bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of Nested Polymerase Chain Reaction Based on Sequence-Based Typing of Clinical Samples to Determine the Source of Infection for Hospital-Acquired Legionnaires' Disease
Authors: Scaturro Maria , Fontana Stefano , Ricci Maria Luisa
Published: April 2011

The source of infection of a hospital-acquired Legionnaires' disease case was determined for the first time by nested polymerase chain reaction based on sequence-based typing. The typing was performed directly on DNA extracted from tissue samples, allowing a rapid epidemiological correlation with environmental isolates.
DISCOVERY OF A MULTIPLY LENSED SUBMILLIMETER GALAXY IN EARLY HerMES
HERSCHEL/SPIRE
*

DATA
Authors: Conley A. , Cooray A. , Vieira J. D. , Solares E. A. González , Kim S. , Aguirre J. E. , Amblard A. , Auld R. , Baker A. J. , Beelen A. , Blain A. , Blundell R. , Bock J. , Bradford C. M. , Bridge C. , Brisbin D. , Burgarella D. , Carpenter J. M. , Chanial P. , Chapin E. , Christopher N. , Clements D. L. , Cox P. , Djorgovski S. G. , Dowell C. D. , Eales S. , Earle L. , Ellsworth-Bowers T. P. , Farrah D. , Franceschini A. , Frayer D. , Fu H. , Gavazzi R. , Glenn J. , Griffin M. , Gurwell M. A. , Halpern M. , Ibar E. , Ivison R. J. , Jarvis M. , Kamenetzky J. , Krips M. , Levenson L. , Lupu R. , Mahabal A. , Maloney P. D. , Maraston C. , Marchetti L. , Marsden G. , Matsuhara H. , Mortier A. M. J. , Murphy E. , Naylor B. J. , Neri R. , Nguyen H. T. , Oliver S. J. , Omont A. , Page M. J. , Papageorgiou A. , Pearson C. P. , Pérez-Fournon I. , Pohlen M. , Rangwala N. , Rawlings J. I. , Raymond G. , Riechers D. , Rodighiero G. , Roseboom I. G. , Rowan-Robinson M. , Schulz B. , Scott Douglas , Scott K. , Serra P. , Seymour N. , Shupe D. L. , Smith A. J. , Symeonidis M. , Tugwell K. E. , Vaccari M. , Valiante E. , Valtchanov I. , Verma A. , Viero M. P. , Vigroux L. , Wang L. , Wiebe D. , Wright G. , Xu C. K. , Zeimann G. , Zemcov M. , Zmuidzinas J.
Published: April 2011

We report the discovery of a bright (f(250 μm)>400 mJy),
multiply lensed submillimeter galaxy HERMES J105751.1+573027 in
Herschel/SPIRE Science Demonstration Phase data from the
HerMES project. Interferometric 880 μm Submillimeter Array observations resolve
at least four images with a large separation of ∼9″. A high-resolution adaptive
optics Kp
image with Keck/NIRC2 clearly shows strong
lensing arcs. Follow-up spectroscopy gives a redshift of z =
2.9575, and the lensing model gives a total magnification of μ ∼ 11 ± 1. The
large image separation allows us to study the multi-wavelength spectral energy
distribution (SED) of the lensed source unobscured by the central lensing mass.
The far-IR/millimeter-wave SED is well described by a modified blackbody fit
with an unusually warm dust temperature, 88 ± 3 K. We derive a lensing-corrected
total IR luminosity of (1.43 ± 0.09) ×
1013 
L
☉, implying a star formation
rate of ∼2500 M
☉ yr−1. However, models
primarily developed from brighter galaxies selected at longer wavelengths are a
poor fit to the full optical-to-millimeter SED. A number of other strongly
lensed systems have already been discovered in early Herschel
data, and many more are expected as additional data are collected.
Various characterizations of product Hardy space
Authors: Li Ji , Song Liang , Tan Chaoqiang
Published: April 2011

This article deals with the characterizations of Hardy space

H
1

H^1

on

R

n

×

R

m

\mathbb {R}^n\times \mathbb {R}^m

using different norms on distinct variables. This result can be applied to the boundedness of certain operators on

H
1

(

R

n

×

R

m

)

H^1(\mathbb {R}^n\times \mathbb {R}^m)

.
The Radon-Nikodym property for some Banach algebras related to the Fourier algebra
Authors: Granirer Edmond
Published: April 2011

The Radon-Nikodym property for the Banach algebrasApr(G)=Ap∩Lr(G)A_p^r(G)=A_p\cap L^r(G), whereA2(G)A_2(G)is the Fourier algebra, is investigated. A complete solution is given for amenable groupsGGif1>p>∞1>p>\inftyand for arbitraryGGifp=2p=2andA2(G)A_2(G)has a multiplier bounded approximate identity. The results are new even forG=RnG=\mathbb {R}^n.
CytoModeler: a tool for bridging large-scale network analysis and dynamic quantitative modeling
Authors: Xia Tian , Van Hemert John , Dickerson Julie A.
Published: April 2011

Summary: CytoModeler is an open-source Java application based on the Cytoscape platform. It integrates large-scale network analysis and quantitative modeling by combining omics analysis on the Cytoscape platform, access to deterministic and stochastic simulators, and static and dynamic network context visualizations of simulation results.

Availability: Implemented in Java, CytoModeler runs with Cytoscape 2.6 and 2.7. Binaries, documentation and video walkthroughs are freely available at http://vrac.iastate.edu/~jlv/cytomodeler/.

Contact:  julied@iastate.edu; netscape@iastate.edu

Supplementary Information:  Supplementary data are available at Bioinformatics online.
Fisheries, food security, climate change, and biodiversity: characteristics of the sector and perspectives on emerging issues
Authors: Rice Jake C. , Garcia Serge M.
Published: April 2011

Rice, J. C., and Garcia, S. M. 2011. Fisheries, food security, climate change, and biodiversity: characteristics of the sector and perspectives on emerging issues. – ICES Journal of Marine Science, 68: 1343–1353. This paper reviews global projections to 2050 for human population growth and food production, both assuming constant climate and taking account of climate-related changes in growing conditions. It also reviews statistics on nutritional protein requirements, as well as how those requirements are met by fish on a regional basis. To meet projected food requirements, the production of fish has to increase by ∼50% from current levels. The paper also summarizes the main pressures on marine biodiversity that are expected to result from the impacts of changing climate on marine ecosystems, as well as the management measures and policy actions promoted to address those pressures. It highlights that most of the actions being proposed to address pressures on marine biodiversity are totally incompatible with the actions considered necessary to meet future food security needs, particularly in less developed parts of the world. The paper does not propose a solution to these conflicting pulls on policies for conservation and sustainable use. Rather, it emphasizes that there is a need for the two communities of experts and policy-makers to collaborate in finding a single compatible suite of policies and management measures, to allow coherent action on these crucial and difficult problems.
The iron-oxidizing proteobacteria
Authors: Hedrich Sabrina , Schlömann Michael , Johnson D. Barrie
Published: April 2011

The ‘iron bacteria’ are a collection of morphologically and phylogenetically heterogeneous prokaryotes. They include some of the first micro-organisms to be observed and described, and continue to be the subject of a considerable body of fundamental and applied microbiological research. While species of iron-oxidizing bacteria can be found in many different phyla, most are affiliated with the Proteobacteria. The latter can be subdivided into four main physiological groups: (i) acidophilic, aerobic iron oxidizers; (ii) neutrophilic, aerobic iron oxidizers; (iii) neutrophilic, anaerobic (nitrate-dependent) iron oxidizers; and (iv) anaerobic photosynthetic iron oxidizers. Some species (mostly acidophiles) can reduce ferric iron as well as oxidize ferrous iron, depending on prevailing environmental conditions. This review describes what is currently known about the phylogenetic and physiological diversity of the iron-oxidizing proteobacteria, their significance in the environment (on the global and micro scales), and their increasing importance in biotechnology.
Arsenate reduction and expression of multiple chromosomal ars operons in Geobacillus kaustophilus A1
Authors: Cuebas Mariola , Villafane Aramis , McBride Michelle , Yee Nathan , Bini Elisabetta
Published: April 2011

Geobacillus kaustophilusstrain A1 was previously isolated from a geothermal environment for its ability to grow in the presence of high arsenate levels. In this study, the molecular mechanisms of arsenate resistance of the strain were investigated. As(V) was reduced to As(III), as shown by HPLC analysis. Consistent with the observation that the micro-organism is not capable of anaerobic growth, no respiratory arsenate reductases were identified. Using specific PCR primers based on the genome sequence ofG. kaustophilusHTA426, three unlinked genes encoding detoxifying arsenate reductases were detected in strain A1. These genes were designatedarsC1,arsC2andarsC3. WhilearsC3is a monocistronic locus, sequencing of the regions flankingarsC1andarsC2revealed the presence of additional genes encoding a putative arsenite transporter and an ArsR-like regulator upstream of each arsenate reductase, indicating the presence of sequences with putative roles in As(V) reduction, As(III) export and arsenic-responsive regulation. RT-PCR demonstrated that both sets of genes were co-transcribed. Furthermore,arsC1andarsC2, monitored by quantitative real-time RT-PCR, were upregulated in response to As(V), whilearsC3was constitutively expressed at a low level. A mechanism for regulation of As(V) detoxification byGeobacillusthat is both consistent with our findings and relevant to the biogeochemical cycle of arsenic and its mobility in the environment is proposed.
A novel multilocus sequence typing scheme for the opportunistic pathogen Propionibacterium acnes and characterization of type I cell surface-associated antigens
Authors: McDowell Andrew , Gao Anna , Barnard Emma , Fink Colin , Murray Philip I. , Dowson Chris G. , Nagy Istvan , Lambert Peter A. , Patrick Sheila
Published: April 2011

We have developed a novel multilocus sequence typing (MLST) scheme and database (http://pubmlst.org/pacnes/) forPropionibacterium acnesbased on the analysis of seven core housekeeping genes. The scheme, which was validated against previously described antibody, single locus and random amplification of polymorphic DNA typing methods, displayed excellent resolution and differentiated 123 isolates into 37 sequence types (STs). An overall clonal population structure was detected with six eBURST groups representing the major clades I, II and III, along with two singletons. Two highly successful and global clonal lineages, ST6 (type IA) and ST10 (type IB1), representing 64 % of this current MLST isolate collection were identified. The ST6 clone and closely related single locus variants, which comprise a large clonal complex CC6, dominated isolates from patients with acne, and were also significantly associated with ophthalmic infections. Our data therefore support an association between acne andP. acnesstrains from the type IA cluster and highlight the role of a widely disseminated clonal genotype in this condition. Characterization of type I cell surface-associated antigens that are not detected in ST10 or strains of type II and III identified two dermatan-sulphate-binding proteins with putative phase/antigenic variation signatures. We propose that the expression of these proteins by type IA organisms contributes to their role in the pathophysiology of acne and helps explain the recurrent nature of the disease. The MLST scheme and database described in this study should provide a valuable platform for future epidemiological and evolutionary studies ofP. acnes.
Arabidopsis cryptochrome 1 interacts with SPA1 to suppress COP1 activity in response to blue light
Authors: Liu Bin , Zuo Zecheng , Liu Hongtao , Liu Xuanming , Lin Chentao
Published: April 2011

Plant photoreceptors mediate light suppression of the E3 ubiquitin ligase COP1 (CONSTITUTIVE PHOTOMORPHOGENIC 1) to affect gene expression and photomorphogenesis. However, how photoreceptors mediate light regulation of COP1 activity remains unknown. We report here that Arabidopsis blue-light receptor cryptochrome 1 (CRY1) undergoes blue-light-dependent interaction with the COP1-interacting protein SPA1 (SUPPRESSOR OF PHYTOCHROME A). We further show that the CRY1–SPA1 interaction suppresses the SPA1–COP1 interaction and COP1-dependent degradation of the transcription factor HY5. These results are consistent with a hypothesis that photoexcited CRY1 interacts with SPA1 to modulate COP1 activity and plant development.
Crystal structure of the Mre11–Rad50–ATPγS complex: understanding the interplay between Mre11 and Rad50
Authors: Lim Hye Seong , Kim Jin Seok , Park Young Bong , Gwon Gwang Hyeon , Cho Yunje
Published: April 2011

Communication between Mre11 and Rad50 in the MR complex is critical for the sensing, damage signaling, and repair of DNA double-strand breaks. To understand the basis for interregulation between Mre11 and Rad50, we determined the crystal structure of the Mre11–Rad50–ATPγS complex. Mre11 brings the two Rad50 molecules into close proximity and promotes ATPase activity by (1) holding the coiled-coil arm of Rad50 through its C-terminal domain, (2) stabilizing the signature motif and P loop of Rad50 via its capping domain, and (3) forming a dimer through the nuclease domain. ATP-bound Rad50 negatively regulates the nuclease activity of Mre11 by blocking the active site of Mre11. Hydrolysis of ATP disengages Rad50 molecules, and, concomitantly, the flexible linker that connects the C-terminal domain and the capping domain of Mre11 undergoes substantial conformational change to relocate Rad50 and unmask the active site of Mre11. Our structural and biochemical data provide insights into understanding the interplay between Mre11 and Rad50 to facilitate efficient DNA damage repair.
Antitumoral efficacy by systemic delivery of heparin conjugated polyethylenimine–plasmid interleukin‐15 complexes in murine models of lung metastasis
Authors: Zhou Xikun , Li Xiaolei , Gou Maling , Qiu Ji , Li Jing , Yu Chuanjiang , Zhang Yinbin , Zhang Nannan , Teng Xiu , Chen Zhongwen , Luo Can , Wang Zhen , Liu Xiao , Shen Guobo , Yang Li , Qian Zhiyong , Wei Yuquan , Li Jiong
Published: April 2011

Gene therapy shows promising application in cancer therapy, but the lack of an ideal gene delivery system is still a tough challenge for cancer gene therapy. Previously, we prepared a novel cationic nanogel, heparin‐polyethylenimine (HPEI), which had potential application in gene delivery. In the present study, we constructed a plasmid with high expression efficiency of interleukin‐15 (IL15) and investigated the effects HPEI–plasmid IL15 (HPEI–pIL15) complexes on the distribution level of the lung. We then evaluated the anticancer effect of HPEI–pIL15 complexes on lung metastases of B16‐F10 melanoma and CT26 colon carcinoma. These results demonstrated that intravenous injection of the HPEI–pIL15 complex exhibited the highest plasmid distribution level in the lung compared with that of PEI2K–pIL15 and PEI25K–pIL15, and mice treated with HPEI–pIL15 had a lower tumor metastasis index compared with other treatment groups. Moreover, the number of natural killer cells, which were intermingled among the tumor cells, and the level of tumor necrosis factor‐α and interferon‐γ in the serum also increased in the pIL15‐treated mice. Furthermore, the cytotoxic activity of spleen cells also increased significantly in the HPEI–pIL15 group. In addition, induction of apoptosis and inhibition of cell proliferation in lung tumor foci in the HPEI–pIL15 group was observed. Taken together, treating lung metastasis cancer with the HPEI nanogels delivered by plasmid IL15 might be a new and interesting cancer gene therapy protocol. (Cancer Sci 2011; 102: 1403–1409)
Validation of the histone methyltransferase EZH2 as a therapeutic target for various types of human cancer and as a prognostic marker
Authors: Takawa Masashi , Masuda Ken , Kunizaki Masaki , Daigo Yataro , Takagi Katsunori , Iwai Yukiko , Cho Hyun‐Soo , Toyokawa Gouji , Yamane Yuka , Maejima Kazuhiro , Field Helen I. , Kobayashi Takaaki , Akasu Takayuki , Sugiyama Masanori , Tsuchiya Eijyu , Atomi Yutaka , Ponder Bruce A. J. , Nakamura Yusuke , Hamamoto Ryuji
Published: April 2011

The emphasis in anticancer drug discovery has always been on finding a drug with great antitumor potential but few side‐effects. This can be achieved if the drug is specific for a molecular site found only in tumor cells. Here, we find the enhancer of zeste homolog 2 (EZH2) to be highly overexpressed in lung and other cancers, and show that EZH2 is integral to proliferation in cancer cells. Quantitative real‐time PCR analysis revealed higher expression of EZH2 in clinical bladder cancer tissues than in corresponding non‐neoplastic tissues (P < 0.0001), and we confirmed that a wide range of cancers also overexpress EZH2, using cDNA microarray analysis. Immunohistochemical analysis showed positive staining for EZH2 in 14 of 29 cases of bladder cancer, 135 of 292 cases of non‐small‐cell lung cancer (NSCLC), and 214 of 245 cases of colorectal cancer, whereas no significant staining was observed in various normal tissues. We found elevated expression of EZH2 to be associated with poor prognosis for patients with NSCLC (P = 0.0239). In lung and bladder cancer cells overexpressing EZH2, suppression of EZH2 using specific siRNAs inhibited incorporation of BrdU and resulted in significant suppression of cell growth, even though no significant effect was observed in the normal cell strain CCD‐18Co, which has undetectable EZH2. Because EZH2 expression was scarcely detectable in all normal tissues we examined, EZH2 shows promise as a tumor‐specific therapeutic target. Furthermore, as elevated levels of EZH2 are associated with poor prognosis of patients with NSCLC, its overexpression in resected specimens could prove a useful molecular marker, indicating the necessity for a more extensive follow‐up in some lung cancer patients after surgical treatment. (Cancer Sci 2011; 102: 1298–1305)
Autologous CTL response against cancer stem‐like cells/cancer‐initiating cells of bone malignant fibrous histiocytoma
Authors: Kano Masanobu , Tsukahara Tomohide , Emori Makoto , Murase Masaki , Torigoe Toshihiko , Kawaguchi Satoshi , Wada Takuro , Yamashita Toshihiko , Sato Noriyuki
Published: April 2011

Malignant fibrous histiocytoma (MFH) of the bone is an aggressive tumor with high rates of local recurrence and metastasis. The development of novel therapeutic approaches is critical to improve the prognosis of patients with MFH. We reported previously that the side population (SP) cells of the MFH2003 bone MFH cell line have the characteristics of cancer stem‐like cells (CSC)/cancer‐initiating cells. In the present study, to establish immunotherapy targeting CSC, we analyzed cell surface immune molecules on SP cells of the MHF2003 cell line, as well as autologous CTL responses against these SP cells in the tumor microenvironment and peripheral circulating lymphocytes, using autologous tumor‐infiltrating lymphocytes and autologous CTL clones derived from peripheral blood, respectively. We found that the SP cells expressed human leukocyte antigen (HLA) Class I molecules on the cell surface. The autologous tumor‐infiltrating lymphocyte line TIL2003 recognized both the SP and main population cells of the MFH2003 cell line. Next, we induced the CTL clone Tc4C‐6 by mixed lymphocyte tumor cell culture using autologous peripheral blood mononuclear cells and freshly isolated SP cells, followed by a limiting dilution procedure. The Tc4C‐6 clone showed specific cytotoxicity against the SP cells. Moreover, the cytotoxicity against SP cells was blocked by the anti‐HLA Class I antibody W6/32. In conclusion, the findings of the present study support the idea that CSC of bone MFH are recognized by autologous CTL in the tumor microenvironment and peripheral circulating lymphocytes. Thus, CTL‐based immunotherapy could target CSC of bone sarcoma to help prevent tumor recurrence. (Cancer Sci 2011; 102: 1443–1447)
Guidelines for supportive care in multiple myeloma 2011
Authors: Snowden John A. , Ahmedzai Sam H. , Ashcroft John , D’Sa Shirley , Littlewood Timothy , Low Eric , Lucraft Helen , Maclean Rhona , Feyler Sylvia , Pratt Guy , Bird Jennifer M. ,   On behalf of the Haemato‐oncology Task Force of the British Committee for Standards in Haematology and UK Myeloma Forum
Published: April 2011

Supportive care plays an increasingly important role in the modern management of multiple myeloma. While modern treatments have significantly prolonged overall and progression free survival through improved disease control, the vast majority of patients remain incurable, and live with the burden of the disease itself and the cumulative side effects of treatments. Maintenance of quality of life presents challenges at all stages of the disease from diagnosis through the multiple phases of active treatment to the end of life. Written on behalf of the British Committee for Standards in Haematology (BCSH) and the UK Myeloma Forum (UKMF), these evidence based guidelines summarize the current national consensus for supportive and symptomatic care in multiple myeloma in the following areas; pain management, peripheral neuropathy, skeletal complications, infection, anaemia, haemostasis and thrombosis, sedation, fatigue, nausea, vomiting, anorexia, constipation, diarrhoea, mucositis, bisphosphonate‐induced osteonecrosis of the jaw, complementary therapies, holistic needs assessment and end of life care. Although most aspects of supportive care can be supervised by haematology teams primarily responsible for patients with multiple myeloma, multidisciplinary collaboration involving specialists in palliative medicine, pain management, radiotherapy and surgical specialities is essential, and guidance is provided for appropriate interdisciplinary referral. These guidelines should be read in conjunction with the BCSH/UKMF Guidelines for the Diagnosis and Management of Multiple Myeloma 2011.
Management of Paroxysmal Nocturnal Haemoglobinuria: a personal view
Authors: Luzzatto Lucio , Gianfaldoni Giacomo , Notaro Rosario
Published: April 2011

Paroxysmal nocturnal haemoglobinuria (PNH) is a serious form of acquired haemolytic anaemia with several features that make it unique, including the fact that it is caused by clonal expansion, in the context of bone marrow failure, of a haematopoietic stem cell that has a somatic mutation in a gene crucial for the synthesis of glycosylphosphatidylinositol anchors; and that this also produces a life‐threatening acquired thrombophilic state. Until recently, the two only main options for patients with PNH were either allogeneic bone marrow transplantation or supportive management, including blood transfusion: both options require some skill and good patient‐doctor collaboration. Since the start of this millennium a major advance has been the introduction of eculizumab, a monoclonal antibody that targets the C5 protein of the complement system: blockade of C5 prevents activation of the complement distal pathway, and thus abrogates the complement‐mediated intravascular haemolysis that severely plagues patients with PNH. This review outlines an approach to the management of all three major components of the clinical picture of PNH – namely haemolysis, thrombosis and bone marrow failure – based on the literature and on personal experience. We consider specifically how the use of eculizumab has modified other aspects of the management of PNH, and even the pathophysiology itself of this disease. Finally, we develop a treatment algorithm which others might find helpful.
Oral dehydroepiandrosterone replacement in older adults: effects on central adiposity, glucose metabolism and blood lipids
Authors: Jankowski Catherine M. , Gozansky Wendolyn S. , Van Pelt Rachael E. , Wolfe Pamela , Schwartz Robert S. , Kohrt Wendy M.
Published: April 2011

Objective  To determine the effects of dehydroepiandrosterone (DHEA) therapy on changes in central adiposity, insulin action and blood lipids. Many of the actions of DHEA in humans are thought to be mediated through its conversion to sex hormones, which are modulators of adiposity, muscularity and insulin sensitivity. The effects of DHEA replacement on regional tissue composition, glucose metabolism and blood lipid profile in older adults have been inconsistent.

Design  A randomized, double‐blinded, placebo‐controlled trial. The intervention was oral DHEA 50 mg/day or placebo for 12 months.

Participants  Fifty‐eighty women and 61 men, aged 60–88 years, with low serum DHEA sulphate (DHEAS) levels at study entry.

Measurements  Computed tomography measures of abdominal fat areas, thigh muscle and fat areas, DXA‐derived trunk fat mass, serum glucose and insulin responses to an oral glucose challenge, and fasted serum total cholesterol, HDL‐cholesterol, LDL‐cholesterol and triglycerides were assessed before and after the intervention.

Results  There were no significant (P > 0·05) differences between the DHEA and placebo groups in the changes in regional tissue composition or glucose metabolism. HDL‐cholesterol (P = 0·01) and fasted triglycerides (P = 0·02) decreased in women and men taking DHEA.

Conclusion  Restoring serum DHEAS levels in older adults to young adult levels for 1 year does not appear to reduce central adiposity or improve insulin action. The benefit of DHEA on decreasing serum triglycerides must be weighed against the HDL‐lowering effect.
UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development
Authors: Ahmed S. Faisal , Achermann John C. , Arlt Wiebke , Balen Adam H. , Conway Gerry , Edwards Zoe L. , Elford Sue , Hughes Ieuan A. , Izatt Louise , Krone Nils , Miles Harriet L. , O’Toole Stuart , Perry Les , Sanders Caroline , Simmonds Margaret , Wallace A. Michael , Watt Andrew , Willis Debbie
Published: April 2011

It is paramount that any child or adolescent with a suspected disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD. If there is any doubt, the case should be discussed with the regional team. In most cases, particularly in the case of the newborn, the paediatric endocrinologist within the regional DSD team acts as the first point of contact. The underlying pathophysiology of DSD and the strengths and weaknesses of the tests that can be performed should be discussed with the parents and affected young person and tests undertaken in a timely fashion. This clinician should be part of a multidisciplinary team experienced in management of DSD and should ensure that the affected person and parents are as fully informed as possible and have access to specialist psychological support. Finally, in the field of rare conditions, it is imperative that the clinician shares the experience with others through national and international clinical and research collaboration.
Hyper‐activation of the TCP4 transcription factor inArabidopsis thalianaaccelerates multiple aspects of plant maturation
Authors: Sarvepalli Kavitha , Nath Utpal
Published: April 2011

Plant organs are initiated as primordial outgrowths, and require controlled cell division and differentiation to achieve their final size and shape. Superimposed on this is another developmental program that orchestrates the switch from vegetative to reproductive to senescence stages in the life cycle. These require sequential function of heterochronic regulators. Little is known regarding the coordination between organ and organismal growth in plants. TheTCPgene family encodes transcription factors that control diverse developmental traits, and a subgroup of class IITCPgenes regulate leaf morphogenesis. Absence of these genes results in large, crinkly leaves due to excess division, mainly at margins. It has been suggested that these class II TCPs modulate the spatio‐temporal control of differentiation in a growing leaf, rather than regulating cell proliferationper se. However, the link between class II TCP action and cell growth has not been established. As loss‐of‐function mutants of individualTCPgenes in Arabidopsis are not very informative due to gene redundancy, we generated a transgenic line that expressed a hyper‐activated form of TCP4 in its endogenous expression domain. This resulted in premature onset of maturation and decreased cell proliferation, leading to much smaller leaves, with cup‐shaped lamina in extreme cases. Further, the transgenic line initiated leaves faster than wild‐type and underwent precocious reproductive maturation due to a shortened adult vegetative phase. Early senescence and severe fertility defects were also observed. Thus, hyper‐activation of TCP4 revealed its role in determining the timing of crucial developmental events, both at the organ and organism level.
LOV KELCH PROTEIN2 and ZEITLUPE repress Arabidopsis photoperiodic flowering under non‐inductive conditions, dependent on FLAVIN‐BINDING KELCH REPEAT F‐BOX1
Authors: Takase Tomoyuki , Nishiyama Yuuki , Tanihigashi Haruna , Ogura Yasunobu , Miyazaki Yuji , Yamada Yumiko , Kiyosue Tomohiro
Published: April 2011

LOV KELCH PROTEIN2 (LKP2), ZEITLUPE (ZTL)/LOV KELCH PROTEIN1 (LKP1) and FLAVIN‐BINDING KELCH REPEAT F‐BOX1 (FKF1) constitute a family of Arabidopsis F‐box proteins that regulate the circadian clock. Over‐expression of LKP2 or ZTL causes arrhythmicity of multiple clock outputs under constant light and in constant darkness. Here, we show the significance of LKP2 and ZTL in the photoperiodic control of flowering time in Arabidopsis. In plants over‐expressing LKP2, CO and FT expression was down‐regulated under long‐day conditions. LKP2 and ZTL physically interacted with FKF1, which was recruited from the nucleus into cytosolic speckles. LKP2 and ZTL inhibited the interaction of FKF1 with CYCLING DOF FACTOR 1, a ubiquitination substrate for FKF1 that is localized in the nucleus. The Kelch repeat regions of LKP2 and ZTL were sufficient for their physical interaction with FKF1 and translocation of FKF1 to the cytoplasm. Over‐expression of LKP2 Kelch repeats induced late flowering under long‐day conditions. lkp2 ztl double mutant plants flowered earlier than wild‐type plants under short‐day (non‐inductive) conditions, and both CO and FT expression levels were up‐regulated in the double mutant plants. The early flowering of lkp2 ztl was dependent on FKF1. LKP2, ZTL or both affected the accumulation of FKF1 protein during the early light period. These results indicate that an important role of LKP2 and ZTL in the photoperiodic pathway is repression of flowering under non‐inductive conditions, and this is dependent on FKF1.
Clinical features and prognosis of early colorectal cancer treated by endoscopic mucosal resection
Authors: Kim Mi Na , Kang Jung Mook , Yang Jong In , Kim Byoung Kwon , Im Jong Pil , Kim Sang Gyun , Jung Hyun Chae , Song In Sung , Kim Joo Sung
Published: April 2011

Background and Aims:  The incidence of early colorectal cancer (ECC) has been increasing. The aim of this study was to evaluate the clinical outcome and prognosis of ECC treated by endoscopic mucosal resection (EMR).

Methods:  A total of 129 ECC patients who were initially treated by EMR between April 2005 and August 2007 were enrolled. Clinicopathological characteristics and prognoses were evaluated retrospectively.

Results:  En bloc resection was performed in 85% of ECC patients, and piecemeal resection was performed in 15% of patients. Clear lateral and deep margins were achieved in 86% of cases. Of the 129 patients, 64 were found to have intramucosal cancer and 65 had submucosal cancer. Clinical characteristics were not different between patients with intramucosal cancer and submucosal cancer; however, poor differentiation and the absence of background adenoma showed significant association with submucosal cancer. Seven patients with submucosal cancer underwent subsequent surgical resection; five had lymphovascular invasion or a positive resection margin, one had perforation, and one patient requested surgical resection. Of these seven patients, one had residual cancer and two had lymph node metastasis. All patients with intramucosal cancer had no recurrence during the follow‐up period. Seven patients with submucosal cancer showed adverse outcomes within 3 years, such as residual/recurrence of primary cancer or lymph node metastasis; five showed lymphovascular invasion or a positive deep margin, and two had no histological risk factors.

Conclusions:  Our results suggest that intramucosal cancer shows good prognosis, and a cure could be expected after EMR; however, adverse outcomes can occur in submucosal cancer. Therefore, meticulous endoscopic follow up is needed in patients with submucosal cancer for at least 3 years after EMR.
Prevalence of gastroesophageal reflux disease in a general population in Taiwan
Authors: Hung Li‐Ju , Hsu Ping‐I , Yang Chun‐Yuh , Wang E‐Ming , Lai Kwok‐Hung
Published: April 2011

Background and Aim:  To evaluate the prevalence and risk factors of gastroesophageal reflux disease (GERD) in a general population in Taiwan.

Methods:  A validated symptom questionnaire, the Chinese GERD questionnaire, was utilized to determine the prevalence of GERD within a community in Taiwan. A cut‐off value for GERD diagnosis was a total score ≥12. Additionally, demographic data, including sex, age, body mass index, and consumption of tobacco and alcohol, were recorded, and a logistic regression analysis was conducted to search the independent risk factors for the development of GERD in a general population.

Results:  In total, 1238 residents were recruited for this study. The monthly frequencies of heartburn, epigastric acidic discomfort, and acid regurgitation were 4.4%, 3.7%, and 2.9%, respectively. The GERD prevalence was 25% in the community. The multivariate analysis showed that female sex and age of 40–49 years and 50–59 years were independent risk factors related to the development of GERD, with odd ratios of 1.71, 3.65, and 2.41, respectively (95% confidence intervals: 1.26–2.34, 1.62–8.21, and 1.11–2.54, respectively).

Conclusions:  GERD has become a common disorder in the general population in Taiwan. Female sex and age of 40–49 years and 50–59 years are risk factors for the development of GERD within a community.
Survival of patients with advanced hepatocellular carcinoma: Sorafenib versus other treatments
Authors: Kim Hwi Young , Park Joong‐Won , Nam Byung‐Ho , Kim Hyun Keun , Choi Joon‐Il , Kim Tae Hyun , Kim Hyun Beom , Kim Chang‐Min
Published: April 2011

Background and Aim:  Although sorafenib is recommended for patients with advanced hepatocellular carcinoma (HCC), a substantial portion of HCC patients in Asia are still treated with other treatments, mainly due to the prohibitive cost of sorafenib. We aimed to evaluate the clinical outcome of patients treated with sorafenib and those treated with other modalities in a single‐center cohort.

Methods:  We reviewed the medical records of two groups of consecutive patients with advanced HCC, according to applied treatment modalities, between January 2007 and September 2009 as follows: patients who received sorafenib for 6 weeks or more (n = 123) and patients who were treated with one or more of other treatments, including transarterial chemoembolization, radiation, and cytotoxic chemotherapy (n = 253).

Results:  Overall survival did not differ significantly between these two groups (8.4 vs 8.2 months; P = 0.601). Significant prognostic factors were high α‐fetoprotein (≥ 200 ng/mL), massive/infiltrative intrahepatic tumors, macrovascular invasion, extrahepatic spread, and higher tumor‐node‐metastasis stage. Subgroup analysis, according to these factors, showed that sorafenib resulted in superior survival in patients with extrahepatic spread (hazard ratio [HR] = 0.539; P = 0.003) and massive/infiltrative tumors (HR = 0.680; P = 0.036). In the absence of each prognostic factor, other treatments were better than sorafenib.

Conclusions:  Considering the survival benefit for sorafenib over other treatments in patients with extrahepatic spread and massive/infiltrative intrahepatic tumors, these characteristics might be regarded as compelling indications for sorafenib.
Clinical significance of normal chest radiographs among HIV‐seropositive patients with suspected tuberculosis in Uganda
Authors: YOO SAMUEL D. , CATTAMANCHI ADITHYA , DEN BOON SASKIA , WORODRIA WILLIAM , KISEMBO HARRIET , HUANG LAURENCE , DAVIS J. LUCIAN
Published: April 2011

Background and objective:  The frequency, aetiologies and outcomes of normal chest radiographs (CXRs) among HIV‐seropositive patients with suspected pulmonary tuberculosis (TB) have been infrequently described.

Methods:  Consecutive HIV‐seropositive adults hospitalized for cough of ≥2 weeks duration at Mulago Hospital (Kampala, Uganda), between September 2007 and July 2008, were enrolled. Baseline CXRs were obtained on admission. Patients with sputum smears that were negative for acid‐fast bacilli (AFB) were referred for bronchoscopy with bronchoalveolar lavage (BAL). BAL fluid was examined for mycobacteria, Pneumocystis jirovecii and other fungi. Patients were followed for 2 months after enrolment.

Results:  Of the 334 patients, 54 (16%) had normal CXRs. These patients were younger (median age 30 vs 34 years, P = 0.002), had lower counts of CD4+ T lymphocytes (median 13 vs 57 cells/µL, P < 0.001), and were less likely to be smear positive for AFB (17% vs 39%, P = 0.002) than those with abnormal CXRs. Pulmonary TB was the most frequent diagnosis (44%) among those with normal CXRs, followed by unknown diagnoses, pulmonary aspergillosis and pulmonary cryptococcosis. The frequency of normal CXRs was 12% among pulmonary TB patients. There was a trend towards increased 2‐month mortality among patients with normal CXRs compared to those with abnormal CXRs (40% vs 29%, P = 0.15).

Conclusions:  Normal CXR findings were common among HIV‐seropositive patients with suspected TB, especially those who were young, those with low CD4+ T cell counts and those with sputum smears that were negative for AFB. Mortality was high among those with normal CXRs. Normal CXR findings should not preclude further diagnostic evaluation in this population.
Prevalence of Type 1 diabetes autoantibodies (GAD and IA2) in Sardinian children and adolescents with autoimmune thyroiditis
Authors: Pilia S. , Casini M. R. , Cambuli V. M. , Ibba A. , Civolani P. , Zavattari P. , Incani M. , Mossa P. , Baroni M. G. , Mariotti S. , Loche S.
Published: April 2011

Diabet. Med. 28, 896–899 (2011)

Aims  Type 1 diabetes and autoimmune thyroiditis are common autoimmune diseases characterized by the presence of autoantibodies against tissue‐specific components. Non‐thyroid‐specific autoantibodies are frequent in patients with autoimmune thyroiditis. The prevalence of Type 1 diabetes autoantibodies in patients with autoimmune thyroiditis is unknown.

Methods  The prevalence of Type 1 diabetes autoantibodies (GAD and IA2) was analysed in 236 Sardinian children and adolescents with autoimmune thyroiditis. GAD and IA2 antibodies were measured at the time of the diagnosis of autoimmune thyroiditis and re‐evaluated after 1 year in the children who were shown to be positive. Autoantibody prevalence was evaluated in 949 healthy age‐matched controls.

Results  The prevalence of GAD and/or IA2 antibodies was 8% in the children and adolescents with autoimmune thyroiditis and 4.1% in control subjects (P = 0.017). When Type 1 diabetes autoantibodies were separately analysed, the difference remained significant for IA2 (3.39% in autoimmune thyroiditis vs. 1.16% in control subjects, P = 0.012), but not for GAD (5.1% in autoimmune thyroiditis vs. 3.79% in control subjects, P = 0.367). Seven of 10 children with autoimmune thyroiditis and detectable Type 1 diabetes autoantibodies at the diagnosis remained positive after 1 year. In the course of 2 years of follow‐up, two patients who were positive for Type 1 diabetes autoantibodies at the time of diagnosis of autoimmune thyroiditis developed diabetes.

Conclusions  This is the first study reporting the prevalence of Type 1 diabetes autoantibodies in a selected cohort of genetically homogeneous children and adolescents with autoimmune thyroiditis. The main finding was that the prevalence of Type 1 diabetes autoantibodies and of newly diagnosed Type 1 diabetes in patients with autoimmune thyroiditis was significantly higher than that observed in the general paediatric population, suggesting that children with autoimmune thyroiditis are at increased risk of developing Type 1 diabetes.
The Finnish Diabetes Risk Score is associated with insulin resistance but not reduced β‐cell function, by classical and model‐based estimates
Authors: Brodovicz K. G. , Dekker J. M. , Rijkelijkhuizen J.M. , Rhodes T. , Mari A. , Alssema M. , Nijpels G. , Williams‐Herman D.E. , Girman C. J.
Published: April 2011

Diabet. Med. 28, 1078–1081 (2011)

Aims  The Finnish Diabetes Risk Score (FINDRISC) is widely used for risk stratification in Type 2 diabetes prevention programmes. Estimates of β‐cell function vary widely in people without diabetes and reduced insulin secretion has been described in people at risk for diabetes. The aim of this analysis was to evaluate FINDRISC as a tool to characterize reduced β‐cell function in individuals without known diabetes.

Methods  In this population‐based cohort from the Hoorn municipal registry, subjects received an oral glucose tolerance test and a meal tolerance test on separate days, in random order, within 2 weeks. One hundred and eighty‐six subjects, age 41–66 years, with no known Type 2 diabetes were included. Of those, 163 (87.6%) had normal glucose metabolism and 23 (12.4%) had abnormal glucose metabolism (19 with impaired glucose metabolism; four with newly diagnosed Type 2 diabetes based on study results). Insulin sensitivity and β‐cell function (classical: insulinogenic index; ratio of areas under insulin/glucose curves; model‐based: glucose sensitivity; rate sensitivity; potentiation) estimates were calculated from oral glucose tolerance test and meal tolerance test data.

Results  FINDRISC was associated with insulin sensitivity (r = −0.41, P < 0.0001), insulin/glucose areas under the curve (meal tolerance test: r = 0.29, P < 0.0001; oral glucose tolerance test: r = 0.21, P = 0.01) and potentiation factor (meal tolerance test: r = 0.21, P = 0.01). After adjusting for insulin sensitivity, these associations with β‐cell function were no longer significant.

Conclusions  After adjustment for insulin sensitivity, FINDRISC was not associated with reduced β‐cell function in subjects without known Type 2 diabetes. While insulin secretion and insulin sensitivity are both components in Type 2 diabetes development, insulin sensitivity appears to be the dominant component behind the association between FINDRISC and diabetes risk.
HbA1c in adults without known diabetes from southern Europe. Impact of the new diagnostic criteria in clinical practice
Authors: Bernal‐Lopez M. R. , Santamaría‐Fernandez S. , Lopez‐Carmona D. , Tinahones F. J. , Mancera‐Romero J. , Peña‐Jimenez D. , Jansen‐Chaparro S. , Baca‐Osorio A. J. , Cuesta‐Muñoz A. L. , Serrano‐Rios M. , Gomez‐Huelgas R.
Published: April 2011

Diabet. Med. 28, 1319–1322 (2011)

Aims  To analyse the differences in the prevalence of diabetes and dysglycaemia using fasting plasma glucose and HbA1c criteria.

Methods  Analytical cross‐sectional study undertaken in a random sample of 2144 individuals (age 18–80 years) without known diabetes from the primary care setting in Malaga (Spain). Dysglycaemia was defined as fasting plasma glucose 5.6–6.9 mmol/l or HbA1c 39–46 mmol/mol (5.7–6.4%) and diabetes as fasting plasma glucose ≥ 7.0 mmol/l or HbA1c≥ 48 mmol/mol (≥ 6.5%).

Results  The proportion of subjects who were normoglycaemic was significantly higher using fasting plasma glucose than HbA1c (83.5 vs. 65%) (P < 0.0001). Compared with fasting plasma glucose, HbA1c detects more cases of dysglycaemia (32 vs. 14.8%) (P < 0.0001) and diabetes (3 vs. 1.7%) (P < 0.0001).

Conclusions  In our environment, using HbA1c for the diagnosis of pre‐diabetes and diabetes could increase the target population for preventive and therapeutic measures. Further cost‐effectiveness studies are needed before the widespread diagnostic use of HbA1c can be recommended.
Circulating LL‐37 is a biomarker for eczema severity in children
Authors: Leung T.F. , Ching K.W. , Kong A.P.S. , Wong G.W.K. , Chan J.C.N. , Hon K.L.
Published: April 2011

Background  Eczema lesions are characterized by impaired expression of antimicrobial peptides such as cathelicidin, which play crucial roles in the innate immune defence against cutaneous infections. LL‐37 corresponds to amino acids 134–170 of human cathelicidin and is a multifunctional host defence molecule essential for normal immune responses to infection and tissue injury.

Objectives  The aim of this study was to investigate the relationship between childhood eczema and circulating LL‐37 levels.

Methods  One hundred and forty‐four eczema children and 36 controls were recruited. Eczema severity was assessed by SCORing Atopic Dermatitis (SCORAD) and serum LL‐37 concentration measured using enzyme immunoassay. Patients’ skin hydration and transepidermal water loss at forearms were measured using Corneometer and Tewameter.

Results  Patients’ mean SCORAD was 49.2 and their disease was classified as mild (n = 28; 12.8%), moderate (n = 95; 43.6%) and severe (n = 95; 43.6%). Serum LL‐37 concentrations did not differ between eczema patients and controls (mean: 832 pg/mL vs. 952 pg/mL, P = 0.471). However, serum LL‐37 concentrations increased with increasing eczema severity among the patients (P = 0.005 for trend). This biomarker shows weakly positive correlation with patients’ objective SCORAD (r = 0.207, P = 0.013) and age (r = 0.170, P = 0.041), but not skin hydration or transepidermal water loss (P > 0.09). Linear regression confirmed significant association between objective SCORAD and serum LL‐37 when adjusted for age and gender as covariates (β = 0.171, P = 0.038). On the other hand, serum LL‐37 did not differ between patients with and without heavy growth of staphylococci (P = 0.151).

Conclusions  Circulating LL‐37 may be a biomarker for severity of childhood eczema, which supports the importance of innate immunity in eczema pathogenesis.
HNA‐3a–specific antibodies recognize choline transporter–like protein‐2 peptides containing arginine, but not glutamine at Position 154
Authors: Curtis Brian R. , Sullivan Mia J. , Holyst M. Trudy , Szabo Aniko , Bougie Daniel W. , Aster Richard H.
Published: April 2011

BACKGROUND: Antibodies specific for the neutrophil antigen HNA‐3a cause severe, sometimes fatal transfusion‐related acute lung disease (TRALI) when transfused, but it has not been possible to screen blood donors for anti‐HNA‐3a because using neutrophils as targets was impractical and molecular properties of the antigen were unknown. Recently it was shown that HNA‐3a is carried on choline transporter–like protein‐2 (CTL2) and that the HNA‐3a/b phenotype is closely correlated with an R154Q amino acid polymorphism in CTL2. However, it has not been shown by direct experiment that R154 is essential for the HNA‐3a epitope.

STUDY DESIGN AND METHODS: Preliminary attempts to express recombinant full‐length CTL2 (R154) recognized by anti‐HNA‐3a were unsuccessful. We therefore tested HNA‐3a–specific antibodies from donors implicated in TRALI reactions for reactivity against chemically synthesized linear and cyclic CTL2 peptides containing R154 or Q154.

RESULTS: Nine of 20 HNA‐3a antibodies recognized the R154, but not the Q154 version of a cyclic 36‐residue CTL2 peptide (D131‐K166). However, 11 others failed to distinguish between the two versions of this peptide.

CONCLUSION: The findings provide direct evidence that R154 in the context of CTL2 D131‐K166 is necessary to create the HNA‐3a epitope but, in the context of cyclic CTL2 peptide D131‐K166, is sufficient to detect only about one‐half of the HNA‐3a–specific antibodies implicated in TRALI. It is likely that fragments of CTL2 longer than can be made on a large scale with an automated synthesizer will be needed to produce a target capable of detecting all examples of anti‐HNA‐3a in donated blood.