR kinase, a key player in the regulation of glial functions: Relevance for the therapy of multiple sclerosis
Authors: Dello Russo Cinzia , Lisi Lucia , Feinstein Douglas L. , Navarra Pierluigi
Published: October 2012

The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase with a central role in the regulation of cell growth and proliferation, and several intracellular processes, such as mRNA transcription and translation, autophagy and cytoskeletal organization. The relevance of this pathway in the regulation of the immune system is well characterized. mTOR is essential for the proper activation and proliferation of effector T cells, restricts the development of regulatory T cells, and downregulates innate immune responses. Recently, a direct role of mTOR in the modulation of glial functions has also been recognized. Data from our group and others support the notion that mTOR is involved in microglial proinflammatory activation. The kinase regulates several intracellular processes in astrocytes, among which the rate of mRNA degradation of the inducible form of NO synthase. Therefore, the inhibition of mTOR kinase activity in glial cells results in anti‐inflammatory actions, suggesting possible beneficial effects of mTOR inhibitors (like rapamycin) in the treatment of inflammatory‐based pathologies of the central nervous system. In contrast, mTOR plays an important role in the regulation of oligodendrocyte development and myelination process as well as several neuronal functions, which may limit this therapeutic approach. Nevertheless, as reviewed here, there is robust evidence that rapamycin ameliorates the clinical course of both the relapsing‐remitting and the chronic experimental autoimmune encephalomyelitis (EAE), and significantly reduces the hyperalgesia observed before clinical development of EAE. These findings may have important clinical implications for the therapy of multiple sclerosis. © 2012 Wiley Periodicals, Inc.
An Evaluation of Body Image Assessments in Hispanic College Women: The Multidimensional Body‐Self Relations Questionnaire and the Appearance Schemas Inventory–Revised
Authors: Smith Ashlea R. , Davenport Becky R.
Published: October 2012

The authors evaluated the utility of the Multidimensional Body‐Self Relations Questionnaire (MBSRQ; Brown, Cash, & Mikulka, 1990) and the Appearance Schemas Inventory–Revised (ASI‐R; Cash, Melnyk, & Hrabosky, 2004) by administering the instruments to Hispanic female college students. Results indicated that the means of the MBSRQ and the ASI‐R differed significantly from previously published norms but evidenced adequate internal consistency reliability. However, further research is needed to examine these constructs within this population.
Lived Experiences of College‐Age Transsexual Individuals
Authors: Goodrich Kristopher M.
Published: October 2012

This article reviews the lived experiences of 4 college‐age transsexual individuals. A qualitative study using grounded theory was conducted to investigate their experiences influencing their later educational persistence. Results suggested that level of discomfort, perceived social supports, level of secrecy, and academic achievement all affected participants’ decision making regarding persistence. This process appeared best explained by participants’ expressed hierarchy of needs. Implications for clinical practice and future research are discussed.
Collecting Multidimensional Client Data Using Repeated Measures: Experiences of Clients and Counselors Using the CCAPS‐34
Authors: Martin Jessica L. , Hess Timothy R. , Ain Stacie C. , Nelson Dana L. , Locke Benjamin D.
Published: October 2012

Many college counseling centers do not collect client data at each session because of perceived burdens. This study explored 55 clients’ and 16 doctoral counselor trainees’ experiences collecting and using data on client distress at each session over the course of counseling at a large public university's counseling center. Results indicated that the majority of both clients and counselors found the process convenient and clinically useful. Findings, clinical implications, and future directions are discussed.
Characteristics of High‐Risk College Student Drinkers Expressing High and Low Levels of Distress
Authors: Graceffo James M. , Hayes Jeffrey A. , Chun‐Kennedy Caitlin , Locke Benjamin D.
Published: October 2012

The aim of this study was to identify variables that reliably differentiated between 2 groups of students who reported binge drinking at the same rate (6 to more than 10 times within the previous 2 weeks) but who exhibited different distress associated with their behavior. Results indicated that students who received an external expression of concern were more likely to be concerned themselves about their alcohol use. The clinical utility of this finding is discussed.
Extending the Humanistic Vision: Toward a Humanities Foundation for the Counseling Profession
Authors: HANSEN JAMES T.
Published: October 2012

Founding humanists argued that counseling should be ideologically grounded in the humanities. Currently, professional counseling culture is largely structured by scientific assumptions, which, the author maintains, have had a detrimental impact on the profession. Specific recommendations for shifting professional counseling culture to a humanities foundation are offered.
Humanities and Science: A Necessary Unity for the Counseling Profession
Authors: GUTERMAN JEFFREY T. , MARTIN CLAYTON V. , KOPP DAVID M.
Published: October 2012

This article is a reply to Hansen's (2012) call for the counseling profession to embrace a purely humanistic ideology for counseling. The authors suggest the relationship between humanities and science set forth by Hansen does not emphasize the both‐and aspects of these ideologies. An integrative framework is considered for counseling.
Extending the Dialogue About Science and Humanities in Counseling: A Reply to Hansen
Authors: MARTIN CLAYTON V. , GUTERMAN JEFFREY T. , KOPP DAVID M.
Published: October 2012

This is a reply to Hansen's (2012b) rejoinder to the authors (Guterman, Martin, & Kopp, 2012), which is a response to Hansen's (2012a) keystone article about the relationship between humanities and science in counseling. In this reply, the authors provide remaining clarifications, points of disagreement, and suggestions for future directions in the field of counseling.
A Return to the Human in Humanism: A Response to Hansen's Humanistic Vision
Authors: LEMBERGER MATTHEW E.
Published: October 2012

In his extension of the humanistic vision, Hansen (2012) recommends that counseling practitioners and scholars adopt operations that are consistent with his definition of a multiple‐perspective philosophy. Alternatively, the author of this article believes that Hansen has reduced the capacity of the human to interpret meaning through quantitative research methodologies, diagnostic assessment, and other forms of counseling practice.
Rejoinder to Lemberger
Authors: HANSEN JAMES T.
Published: October 2012

Lemberger (2012) argues that the author (Hansen, 2012) has no basis for recommending differential weightings or priorities to humanism and science, because those ideologies are only meaningful as they are subjectively interpreted within the counseling encounter. The author responds that their positions are completely compatible, but his focus was on culture and Lemberger's was on individuals.
A Reply to Hansen's Cultural Humanism
Authors: LEMBERGER MATTHEW E.
Published: October 2012

Hansen (2012b) responds to the author's (Lemberger, 2012) critique of his humanistic vision by dividing their arguments as either individual or cultural in design. In this reply, the author contends that the individual cannot be extracted from her or his culture and, therefore, what is sufficient for a humanistic counseling culture must also be sufficient for each individual inspired by humanism.
Rejoinder to Brady‐Amoon
Authors: HANSEN JAMES T.
Published: October 2012

The author agrees with virtually all of Brady‐Amoon's (2012) conclusions. However, Brady‐Amoon and the author disagree about some of the theoretical points that lead to these shared conclusions. He overviews these disagreements and highlights their common vision for the future of the counseling profession.
Reaffirming the Role of Science and Diversity in Counseling: A Reply to Hansen
Authors: BRADY‐AMOON PEGGY
Published: October 2012

Overall, Hansen (2012a) and the author (Brady‐Amoon, 2012) share a humanistic vision for the future of counseling. In this continued dialogue, the author argues that a broad‐based philosophy of science that encompasses renewed respect for diversity remains essential for the future of the profession.
Extending the Humanistic Vision: Closing Thoughts
Authors: HANSEN JAMES T.
Published: October 2012

The author reflects on the collaborations that led to this special issue. The author also reviews some of his original ideas, comments on the values embodied in this issue, and outlines some of his hopes for the future of the counseling profession.
Changes in bone sclerostin levels in mice after ovariectomy vary independently of changes in serum sclerostin levels
Authors: Jastrzebski Sandra , Kalinowski Judith , Stolina Marina , Mirza Faryal , Torreggiani Elena , Kalajzic Ivo , Won Hee Yeon , Lee Sun-Kyeong , Lorenzo Joseph
Published: October 2012

We examined the effects that ovariectomy had on sclerostin mRNA and protein levels in the bones of 8-week-old mice that were either sham-operated (SHAM) or ovariectomized (OVX) and then euthanized 3 or 6 weeks later. In this model, bone loss occurred between 3 and 5 weeks postsurgery. In calvaria, ovariectomy significantly decreased sclerostin mRNA levels at 6 weeks postsurgery (by 52%) but had no significant effect at 3 weeks. In contrast, sclerostin mRNA levels were significantly lower in OVX femurs at 3 weeks postsurgery (by 53%) but equal to that of SHAM at 6 weeks. The effects of ovariectomy on sclerostin were not a global response of osteocytes because they were not mimicked by changes in the mRNA levels for two other relatively osteocyte-specific genes: DMP-1 and FGF-23. Sclerostin protein decreased by 83% and 60%, at 3 and 6 weeks postsurgery in calvaria, respectively, and by 38% in lumbar vertebrae at 6 weeks. We also detected decreases in sclerostin by immunohistochemistry in cortical osteocytes of the humerus at 3 weeks postsurgery. However, there were no significant effects of ovariectomy on sclerostin protein in femurs or on serum sclerostin at 3 and 6 weeks postsurgery. These results demonstrate that ovariectomy has variable effects on sclerostin mRNA and protein in mice, which are dependent on the bones examined and the time after surgery. Given the discrepancy between the effects of ovariectomy on serum sclerostin levels and sclerostin mRNA and protein levels in various bones, these results argue that, at least in mice, serum sclerostin levels may not accurately reflect changes in the local production of sclerostin in bones. Additional studies are needed to evaluate whether this is also the case in humans. © 2013 American Society for Bone and Mineral Research.
Adaptor protein complex 2–mediated, clathrin-dependent endocytosis, and related gene activities, are a prominent feature during maturation stage amelogenesis
Authors: Lacruz Rodrigo S , Brookes Steven J , Wen Xin , Jimenez Jaime M , Vikman Susanna , Hu Ping , White Shane N , Lyngstadaas S Petter , Okamoto Curtis T , Smith Charles E , Paine Michael L
Published: October 2012

Molecular events defining enamel matrix removal during amelogenesis are poorly understood. Early reports have suggested that adaptor proteins (AP) participate in ameloblast-mediated endocytosis. Enamel formation involves the secretory and maturation stages, with an increase in resorptive function during the latter. Here, using real-time PCR, we show that the expression of clathrin and adaptor protein subunits are upregulated in maturation stage rodent enamel organ cells. AP complex 2 (AP-2) is the most upregulated of the four distinct adaptor protein complexes. Immunolocalization confirms the presence of AP-2 and clathrin in ameloblasts, with strongest reactivity at the apical pole. These data suggest that the resorptive functions of enamel cells involve AP-2 mediated, clathrin-dependent endocytosis, thus implying the likelihood of specific membrane-bound receptor(s) of enamel matrix protein debris. The mRNA expression of other endocytosis-related gene products is also upregulated during maturation including: lysosomal-associated membrane protein 1 (Lamp1); cluster of differentiation 63 and 68 (Cd63 and Cd68); ATPase, H+ transporting, lysosomal V0 subunit D2 (Atp6v0d2); ATPase, H+ transporting, lysosomal V1 subunit B2 (Atp6v1b2); chloride channel, voltage-sensitive 7 (Clcn7); and cathepsin K (Ctsk). Immunohistologic data confirms the expression of a number of these proteins in maturation stage ameloblasts. The enamel of Cd63-null mice was also examined. Despite increased mRNA and protein expression in the enamel organ during maturation, the enamel of Cd63-null mice appeared normal. This may suggest inherent functional redundancies between Cd63 and related gene products, such as Lamp1 and Cd68. Ameloblast-like LS8 cells treated with the enamel matrix protein complex Emdogain showed upregulation of AP-2 and clathrin subunits, further supporting the existence of a membrane-bound receptor-regulated pathway for the endocytosis of enamel matrix proteins. These data together define an endocytotic pathway likely used by ameloblasts to remove the enamel matrix during enamel maturation. © 2013 American Society for Bone and Mineral Research.
Annual intravenous zoledronic acid for three years increased cancellous bone matrix mineralization beyond normal values in the HORIZON biopsy cohort
Authors: Misof Barbara M , Roschger Paul , Gabriel Daniela , Paschalis Eleftherios P , Eriksen Erik F , Recker Robert R , Gasser Jürg A , Klaushofer Klaus
Published: October 2012

The efficacy of 3 years of annual intravenous administration of zoledronic acid (ZOL) in reducing vertebral and nonvertebral fractures in postmenopausal osteoporosis has been shown by the HORIZON pivotal fracture trial. Histomorphometric analysis of transiliac bone biopsies from the HORIZON participants revealed significantly improved trabecular architecture and reduced bone remodeling for the ZOL-treated versus placebo-treated patients. The aim of our study was to evaluate the cancellous and cortical bone mineralization density distribution (BMDD) in these biopsies by quantitative backscattered electron imaging (qBEI). The study cohort comprised 82 patients on active treatment (ZOL, yearly doses of 5 mg) and 70 treated with placebo, and all received adequate Ca and VitD supplementation. Comparison of ZOL-treated versus placebo-treated cancellous (Cn.) and cortical (Ct.) BMDD-derived variables resulted in significantly higher average (Cn.CaMean + 3.2%, Ct.CaMean + 2.7%) and mode calcium concentrations (Cn.CaPeak + 2.1%, Ct.CaPeak + 1.5%), increased percentages of highly mineralized bone areas (Cn.CaHigh + 64%, Ct.CaHigh + 31%), lower heterogeneity of mineralization (Cn.CaWidth −14%, Ct.CaWidth −13%), and decreased percentages of low mineralized bone areas (Cn.CaLow −22%, Ct.CaLow −26%) versus placebo (all p < 0.001). Cn. BMDD from the patients on active treatment also revealed a statistically significant shift to higher Ca concentrations when compared to a historical normal reference BMDD. These differences in BMDD from ZOL patients compared to the other groups were in line with the correlation of BMDD variables with previously determined cancellous mineralizing surface per bone surface (Cn. MS/BS, a primary histomorphometric index for bone turnover), showing that those with lower Cn. MS/BS had a higher degree of bone matrix mineralization. However, the differences in BMDD variables between the study groups remained when adjusted for Cn. MS/BS, suggesting that other factors in addition to reduced bone turnover might contribute to the higher bone matrix mineralization after ZOL treatment. © 2013 American Society for Bone and Mineral Research.
Ethnic variability in bone geometry as assessed by hip structure analysis: Findings from the hip strength across the menopausal transition study
Authors: Danielson Michelle E , Beck Thomas J , Lian Yinjuan , Karlamangla Arun S , Greendale Gail A , Ruppert Kristine , Lo Joan , Greenspan Susan , Vuga Marike , Cauley Jane A
Published: October 2012

Racial/ethnic origin plays an important role in fracture risk. Racial/ethnic differences in fracture rates cannot be fully explained by bone mineral density (BMD). Studies examining the influence of bone geometry and strength on fracture risk have focused primarily on older adults and have not included people from diverse racial/ethnic backgrounds. Our goal was to explore racial/ethnic differences in hip geometry and strength in a large sample of midlife women. We performed hip structure analysis (HSA) on hip dual-energy X-ray absorptiometry (DXA) scans from 1942 premenopausal and early perimenopausal women. The sample included white (50%), African American (27%), Chinese (11%), and Japanese (12%) women aged 42 to 52 years. HSA was performed using software developed at Johns Hopkins University. African American women had higher conventional (8.4% to 9.7%) and HSA BMD (5.4% to 19.8%) than other groups with the exception being Japanese women, who had the highest HSA BMD (9.7% to 31.4%). HSA indices associated with more favorable geometry and greater strength and resistance to fracture were more prevalent in African American and Japanese women. Femurs of African American women had a smaller outer diameter, a larger cross-sectional area and section modulus, and a lower buckling ratio. Japanese women presented a different pattern with a higher section modulus and lower buckling ratio, similar to African American women, but a wider outer diameter; this was offset by a greater cross-sectional area and a more centrally located centroid. Chinese women had similar conventional BMD as white women but a smaller neck region area and HSA BMD at both regions. They also had a smaller cross-sectional area and section modulus, a more medially located centroid, and a higher buckling ratio than white women. The observed biomechanical differences may help explain racial/ethnic variability in fracture rates. Future research should explore the contribution of hip geometry to fracture risk across all race/ethnicities. © 2013 American Society for Bone and Mineral Research.
Inflammatory eye reactions in patients treated with bisphosphonates and other osteoporosis medications: Cohort analysis using a national prescription database
Authors: Pazianas Michael , Clark Emma M , Eiken Pia A , Brixen Kim , Abrahamsen Bo
Published: October 2012

Ocular inflammatory reactions have been described in patients on bisphosphonate treatment. We estimated the incidence rate of ocular inflammation at 3 and 12 months in patients treated for osteoporosis using a register-based cohort linked to prescription data (hospitals and private practice) and hospital data. From January 1, 1997 to December 31, 2007, a total of 88,202 patients beginning osteoporosis therapy were identified. Of those patients, 82,404 (93%) began oral bisphosphonates and 5798 (7%) nonbisphosphonates. Within the first year of treatment, 4769 (5.4%) of patients on osteoporosis therapy filled one or more prescriptions for topical eye steroids (TES). TES treatment rates (per 1000 patient-years) in the first year of osteoporosis treatment were 44 (95% confidence interval [CI] 42 to 46) for alendronate, 40 (95% CI 38 to 43) for etidronate, 45 (95% CI 35 to 57) for risedronate, 32 (95% CI 27 to 37) for raloxifene, and 64 (95% CI 49 to 83) for strontium ranelate. After adjustment for age, Charlson index, and the number of comedications, pulmonary disease in men was associated with an increased use of TES (odds ratio [OR] = 1.48; 95% CI 1.17 to 1.86; p = 0.001). In women, malignant disease (OR = 1.27; 95% CI 1.02 to 1.60; p = 0.04) and pulmonary disease (OR = 1.32; 95% CI 1.07 to 1.62; p = 0.01) were significant predictors at 3 months and rheumatic diseases at 12 months (OR = 1.20; 95% CI 1.10 to 1.31; p < 0.001). There was no significant difference between the different drug classes (bisphosphonates versus nonbisphosphonates, alendronate versus nonalendronate-bisphosphonates) for risk of ocular inflammation, with age and the number of comedications being the only significant predictors. Hospital-treated uveitis (48 patients, or 0.05%) showed a similar trend. In conclusion, after initiation of treatment for osteoporosis, the risk of inflammatory eye reactions requiring TES is relatively low and not significantly different between bisphosphonate and nonbisphosphonate users. Patients with a rheumatic or pulmonary disease are at increased risk. © 2013 American Society for Bone and Mineral Research.
Differing effects of PTH 1–34, PTH 1–84, and zoledronic acid on bone microarchitecture and estimated strength in postmenopausal women with osteoporosis: An 18-month open-labeled observational study using HR-pQCT
Authors: Hansen Stinus , Hauge Ellen M , Beck Jensen Jens-Erik , Brixen Kim
Published: October 2012

Whereas the beneficial effects of intermittent treatment with parathyroid hormone (PTH) (intact PTH 1–84 or fragment PTH 1–34, teriparatide) on vertebral strength is well documented, treatment may not be equally effective in the peripheral skeleton. We used high-resolution peripheral quantitative computed tomography (HR-pQCT) to detail effects on compartmental geometry, density, and microarchitecture as well as finite element (FE) estimated integral strength at the distal radius and tibia in postmenopausal osteoporotic women treated with PTH 1–34 (20 µg sc daily, n = 18) or PTH 1–84 (100 µg sc daily, n = 20) for 18 months in an open-label, nonrandomized study. A group of postmenopausal osteoporotic women receiving zoledronic acid (5 mg infusion once yearly, n = 33) was also included. Anabolic therapy increased cortical porosity in radius (PTH 1–34 32 ± 37%, PTH 1–84 39 ± 32%, both p < 0.001) and tibia (PTH 1–34 13 ± 27%, PTH 1–84 15 ± 22%, both p < 0.001) with corresponding declines in cortical density. With PTH 1–34, increases in cortical thickness in radius (2.0 ± 3.8%, p < 0.05) and tibia (3.8 ± 10.4%, p < 0.01) were found. Trabecular number increased in tibia with both PTH 1–34 (4.2 ± 7.1%, p < 0.05) and PTH 1–84 (5.3 ± 8.3%, p < 0.01). Zoledronic acid did not impact cortical porosity at either site but increased cortical thickness (3.0 ± 3.5%, p < 0.01), total (2.7 ± 2.5%, p < 0.001) and cortical density (1.5 ± 2.0%, p < 0.01) in tibia as well as trabecular volume fraction in radius (2.5 ± 5.1%, p < 0.05) and tibia (2.2 ± 2.2%, p < 0.01). FE estimated bone strength was preserved, but not increased, with PTH 1–34 and zoledronic acid at both sites, whereas it decreased with PTH 1–84 in radius (−2.8 ± 5.8%, p < 0.05) and tibia (–3.9 ± 4.8%, p < 0.001). Conclusively, divergent treatment-specific effects in cortical and trabecular bone were observed with anabolic and zoledronic acid therapy. The finding of decreased estimated strength with PTH 1–84 treatment was surprising and warrants confirmation. © 2013 American Society for Bone and Mineral Research.
Gene-gene interaction between RBMS3 and ZNF516 influences bone mineral density
Authors: Yang Tie-Lin , Guo Yan , Li Jian , Zhang Lei , Shen Hui , Li Siyang M , Li Siyuan K , Tian Qing , Liu Yong-Jun , Papasian Christopher J , Deng Hong-Wen
Published: October 2012

Osteoporosis is characterized by low bone mineral density (BMD), a highly heritable trait that is determined, in part, by the actions and interactions of multiple genes. Although an increasing number of genes have been identified to have independent effects on BMD, few studies have been performed to identify genes that interact with one another to affect BMD. In this study, we performed gene-gene interaction analyses in selected candidate genes in individuals with extremely high versus low hip BMD (20% tails of the distributions), in two independent U.S. Caucasian samples. The first sample contained 916 unrelated subjects with extreme hip BMD Z-scores selected from a population composed of 2286 subjects. The second sample consisted of 400 unrelated subjects with extreme hip BMD Z-scores selected from a population composed of 1000 subjects. Combining results from these two samples, we found one interacting gene pair (RBMS3 versus ZNF516) which, even after Bonferroni correction for multiple testing, showed consistently significant effects on hip BMD. RMBS3 harbored two single-nucleotide polymorphisms (SNPs), rs6549904 and rs7640046, both of which had significant interactions with an SNP, rs4891159, located on ZNF516 (p = 7.04 × 10−11 and 1.03 × 10−10). We further validated these results in two additional samples of Caucasian and African descent. The gene pair, RBMS3 versus ZNF516, was successfully replicated in the Caucasian sample (p = 8.07 × 10−3 and 2.91 × 10−3). For the African sample, a significant interaction was also detected (p = 0.031 and 0.043), but the direction of the effect was opposite to that observed in the three Caucasian samples. By providing evidence for genetic interactions underlying BMD, this study further delineates the genetic architecture of osteoporosis. © 2013 American Society for Bone and Mineral Research.
Impact of calcium and vitamin D insufficiencies on serum parathyroid hormone and bone mineral density: Analysis of the fourth and fifth Korea National Health and Nutrition Examination Survey (KNHANES IV-3, 2009 and KNHANES V-1, 2010)
Authors: Joo Nam-Seok , Dawson-Hughes Bess , Kim Young-Sang , Oh Kyungwon , Yeum Kyung-Jin
Published: October 2012

The relative contributions of calcium and vitamin D to calcium metabolism and bone mineral density (BMD) have been examined previously, but not in a population with very low calcium intake. To determine the relative importance of dietary calcium intake and serum 25-hydroxyvitamin D [25(OH)D] concentration to calcium metabolism and bone mass in a population with low calcium intake, a total of 4662 adults (2567 men and 2095 women) ≥50 years of age from the 2009–2010 Korea National Health and Nutrition Examination Survey (KNHANES) were divided into groups according to dietary calcium intakes (quintiles means: 154, 278, 400, 557, and 951 mg/d) and serum 25(OH)D concentrations (<50, 50–75, and >75 nmol/L). Serum intact parathyroid hormone (PTH) and femoral neck and lumbar spine BMD were evaluated according to dietary calcium intake and serum 25(OH)D. Mean calcium intake was 485 mg/d; mean serum 25(OH)D concentration was 48.1 nmol/L; PTH was 68.4 pg/mL; femoral neck BMD was 0.692 g/cm2; and lumbar spine BMD was 0.881 g/cm2. Lower dietary calcium intakes were significantly associated with higher serum PTH concentrations and lower femoral neck BMD, not only at lower (<50 nmol/L) but also at higher (>75 nmol/L) serum 25(OH)D concentrations. Serum PTH was highest and femoral neck BMD was lowest in the group, with a serum 25(OH)D less than 50 nmol/L. In this low-intake population, calcium intake is a significant determinant of serum PTH and BMD at higher as well as lower 25(OH)D levels. This finding indicates that low calcium intake cannot be compensated for with higher 25(OH)D levels alone. As expected, serum 25(OH)D levels were inversely associated with serum PTH and BMD. A calcium intake of at least 668 mg/d and a serum 25(OH)D level of at least 50 nmol/L may be needed to maintain bone mass in this calcium deficient population. © 2013 American Society for Bone and Mineral Research.
The Roles of Identity Formation and Moral Identity in College Student Mental Health, Health‐risk Behaviors, and Psychological Well‐Being
Authors: Hardy Sam A. , Francis Stephen W. , Zamboanga Byron L. , Kim Su Yeong , Anderson Spencer G. , Forthun Larry F.
Published: October 2012

Objectives

This study examined the roles of identity formation and moral identity in predicting college student mental health (anxiety and depressive symptoms), health‐risk behaviors (hazardous alcohol use and sexual risk taking), and psychological well‐being (self‐esteem and meaning).

Method

The sample comprised 9,500 college students (aged 18–25 years, mean = 19.78, standard deviation = 1.61; 73% female; 62% European American), from 31 different universities, who completed an online self‐report survey.

Results

Structural equation models found that identity maturity (commitment making and identity synthesis) predicted 5 of the health outcomes (except sexual risk taking), and moral identity predicted all of the health outcomes. In most cases identity maturity and moral identity also interacted in predicting mental health and psychological well‐being, but not health‐risk behaviors.

Conclusions

The maturity and specific contents of identity may both play unique and often interactive roles in predicting college student health. Thus, college student health might be bolstered by helping them establish appropriate identity commitments.