bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of Semiconductor Films Epitaxially Grown on Thin Metal Oxide Buffer Layers
Authors: Zaumseil P. , Giussani A. , Seifarth O. , Arguirov Tzanimir , Schubert M.A. , Schroeder T.
Published: October 2009

Silicon and germanium films epitaxially grown on metal oxide buffer layers on Si(111)
substrates are characterized by different X-ray techniques, transmission electron microscopy and
Raman spectroscopy. Pr2O3 and Y2O3 or a combination of both is used as buffer material. X-ray
pole figure measurements and grazing incident X-ray diffraction prove that epi-semiconductor layers
can be grown single crystalline with exactly the same in-plane orientation as the Si(111) substrate.
Epi-Ge layers show a small fraction (less than 0.5 vol. %) of so-called type B rotation twin
regions located near the oxide-Ge interface. The main structural defects for both epi materials are
micro twin lamellas lying in {111} planes 70° inclined to the wafer surface that may reach through
the whole layer from the oxide interface to the surface. Furthermore, TEM confirms the existence of
stacking faults and threading dislocations. X-ray grazing incident diffraction and Raman measurements
show that epi-Ge layers on Pr2O3 buffer are nearly fully relaxed, while epi-Si layers on
Y2O3/Pr2O3 double buffer are compressive strained depending on their own thickness and the thickness
of the underlying Y2O3 layer. It is demonstrated that the epi-layer quality can be improved by
post-deposition annealing procedures.
Investigation of the Mechanical Properties of Thin Films by Bulge Test
Authors: Hémel Audrey , Jacques Alain , Schenk Thomas , Kruml Tomáš
Published: October 2009

A new bulge test device has been built, with the aim to perform mechanical tests on membranes with a thickness in the 100 nm to 10 µm range, between room temperature and 900°C. The first tests on Si3N4 and gold films give results consistent with literature data.
Investigations on the Behaviour of Carbon during Inductive Melting of Multicrystalline Silicon
Authors: Raabe Lutz , Ehrig Jan , Würzner Sindy , Pätzold Olf , Stelter Michael , Möller Hans Joachim
Published: October 2009

The influence of the CO concentration in the gas phase on the distribution of carbon in Bridgman-grown, multicrystalline silicon is studied. The growth experiments were conducted in a high-vacuum induction furnace either under a CO enriched atmosphere or under CO free conditions. Furthermore, thermodynamic calculations in the system silicon/oxygen/carbon were done. In crystal growth under a CO enriched atmosphere a SiC-containing layer is formed on the top surface of the melt in agreement with the calculated phase diagram. In this case, the level of substitutional carbon in the cystal was found to be almost constant, whereas the axial carbon concentration in crystals grown under CO free conditions increases monotonously according to Scheil's law.
Theoretical Study of Ionized Impurities in Silicon Nanowire MOS Transistors
Authors: Bescond Marc , Lannoo Michel , Raymond L. , Michelini F.
Published: October 2009

This study presents ionized impurity impacts on silicon nanowire MOS transistors. We
calculate the current characteristics with a self-consistent three-dimensional (3D) Green’s function
approach and show the effects of both acceptor and donor impurities on the physical electron
properties. In particular, we emphasize that the presence of a donor induces different transport
phenomena according to the applied gate bias. Our results show that the influence of a single
impurity strongly depends on its position and induces high transistor performance variability with
current modifications from 50% to two orders of magnitude.
Silicon Cluster Aggregation in Silica Layers
Authors: Fitting Hans Joachim , Fitting Kourkoutis L. , Salh R. , Kolesnikova E.V. , Zamoryanskaya M.V. , von Czarnowski A. , Schmidt Bernd
Published: October 2009

Scanning transmission electron microscopy (STEM) in combination with electron energy loss spectroscopy (EELS) and cathodoluminescence (CL) have been used to investigate Si+-implanted amorphous silicon dioxide layers and the formation of Si nanoclusters. The microstructure of the Si doped silica films was studied by energy filtered transmission electron microscopy (EFTEM) in a 200 kV FEI Tecnai F20 TEM. The samples were amorphous, thermally grown 500 nm SiO2 layers on Si substrate doped by Si+ ions with an energy of 150 keV up to an atomic dopant fraction of about 4 at%. A thermal post-annealing leads to formation of silicon clusters with sizes 1-5 nm and concentrations of about 1018 cm-3. Respective cathodoluminescence spectra in the near IR region indicate such structural changes by appearance of an additional band at 1.35 eV as well as additional emission bands in the visible green-yellow region.
Determination of the Origin of Dislocation Related Luminescence from Silicon Using Regular Dislocation Networks
Authors: Mchedlidze Teimuraz , Kononchuk Oleg , Arguirov Tzanimir , Trushin Maxim , Reiche Manfred , Kittler Martin
Published: October 2009

The investigation of regular dislocation networks (DN) formed by direct wafer bonding suggests that the D1 and D2 peaks of dislocation-related luminescence (DRL) in silicon is linked to screw dislocations, whereas edge dislocations are responsible for D3 and D4 DRL peaks. Non-radiative recombination activity in DN could be attributed to edge dislocations and could be related to enhanced ability of these dislocations to getter impurity atoms. Obtained relation of DRL intensity with the density of screw dislocations suggests existence of the optimum twist angle for the wafer-bonding geometry for which the DRL intensity has a maximum. The dependence of DRL intensity on the spacing between screw dislocations has the maximum at about 7 nm. Reported radiative and non-radiative recombination properties of DN present substantial interest not only for possible LED applications in all-Si photonics but also for photovoltaics, since DNs represent a model system for grain boundaries controlling carrier lifetime in microcrystalline-Si material.
Strained Silicon Devices
Authors: Reiche Manfred , Moutanabbir O. , Hoentschel Jan , Gösele U.M. , Flachowsky Stefan , Horstmann Manfred
Published: October 2009

Strained silicon channels are one of the most important Technology Boosters for further Si CMOS developments. The mobility enhancement obtained by applying appropriate strain provides higher carrier velocity in MOS channels, resulting in higher current drive under a fixed supply voltage and gate oxide thickness. The physical mechanism of mobility enhancement, methods of strain generation and their application for advanced VLSI devices is reviewed.
Si Wafer Bonding: Structural Features of the Interface
Authors: Vdovin V.I. , Zakharov N.D. , Pippel Eckhard , Werner P. , Milvidskii M.G. , Ries M. , Seacrist M. , Falster Robert J.
Published: October 2009

Kinetics of oxide layer dissolution and atomic structure of Si-Si interface in Si wafer bonded structures have been investigated by transmission electron microscopy. Samples of Si(001)/SiO2/Si(001) and Si(110)/SiO2/Si(001) structures were fabricated by direct hydrophilic wafer bonding of 200 mm wafers followed by high temperature annealing. It is found that the decomposition rate of oxide layer and formation of Si-Si bonded interface depends very much on lattice mismatch and twist angle.
The Bile Acid Receptor FXR Is a Modulator of Intestinal Innate Immunity
Authors: Vavassori Piero , Mencarelli Andrea , Renga Barbara , Distrutti Eleonora , Fiorucci Stefano
Published: October 2009

The farnesoid X receptor (FXR) is a bile acid-regulated nuclear receptor expressed in enterohepatic tissues. In this study we investigated whether FXR is expressed by cells of innate immunity and regulates inflammation in animal models of colitis. Acute (7 days) and chronic (8 wk) colitis were induced in wild-type and FXR−/− mice by intrarectal administration of trinitrobenzensulfonic acid or by 7-day administration of 5% dextran sulfate in drinking water. The results of this experiment demonstrate that FXR is expressed by and exerts counterregulatory effects on cells of innate immunity. Exposure of LPS-activated macrophages to 6-ethyl chenodeoxycholic acid (6E-CDCA; INT-747) a synthetic FXR ligand, results in a reciprocal regulation of NF-κB dependent-genes (TNF-α, IL-1β, IL-6, COX-1, COX-2, and iNOS) and induction of SHP, a FXR-regulated gene. FXR activation stabilizes the nuclear corepressor NCoR on the NF-κB responsive element on the IL-1β promoter. Colon inflammation in Crohn’s disease patients and in rodent models of colitis is associated with a reduced expression of FXR mRNA. Using two rodent models of colon inflammation, we show that progression of these immune-mediated disorders is exacerbated in FXR−/− mice (p < 0.01). In vivo treatment with INT-747 attenuates organ injury and immune cell activation. FXR activation increased the colon expression of I-BABP, FXR, and SHP while reducing IL-1β, IL-2, IL-6, TNF-α, and IFN-γ mRNA expression and attenuating disease severity. In aggregate, these findings provide evidence that FXR is an essential component of a network of nuclear receptors that regulate intestinal innate immunity and homeostasis.
Recognition of Fungal Protease Activities Induces Cellular Activation and Eosinophil-Derived Neurotoxin Release in Human Eosinophils
Authors: Matsuwaki Yoshinori , Wada Kota , White Thomas A. , Benson Linda M. , Charlesworth M. Cristine , Checkel James L. , Inoue Yoshinari , Hotta Kyoko , Ponikau Jens U. , Lawrence Christopher B. , Kita Hirohito
Published: October 2009

Eosinophils are multifunctional leukocytes implicated in the pathogenesis of asthma and in immunity to certain organisms. Associations between exposure to an environmental fungus, such as Alternaria, and asthma have been recognized clinically. Protease-activated receptors (PARs) are G protein-coupled receptors that are cleaved and activated by serine proteases, but their roles in innate immunity remain unknown. We previously found that human eosinophils respond vigorously to Alternaria organisms and to the secretory product(s) of Alternaria with eosinophils releasing their proinflammatory mediators. In this study, we investigated the roles of protease(s) produced by Alternaria and of PARs expressed on eosinophils in their immune responses against fungal organisms. We found that Alternaria alternata produces aspartate protease(s) and that human peripheral blood eosinophils degranulate in response to the cell-free extract of A. alternata. Eosinophils showed an increased intracellular calcium concentration in response to Alternaria that was desensitized by peptide and protease ligands for PAR-2 and inhibited by a PAR-2 antagonistic peptide. Alternaria-derived aspartate protease(s) cleaved PAR-2 to expose neo-ligands; these neo-ligands activated eosinophil degranulation in the absence of proteases. Finally, treatment of Alternaria extract with aspartate protease inhibitors, which are conventionally used for HIV-1 and other microbes, attenuated the eosinophils’ responses to Alternaria. Thus, fungal aspartate protease and eosinophil PAR-2 appear critical for the eosinophils’ innate immune response to certain fungi, suggesting a novel mechanism for pathologic inflammation in asthma and for host-pathogen interaction.
Defining the Turkey MHC: Sequence and Genes of the B Locus
Authors: Chaves Lee D. , Krueth Stacy B. , Reed Kent M.
Published: October 2009

The MHC, the most polymorphic and gene dense region in the vertebrate genome, contains many loci essential to immunity. In mammals, this region spans ∼4 Mb. Studies of avian species have found the MHC to be greatly reduced in size and gene content with an overall locus organization differing from that of mammals. The chicken MHC has been mapped to two distinct regions (MHC-B and -Y) of a single chromosome. MHC-B haplotypes possess tightly linked genes encoding the classical MHC molecules and few other disease resistance genes. Furthermore, chicken haplotypes possess a dominantly expressed class I and class II B locus that have a significant effect on the progression or regression of pathogenic disease. In this study, we present the MHC-B region of the turkey (Meleagris gallopavo) as a similarly constricted locus, with 34 genes identified within a 0.2-Mb region in near-perfect synteny with that of the chicken MHC-B. Notable differences between the two species are three BG and class II B loci in the turkey compared with one BG and two class II B loci in the chicken MHC-B. The relative size and high level of similarity of the turkey MHC in relation to that of the chicken suggest that similar associations with disease susceptibility and resistance may also be found in turkey.
Ca2+ Waves Initiate Antigen-Stimulated Ca2+ Responses in Mast Cells
Authors: Cohen Roy , Torres Alexis , Ma Hong-Tao , Holowka David , Baird Barbara
Published: October 2009

Ca2+ mobilization is central to many cellular processes, including stimulated exocytosis and cytokine production in mast cells. Using single cell stimulation by IgE-specific Ag and high-speed imaging of conventional or genetically encoded Ca2+ sensors in rat basophilic leukemia and bone marrow-derived rat mast cells, we observe Ca2+ waves that originate most frequently from the tips of extended cell protrusions, as well as Ca2+ oscillations throughout the cell that usually follow the initiating Ca2+ wave. In contrast, Ag conjugated to the tip of a micropipette stimulates local, repetitive Ca2+ puffs at the region of cell contact. Initiating Ca2+ waves are observed in most rat basophilic leukemia cells stimulated with soluble Ag and are sensitive to inhibitors of Ca2+ release from endoplasmic reticulum stores and to extracellular Ca2+, but they do not depend on store-operated Ca2+ entry. Knockdown of transient receptor potential channel (TRPC)1 and TRPC3 channel proteins by short hairpin RNA reduces the sensitivity of these cells to Ag and shifts the wave initiation site from protrusions to the cell body. Our results reveal spatially encoded Ca2+ signaling in response to immunoreceptor activation that utilizes TRPC channels to specify the initiation site of the Ca2+ response.
CMV-Specific TCR-Transgenic T Cells for Immunotherapy
Authors: Schub Andrea , Schuster Ingrid G. , Hammerschmidt Wolfgang , Moosmann Andreas
Published: October 2009

Reactivation of CMV can cause severe disease after allogeneic hemopoietic stem cell transplantation. Adoptive T cell therapy was successfully used for patients who had received transplants from CMV-positive donors. However, patients with transplants from CMV-negative donors are at highest risk, and an adoptive therapy is missing because CMV-specific T cells are not available from such donors. To address this problem, we used retroviral transfer of CMV-specific TCR genes. We generated CMV-specific T cell clones of several HLA restrictions recognizing the endogenously processed Ag pp65. The genes of four TCRs were cloned and transferred to primary T cells from CMV-negative donors. These CMV-TCR-transgenic T cells displayed a broad spectrum of important effector functions (secretion of IFN-γ and IL-2, cytotoxicity, proliferation) in response to endogenously processed pp65 and could be enriched and expanded by strictly Ag-specific stimulation. Expansion of engineered T cells was accompanied by an increase in specific effector functions, indicating that the transferred specificity is stable and fully functional. Hence, we expect these CMV-TCR-transgenic T cells to be effective in controlling acute CMV disease and establishing an antiviral memory.
IL-22 Produced by Human NK Cells Inhibits Growth of Mycobacterium tuberculosis by Enhancing Phagolysosomal Fusion
Authors: Dhiman Rohan , Indramohan Mohanalaxmi , Barnes Peter F. , Nayak Ramesh C. , Paidipally Padmaja , Rao L. Vijaya Mohan , Vankayalapati Ramakrishna
Published: October 2009

We determined whether human NK cells could contribute to immune defenses against Mycobacterium tuberculosis through production of IL-22. CD3−CD56+ NK cells produced IL-22 when exposed to autologous monocytes and γ-irradiated M. tuberculosis, and this depended on the presence of IL-15 and IL-23, but not IL-12 or IL-18. IL-15-stimulated NK cells expressed 10.6 times more DAP10 mRNA compared with control NK cells, and DAP10 siRNA inhibited IL-15-mediated IL-22 production by NK cells. Soluble factors produced by IL-15-activated NK cells inhibited growth of M. tuberculosis in macrophages, and this effect was reversed by anti-IL-22. Addition of rIL-22 to infected macrophages enhanced phagolysosomal fusion and reduced growth of M. tuberculosis. We conclude that NK cells can contribute to immune defenses against M. tuberculosis through production of IL-22, which inhibits intracellular mycobacterial growth by enhancing phagolysosomal fusion. IL-15 and DAP-10 elicit IL-22 production by NK cells in response to M. tuberculosis.
A Proposal for Dividing Slovenia into Provinces
Authors: Pogačnik Andrej , Zavodnik Lamovšek Alma , Drobne Samo
Published: October 2009

This paper discusses a model developed for evaluating the division of Slovenia into provinces based on 19 criteria. We used them to evaluate six models of provinces. Due to the similarities between some of the models, this paper presents only the results of the divisions into one, three, six, and fourteen provinces. The quantitative evaluation results show that the division into three provinces seems to be the most appropriate solution. However, if there is a desire to have sufficiently large provinces that are able to independently direct their development in line with the principles of sustainable development and in accordance with the principles of the protection of natural and cultural heritage values, thereby simultaneously responding to the challenges of globalisation and climate change, then we, the authors of this paper, believe that the division of Slovenia into six provinces is the most appropriate solution. These provinces are already small enough so that their population can identify itself with them.

KEYWORDS: • province • region • province model • number of provinces • evaluation of provinces • Slovenia
Jurisdiction in the Territorial Hierarchical Administration Office: An Example of the Historical Land of Styria from 1186 to 1850
Authors: Holcman Borut , Kocher Gernot
Published: October 2009

Division of administrative powers is the result of concrete decisions made by the supreme power holders (ius eminens) to be present in the daily life of an individual. Quarters, district offices (in Slovene: “kresije” [pl.]), counting offices, recruitment districts, and district boards were those agents of power that were used by the supreme power holder to ensure the common good through them. The holder‟s power originated from the supreme power holder. It was restricted by the degree at which he operated. According to the nature of things, the power was subordinated by the delegated competences, and they functioned on the principle of subsidiarity, or it was autonomous under control in the case of the Church. Pragmatism of each supreme power holder is reflected in observing the divisions in operation. They most frequently emerged from the controlled autonomy.

KEYWORDS: • jurisdiction • administration • institution • hierarchical character of bureaucratic apparatus • administrative history • Roman Catholic Church
Pain in medical inpatients: an under-recognised problem?
Authors: Conway Morris A , Howie N
Published: October 2009

Pain is a common feature of a range of illnesses. Although it is perceived as a significant problem for surgical patients and those with terminal malignancy, there is a paucity of evidence regarding the prevalence of pain in general medical patients. This study set out to determine pain prevalence and the contribution of chronic pain in a teaching hospital medical unit. All wards on the medical unit were visited on three consecutive days and all eligible patients were asked to complete a questionnaire indicating occurrence and severity of pain. Their analgesic prescriptions were also reviewed. A total of 156 patients took part, representing 85% of all inpatients. Chronic pain prior to admission was a common finding, being reported by 57 (37%) of patients and was associated with the occurrence of pain and severe pain (pain score >6) while an inpatient. Overall, 53% of patients experienced pain, 38% had severe pain and 18% had less than 50% analgesic efficacy. Prescription of non-recommended analgesics was common, and was strongly associated with the occurrence of pain (odds ratio 12, 95% confidence interval 4–38). Large numbers of patients had contraindications to commonly prescribed medications. Dissatisfaction was closely linked to poor response to prescribed analgesics, non-recommended prescription and severe pain. Pain is common among medical patients. Chronic pain is a major problem and complicates the issue of analgesic prescription. There is considerable scope for improvement in the management of pain among medical patients. However, pain control for these patients is likely to be more complex than for surgical patients.
Quantification of dynamic mixing performance of single screws of different configurations by visualization and image analysis
Authors: Wong A. C.‐Y. , Lam Y. , Wong A. C. M.
Published: October 2009

The visualization and image analysis techniques developed by the authors for the study of quantifying the dynamic quality of mixing of a single‐screw extruder were employed to investigate the mixing performance of screws of different configurations. The mixing quality was quantified by calculating the variances of the light intensity of the bitmap files cropped from the films taken at the screw length of 15D and 17D of a 45‐mm screw diameter single‐screw extruder. Temperature and screw speed were the two variables studied. While temperature and back pressure were found to have little effect on the mixing quality, screw speed was demonstrated to be a major factor responsible for the mixing fluctuation observed during extrusion. In fact, screw speed and mixing fluctuation appeared to have a relationship that the higher the screw speed, the bigger the fluctuation (i.e., poorer quality of mixing). The experimental results also revealed that the secondary flight of a barrier screw might be essential to improve the quality of mixing. © 2009 Wiley Periodicals, Inc. Adv Polym Techn 28:1–15, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/adv.20142
Drying‐induced birefringence of polyimide optical films
Authors: Chen Po‐Ju , Liu Ta‐Jo , Wu Ping‐Yao , Tseng Chi‐Fu , Leu Chyi‐Ming
Published: October 2009

Drying‐induced birefringence of polyimide film was investigated. The polyimide solutions were coated and dried on two different types of substrates and then removed for optical measurements. The operating window, which was a region for stable and uniform film formation, was determined experimentally. The out‐of‐plane birefringence (OPBR) was found to increase with decreasing dry film thickness, and the increase became more significant for films less than 10 μm thick. The experimental OPBR results were compared with the predictions of two theoretical models. The results agreed reasonably well with the one‐dimensional model of Lei et al. (J Appl Polym Sci. 2001;81:1000‐1013). On the other hand, a simple viscoelastic model, which is an extension of the elastic model of Croll (J Appl Polym Sci. 1979;23:847‐858), could provide clear physical insight, but its applicability was somewhat limited. The effects of several variables such as elasticity number, solidification concentration, yield stress, and mass transfer rate on OPBR were examined. © 2009 American Institute of Chemical Engineers AIChE J, 2010
Kinetic study of the decomposition of 2‐butanol on carbon‐based acid catalyst
Authors: Bedia J. , Ruiz‐Rosas R. , Rodríguez‐Mirasol J. , Cordero T.
Published: October 2009

The catalytic conversion of 2‐butanol on a carbon‐based acid catalyst prepared by chemical activation of olive stone with phosphoric acid was investigated. The carbon catalyst showed a considerable amount of surface phosphorus, presumably in form of phosphate groups, as revealed by XPS, despite a washing step carried out after the activation process. Conversion of 2‐butanol yields mainly dehydration products, mostly cis‐2‐butene and trans‐2‐butene with lower amounts of 1‐butene, and a very small amount of mek as dehydrogenation product. Kinetic interpretation of the experimental data was performed using two elimination mechanisms for the dehydration reaction; an E1‐mechanism (two‐step mechanism) and an E2‐mechanism (one‐step mechanism). The rate expressions derived from both models fit properly the experimental results, suggesting that probably the two mechanisms occur simultaneously. This is supported by the similar rate constant obtained for the formation of the carbocation and the olefins in the E1 and E2 mechanisms, respectively. © 2009 American Institute of Chemical Engineers AIChE J, 2010
Fluidization enhancement of agglomerates of metal oxide nanopowders by microjets
Authors: Quevedo Jose A. , Omosebi Ayokunle , Pfeffer Robert
Published: October 2009

The quality of gas–solid fluidization of agglomerates of nanoparticles has been greatly enhanced by adding a secondary flow in the form of a high‐velocity jet produced by one or more micronozzles pointing vertically downward toward the distributor. The micronozzles produced a jet with sufficient velocity (hundreds of meters per second), turbulence, and shear to break‐up large nanoagglomerates, prevent channeling, curtail bubbling, and promote liquid‐like fluidization. For example, Aerosil R974, an agglomerate particulate fluidization (APF) type nanopowder, expanded up to 50 times its original bed height, and difficult to fluidize agglomerate bubbling fluidization (ABF) type nanopowders, such as Aeroxide TiO2 P25, were converted to APF type behavior, showing large bed expansions and homogeneous fluidization without bubbles. Microjet‐assisted nanofluidization was also found to improve solids motion and prevent powder packing in an internal, is easily scaled‐up, and can mix and blend different species of nanoparticles on the nanoscale. © 2009 American Institute of Chemical Engineers AIChE J, 2010
Polyamide‐imide nanofiltration hollow fiber membranes with elongation‐induced nano‐pore evolution
Authors: Sun Shi Peng , Wang Kai Yu , Rajarathnam D. , Hatton T. Alan , Chung Tai‐Shung
Published: October 2009

The molecular design of nanoporous membranes with desired morphology and selectivity has attracted significant interest over the past few decades. A major problem in their applications is the trade‐off between sieving property and permeability. Here, we report the discovery of elongation‐induced nano‐pore evolution during the external stretching of a novel polyamide‐imide nanofiltration hollow fiber membrane in a dry‐jet wet‐spinning process that simultaneously leads to a decreased pore size but increased pure water permeability. The molecular weight cutoff, pore size, and pore size distribution were finely tuned using this approach. AFM and polarized FTIR verified the nano‐pore morphological evolution and an enhanced molecular orientation in the surface skin layer. The resultant nanofiltration membranes exhibit highly effective fractionation of the monovalent and divalent ions of NaCl/Na2SO4 binary salt solutions. More than 99.5% glutathione can be rejected by the nanofiltration membranes at neutral pH, offering the feasibility of recovering this tripeptide. © 2009 American Institute of Chemical Engineers AIChE J, 2010
Premolar hypodontia is a common feature in Sotos syndrome with a mutation in the NSD1 gene
Authors: Kotilainen Johanna , Pohjola Pia , Pirinen Sinikka , Arte Sirpa , Nieminen Pekka
Published: October 2009

The major diagnostic manifestations in Sotos syndrome include frontal bossing, downward slanting palpebral fissures, a prominent jaw, learning disability, and childhood overgrowth. Over 90% of clinically diagnosed patients have an abnormality in the NSD1 gene. We investigated the dental manifestations of this disorder and found one or several premolar teeth were absent in 9 out of 13 (69%) affected children and adolescents. A heterozygous mutation in the NSD1 gene was identified in 12 patients, including all patients with hypodontia. The severity of the hypodontia seemed to increase with the severity of aberration of the NSD1. More than 50% of the patients had enamel defects or excessive tooth wear. Dental age, based on tooth formation, was within the normal range. A characteristic occlusion for Sotos syndrome could not be identified. As agenesis of premolars was a common feature in these patients affected with Sotos syndrome, we recommend panoramic radiography at the age of 7 years. If premolars are missing, proper preventive and restorative care is necessary to maintain the deciduous molars. © 2009 Wiley‐Liss, Inc.
Maternal knowledge and attitudes about newborn screening for sickle cell disease and cystic fibrosis
Authors: Lang Colleen Walsh , Stark Alex P. , Acharya Kruti , Ross Lainie Friedman
Published: October 2009

Illinois introduced mandatory newborn screening (NBS) for sickle cell disease (SCD) in 1989 and for cystic fibrosis (CF) in 2008. We examined maternal understanding of NBS for SCD and CF, and their knowledge of the genetics, symptoms, and treatments of both conditions. Our methods consisted of conducting interviews of inpatient post‐partum women (>18 years and English speaking). Our results showed that of the 388 eligible participants, 34 self‐identified as sickle cell carriers, 1 with SCD and 1 as a CF carrier. Almost 3/4 were African American (282/387). Although all but 5 women had prenatal care, only 35% (133/378) recalled their prenatal care provider mentioning NBS, and only 56% (217/388) of participants recalled nursery staff mentioning NBS. There was more self‐reported familiarity with SCD (3.32/5) than CF (1.97/5, P < 0.001). Over 2/3 (260/388) of participants could not answer CF knowledge questions because they had never heard of CF. Among those who had heard of the conditions, mean knowledge scores were 66% for SCD (n = 372) and 63% for CF (n = 128). Bivariate analysis identified education, age, race, marital status, and insurance status as statistically significant. After linear regression education remained significant for both conditions. We conclude that in a sample of predominantly African American post‐partum women, we found poor understanding of NBS, greater familiarity with SCD, and significant knowledge gaps for both SCD and CF. There are many missed educational opportunities for educating parents about NBS and specific conditions included in NBS panels in both the obstetric clinics and the nursery. © 2009 Wiley‐Liss, Inc.
Psychosocial aspects of patients with Niemann‐Pick disease, type B
Authors: Henderson Shelly L. , Packman Wendy , Packman Seymour
Published: October 2009

Health‐care providers have only begun to understand the medical aspects of Niemann–Pick disease type B (NPDB), a relatively rare disease. Even less information is known about the psychological effects of living with NPDB. Patients with NPDB and their families face numerous psychological stressors including extensive medical testing, uncertainty of diagnosis, living and coping with a chronic illness, and grief and bereavement surrounding this progressively debilitating, and, ultimately, fatal disease. We used a qualitative case study approach to explore the human experiences of NPDB patients and families. To assess psychosocial adjustment, all participants were administered a semi‐structured, qualitative interview, as well as quantitative measures. Five major findings emerged: (1) limited physical activity, social isolation, and peer rejection were identified as significant stressors; (2) stressors had a specific impact during the age span of 10–16 years; (3) parents and adult patients expressed frustration regarding the lack of available information and treatment; (4) patients described close family relationships as a way of coping with illness; and (5) adult patients identified early medical experiences as having a considerable psychological impact. The results of this investigation highlight and expand awareness of the psychological and social needs of NPDB patients and families. This study calls for a collaborative, multidisciplinary effort in the treatment of these patients and their families. © 2009 Wiley‐Liss, Inc.
Pure distal trisomy 2q: A rare chromosomal abnormality with recognizable phenotype
Authors: Elbracht Miriam , Roos Andreas , Schönherr Nadine , Busse Sabine , Damen Reinhild , Zerres Klaus , Rudnik‐Schöneborn Sabine , Schüler Herdit Monika
Published: October 2009

We present clinical and molecular cytogenetic results of two unrelated patients with isolated distal trisomy of 2q33‐qter and 2q35‐q37.3 and a remarkable similar facial appearance. Common craniofacial features included a high hairline, broad nasal bridge, prominent nasal tip, thin upper lip vermillion, and large ears. Contrary to patients with duplications proximal to 2q33, the children with pure trisomy distal to 2q35 have normal or increased body measurements and show no major malformations. Moderate psychomotor delay was a constant finding. © 2009 Wiley‐Liss, Inc.
Ellis–van Creveld syndrome and Weyers acrodental dysostosis are caused by cilia‐mediated diminished response to hedgehog ligands
Authors: Ruiz‐Perez Victor L. , Goodship Judith A.
Published: October 2009

Ellis–van Creveld syndrome (EvC; OMIM 225500) is a recessive disorder comprising chondrodysplasia, polydactyly, nail dysplasia, orofacial abnormalities and, in a proportion of patients, cardiovascular malformations. Weyers acrodental dysostosis (Weyers; OMIM 193530) is an allelic dominant disorder comprising polydactyly, nail dysplasia, and orofacial abnormalities. EvC results from loss‐of‐function mutations in EVC or EVC2, the phenotype associated with the mutations in these two genes being indistinguishable. Three convincing causative mutations have been identified in patients with Weyers acrodental dysostosis, which are clustered in the last coding exon of EVC2 and lead to production of a truncated protein lacking the final 43 amino acids. Localization and function of EVC and EVC2 are inferred from studying the murine orthologs. Both Evc and Evc2 proteins localize to the basal bodies of primary cilia and analysis of an Ellis–van Creveld mouse model, which includes the limb shortening and tooth abnormalities of EvC patients, has demonstrated Hedgehog signaling defects in the absence of Evc. The loss of Evc2 has not been studied directly, but Hedgehog signaling is impaired when a mutant murine Evc2 Weyer variant is expressed in vitro. We conclude that the phenotypic abnormalities in EvC and Weyers syndrome result from tissue specific disruption of the response to Hh ligands. © 2009 Wiley‐Liss, Inc.
Disorders of left–right asymmetry: Heterotaxy and situs inversus
Authors: Sutherland Mardi J. , Ware Stephanie M.
Published: October 2009

Cilia function is critical to the development of proper organ laterality. Primary ciliary dyskinesia (PCD) causes randomization of situs. Heterotaxy, or situs ambiguus, is an abnormal arrangement of the thoracic and abdominal organs that results in congenital anomalies. Animal models and developmental biological approaches have defined pathways required during embryogenesis for proper left–right pattern formation. New candidates for genetic causes of human laterality disorders have emerged from recent studies on the assembly, transport, and signaling functions of cilia at the node as well as identification of cilia within the developing heart. There is evidence that deleterious genetic variants within one or more developmental pathways may disrupt signaling in a synergistic or combinatorial fashion to cause congenital anomalies. The molecular pathways underlying PCD and heterotaxy are being discovered at a rapid pace, and there is increasing recognition of the overlap between these two categories of laterality disorders and their relationship to isolated cardiovascular malformations. This review focuses on the clinical manifestations, molecular mechanisms, and human genetics of these disorders of laterality. © 2009 Wiley‐Liss, Inc.
Diaryliodonium Salts: A Journey from Obscurity to Fame
Authors: Merritt Eleanor A. , Olofsson Berit
Published: October 2009

The recent groundbreaking developments in the application of diaryliodonium salts in cross‐coupling reactions has brought this class of previously underdeveloped reagents to the forefront of organic chemistry. With the advent of novel, facile, and efficient synthetic routes to these compounds, many more applications can be foreseen. Herein we provide an overview of the historical and recent advances in the synthesis and applications of diaryliodonium salts.
Out‐of‐pocket expenses and their burden in patients with rheumatoid arthritis
Authors: Wolfe Frederick , Michaud Kaleb
Published: October 2009

Objective

To describe and understand the burden of out‐of‐pocket expenses in patients with rheumatoid arthritis (RA).

Methods

We studied out‐of‐pocket expenses and their burden in 8,545 US patients with RA. We determined direct medical costs, out‐of‐pocket expenses, the burden of out‐of‐pocket expenses, household income, and measures of RA severity and outcome. In addition, patients were classified into 3 groups based on the level of burden caused by out‐of‐pocket expenses: no or limited problem (I am able to pay the bills without much problem); moderate problem (paying the bills takes away some money I need for other activities); and a great problem (I can't purchase all of the medications or medical care that I need).

Results

A total of 43.6% of patients reported problems paying medical bills after insurance payments and 9.0% reported severe or great problems. Problems with expenses were associated with measures of RA severity, but also and particularly with lower household income and absence of health insurance. The proportion of household income that was consumed by out‐of‐pocket spending for the 3 groups was 2.4%, 7.2%, and 19.2%, respectively, and the percentage of patients meeting the 185% poverty level for these groups was 12.3%, 24.4%, and 51.3%, respectively.

Conclusion

The out‐of‐pocket burden is substantial, particularly in those <65 years of age. Out‐of‐pocket expenses exert their severity predominantly on those with the most severe RA who have the least ability to pay. Household income is the primary determinant of out‐of‐pocket burden, followed by RA severity, and type of health insurance.
Effect of certolizumab pegol with methotrexate on home and work place productivity and social activities in patients with active rheumatoid arthritis
Authors: Kavanaugh Arthur , Smolen Josef S. , Emery Paul , Purcaru Oana , Keystone Edward , Richard Lance , Strand Vibeke , van Vollenhoven Ronald F.
Published: October 2009

Objective

To assess the impact of certolizumab pegol (CZP), a novel PEGylated anti–tumor necrosis factor, in combination with methotrexate (MTX) on productivity outside and within the home, and on participation in family, social, and leisure activities in adult patients with rheumatoid arthritis (RA).

Methods

The efficacy and safety of CZP (200 mg and 400 mg) plus MTX were assessed in 2 phase III, multicenter, double‐blind, placebo‐controlled trials (Rheumatoid Arthritis Prevention of Structural Damage [RAPID] 1 and RAPID 2). The novel, validated, RA‐specific Work Productivity Survey (WPS‐RA) was used to assess work place and home productivity. WPS‐RA responses were collected at baseline and every 4 weeks until withdrawal/study completion.

Results

At baseline, 41.6% and 39.8% of subjects were employed outside the home in RAPID 1 and RAPID 2, respectively. Compared with placebo plus MTX, CZP plus MTX significantly reduced work absenteeism and presenteeism among patients working outside the home. Significant reductions in number of household days lost, household days with productivity reduced by ≥50%, and days lost due to RA for participation in family, social, and leisure activities were reported by patients in active treatment relative to placebo plus MTX. Improvements in all measures were observed with CZP plus MTX as early as week 4, and maintained until the study end (12 months in RAPID 1, 6 months in RAPID 2). Findings were consistent with clinical improvements with CZP plus MTX in both trials.

Conclusion

CZP plus MTX improved productivity outside and within the home and resulted in more participation in social activities compared with placebo plus MTX. These observations suggest that considerable indirect cost gains might be achieved with this therapeutic agent in RA.
Screening of chondrogenic factors with a real‐time fluorescence‐monitoring cell line ATDC5‐C2ER: Identification of sorting nexin 19 as a novel factor
Authors: Kan Akinori , Ikeda Toshiyuki , Saito Taku , Yano Fumiko , Fukai Atushi , Hojo Hironori , Ogasawara Toru , Ogata Naoshi , Nakamura Kozo , Chung Ung‐Il , Kawaguchi Hiroshi
Published: October 2009

Objective

To establish a cell culture system for noninvasive and real‐time monitoring of chondrogenic differentiation in order to screen for chondrogenic factors.

Methods

The optimum reporter construct transfected into chondrogenic ATDC5 cells was selected by a luciferase reporter assay and fluorescence analysis during cultures with insulin. The established cell line was validated according to its fluorescence following stimulation with SOX proteins, bone morphogenetic protein 2 (BMP‐2), or transforming growth factor β (TGFβ) and was compared with the level of messenger RNA for COL2A1 as well as with the degree of Alcian blue staining. Screening of chondrogenic factors was performed by expression cloning using a retroviral expression library prepared from human tracheal cartilage. The expression pattern of the identified molecule was examined by in situ hybridization and immunohistochemistry. Functional analysis was performed by transfection of the identified gene, the small interfering RNA, and the mutated gene.

Results

We established an ATDC5 cell line with 4 repeats of a highly conserved enhancer ligated to a COL2A1 basal promoter and the DsRed2 reporter (ATDC5‐C2ER). Fluorescence was induced under the stimulations with SOX proteins, BMP‐2, or TGFβ, showing good correspondence to the chondrogenic markers. Screening using the ATDC5‐C2ER system identified several chondrogenic factors, including sorting nexin 19 (SNX19). SNX19 was expressed in the limb cartilage of mouse embryos and in the degraded cartilage of adult mouse knee joints during osteoarthritis progression. The gain‐of‐function and loss‐of‐function analyses revealed a potent chondrogenic activity of SNX19.

Conclusion

We established the ATDC5‐C2ER system for efficient monitoring of chondrogenic differentiation by fluorescence analysis, and we identified a novel chondrogenic factor (SNX19) using this system. This system will be useful for elucidating the molecular network of chondrogenic differentiation.
Circulating mesenchymal stem cells with abnormal osteogenic differentiation in patients with osteoporosis
Authors: Carbonare Luca Dalle , Valenti Maria Teresa , Zanatta Mirko , Donatelli Luca , Lo Cascio Vincenzo
Published: October 2009

Objective

While the role of osteoclasts in bone loss has been well investigated, the involvement of osteoblast‐lineage cells has not been completely elucidated. Several genes contribute to normal osteoblastic differentiation from mesenchymal stem cells (MSCs), but an understanding of their role in the pathogenesis of osteoporosis is still lacking. The present study was undertaken to evaluate a possible alteration of osteogenic gene expression as a mechanism contributing to bone loss.

Methods

We studied the osteogenic differentiation process in MSCs obtained from the peripheral blood of 31 patients with osteoporosis and 20 normal donors. The cells were evaluated by colony‐forming unit–fibroblastic assay and cultured in osteogenic medium to analyze the transcription factors runt‐related transcription factor 2 (RUNX‐2) and Sp7 and the bone‐related genes COL1A1, SPARC, and SPP1 after 3, 8, and 15 days of differentiation. In addition, to determine possible differences between the 2 groups in terms of osteoclastic and osteoblastic activation, we quantified the osteoprotegerin (OPG) and RANKL levels in the supernatants of osteoblastic culture.

Results

Circulating MSCs were increased in osteoporosis patients compared with normal donors. In contrast, gene expression analysis revealed down‐regulation of RUNX2, Sp7, COL1A1, SPARC, and SPP1 in patients with osteoporosis, associated with a lower OPG:RANKL ratio.

Conclusion

These results suggest that an alteration of osteoblastic differentiation may contribute to the pathogenesis of osteoporosis. The noninvasive approach used in the present study could be proposed as a useful tool for studying mesenchymal involvement in bone diseases.
B lymphocyte stimulator expression in pediatric systemic lupus erythematosus and juvenile idiopathic arthritis patients
Authors: Hong Sandy D. , Reiff Andreas , Yang Hai‐Tao , Migone Thi‐Sau , Ward Christopher D. , Marzan Katherine , Shaham Bracha , Phei Wee Choo , Garza Judith , Bernstein Bram , Stohl William
Published: October 2009

Objective

To assess the expression of B lymphocyte stimulator (BLyS) in patients with pediatric systemic lupus erythematosus (SLE) or juvenile idiopathic arthritis (JIA).

Methods

Blood samples collected from patients with pediatric SLE (n = 56) and patients with JIA (n = 54) at the beginning and end of a 6‐month interval were analyzed for plasma BLyS protein levels by enzyme‐linked immunosorbent assay and for blood leukocyte full‐length BLyS and ΔBLyS messenger RNA (mRNA) levels by quantitative real‐time polymerase chain reaction (normalized to 18S expression). Healthy siblings (n = 34) of these patients served as controls.

Results

In pediatric SLE, plasma BLyS protein and blood leukocyte BLyS mRNA levels were each significantly elevated, and plasma BLyS protein levels, but not blood leukocyte BLyS mRNA levels, were correlated with disease activity. In contrast, plasma BLyS protein levels were normal in JIA despite blood leukocyte BLyS mRNA levels being elevated to degrees similar to those in pediatric SLE. Among JIA patients, neither BLyS parameter was correlated with disease activity. In both pediatric SLE and JIA, the BLyS expression profiles remained stable at 6 months.

Conclusion

Our findings indicate that, as previously noted in adult SLE, plasma BLyS protein and blood leukocyte BLyS mRNA levels are elevated in pediatric SLE. The correlation of plasma BLyS protein levels with disease activity points to BLyS as a candidate therapeutic target in pediatric SLE. Contrary to previous observations in adults with rheumatoid arthritis, plasma BLyS protein levels are normal in JIA despite elevated blood leukocyte BLyS mRNA levels. The absence of correlation between either of the BLyS parameters and disease activity in JIA calls for circumspection prior to assigning BLyS as a candidate therapeutic target in this disorder.