bluuebunny/crossref_metadata_2025 huggingface dataset:
Electrical detection of pathogenic bacteria via immobilized antimicrobial peptides
Authors: Mannoor Manu S. , Zhang Siyan , Link A. James , McAlpine Michael C.
Published: October 2010

The development of a robust and portable biosensor for the detection of pathogenic bacteria could impact areas ranging from water-quality monitoring to testing of pharmaceutical products for bacterial contamination. Of particular interest are detectors that combine the natural specificity of biological recognition with sensitive, label-free sensors providing electronic readout. Evolution has tailored antimicrobial peptides to exhibit broad-spectrum activity against pathogenic bacteria, while retaining a high degree of robustness. Here, we report selective and sensitive detection of infectious agents via electronic detection based on antimicrobial peptide-functionalized microcapacitive electrode arrays. The semiselective antimicrobial peptide magainin I—which occurs naturally on the skin of African clawed frogs—was immobilized on gold microelectrodes via a C-terminal cysteine residue. Significantly, exposing the sensor to various concentrations of pathogenic
Escherichia coli
revealed detection limits of approximately 1 bacterium/μL, a clinically useful detection range. The peptide-microcapacitive hybrid device was further able to demonstrate both Gram-selective detection as well as interbacterial strain differentiation, while maintaining recognition capabilities toward pathogenic strains of
E. coli
and
Salmonella
. Finally, we report a simulated “water-sampling” chip, consisting of a microfluidic flow cell integrated onto the hybrid sensor, which demonstrates real-time on-chip monitoring of the interaction of
E. coli
cells with the antimicrobial peptides. The combination of robust, evolutionarily tailored peptides with electronic read-out monitoring electrodes may open exciting avenues in both fundamental studies of the interactions of bacteria with antimicrobial peptides, as well as the practical use of these devices as portable pathogen detectors.
Direct involvement of σ-1 receptors in the dopamine D
1
receptor-mediated effects of cocaine
Authors: Navarro Gemma , Moreno Estefanía , Aymerich Marisol , Marcellino Daniel , McCormick Peter J. , Mallol Josefa , Cortés Antoni , Casadó Vicent , Canela Enric I. , Ortiz Jordi , Fuxe Kjell , Lluís Carmen , Ferré Sergi , Franco Rafael
Published: October 2010

It is well known that cocaine blocks the dopamine transporter. This mechanism should lead to a general increase in dopaminergic neurotransmission, and yet dopamine D
1
receptors (D
1
Rs) play a more significant role in the behavioral effects of cocaine than the other dopamine receptor subtypes. Cocaine also binds to σ-1 receptors, the physiological role of which is largely unknown. In the present study, D
1
R and σ
1
R were found to heteromerize in transfected cells, where cocaine robustly potentiated D
1
R-mediated adenylyl cyclase activation, induced MAPK activation per se and counteracted MAPK activation induced by D
1
R stimulation in a dopamine transporter-independent and σ
1
R-dependent manner. Some of these effects were also demonstrated in murine striatal slices and were absent in σ
1
R KO mice, providing evidence for the existence of σ
1
R-D
1
R heteromers in the brain. Therefore, these results provide a molecular explanation for which D
1
R plays a more significant role in the behavioral effects of cocaine, through σ
1
R-D
1
R heteromerization, and provide a unique perspective toward understanding the molecular basis of cocaine addiction.
Hierarchical order of coexisting pre- and postsynaptic forms of long-term potentiation at synapses in amygdala
Authors: Shin Ryong-Moon , Tully Keith , Li Yan , Cho Jun-Hyeong , Higuchi Makoto , Suhara Tetsuya , Bolshakov Vadim Y.
Published: October 2010

Synaptic rules that may determine the interaction between coexisting forms of long-term potentiation (LTP) at glutamatergic central synapses remain unknown. Here, we show that two mechanistically distinct forms of LTP could be induced in thalamic input to the lateral nucleus of the amygdala (LA) with an identical presynaptic stimulation protocol, depending on the level of postsynaptic membrane polarization. One form of LTP, resulting from pairing of postsynaptic depolarization and low-frequency presynaptic stimulation, was both induced and expressed postsynaptically (“post-LTP”). The same stimulation in the absence of postsynaptic depolarization led to LTP, which was induced and expressed presynaptically (“pre-LTP”). The inducibility of coexisting pre- and postsynaptic forms of LTP at synapses in thalamic input followed a well-defined hierarchical order, such that pre-LTP was suppressed when post-LTP was induced. This interaction was mediated by activation of cannabinoid type 1 receptors by endogenous cannabinoids released in the lateral nucleus of the amygdala in response to activation of the type 1 metabotropic glutamate receptor. These results suggest a previously unknown mechanism by which the hierarchy of coexisting forms of long-term synaptic plasticity in the neural circuits of learned fear could be established, possibly reflecting the hierarchy of memories for the previously experienced fearful events according to their aversiveness level.
Connectivity-driven white matter scaling and folding in primate cerebral cortex
Authors: Herculano-Houzel Suzana , Mota Bruno , Wong Peiyan , Kaas Jon H.
Published: October 2010

Larger brains have an increasingly folded cerebral cortex whose white matter scales up faster than the gray matter. Here we analyze the cellular composition of the subcortical white matter in 11 primate species, including humans, and one Scandentia, and show that the mass of the white matter scales linearly across species with its number of nonneuronal cells, which is expected to be proportional to the total length of myelinated axons in the white matter. This result implies that the average axonal cross-section area in the white matter,
a
, does not scale significantly with the number of neurons in the gray matter,
N
. The surface area of the white matter increases with

N
0.87

, not

N
1.0

. Because this surface can be defined as the product of
N
,
a
, and the fraction
n
of cortical neurons connected through the white matter, we deduce that connectivity decreases in larger cerebral cortices as a slowly diminishing fraction of neurons, which varies with

N
−0.16

, sends myelinated axons into the white matter. Decreased connectivity is compatible with previous suggestions that neurons in the cerebral cortex are connected as a small-world network and should slow down the increase in global conduction delay in cortices with larger numbers of neurons. Further, a simple model shows that connectivity and cortical folding are directly related across species. We offer a white matter-based mechanism to account for increased cortical folding across species, which we propose to be driven by connectivity-related tension in the white matter, pulling down on the gray matter.
Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles
Authors: Clemons Paul A. , Bodycombe Nicole E. , Carrinski Hyman A. , Wilson J. Anthony , Shamji Alykhan F. , Wagner Bridget K. , Koehler Angela N. , Schreiber Stuart L.
Published: October 2010

Using a diverse collection of small molecules generated from a variety of sources, we measured protein-binding activities of each individual compound against each of 100 diverse (sequence-unrelated) proteins using small-molecule microarrays. We also analyzed structural features, including complexity, of the small molecules. We found that compounds from different sources (commercial, academic, natural) have different protein-binding behaviors and that these behaviors correlate with general trends in stereochemical and shape descriptors for these compound collections. Increasing the content of
sp
3
-hybridized and stereogenic atoms relative to compounds from commercial sources, which comprise the majority of current screening collections, improved binding selectivity and frequency. The results suggest structural features that synthetic chemists can target when synthesizing screening collections for biological discovery. Because binding proteins selectively can be a key feature of high-value probes and drugs, synthesizing compounds having features identified in this study may result in improved performance of screening collections.
A seed coat bedding assay shows that RGL2-dependent release of abscisic acid by the endosperm controls embryo growth in
Arabidopsis
dormant seeds
Authors: Lee Keun Pyo , Piskurewicz Urszula , Turečková Veronika , Strnad Miroslav , Lopez-Molina Luis
Published: October 2010

Seed dormancy is an ecologically important adaptive trait in plants whereby germination is repressed even under favorable germination conditions such as imbibition with water. In
Arabidopsis
and most plant species, dormancy absolutely requires an unidentified seed coat germination-repressive activity and constitutively higher abscisic acid (ABA) levels upon seed imbibition. The mechanisms underlying these processes and their possible relationship are incompletely understood. We developed a “seed coat bedding” assay monitoring the growth of dissected embryos cultured on a layer of seed coats, allowing combinatorial experiments using dormant, nondormant, and various genetically modified seed coat and embryonic materials. This assay, combined with direct ABA measurements, revealed that, upon imbibition, dormant coats, unlike nondormant coats, actively produce and release ABA to repress embryo germination, whatever the embryo origin, i.e., from dormant, nondormant, or never dormant
aba
seeds, unable to synthesize ABA. The persistent high ABA levels in imbibed dormant seeds requires the permanent expression of the DELLA gene
RGL2
, where it remains insensitive to gibberellins (GA) unlike in nondormant seeds. These findings present the seed coat as an organ actively controlling germination upon seed imbibition and provide a framework to investigate how environmental factors break seed dormancy.
Multiple mating and its relationship to alternative modes of gestation in male-pregnant versus female-pregnant fish species
Authors: Avise John C. , Liu Jin-Xian
Published: October 2010

We construct a verbal and graphical theory (the “fecundity-limitation hypothesis”) about how constraints on the brooding space for embryos probably truncate individual fecundity in male-pregnant and female-pregnant species in ways that should differentially influence selection pressures for multiple mating by males or by females. We then review the empirical literature on genetically deduced rates of multiple mating by the embryo-brooding parent in various fish species with three alternative categories of pregnancy: internal gestation by males, internal gestation by females, and external gestation (in nests) by males. Multiple mating by the brooding gender was common in all three forms of pregnancy. However, rates of multiple mating as well as mate numbers for the pregnant parent averaged higher in species with external as compared with internal male pregnancy, and also for dams in female-pregnant species versus sires in male-pregnant species. These outcomes are all consistent with the theory that different types of pregnancy have predictable consequences for a parent's brood space, its effective fecundity, its opportunities and rewards for producing half-sib clutches, and thereby its exposure to selection pressures for seeking multiple mates. Overall, we try to fit these fecundity-limitation phenomena into a broader conceptual framework for mating-system evolution that also includes anisogamy, sexual-selection gradients, parental investment, and other selective factors that can influence the relative proclivities of males versus females to seek multiple sexual partners.
An essential transcription factor, SciP, enhances robustness of
Caulobacter
cell cycle regulation
Authors: Tan Meng How , Kozdon Jennifer B. , Shen Xiling , Shapiro Lucy , McAdams Harley H.
Published: October 2010

A cyclical control circuit composed of four master regulators drives the
Caulobacter
cell cycle. We report that SciP, a helix-turn-helix transcription factor, is an essential component of this circuit. SciP is cell cycle-controlled and co-conserved with the global cell cycle regulator CtrA in the α-proteobacteria. SciP is expressed late in the cell cycle and accumulates preferentially in the daughter swarmer cell. At least 58 genes, including many flagellar and chemotaxis genes, are regulated by a type 1 incoherent feedforward motif in which CtrA activates
sciP
, followed by SciP repression of
ctrA
and CtrA target genes. We demonstrate that SciP binds to DNA at a motif distinct from the CtrA binding motif that is present in the promoters of genes co-regulated by SciP and CtrA. SciP overexpression disrupts the balance between activation and repression of the CtrA-SciP coregulated genes yielding filamentous cells and loss of viability. The type 1 incoherent feedforward circuit motif enhances the pulse-like expression of the downstream genes, and the negative feedback to
ctrA
expression reduces peak CtrA accumulation. The presence of SciP in the control network enhances the robustness of the cell cycle to varying growth rates.
Japanese social workers' healthy behaviours as related to masculinity: Focus on mental health workers and caregivers of children and nursing home residents
Authors: Hirokawa Kumi , Yagi Akihiro , Miyata Yo
Published: October 2010

Due to the rapid ageing of the Japanese population, the demand for social services is increasing. However, these professions are not generally recognized yet. According to the report by Kawata (1984, 1986), social workers were distressed by low pay and low recognition for the profession, an inflexible, hierarchical administration system, and staff shortages. However, few studies have focused on social workers' healthy behaviours. The present study focused on the healthy behaviours of Japanese social workers and examined the relationship of these habits to masculinity and femininity, in addition to gender differences. To identify the healthy behaviours of social workers, we compared the behaviours of 32 mental health workers and 63 caregivers to those of 91 members of the general public who attended a summer course. Four questionnaires were administered: health locus of control (Watanabe, 1985), healthy behaviours (Munakata, 1996), health state, and Masculinity‐Humanity‐Femininity scale (Ito, 1978). The results revealed that females scored higher in masculinity than males, and females tended to assess their health state as poorer and were more active in preventive health than males. Social workers practice preventive healthy behaviours more than the general public. Between the two types of social workers, mental health workers tend to rely on medical services and believe that health and sickness are matters of luck, whereas caregivers tend to believe they can control their health by themselves. In the health locus of control, external control was more closely associated with poor health than internal control, and it was negatively correlated with masculinity. As masculinity is related to healthy behaviours, it may be an important factor influencing them. Both masculinity and femininity could be desirable, not for only better caregiving but also for the social workers' own health.
Coordinate suppression of B cell lymphoma by PTEN and SHIP phosphatases
Authors: Miletic Ana V. , Anzelon-Mills Amy N. , Mills David M. , Omori Sidne A. , Pedersen Irene M. , Shin Dong-Mi , Ravetch Jeffrey V. , Bolland Silvia , Morse Herbert C. , Rickert Robert C.
Published: October 2010

The inositol phosphatases phosphatase and tensin homologue (PTEN) and Src homology 2 domain–containing inositol phosphatase (SHIP) negatively regulate phosphatidylinositol-3-kinase (PI3K)–mediated growth, survival, and proliferation of hematopoietic cells. Although deletion of PTEN in mouse T cells results in lethal T cell lymphomas, we find that animals lacking PTEN or SHIP in B cells show no evidence of malignancy. However, concomitant deletion of PTEN and SHIP (bPTEN/SHIP−/−) results in spontaneous and lethal mature B cell neoplasms consistent with marginal zone lymphoma or, less frequently, follicular or centroblastic lymphoma. bPTEN/SHIP−/− B cells exhibit enhanced survival and express more MCL1 and less Bim. These cells also express low amounts of p27kip1 and high amounts of cyclin D3 and thus appear poised to undergo proliferative expansion. Unlike normal B cells, bPTEN/SHIP−/− B cells proliferate to the prosurvival factor B cell activating factor (BAFF). Interestingly, although BAFF availability may promote lymphoma progression, we demonstrate that BAFF is not required for the expansion of transferred bPTEN/SHIP−/− B cells. This study reveals that PTEN and SHIP act cooperatively to suppress B cell lymphoma and provides the first direct evidence that SHIP is a tumor suppressor. As such, assessment of both PTEN and SHIP function are relevant to understanding the etiology of human B cell malignancies that exhibit augmented activation of the PI3K pathway.
R3D Align: global pairwise alignment of RNA 3D structures using local superpositions
Authors: Rahrig Ryan R. , Leontis Neocles B. , Zirbel Craig L.
Published: October 2010

Motivation: Comparing 3D structures of homologous RNA molecules yields information about sequence and structural variability. To compare large RNA 3D structures, accurate automatic comparison tools are needed. In this article, we introduce a new algorithm and web server to align large homologous RNA structures nucleotide by nucleotide using local superpositions that accommodate the flexibility of RNA molecules. Local alignments are merged to form a global alignment by employing a maximum clique algorithm on a specially defined graph that we call the ‘local alignment’ graph.

Results: The algorithm is implemented in a program suite and web server called ‘R3D Align’. The R3D Align alignment of homologous 3D structures of 5S, 16S and 23S rRNA was compared to a high-quality hand alignment. A full comparison of the 16S alignment with the other state-of-the-art methods is also provided. The R3D Align program suite includes new diagnostic tools for the structural evaluation of RNA alignments. The R3D Align alignments were compared to those produced by other programs and were found to be the most accurate, in comparison with a high quality hand-crafted alignment and in conjunction with a series of other diagnostics presented. The number of aligned base pairs as well as measures of geometric similarity are used to evaluate the accuracy of the alignments.

Availability: R3D Align is freely available through a web server http://rna.bgsu.edu/R3DAlign. The MATLAB source code of the program suite is also freely available for download at that location.

Supplementary information:  Supplementary data are available at Bioinformatics online.

Contact:  r-rahrig@onu.edu
MEDELLER: homology-based coordinate generation for membrane proteins
Authors: Kelm Sebastian , Shi Jiye , Deane Charlotte M.
Published: October 2010

Motivation: Membrane proteins (MPs) are important drug targets but knowledge of their exact structure is limited to relatively few examples. Existing homology-based structure prediction methods are designed for globular, water-soluble proteins. However, we are now beginning to have enough MP structures to justify the development of a homology-based approach specifically for them.

Results: We present a MP-specific homology-based coordinate generation method, MEDELLER, which is optimized to build highly reliable core models. The method outperforms the popular structure prediction programme Modeller on MPs. The comparison of the two methods was performed on 616 target–template pairs of MPs, which were classified into four test sets by their sequence identity. Across all targets, MEDELLER gave an average backbone root mean square deviation (RMSD) of 2.62 Å versus 3.16 Å for Modeller. On our ‘easy’ test set, MEDELLER achieves an average accuracy of 0.93 Å backbone RMSD versus 1.56 Å for Modeller.

Availability and Implementation:  http://medeller.info; Implemented in Python, Bash and Perl CGI for use on Linux systems; Supplementary data are available at http://www.stats.ox.ac.uk/proteins/resources.

Contact:  kelm@stats.ox.ac.uk

Supplementary information:  Supplementary data are available at Bioinformatics online.
PyETV: a PyMOL evolutionary trace viewer to analyze functional site predictions in protein complexes
Authors: Lua Rhonald C. , Lichtarge Olivier
Published: October 2010

Summary: PyETV is a PyMOL plugin for viewing, analyzing and manipulating predictions of evolutionarily important residues and sites in protein structures and their complexes. It seamlessly captures the output of the Evolutionary Trace server, namely ranked importance of residues, for multiple chains of a complex. It then yields a high resolution graphical interface showing their distribution and clustering throughout a quaternary structure, including at interfaces. Together with other tools in the popular PyMOL viewer, PyETV thus provides a novel tool to integrate evolutionary forces into the design of experiments targeting the most functionally relevant sites of a protein.

Availability: The PyETV module is written in Python. Installation instructions and video demonstrations may be found at the URL http://mammoth.bcm.tmc.edu/traceview/HelpDocs/PyETVHelp/pyInstructions.html.

Contact:  lichtarge@bcm.tmc.edu
OmicsAnalyzer: a Cytoscape plug-in suite for modeling omics data
Authors: Xia Tian , Hemert John V. , Dickerson Julie A.
Published: October 2010

Summary: OmicsAnalyzer is a Cytoscape plug-in for visual omics-based network analysis that (i) integrates hetero-omics data for one or more species; (ii) performs statistical tests on the integrated datasets; and (iii) visualizes results in a network context.

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

Contact:  julied@iastate.edu; netscape@iastate.edu
ResDe: a new tool for visual definition of distance restraints for crystallographic refinement
Authors: Hintze Bradley J. , Johnson Sean J.
Published: October 2010

Manually defined distance restraints can be useful during structure refinement, particularly in low-resolution refinement where the additional restraints are needed to maintain appropriate stereochemical geometry. A large number of restraints are often required when refining macromolecular structures. Currently, restraint definition requires manual editing of a text file, which can be a daunting task when working with a large number of restraints.ResDe(Restraint Definer) is a suite of Python-based tools that allows the user to quickly define and edit restraints using thePyMOLgraphical interface.
On uncertainty estimates of crystallographic quantities including cell-parameter uncertainties
Authors: Schwarzenbach Dieter
Published: October 2010

In a recent publication, Haestier [J. Appl. Cryst.(2009),42, 798–809] has proposed a method to take care of the unit-cell-parameter uncertainties in the calculation of geometric quantities such as interatomic distances and bond angles by modifying the uncertainties of the atomic coordinates. This problem is addressed here with a different approach, which gives additional insight. For the cell-edge uncertainties, Haestier's results are confirmed and their importance is easily appreciated. However, for the cell-angle uncertainties, it is proved that there exists no simple solution short of calculating the derivatives of the quantity of interest with respect to the angles. Simple rules of thumb are presented for guessing the importance of edge-length uncertainties.
Hispidulin, a small flavonoid molecule, suppresses the angiogenesis and growth of human pancreatic cancer by targeting vascular endothelial growth factor receptor 2‐mediated PI3K/Akt/mTOR signaling pathway
Authors: He Lijun , Wu Yuanyuan , Lin Lei , Wang Jieqiong , Wu Yougen , Chen Yihua , Yi Zhengfang , Liu Mingyao , Pang Xiufeng
Published: October 2010

Hispidulin, an active component from Artemisia vestita, a traditional Tibetan medicinal plant, has been shown to possess anti‐inflammatory and anti‐oxidative activities. However, the functional role of hispidulin on tumor growth and angiogenesis has not been elucidated. We found that hispidulin significantly inhibited human pancreatic tumor growth in xenograft mice when s.c. treated at a dosage of 20 mg/kg daily, and this effect was accompanied with a potent inhibition on angiogenesis. When examining the cytotoxicity of hispidulin on HUVECs and pancreatic cancer cells in vitro, we found that HUVECs were more susceptible to the treatment, suggesting angiogenesis might be the primary target of hispidulin. Our results further showed that hispidulin inhibited vascular endothelial growth factor (VEGF)‐induced cell migration, invasion, and capillary‐like structure formation of HUVECs in a dose‐dependent manner. In ex vivo and in vivo angiogenesis assays, we showed that hispidulin suppressed VEGF‐induced microvessel sprouting of rat aortic rings and corneal neovascularization in C57/BL6 mice. To understand the underlying molecular basis, we next examined the effects of hispidulin on different molecular components in treated HUVECs, and found that hispidulin suppressed the VEGF‐triggered activation of VEGF receptor 2, PI3K, Akt, mTOR, and ribosomal protein S6 kinase, but had little effect on focal adhesion kinase or extracellular signal‐regulated kinase at an effective concentration. Taken together, our results indicate that hispidulin targets the VEGF receptor 2‐mediated PI3K/Akt/mTOR signaling pathway in endothelial cells, leading to the suppression of pancreatic tumor growth and angiogenesis. (Cancer Sci 2011; 102: 219–225)
Hedgehog signaling pathway mediates the progression of non‐invasive breast cancer to invasive breast cancer
Authors: Souzaki Masae , Kubo Makoto , Kai Masaya , Kameda Chizu , Tanaka Haruo , Taguchi Tomoaki , Tanaka Masao , Onishi Hideya , Katano Mitsuo
Published: October 2010

The purpose of this study is to clarify the contribution of the Hedgehog signaling pathway (Hh pathway) to the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). A total of 149 surgically resected mammary disease specimens and 12 sentinel lymph nodes with micro‐metastasis (Ly‐met) were studied. The degree of Hh pathway activation was estimated from the Gli1 nuclear staining ratio (%Gli1 nuclear translocation) in cancer cells. The invasiveness of breast cancer cells was determined using Matrigel assays. A serial increase of %Gli1 nuclear translocation to IDC from non‐neoplastic diseases was confirmed. In tumor specimens, %Gli1 nuclear translocation correlated with the invasiveness of each type of mammary disease and also correlated with invasion‐related histopathological parameters. The %Gli1 nuclear translocation in lymph nodes with micro‐metastasis was similar to that in primary sites and higher than that in DCIS with microinvasion and DCIS. Blockade of the Hh pathway decreased the invasiveness of breast cancer cells. In IDC, %Gli1 nuclear translocation correlated with the expression of estrogen receptor‐α. Estrogen increased %Gli1 nuclear translocation and the invasiveness of estrogen receptor‐α‐positive cells. The Hh pathway mediates progression from a non‐invasive phenotype to an invasive phenotype and %Gli1 nuclear translocation may be useful as a predictive marker for evaluating the ability of invasiveness. (Cancer Sci 2011; 102: 373–381)
Dizziness and the genetic influences on subjective experiences to initial cigarette use
Authors: Haberstick Brett C. , Ehringer Marissa A. , Lessem Jeffrey M. , Hopfer Christian J. , Hewitt John K.
Published: October 2010

Aim  To examine individual differences in positive and negative subjective experiences to initial cigarette use.

Design  Retrospective self‐reports of initial subjective experiences were examined to estimate the genetic and environmental influences and the extent of their covariation across different effects.

Participants  Data was drawn from 2482 young adult same‐and opposite sex twins‐ and siblings participating in the National Longitudinal Study of Adolescent Health.

Measurement  Subjective experiences were retrospectively collected using the Early Smoking Experience (ESE) questionnaire.

Findings  Positive experiences evidenced moderate heritable contributions (40%, 95% CI: 0.22 to 0.56), as did an overall hedonic measure (34%, 95% CI: 0.22 to 0.46) and dizziness (34%, 95% CI: 0.15 to 0.52). Negative experiences evidenced small heritable contributions (13%, 95% CI: 0.00 to 0.36). Individual specific environmental influences were strong and accounted for the remaining proportion of observed variation in these experiences. Multivariate genetic modeling identified a moderately heritable underlying factor (37%, 95% CI: 0.22 to 0.52) that influenced the covariation of diverse subjective experiences and loaded most heavily on dizziness. Positive experiences also evidence residual genetic influences that were uncorrelated with other subjective experiences.

Conclusions  How a person experiences their initial few cigarettes is due to both heritable contributions and environmental experiences unique to the person. The covariation of diverse subjective experiences appears to be due to a heritable latent sensitivity to the chemicals contained in an average cigarette and is best indexed by dizziness.
Alcohol marketing research: the need for a new agenda
Authors: Meier Petra S.
Published: October 2010

Aims  This paper aims to contribute to a rethink of marketing research priorities to address policy makers' evidence needs in relation to alcohol marketing.

Method  Discussion paper reviewing evidence gaps identified during an appraisal of policy options to restrict alcohol marketing.

Findings  Evidence requirements can be categorized as follows: (i) the size of marketing effects for the whole population and for policy‐relevant population subgroups, (ii) the balance between immediate and long‐term effects and the time lag, duration and cumulative build‐up of effects and (iii) comparative effects of partial versus comprehensive marketing restrictions on consumption and harm. These knowledge gaps impede the appraisal and evaluation of existing and new interventions, because without understanding the size and timing of expected effects, researchers may choose inadequate time‐frames, samples or sample sizes. To date, research has tended to rely on simplified models of marketing and has focused disproportionately on youth populations. The effects of cumulative exposure across multiple marketing channels, targeting of messages at certain population groups and indirect effects of advertising on consumption remain unclear.

Conclusion  It is essential that studies into marketing effect sizes are geared towards informing policy decision‐makers, anchored strongly in theory, use measures of effect that are well‐justified and recognize fully the complexities of alcohol marketing efforts.
Cessation of groin injecting behaviour among patients on oral opioid substitution treatment
Authors: Senbanjo Richard , Hunt Neil , Strang John
Published: October 2010

Aims  To identify factors that might influence cessation of groin injecting (GI) among patients receiving oral opioid substitution treatment (OST).

Design  A cross‐sectional survey.

Setting  Drug treatment centres in South East England.

Participants  Groin injectors (GIs) attending an ultrasound ‘health‐check’ clinic.

Measurements  Clinical data and ultrasound images; comparing 65 patients who had injected drugs in the femoral vein (fv) in the previous month (current GIs) with 49 former groin injectors (former GIs).

Findings  Most of the 114 clinic attendees were men (69.3%) and white European (95.6%). Mean age, duration of GI and time in treatment were 36.4 years, 54.8 months and 20.5 months, respectively. Former GIs were significantly older (P < 0.001) and had been injecting (P < 0.05) and in treatment (P < 0.05) for longer than current GIs. History of deep vein thrombosis (DVT, P < 0.05) and septicaemia (P < 0.05); moderate/severe chronic venous disease (CVD, P < 0.01); and ‘very severe’ fv damage on ultrasonography (P < 0.05) were more common among former GIs. A logistic regression model correcting for the effects of covariants revealed age (B 0.08; Wald 7.1; P < 0.01) and severity of venous disease (B 1.1; Wald 4.1; P < 0.05) as the strongest predictors of behaviour change.

Conclusions  GI cessation is associated with longer time in treatment, increasing age and the presence of CVD and severely damaged fv. GI appears to be an intractable behaviour that often persists despite OST and severe health complications. Persistent GI should prompt a review of whether OST is optimized and whether other interventions are needed to promote behaviour change prior to the development of serious harm.
Use of thromboelastometry in the assessment of coagulation before epidural insertion after massive transfusion
Authors: Walker C. , Ingram M. , Edwards D. , Wood P.
Published: October 2010

A British soldier presented to the UK Field Hospital, Afghanistan with bilateral traumatic lower limb amputations. Resuscitation and surgery followed accepted damage control principles. Blood component therapy was in keeping with UK military guidelines and included platelets and cryoprecipitate. The patient’s trachea was extubated following insertion of an effective epidural. Ten days later, in the UK, he developed neurological symptoms and the presence of a subdural haematoma was confirmed on magnetic resonance imaging. Conventional laboratory coagulation results in this patient were above accepted limits for epidural insertion; however, thromboelastometry before insertion was suggestive of reduced platelet function. This case highlights the risk of relying solely on platelet count as a marker of platelet function following massive transfusion. Thromboelastometry provides additional information for the assessment of coagulation and should form part of the assessment of coagulation following massive transfusion before epidural insertion.
Different clinical severity of first episodes and recurrences of thrombotic thrombocytopenic purpura
Authors: Lotta Luca A. , Mariani Mariagabriella , Consonni Dario , Mancini Ilaria , Palla Roberta , Maino Alberto , Vucelic Dragica , Pizzuti Michele , Mannucci Pier M. , Peyvandi Flora
Published: October 2010

The clinical course of thrombotic thrombocytopenic purpura (TTP) is characterized by recurrent disease episodes in up to 50% of cases. The clinical presentation and severity of different TTP episodes have not been systematically compared. Laboratory and clinical information from 51 patients with recurrent disease, derived from 136 patients with TTP included in the Milan TTP registry (URL: http://www.ttpdatabase.org), were used to compare mortality, symptoms and disease‐related laboratory measurements in different disease episodes. The prevalence of severe neurological symptoms (coma, seizures, and focal neurological defects) was significantly lower in recurrences than in the first episode. Platelet counts and haemoglobin levels at presentation were higher in recurrences than in the first disease episode, and lactate dehydrogenase levels were lower. Also, mortality tended to be lower in the second and third disease episodes than in the first. Recurrences of TTP are generally milder than first episodes. These differences in severity should be taken into account in clinical research on TTP and in patient management.
Early and treatment‐related deaths in childhood acute myeloid leukaemia in the Nordic countries: 1984–2003
Authors: Molgaard‐Hansen Lene , Möttönen Merja , Glosli Heidi , Jónmundsson Guðmundur K. , Abrahamsson Jonas , Hasle Henrik ,   On behalf of the Nordic Society of Paediatric Haematology and Oncology (NOPHO)
Published: October 2010

Despite major improvements in the cure rate of childhood acute myeloid leukaemia (AML), 5–15% of patients still die from treatment‐related complications. In a historical prospective cohort study, we analysed the frequency, clinical features and risk factors for early deaths (ED) and treatment‐related deaths (TRD) in 525 children included in the Nordic Society of Paediatric Haematology and Oncology (NOPHO)‐AML‐84, ‐88 and ‐93 trials. Seventy patients (13%) died before starting treatment or from treatment‐related complications. The death rate rose from 11% in NOPHO‐AML‐84 to 29% in ‐88, but then fell to 8% in ‐93. Sixteen patients (3%) died within the first 2 weeks, mainly from bleeding or leucostasis. Hyperleucocytosis, age <2 or ≥10 years were risk factors. After day 15, 10% of patients died from treatment‐related complications with infection as the main cause of death. Risk factors were age <2 or ≥10 years and treatment according to the NOPHO‐AML‐88 protocol. The number of EDs and TRDs in AML is high. Therefore optimal antifungal prophylaxis is essential, and studies on the benefit of antibacterial prophylaxis and individual risk factors for ED and TRD are needed.
One hundred years of sickle cell disease
Authors: Serjeant Graham R.
Published: October 2010

The first formal report of sickle cell disease occurred 100 years ago. This review traces the early historical reports, the evolution of understanding of the genetics, the molecular and chemical basis of sickle haemoglobin, and the advances made over the last 30–40 years in improving the management. Newborn screening and close follow‐up, especially early in life, has significantly improved survival but these advances require resources and sophisticated infrastructure. In sub‐Saharan Africa over 250 000 births annually suggest that these advances are unlikely to be implemented within the foreseeable future. Prevention of the disease where possible, could reduce the numbers of new patients allowing better facilities for the care of others. As the disease results from the inheritance of abnormal haemoglobin genes from both parents, it is eminently preventable. The unanswered question, whether genotype detection and counselling will influence reproductive decisions, is currently being addressed by a project in central Jamaica.
Expression of prostate stem cell antigen in high‐grade prostatic intraepithelial neoplasia and prostate cancer
Authors: Barbisan Francesca , Mazzucchelli Roberta , Santinelli Alfredo , Scarpelli Marina , Lopez‐Beltran Antonio , Cheng Liang , Montironi Rodolfo
Published: October 2010

Barbisan F, Mazzucchelli R, Santinelli A, Scarpelli M, Lopez‐Beltran A, Cheng L & Montironi R (2010) Histopathology57, 572–579 Expression of prostate stem cell antigen in high‐grade prostatic intraepithelial neoplasia and prostate cancer

Aims:  To investigate prostate stem cell antigen (PSCA) and Ki‐67 expression in normal‐looking epithelium (NEp), atrophy, high‐grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma (PCa).

Methods and results:  PSCA and Ki‐67 were evaluated immunohistochemically in NEp, atrophy, HGPIN and PCa in 20 radical prostatectomies (RPs) and 20 cystoprostatectomies (CyPs). The proportions of PSCA positive cells and of cases with PSCA expression increased from NEp through atrophy and HGPIN to PCa. The differences between NEp and HGPIN and PCa and between atrophy and HGPIN and PCa were statistically significant for the away and adjacent locations, in both the RP and CyP groups. The differences between HGPIN and PCa were statistically significant in the RP group when it was away from PCa and in the CyP group when it was adjacent to and away from PCa. The values in the RPs were slightly greater than in the CyPs, the differences being not statistically significant. The proportions of Ki‐67 positive nuclei increased from atrophy and NEp to HGPIN and PCa. The correlation between the proportion of Ki‐67 positive nuclei and that of PSCA‐positive cells was statistically significant.

Conclusions:  PSCA expression, deregulated in atrophy and HGPIN, is a marker associated with neoplastic transformation of prostate cells, both in RPs and CyPs.
Histological changes in patients with chronic upper gastrointestinal ischaemia
Authors: Van Noord Désirée , Biermann Katharina , Moons Leon MG , Pattynama Peter MT , Verhagen Hence JM , Kuipers Ernst J , Mensink Peter BF
Published: October 2010

van Noord D, Biermann K, Moons L M G, Pattynama P M T, Verhagen H J M, Kuipers E J & Mensink P B F (2010) Histopathology57, 615–621 Histological changes in patients with chronic upper gastrointestinal ischaemia

Aims:  Diagnosing chronic upper gastrointestinal ischaemia (CUGI) remains a challenge in clinical practice. Histological examination of biopsy material currently plays no role in the diagnosis of transient CUGI, as little is known about gastrointestinal histology in these patients. The aim of this study was to investigate upper gastrointestinal histology in patients with well‐defined CUGI.

Methods and results:  Consecutive patients suspected of CUGI were included prospectively and underwent a diagnostic work‐up existing of upper endoscopy, gastrointestinal tonometry and computed tomography (CT) or magnetic resonance (MR) angiography. Results were discussed in a multidisciplinary team and a consensus diagnosis was made. Endoscopic biopsy samples were taken from the descending duodenum, gastric antrum and corpus, and scored using the Sydney, Vienna, Chiu, Marsh and Operative Link for Gastritis Assessment (OLGA) classifications. Gastropathy was scored present or absent. Seventy‐nine patients were analysed in 8 months. CUGI was diagnosed in 41 patients (52%): 36 males, mean age 60 (17–86) years. Prevalence of gastropathy was significantly higher in patients with ischaemia (P = 0.025). No other differences were found between patients with and without ischaemia.

Conclusions:  Histological examination of biopsy samples plays no definitive role in diagnosing CUGI, but the presence of histological signs of reactive gastropathy can be used to support the clinical diagnosis of ischaemia.
Immunohistochemical expression of p16INK4A protein as a helpful marker of a subset of potentially malignant oral epithelial lesions: study on a series with long‐term follow‐up
Authors: Montebugnoli Lucio , Cervellati Fabio , Cocchi Roberto , Farnedi Anna , Pennesi Maria Gabriella , Flamminio Federica , Foschini Maria Pia
Published: October 2010

Montebugnoli L, Cervellati F, Cocchi R, Farnedi A, Pennesi M G, Flamminio F & Foschini M P (2010) Histopathology57, 528–534 Immunohistochemical expression of p16INK4A protein as a helpful marker of a subset of potentially malignant oral epithelial lesions: study on a series with long‐term follow‐up

Aim:  To examine a group of lesions that progressed to oral squamous cell carcinoma (OSCC) to determine whether p16INK4A expression is an early finding during malignant transformation, and whether immunohistochemical evaluation of p16INK4A is an appropriate prognostic marker.

Methods and results:  Twenty cases of OSCC were investigated. All cases had had a biopsy on the same site as OSCC performed at least 1 year before OSCC (range 1–11 years; mean 3.15 ± 3.1 years). Twenty specimens from normal oral mucosa served as controls. p16INK4A expression was evaluated by immunohistochemical analysis and cases showing >5% of stained cells were defined as ‘positive’. All 20 control cases were negative for p16INK4A. Oral lesions were p16INK4A‐positive in nine cases and negative in 11. No significant relationship was found between p16INK4A positivity and the presence/absence of dysplasia. Among OSCC, nine tumours showed p16INK4A positivity and 11 showed negativity. A significant relationship (χ2 = 7.1; P < 0.01) was found between the presence/absence of p16INK4A staining in OSCC and the presence/absence of p16INK4A staining in lesions preceding OSCC.

Conclusions:  p16INK4A immunohistochemistry has a potential role in detecting a subset of p16INK4A‐positive lesions with malignant potential.
Endocervical‐like (Müllerian) mucinous borderline tumours of the ovary are frequently associated with the KRAS mutation
Authors: Kim Kyu‐Rae , Choi Jene , Hwang Jeong‐Eun , Baik Young‐Ae , Shim Jeong Yeon , Kim Yong Man , Robboy Stanley J
Published: October 2010

Kim K‐R, Choi J, Hwang J‐E, Baik Y‐A, Shim J Y, Kim Y M & Robboy S J (2010) Histopathology57, 587–596 Endocervical‐like (Müllerian) mucinous borderline tumours of the ovary are frequently associated with the KRAS mutation

Aims:  Clinicopathological aspects of the endocervical‐like mucinous borderline tumour of the ovary (EMBT), including higher frequencies of bilaterality, endometriosis and hormone receptor reactivity, and often admixtures of various Müllerian‐type epithelia, closely resembles endometrioid tumour more than mucinous borderline tumour of the intestinal type (IMBT). Thus, the aims of this study were to determine whether EMBT is really a subtype of mucinous borderline tumours, as shown in the current classification system, and to determine the best classification for EMBT.

Methods and results:  The clinicopathological and immunohistochemical features of 17 EMBTs were analysed, including oestrogen receptor (ER), progesterone receptor (PR), PTEN, cytokeratins (CK) 7 and 20, and β‐catenin. Additionally, mutational analyses of the KRAS (exon 1) and PTEN genes (all nine exons) were performed in all cases, and the results were compared with literature findings for IMBT and endometrioid tumours. Twelve patients (71%) were confirmed histologically to have endometriosis in one or both ovaries. In seven cases, gradual transitions from endometriotic foci to the EMBT were identified. Immunohistochemically, all cases were reactive for ER and PR, with no nuclear expression of β‐catenin. CK7 positivity was strong in all patients, whereas there was no reactivity for CK20. PTEN reactivity was diffuse in the nuclei of epithelial and underlying stromal cells. Sixty‐nine per cent showed KRAS mutations in exon 1 and codon 12, but no PTEN mutation was identified in any of the nine exons.

Conclusion:  Our study suggests that EMBT has features of both mucinous and endometrioid tumours and is an additional tumour type arising in endometriosis. While clinicopathological features of EMBTs are closer to endometrioid tumours, they still have molecular characteristics closer to IMBTs.
LMO2 promotes angiogenesis probably by up‐regulation of bFGF in endothelial cells: an implication of its pathophysiological role in infantile haemangioma
Authors: Sun Zhi‐Jun , Cai Yu , Chen Gang , Wang Rong , Jia Jun , Chen Xin‐Ming , Zheng Li‐Wu , Zhao Yi‐Fang
Published: October 2010

Sun Z‐J, Cai Y, Chen G, Wang R, Jia J, Chen X‐M, Zheng L‐W & Zhao Y‐F (2010)Histopathology57, 622–632 LMO2 promotes angiogenesis probably by up‐regulation of bFGF in endothelial cells: an implication of its pathophysiological role in infantile haemangioma

Aims: Infantile haemangiomas (IHs) are common benign vascular tumours distinctive for their perinatal presentation, rapid growth during the first year of life and subsequent slow involution. Recent research has indicated that endothelial cells of haemangiomas express LIM‐only protein 2 (LMO2). The aim of this study was to investigate the role of LMO2 in the pathogenesis of IHs was investigated.

Methods and results: Immunoreactivity of LMO2 was assessed in specimens of 19 IH. Stable transfection of LMO2 into human endothelial cell lines (EAhy926) was performed to evaluate the role of LMO2 in terms of the change in cell proliferation, cell cycle and cell migration as well as the expression level of angiogenic factors. Immunoreactivity for LMO2 was detected in all IH specimens, specifically in the nucleus of the endothelial cells. The intensity of LMO2 immunostaining decreased significantly from proliferative to involuting stages. Furthermore, the overexpression of LMO2 enhanced the proliferation and migration of the endothelial cells and promoted G0/G1–S‐phase transitionin vitro, together with an up‐regulation of bFGF expression.

Conclusions: LMO2 probably promotes angiogenesis by up‐regulation of bFGF expression and thereby consequently influences progression of IH.