bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypoglycaemia: assessment and management
Authors: Cotterill Andrew , Cowley David , Greer Ristan
Published: July 2011

Hypoglycaemia is defined as a blood glucose level less than 2.6 mmol/l. This is based on the consistent impairment of central nervous system function observed in subjects when blood glucose levels are below this (1). Glucose homeostatic mechanisms should maintain blood glucose level to preserve cognitive function. Hypoglycaemia triggers protective glucose homeostatic mechanisms and persistent hypoglycaemia is the result of a failure of homeostasis. This is a medical emergency with serious short- and long-term consequences, which result from a reduced supply of glucose to the brain. Recurrent and persistent hypoglycaemia does cause significant morbidity and death due to brain damage. In an adult, after recovery of glucose levels, neurological impairment usually recovers over minutes to hours. In children, the duration of hypoglycaemia leading to permanent damage is not known, but is presumed to depend on the age of the child, the frequency of hypoglycaemia, the degree and the rapidity of the fall in glucose, concurrent circumstances such as infection, trauma and hypoxia, the degree of resilience of the brain tissue at the current stage of development. and the energy demands of the particular parts of the brain. The reasons for the increased sensitivity in children appear to relate to the higher energy requirements and immaturity of the homeostatic mechanisms of the brain. In congenital hyperinsulinism of infancy (CHI) the rates of severe neurological impairment remain high at 20–50%, permanent neurological impairment with damage occurring mainly in the cerebral cortex, hippocampus, and caudate putamen. Appropriate long term management of hypoglycaemia requires the correct diagnosis, and this depends on obtaining ‘critical blood and urine samples’ during a hypoglycaemic episode. In the first 48 h of life 20% of normal full–term infants have a blood

glucose level <2.6 mmol/l (2), after this it is relatively uncommon in infancy and childhood with the incidence of various underlying diagnoses varying with age. The causes of hypoglycaemia can be classified into five groups:

◆ excess insulin (or insulin-like factors) for the given circumstances

◆ lack of one or more of the counter regulatory hormones (cortisol, growth hormone)

◆ disturbance of intermediate metabolism causing impairment of gluconeogenesis and/or glycogenolysis

◆ disturbance of fat breakdown or ketone body formation or utilization

◆ lack of nutrient sufficient for current energy demands
Tall stature
Authors: Mullis Primus E.
Published: July 2011

The term tall stature simply means that the child’s height is above the 97th percentile (corresponding to a standard deviation score (SDS) of +1.88). It says nothing about the underlying cause and is not itself a growth abnormality; indeed, most children with tall stature are normal. Although as many children have heights greater than 2 SD above the mean as have heights greater than 2 SD below the mean, tall stature in childhood usually generates less anxiety than shortness and, therefore, referral for tall stature is less common than it is for short stature.
Transition in endocrinology
Authors: Gleeson Helena
Published: July 2011

Adolescence represents the process of becoming an adult. It involves significant biological, psychological and social changes. Transition has been defined as ‘a multi-faceted, active process that attends to the medical, psychosocial and educational/vocational needs of adolescents as they move from child to adult centred care’. There is an increasing focus on improving adolescent healthcare and transition. It is now recognized that adolescents have particular healthcare needs, and that these should be addressed to provide effective management and transition to adult endocrine care.

Growing up with any chronic condition can affect adolescent development, for instance, pubertal and growth delay and failure to reach peak bone mass, delayed social independence, poor body and sexual self-image, and educational and vocational failure. Conversely, normal adolescent development can make chronic condition management problematic through poor adherence to medical regimens and risky health behaviours.

Much of endocrine care and research in adolescence focuses on optimizing hormone replacement therapy to try and normalize or maximize biological aspects of adolescence, growth and puberty in early and mid-adolescence, and peak bone mass and reproductive potential in late adolescence and young adulthood. Despite certain groups of young people with endocrine conditions having documented psychological and social consequences of growing up with this condition, current endocrine practice does little to address these and minimal research has been done into interventions to improve this. For healthcare professionals to engage adolescents effectively, psychological and social aspects need to be considered and studied and communication skills need to be improved.
Semen analysis
Authors: Dondero Franco , Lenzi Andrea , Gandini Loredana
Published: July 2011

Semen analysis remains the most important diagnostic tool for the study of male infertility to date. For this reason, and because of the ease of carrying out this analysis, examination of seminal fluid should be among the first diagnostic steps in cases of suspected infertility, prior to subjecting the man’s partner to long and complex diagnostic tests. The efficacy of an examination of seminal fluid depends on the experience and ability of the seminologist, who must first undertake a subjective analysis of fundamental parameters such as motility and morphology. Moreover, laboratories specialized in such analyses may apply different criteria to the evaluation of sperm parameters, making it extremely difficult to compare tests carried out in different laboratories (1).

In an attempt to resolve these problems of inconsistency, and in order to standardize laboratory techniques, a committee of experts from the WHO established guidelines for semen analysis in 1980 (an updated version was published in 1999) (2).

In recent years, numerous other methods of semen analysis capable of providing in-depth diagnostic information on the fertilising capacity of spermatozoa have become available. The computer-aided sperm analysis (CASA) system is a technique for sperm analysis designed to provide objective data on sperm motility (3). Because of persisting difficulties in software set-up (4), it should not be used for routine analysis, but rather as a research tool. At the same time, significant advances have been made in the study of sperm morphology through the use of scanning and transmission electron microscopes (5). Finally, within the past decade several tests capable of evaluating the integrity of sperm components, such as the membrane, acrosome, DNA, and nuclear protein, have been developed and put into use. These more complex and costly analytical tools should be considered of secondary or tertiary importance, and are to be carried out in specific cases only after standard semen analysis. Standard semen analysis remains the first and fundamental diagnostic tool.
Structural chromosome abnormalities
Authors: Meschede Dieter
Published: July 2011

The term ‘structural chromosome abnormalities’ encompasses pathological alterations of chromosome structure that are detectable through microscopic examination of banded metaphase preparations (Chapter 9.3.5). It excludes smaller lesions diagnosable only with molecular genetic methods. Medium-sized genomic

alterations, e.g. microdeletions demonstrable through molecular-cytogenetic methods such as fluorescence in situ hybridization (FISH), may also be classified as structural chromosome abnormalities. Some structural rearrangements, such as Robertsonian translocations and marker chromosomes, imply a change in chromosome number. By convention, they are regarded as structural and not numerical chromosome abnormalities.

Reciprocal and Robertsonian translocations, inversions, marker chromosomes, X and Y isochromosomes, and Y-chromosomal deletions are of practical importance in male endocrinology (Fig. 9.4.6.1) (1–4). Other classes of structural chromosome abnormalities such as rings, insertions, duplications, three-way and other complex translocations, fragile sites, and chromosome breakage syndromes (5) play no appreciable role in clinical andrology and are not further considered here.

The distinction between balanced and unbalanced structural aberrations is pivotal. The former are characterized by a deviation from normal chromosome structure without accompanying net loss or gain of genetic material. In contrast, the genome of a carrier of an unbalanced aberration is not fully diploid, but nullisomic, monosomic, trisomic, or higher aneuploid for an entire chromosome or parts of it. If no important gene is disrupted at the breakpoints, balanced structural aberrations exert no negative effect on general health. They are of clinical importance through

their potential to adversely affect fertility, and to give rise to unbalanced karyotypes in the carrier’s offspring (5).
Sequelae of extratesticular disease
Authors: Handelsman David J.
Published: July 2011

Systemic disease has major effects on male reproductive health, although these are not always recognised. Management of any medical disorder should include careful consideration of the effects of illness and its treatment on androgen secretion, fertility, and sexuality. A functional reproductive system is a profoundly valued aspect of a healthy life and it is an important, albeit often unstated, expectation of medical care that reproductive function is preserved and protected. Hence, recognition of this important but easily overlooked aspect of medical care should form a part of optimal management of chronic medical illness (1).
The comparative ecology and biogeography of parasites
Authors: Poulin Robert , Krasnov Boris R. , Mouillot David , Thieltges David W.
Published: July 2011

Comparative ecology uses interspecific relationships among traits, while accounting for the phylogenetic non-independence of species, to uncover general evolutionary processes. Applied to biogeographic questions, it can be a powerful tool to explain the spatial distribution of organisms. Here, we review how comparative methods can elucidate biogeographic patterns and processes, using analyses of distributional data on parasites (fleas and helminths) as case studies. Methods exist to detect phylogenetic signals, i.e. the degree of phylogenetic dependence of a given character, and either to control for these signals in statistical analyses of interspecific data, or to measure their contribution to variance. Parasite–host interactions present a special case, as a given trait may be a parasite trait, a host trait or a property of the coevolved association rather than of one participant only. For some analyses, it is therefore necessary to correct simultaneously for both parasite phylogeny and host phylogeny, or to evaluate which has the greatest influence on trait expression. Using comparative approaches, we show that two fundamental properties of parasites, their niche breadth, i.e. host specificity, and the nature of their life cycle, can explain interspecific and latitudinal variation in the sizes of their geographical ranges, or rates of distance decay in the similarity of parasite communities. These findings illustrate the ways in which phylogenetically based comparative methods can contribute to biogeographic research.
Biogeography and ecology: two views of one world
Authors: Jenkins David G. , Ricklefs Robert E.
Published: July 2011

Both biogeography and ecology seek to understand the processes that determine patterns in nature, but do so at different spatial and temporal scales. The two disciplines were not always so different, and are recently converging again at regional spatial scales and broad temporal scales. In order to avoid confusion and to hasten progress at the converging margins of each discipline, the following papers were presented at a symposium in the International Biogeography Society's 2011 meeting, and are now published in this issue of the
Philosophical Transactions of the Royal Society B
. In a novel approach, groups of authors were paired to represent biogeographic and ecological perspectives on each of four topics: niche, comparative ecology and macroecology, community assembly, and diversity. Collectively, this compilation identifies points of agreement and disagreement between the two views on these central topics, and points to future research directions that may build on agreements and reconcile differences. We conclude this compilation with an overview on the integration of biogeography and ecology.
Biogeography and ecology: towards the integration of two disciplines
Authors: Ricklefs Robert E. , Jenkins David G.
Published: July 2011

Although ecology and biogeography had common origins in the natural history of the nineteenth century, they diverged substantially during the early twentieth century as ecology became increasingly hypothesis-driven and experimental. This mechanistic focus narrowed ecology's purview to local scales of time and space, and mostly excluded large-scale phenomena and historical explanations. In parallel, biogeography became more analytical with the acceptance of plate tectonics and the development of phylogenetic systematics, and began to pay more attention to ecological factors that influence large-scale distributions. This trend towards unification exposed problems with terms such as ‘community’ and ‘niche,’ in part because ecologists began to view ecological communities as open systems within the contexts of history and geography. The papers in this issue represent biogeographic and ecological perspectives and address the general themes of (i) the niche, (ii) comparative ecology and macroecology, (iii) community assembly, and (iv) diversity. The integration of ecology and biogeography clearly is a natural undertaking that is based on evolutionary biology, has developed its own momentum, and which promises novel, synthetic approaches to investigating ecological systems and their variation over the surface of the Earth. We offer suggestions on future research directions at the intersection of biogeography and ecology.
The plant pathogen Streptomyces scabies 87-22 has a functional pyochelin biosynthetic pathway that is regulated by TetR- and AfsR-family proteins
Authors: Seipke Ryan F. , Song Lijiang , Bicz Joanna , Laskaris Paris , Yaxley Alice M. , Challis Gregory L. , Loria Rosemary
Published: July 2011

Siderophores are high-affinity iron-chelating compounds produced by bacteria for iron uptake that can act as important virulence determinants for both plant and animal pathogens. Genome sequencing of the plant pathogen Streptomyces scabies 87-22 revealed the presence of a putative pyochelin biosynthetic gene cluster (PBGC). Liquid chromatography (LC)-MS analyses of culture supernatants of S. scabies mutants, in which expression of the cluster is upregulated and which lack a key biosynthetic gene from the cluster, indicated that pyochelin is a product of the PBGC. LC-MS comparisons with authentic standards on a homochiral stationary phase confirmed that pyochelin and not enantio-pyochelin (ent-pyochelin) is produced by S. scabies. Transcription of the S. scabies PBGC occurs via ~19 kb and ~3 kb operons and transcription of the ~19 kb operon is regulated by TetR- and AfsR-family proteins encoded by the cluster. This is the first report, to our knowledge, of pyochelin production by a Gram-positive bacterium; interestingly regulation of pyochelin production is distinct from characterized PBGCs in Gram-negative bacteria. Though pyochelin-mediated iron acquisition by Pseudomonas aeruginosa is important for virulence, in planta bioassays failed to demonstrate that pyochelin production by S. scabies is required for development of disease symptoms on excised potato tuber tissue or radish seedlings.
Plasmodium falciparum NIMA-related kinase Pfnek-1: sex specificity and assessment of essentiality for the erythrocytic asexual cycle
Authors: Dorin-Semblat Dominique , Schmitt Sophie , Semblat Jean-Philippe , Sicard Audrey , Reininger Luc , Goldring Dean , Patterson Shelley , Quashie Neils , Chakrabarti Debopam , Meijer Laurent , Doerig Christian
Published: July 2011

ThePlasmodium falciparumkinome includes a family of four protein kinases (Pfnek-1 to -4) related to the NIMA (never-in-mitosis) family, members of which play important roles in mitosis and meiosis in eukaryotic cells. Only one of these, Pfnek-1, which we previously characterized at the biochemical level, is expressed in asexual parasites. The other three (Pfnek-2, -3 and -4) are expressed predominantly in gametocytes, and a role for nek-2 and nek-4 in meiosis has been documented. Here we show by reverse genetics that Pfnek-1 is required for completion of the asexual cycle in red blood cells and that its expression in gametocytes in detectable by immunofluorescence in male (but not in female) gametocytes, in contrast with Pfnek-2 and Pfnek-4. This indicates that the function of Pfnek-1 is non-redundant with those of the other members of the Pfnek family and identifies Pfnek-1 as a potential target for antimalarial chemotherapy. A medium-throughput screen of a small-molecule library provides proof of concept that recombinant Pfnek-1 can be used as a target in drug discovery.
Characterization of a porin channel in the endosymbiont of the trypanosomatid protozoan Crithidia deanei
Authors: Andrade Iamara da Silva , Vianez-Júnior João Lídio , Goulart Carolina Lage , Homblé Fabrice , Ruysschaert Jean-Marie , Almeida von Krüger Wanda Maria , Bisch Paulo Mascarello , de Souza Wanderley , Mohana-Borges Ronaldo , Motta Maria Cristina Machado
Published: July 2011

Crithidia deaneiis a trypanosomatid protozoan that harbours a symbiotic bacterium. The partners maintain a mutualistic relationship, thus constituting an excellent model for studying metabolic exchanges between the host and the symbiont, the origin of organelles and cellular evolution. According to molecular analysis, symbionts of different trypanosomatid species share high identity and descend from a common ancestor, a β-proteobacterium of the genusBordetella. The endosymbiont is surrounded by two membranes, like Gram-negative bacteria, but its envelope presents special features, since phosphatidylcholine is a major membrane component and the peptidoglycan layer is highly reduced, as described in other obligate intracellular bacteria. Like the process that generated mitochondria and plastids, the endosymbiosis in trypanosomatids depends on pathways that facilitate the intensive metabolic exchanges between the bacterium and the host protozoan. A search of the annotated symbiont genome database identified one sequence with identity to porin-encoding genes of the genusBordetella. Considering that the symbiont outer membrane has a great accessibility to cytoplasm host factors, it was important to characterize this single porin-like protein using biochemical, molecular, computational and ultrastructural approaches. Antiserum against the recombinant porin-like molecule revealed that it is mainly located in the symbiont envelope. Secondary structure analysis and comparative modelling predicted the protein 3D structure as an 18-domain β-barrel, which is consistent with porin channels. Electrophysiological measurements showed that the porin displays a slight preference for cations over anions. Taken together, the data presented herein suggest that theC. deaneiendosymbiont porin is phylogenetically and structurally similar to those described in Gram-negative bacteria, representing a diffusion channel that might contribute to the exchange of nutrients and metabolic precursors between the symbiont and its host cell.
Nuclear factor I/B is an oncogene in small cell lung cancer
Authors: Dooley Alison L. , Winslow Monte M. , Chiang Derek Y. , Banerji Shantanu , Stransky Nicolas , Dayton Talya L. , Snyder Eric L. , Senna Stephanie , Whittaker Charles A. , Bronson Roderick T. , Crowley Denise , Barretina Jordi , Garraway Levi , Meyerson Matthew , Jacks Tyler
Published: July 2011

Small cell lung cancer (SCLC) is an aggressive cancer often diagnosed after it has metastasized. Despite the need to better understand this disease, SCLC remains poorly characterized at the molecular and genomic levels. Using a genetically engineered mouse model of SCLC driven by conditional deletion of Trp53 and Rb1 in the lung, we identified several frequent, high-magnitude focal DNA copy number alterations in SCLC. We uncovered amplification of a novel, oncogenic transcription factor, Nuclear factor I/B (Nfib), in the mouse SCLC model and in human SCLC. Functional studies indicate that NFIB regulates cell viability and proliferation during transformation.
Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesis
Authors: Wei Huijun , Wei Shuang , Gan Boyi , Peng Xu , Zou Weiping , Guan Jun-Lin
Published: July 2011

Autophagy is a conserved cellular process for bulk degradation of intracellular protein and organelles in lysosomes. In contrast to elegant studies of beclin1 using mouse models and cultured cells demonstrating a tumor suppression function for autophagy, knockout of other essential autophagy proteins such as ATG5, ATG7, or FIP200 (FAK family-interacting protein of 200 kDa) in various tissues did not lead to malignant tumor development in vivo. Here, we report that inhibition of autophagy by FIP200 ablation suppresses mammary tumor initiation and progression in a mouse model of breast cancer driven by the PyMT oncogene. Deletion of FIP200 resulted in multiple autophagy defects including accumulation of ubiquitinated protein aggregates and p62/SQSTM1, deficient LC3 conversion, and increased number of mitochondria with abnormal morphology in tumor cells. FIP200 deletion did not affect apoptosis of mammary tumor cells or Ras-transformed mouse embryonic fibroblasts (MEFs), but significantly reduced their proliferation in both systems. We also observed a reduced glycolysis and cyclin D1 expression in FIP200-null mammary tumor cells and transformed MEFs. In addition, gene profiling studies revealed significantly elevated expression of interferon (IFN)-responsive genes in the early tumors of FIP200 conditional knockout mice, which was accompanied by increased infiltration of effector T cells in the tumor microenvironment triggered by an increased production of chemokines including CXCL10 in FIP200-null tumor cells. Together, these data provide strong evidence for a protumorigenesis role of autophagy in oncogene-induced tumors in vivo and suggest FIP200 as a potential target for cancer therapy.
Dynamic transcriptional events in embryonic stem cells mediated by the super elongation complex (SEC)
Authors: Lin Chengqi , Garrett Alexander S. , De Kumar Bony , Smith Edwin R. , Gogol Madelaine , Seidel Christopher , Krumlauf Robb , Shilatifard Ali
Published: July 2011

Transcriptional regulation of developmentally controlled genes is at the heart of differentiation and organogenesis. In this study, we performed global genomic analyses in murine embryonic stem (ES) cells and in human cells in response to activation signals. We identified an essential role for the ELL (eleven–nineteen lysine-rich leukemia gene)/P-TEFb (positive transcription elongation factor)-containing super elongation complex (SEC) in the regulation of gene expression, including several genes bearing paused RNA polymerase II (Pol II). Paused Pol II has been proposed to be associated with loci that respond rapidly to environmental stimuli. However, our studies in ES cells also identified a requirement for SEC at genes without paused Pol II, which also respond dynamically to differentiation signals. Our findings suggest that SEC is a major class of active P-TEFb-containing complexes required for transcriptional activation in response to environmental cues such as differentiation signals.
Translational repression of p53 by RNPC1, a p53 target overexpressed in lymphomas
Authors: Zhang Jin , Cho Seong-Jun , Shu Limin , Yan Wensheng , Guerrero Teri , Kent Michael , Skorupski Katherine , Chen Hongwu , Chen Xinbin
Published: July 2011

The p53 pathway is critical for tumor suppression, as the majority of human cancer has a faulty p53. Here, we identified RNPC1, a p53 target and a RNA-binding protein, as a critical regulator of p53 translation. We showed that ectopic expression of RNPC1 inhibited, whereas knockdown of RNPC1 increased, p53 translation under normal and stress conditions. We also showed that RNPC1 prevented cap-binding protein eIF4E from binding p53 mRNA via its C-terminal domain for physical interaction with eIF4E, and its N-terminal domain for binding p53 mRNA. Consistent with this, we found that RNPC1 directly binds to p53 5′ and 3′untranslated regions (UTRs). Importantly, we showed that RNPC1 inhibits ectopic expression of p53 in a dose-dependent manner via p53 5′ or 3′ UTR. Moreover, we showed that loss of RNPC1 in mouse embryonic fibroblasts increased the level of p53 protein, leading to enhanced premature senescence in a p53-dependent manner. Finally, to explore the clinical relevance of our finding, we showed that RNPC1 was frequently overexpressed in dog lymphomas, most of which were accompanied by decreased expression of wild-type p53. Together, we identified a novel p53–RNPC1 autoregulatory loop, and our findings suggest that RNPC1 plays a role in tumorigenesis by repressing p53 translation.
Bis(μ2-2-(dimethylamino)ethoxo-N,O,O)-di(phenolato-O)ditin(II): a high-resolution single-crystal X-ray diffraction and quantum chemical study
Authors: Korlyukov Alexander A. , Khrustalev Victor N. , Vologzhanina Anna V. , Lyssenko Konstantin A. , Nechaev Mikhail. S. , Antipin Mikhail Yu.
Published: July 2011

Experimental and calculated electron density functions ρ(r) of the title compound in the crystal were obtained. These were compared with ρ(r) for an isolated dimer. Application of the `Atoms in Molecules' theory allowed the visualization of the electron lone pair (Lp) of tin(II) and the calculation of some bond energies and all atomic charges. The stereochemical activity of the Lp was demonstrated and its volume was estimated to be approximately 10 Å3. The energies of N→Sn and Sn—O bonds were found to be 13–18 and 25–52 kJ mol−1. According to the experimental, AM05-PW and PBE0/6-311G(d,p) calculation data, µ2-2-(dimethylamino)ethoxoate accepts 0.68, 0.45 and 0.40 e from the Sn atom. Using the example of µ2-2-(dimethylamino)ethoxoates and complexes of bis(n-butyl)tin(IV) it was demonstrated that the more screened the Sn atom, the better the catalytic activity of its complex in polyurethane synthesis.
Deducing chemical structure from crystallographically determined atomic coordinates
Authors: Bruno Ian J. , Shields Gregory P. , Taylor Robin
Published: July 2011

An improved algorithm has been developed for assigning chemical structures to incoming entries to the Cambridge Structural Database, using only the information available in the deposited CIF. Steps in the algorithm include detection of bonds, selection of polymer unit, resolution of disorder, and assignment of bond types and formal charges. The chief difficulty is posed by the large number of metallo-organic crystal structures that must be processed, given our aspiration that assigned chemical structures should accurately reflect properties such as the oxidation states of metals and redox-active ligands, metal coordination numbers and hapticities, and the aromaticity or otherwise of metal ligands. Other complications arise from disorder, especially when it is symmetry imposed or modelled with the SQUEEZE algorithm. Each assigned structure is accompanied by an estimate of reliability and, where necessary, diagnostic information indicating probable points of error. Although the algorithm was written to aid building of the Cambridge Structural Database, it has the potential to develop into a general-purpose tool for adding chemical information to newly determined crystal structures.
Favorable response to crizotinib in three patients with echinoderm microtubule‐associated protein‐like 4–anaplastic lymphoma kinase fusion‐type oncogene‐positive non‐small cell lung cancer
Authors: Kijima Takashi , Takeuchi Kengo , Tetsumoto Satoshi , Shimada Kazuki , Takahashi Ryo , Hirata Haruhiko , Nagatomo Izumi , Hoshino Shigenori , Takeda Yoshito , Kida Hiroshi , Goya Sho , Tachibana Isao , Kawase Ichiro
Published: July 2011

The echinoderm microtubule‐associated protein‐like 4 (EML4)–anaplastic lymphoma kinase (ALK) is a recently identified fusion‐type oncoprotein that exists in approximately 5% of non‐small cell lung cancer (NSCLC). It has been demonstrated that NSCLC driven by EML4‐ALK is strongly addicted to this fusion‐type oncokinase. A clinical trial of crizotinib (PF‐02341066) sponsored by Pfizer has proven this oncogene addiction in humans by demonstrating a high response rate to inhibition of ALK kinase activity. In the present study, we report on three cases harboring EML4‐ALK rearrangement who were enrolled in the trial (A8081001, NCT00585195). All three patients showed favorable responses to the ALK‐specific tyrosine kinase inhibitor. (Cancer Sci 2011; 102: 1602–1604)
Tectonic setting of Cretaceous basins on the NE Tibetan Plateau: insights from the Jungong basin
Authors: Craddock William H. , Kirby Eric , Dewen Zheng , Jianhui Liu
Published: July 2011

Quantifying the Cenozoic growth of high topography in the Indo‐Asian collision zone remains challenging, due in part to significant shortening that occurred within Eurasia before collision. A growing body of evidence suggests that regions far removed from the suture zone experienced deformation before and during the early phases of Himalayan orogenesis. In the present‐day north‐eastern Tibetan Plateau, widespread deposits of Cretaceous sediment attest to significant basin formation; however, the tectonic setting of these basins remains enigmatic. We present a study of a regionally extensive network of sedimentary basins that are spatially associated with a system of SE‐vergent thrust faults and are now exposed in the high ranges of the north‐eastern corner of the Tibetan Plateau. We focus on a particularly well‐exposed basin, located ∼20 km north of the Kunlun fault in the Anyemaqen Shan. The basin is filled by ∼900 m of alluvial sediments that become finer‐grained away from the basin‐bounding fault. Additionally, beds in the proximal footwall of the basin‐bounding fault exhibit progressive, up‐section shallowing and several intraformational unconformities which can be traced into correlative conformities in the distal part of the basin. The observations show sediment accumulated in the basin during fault motion. Regional constraints on the timing of sediment deposition are provided by both fossil assemblages from the Early Cretaceous, and by K–Ar dating of volcanic rocks that floor and cross‐cut sedimentary fill. We argue that during the Cretaceous, the interior NE Tibetan Plateau experienced NW–SE contractional deformation similar to that documented throughout the Qinling–Dabie orogen to the east. The Songpan‐Ganzi terrane apparently marked the southern limit of this deformation, such that it may have been a relatively rigid block in the Tibetan lithosphere, separating regions experiencing deformation north of the convergent Tethyan margin from regions deforming inboard of the east Asian margin.
A randomized, double‐blind, placebo‐controlled study of the CRTH2 antagonist OC000459 in moderate persistent asthma
Authors: Barnes N. , Pavord I. , Chuchalin A. , Bell J. , Hunter M. , Lewis T. , Parker D. , Payton M. , Collins L. Pearce , Pettipher R. , Steiner J. , Perkins C. M.
Published: July 2011

Background CRTH2 is a G‐protein‐coupled receptor that mediates the activation of Th2 lymphocytes, eosinophils and basophils in response to prostaglandin D2 and may be involved in the pathogenesis of airway inflammation and dysfunction in asthma.

Objective To evaluate the effects of a potent and selective CRTH2 antagonist, OC000459, on the lung function, symptoms and eosinophilic airway inflammation in a double‐blind, parallel group trial in steroid‐free subjects with moderate persistent asthma.

Methods Adult subjects were randomized to oral OC000459 200 mg twice daily (N=65) or a placebo (N=67) for 28 days. The primary end‐point was the change from baseline in pre‐bronchodilator forced expiratory volume in 1 s (FEV1); eosinophilic airway inflammation was assessed by induced sputum differential eosinophil count. The trial was registered on the clinicaltrials.gov database (Identifier NCT01057927).

Results Data were analysed for both the Full Analysis (FA) population and the Per Protocol (PP) population (55 treated with OC000459 and 52 with placebo), which excluded non‐compliant subjects. In the FA population, the mean change in FEV1 was 7.1% on OC000459 compared with 4.3% on placebo (not significant); in the PP population, the mean changes were 9.2% and 1.8%, respectively (P=0.037). Improvement in quality of life was apparent in both FA and PP populations [difference from the placebo in AQLQ(S) total score of 0.29, P=0.0113 and 0.37, P=0.0022, respectively]. OC000459 also improved the night‐time symptom scores (mean reduction of 0.36 vs. 0.11, P=0.008, FA population; 0.37 vs. 0.12, P=0.022, PP population). The geometric mean sputum eosinophil count reduced from 2.1% to 0.7% (P=0.03) after OC000459, but this effect was not significant when compared with the change on placebo (P=0.37). Adverse events on OC000459 were comparable to those on placebo; respiratory infections were notably less common during OC000459 than the placebo treatment.

Conclusion and Clinical Relevance This study provides the first clinical evidence that CRTH2 receptors contribute to airflow limitation, symptoms and eosinophilic airway inflammation in asthma. OC000459 shows promise as a novel oral treatment for asthma and related disorders.

Cite this as: N. Barnes, I. Pavord, A. Chuchalin, J. Bell, M. Hunter, T. Lewis, D. Parker, M. Payton, L. Pearce Collins, R. Pettipher, J. Steiner and C. M. Perkins, Clinical & Experimental Allergy, 2012 (42) 38–48.
Regulation of innate immunity by the nucleotide pathway in children with idiopathic nephrotic syndrome
Authors: Bertelli R , Bodria M , Nobile M , Alloisio S , Barbieri R , Montobbio G , Patrone P , Ghiggeri G M
Published: July 2011

Activation of the oxidative burst and failure of CD4+CD25+ cell regulation have been implicated in idiopathic nephrotic syndrome (iNS). The intimate mechanism is, however, unknown and requires specifically focused studies. We investigated reactive oxygen species (ROS) generation [di-chlorofluorescein-diacetate (DCFDA)] fluorescence assay and the regulatory adenosine 5′-triphosphate (ATP) pathways in the blood of 41 children with iNS, utilizing several agonists and antagonists of nucleotide/nucleoside receptors, including the addition of soluble apyrase. The CD4+CD25+CD39+/CD73+ expression was determined in vivo in parallel during disease activity. Overall, we found that the percentage of CD39+CD4+CD25+ was reduced markedly in iNS by 80% (3·43 ± 0·04% versus 13·14 ± 0·07% of total lymphocytes, P < 0·001). In these patients, reactive oxygen species (ROS) generation by polymorphonuclear neutrophils (PMN) at rest was a function of apyrase (CD39) expressed by CD4+CD25+, with higher rates in patients with very low CD39+CD4+CD25+ levels (< 7·5%). Addition of apyrase reduced ROS generation by 40% in both iNS and controls and was mainly effective in patients. The quota of ROS surviving ATP elimination was higher still in iNS. In vitro studies to limit ROS generation with adenosine analogues (2′-chloroadenosine and 5′-N-ethylcarboxamidoadenosine) produced minor effects. At variance, antagonizing ATP efflux with carbenoxolone or by antagonizing ATP effects (Brilliant Blue G, KN62 and A437089) reduced ROS generation comparable to apyrase. These results confirm a key role of ATP in the regulation of innate immunity and minimize the effect of adenosine. Decreased CD39+CD4+CD25+ expression in iNS highlights an impairment of ATP degradation in this pathology. However, high ROS surviving ATP consumption implies a major role of other regulatory pathways.
Tumour necrosis factor-like weak inducer of apoptosis (TWEAK), an important mediator of endothelial inflammation, is associated with the pathogenesis of Henoch–Schonlein purpura
Authors: Chen T , Guo Z-P , Li M-M , Li J-Y , Jiao X-Y , Zhang Y-H , Liu H-J
Published: July 2011

Tumour necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumour necrosis factor (TNF) family, has been implicated as a proinflammatory cytokine in many types of autoimmune and infectious diseases. However, information about TWEAK in dermatological diseases is limited. Herein, we investigated the role of TWEAK in patients with Henoch–Schonlein purpura (HSP) and the ability of TWEAK on chemokine production in the human dermal microvascular endothelial cell line (HMEC-1). Serum TWEAK levels in patients with HSP, together with patients with psoriasis vulgaris (PV) and atopic dermatitis (AD), were detected by enzyme-linked immunosorbent assay (ELISA). HMEC-1 cells were treated with TWEAK at concentrations ranging from 1 ng/ml to 100 ng/ml. Serum levels of TWEAK were elevated in patients with HSP in the acute stage but not in patients with PV or AD. Moreover, TWEAK levels were correlated with the severity of HSP. TWEAK markedly induced CCL5 and CXCL8 production at both mRNA and protein levels in HMEC-1 cells. In addition, TWEAK-stimulated HMEC-1 supernatant enhanced HL-60 or human acute monocytic leukaemia cell line (THP-1) cell migration. Finally, Western blot data revealed that TWEAK can induce rapid phosphorylation of inhibitor of κB-α (IκBα) in HMEC-1 cells. In conclusion, we show that serum levels of TWEAK were elevated in patients with acute stage HSP. TWEAK may act as a regulator of nuclear factor-κB (NF-κB) activation and chemokine production in human dermal microvascular endothelial cells, thus promoting leucocyte migration in cutaneous vasculitis.
Bringing immunoglobulin knowledge up to date: how should we treat today?
Authors: Misbah S , Kuijpers T , van der Heijden J , Grimbacher B , Guzman D , Orange J
Published: July 2011

Immunoglobulin (Ig) therapy is constantly evolving. Advances in the basic and clinical science of immunoglobulins have provided new perspectives in using polyclonal IgG to treat patients with primary immunodeficiencies. Recent meta-analyses of patient data and outcomes, optimization of IgG administration and better understanding of the IgG receptor variability and clinical effect are new concepts which practising immunologists can use in tailoring their approach to treating patients with primary immunodeficiencies. This manuscript presents the proceedings of a satellite symposium, held in conjunction with the European Society for Immunodeficiencies (ESID) 2010 meeting, to inform attendees about new scientific concepts in IgG therapy, with the goal of empowering expert level evaluation of what optimal IgG therapy is today.
Tulathromycin assay validation and tissue residues after single and multiple subcutaneous injections in domestic goats (Capra aegagrus hircus)
Authors: CLOTHIER K. A. , LEAVENS T. , GRIFFITH R. W. , WETZLICH S. E. , BAYNES R. E. , RIVIERE J. E. , TELL L. A.
Published: July 2011

Clothier, K. A., Leavens, T., Griffith, R. W., Wetzlich, S. E., Baynes, R. E., Riviere, J. E., Tell, L. A. Tulathromycin assay validation and tissue residues after single and multiple subcutaneous injections in domestic goats (Capra aegagrus hircus). J. vet. Pharmacol. Therap. 35, 113–120.

Tulathromycin is a macrolide antimicrobial labeled for treatment of bacterial pneumonia in cattle and swine. The purpose of the present research was to evaluate tissue concentrations of tulathromycin in the caprine species. A tandem mass spectrometry regulatory analytical method that detects the common fragment of tulathromycin in cattle and swine was validated with goat tissues. The method was used to study tulathromycin depletion in goat tissues (liver, kidney, muscle, fat, injection site, and lung) over time. In two different studies, six juvenile and 25 market‐age goats received a single injection of 2.5 mg/kg of tulathromycin subcutaneously; in a third study, 18 juvenile goats were treated with 2.5, 7.5, or 12.5 mg/kg tulathromycin weekly with three subcutaneous injections. Mean tulathromycin tissue concentrations were highest at injection site samples in all studies and all doses. Lung tissue concentrations were greatest at day 5 in market‐age goats while in the multi‐dose animals concentrations demonstrated dose‐dependent increases. Concentrations were below limit of quantification in injection site and lung by day 18 and in liver, kidney, muscle, and fat at all time points. This study demonstrated that tissue levels in goats are very similar to those seen in swine and cattle.
Extended access cocaine self‐administration differentially activates dorsal raphe and amygdala corticotropin‐releasing factor systems in rats
Authors: Zorrilla Eric P. , Wee Sunmee , Zhao Yu , Specio Sheila , Boutrel Benjamin , Koob George F. , Weiss Friedbert
Published: July 2011

Cocaine‐induced neuroadaptation of stress‐related circuitry and increased access to cocaine each putatively contribute to the transition from cocaine use to cocaine dependence. The present study tested the hypothesis that rats receiving extended versus brief daily access to cocaine would exhibit regional differences in levels of the stress‐regulatory neuropeptide corticotropin‐releasing factor (CRF). A secondary goal was to explore how CRF levels change in relation to the time since cocaine self‐administration. Male Wistar rats acquired operant self‐administration of cocaine and were assigned to receive daily long access (6 hours/day, LgA, n = 20) or short access (1 hour/day, ShA, n = 18) to intravenous cocaine self‐administration (fixed ratio 1, ∼0.50 mg/kg/infusion). After at least 3 weeks, tissue CRF immunoreactivity was measured at one of three timepoints: pre‐session, post‐session or 3 hours post‐session. LgA, but not ShA, rats showed increased total session and first‐hour cocaine intake. CRF immunoreactivity increased within the dorsal raphe (DR) and basolateral, but not central, nucleus of the amygdala (BLA, CeA) of ShA rats from pre‐session to 3 hours post‐session. In LgA rats, CRF immunoreactivity increased from pre‐session to 3 hours post‐session within the CeA and DR but tended to decrease in the BLA. LgA rats showed higher CRF levels than ShA rats in the DR and, pre‐session, in the BLA. Thus, voluntary cocaine intake engages stress‐regulatory CRF systems of the DR and amygdala. Increased availability of cocaine promotes greater tissue CRF levels in these extrahypothalamic brain regions, changes associated here with a model of cocaine dependence.
Positioning positivism, critical realism and social constructionism in the health sciences: a philosophical orientation
Authors: Cruickshank Justin
Published: July 2011

CRUICKSHANK J. Nursing Inquiry 2012; 19: 71–82 Positioning positivism, critical realism and social constructionism in the health sciences: a philosophical orientation

This article starts by considering the differences within the positivist tradition and then it moves on to compare two of the most prominent schools of postpositivism, namely critical realism and social constructionism. Critical realists hold, with positivism, that knowledge should be positively applied, but reject the positivist method for doing this, arguing that causal explanations have to be based not on empirical regularities but on references to unobservable structures. Social constructionists take a different approach to postpositivism and endorse a relativist rejection of truth and hold that the task of research is to foster a scepticism that undermines any positive truth claim made. It is argued that social constructionism is a contradictory position.
Ecological selection and sexual dimorphism in the sooty oystercatcher, Haematopus fuliginosus
Authors: APLIN LUCY MARGARET , COCKBURN ANDREW
Published: July 2011

Male and female sooty oystercatchers (subspecies Haematopus fuliginosus fuliginosus; Haematopodidae) have an average difference in bill length of 19%. We studied the relationship between this sexual dimorphism and foraging ecology at coastal sites in southern New South Wales, Australia. Intersexual foraging divergence was most striking in diet, with seven prey classes eaten exclusively by one sex (male: 4, female: 3), and all shared prey classes eaten in different proportions. Intersexual diet partitioning was also observed in energetic rewards gained from foraging, with females gaining highest energetic benefits from eating ascidians and males from eating limpets. Furthermore, within the most commonly consumed prey item, limpets, females gained higher energetic benefit from eating smaller sizes while males gained greater rewards from the largest limpet sizes. Intersexual divergence was also observed in several aspects of foraging behaviour. Finally, there was a significant effect of tidal cycles upon intersexual niche partitioning in this species; the degree of diet divergence varied between tide conditions and females had a consistently more efficient dietary intake on neap tides than males. Diet divergence in the sooty oystercatcher is greater than previously observed in any oystercatcher, and is correlated with the largest sexual bill dimorphism recorded in this family. It is argued that intersexual competition between territorial pairs is operating to diverge male and female bill morphology.
Mechanisms of rainforest persistence and recruitment in frequently burnt wet tropical eucalypt forests
Authors: WILLIAMS PAUL R. , PARSONS MARK , JENSEN RIGEL , TRAN CUONG
Published: July 2011

The role of fire in governing rainforest–eucalypt forest ecotone dynamics is of theoretical interest and has conservation management implications. Several eucalypt forests in the Wet Tropics of Australia have an endangered status due to extensive conversion to rainforest. Rainforest plants are known to survive occasional low intensity fires in the eucalypt forest ecotone. However, the ability of rainforest plants to survive frequent fires remains untested. The timing of rainforest expansion is also a subject of interest, and is generally considered to be delayed until fire has been absent for several years. We used 14 years of data collected across 13 plots in the Wet Tropics of north‐eastern Australia to test predictions regarding rainforest seedling recruitment and post‐fire regenerative capacity. The 13 plots received different numbers of fires, between zero and five, over the 14‐year study. The recruitment of new rainforest plants in the ecotone was most abundant in the initial year after fire. If this post‐fire pulse of recruitment is left undisturbed, it can facilitate the subsequent germination of additional rainforest species. The removal of grass cover, whether temporarily in the immediate post‐fire environment or once a developing rainforest mid strata shades out grasses, appears crucial to abundant rainforest recruitment. A variety of tropical rainforest species can persist under a frequent fire regime through resprouting. The difference in the mode of resprouting, between ground‐level coppicing rainforest plants and canopy resprouting eucalypt forest trees, is the critical mechanism that causes regular fire to maintain an open structure in eucalypt forests. The inability of rainforest species to maintain their height when fires fully scorch their crowns, temporarily resets the forest's open structure and delays the rainforest's ability to dominate through shading out grasses to transform the ecosystem into a closed forest.