bluuebunny/crossref_metadata_2025 huggingface dataset:
Preferential use of protein domain pairs as interaction mediators: order and transitivity
Authors: Itzhaki Zohar , Akiva Eyal , Margalit Hanah
Published: August 2010

Motivation: Many protein–protein interactions (PPIs) are mediated by protein domains. The structural data of multi-domain PPIs reveal the domain pair (or pairs) that mediate a PPI, and implicitly also the domain pairs that are not involved in the interaction. By analyzing such data, preference relations between domain pairs as interaction mediators may be revealed.

Results: Here, we analyze the differential use of domain pairs as mediators of stable interactions based on structurally solved multi-domain protein complexes. Our analysis revealed domain pairs that are preferentially used as interaction mediators and domain pairs that rarely or never mediate interaction, independent of the proteins' context. Between these extremes, there are domain pairs that mediate protein interaction in some protein contexts, while in other contexts different domain pairs predominate over them. By describing the preference relations between domain pairs as a network, we uncovered partial order and transitivity in these relations, which we further exploited for predicting interaction-mediating domains. The preferred domain pairs and the ones over which they predominate differ in several properties, but these differences cannot yet determine explicitly what underlies the differential use of domain pairs as interaction mediators. One property that stood up was the over-abundance of homotypic interactions among the preferred domain pairs, supporting previous suggestions on the advantages in the use of domain self-interaction for mediating protein interactions. Finally, we show a possible association between the preferred domain pairs and the function of the complex where they reside.

Contact:  hanahm@ekmd.huji.ac.il

Supplementary information:  Supplementary data are available at Bioinformatics online.
XMSF: Structure-preserving noise reduction and pre-segmentation in microscope tomography
Authors: Bilbao-Castro J. R. , Sorzano C. O. S. , García I. , Fernández J. J.
Published: August 2010

Summary: Interpretation of electron tomograms is difficult due to the high noise levels. Thus, denoising techniques are needed to improve the signal-to-noise ratio. XMSF (Microscopy Mean Shift Filtering) is a fast, user-friendly application that succeeds in filtering noise while preserving the structures of interest. It is based on the extension to 3D of a method widely applied in other image processing fields under very different scenarios. XMSF has been tested for a variety of tomograms, showing a great potential to become a state-of-the-art filtering program in electron tomography. Applied iteratively, the algorithm yields pre-segmented volumes facilitating posterior segmentation tasks. Moreover, execution times remain low thanks to parallel computing techniques to exploit current multicore computers.

Availability:  http://sites.google.com/site/xmsfilter/

Contact:  jrbcast@ace.ual.es
Spatial and Temporal Distribution of Iris yellow spot virus and Thrips in Colorado Onion Fields
Authors: Schwartz Howard F. , Gent David H. , Fichtner Scott M. , Khosla Rajiv , Mahaffey Linda A. , Camper Matthew A. , Cranshaw Whitney S.
Published: August 2010

Iris yellow spot virus and its onion thrips vector (Thrips tabaci) are yield limiting pests of onion in the western United States. This two-year project investigated the relationship of iris yellow spot to thrips populations, soil properties, and grower management practices in six onion fields during 2005 and 2006 in Colorado. Thrips density (average number of thrips per plant per day) was negatively associated with soil pH (r = -0.61). The incidence of iris yellow spot at harvest was positively associated with organic matter, zinc, potassium, percent sodium, percent hydrogen, copper, iron, and soil pH. Thrips-days had a clear non-linear association with disease incidence at harvest. Onion plant population was positively associated with levels of iron, phosphorus, potassium, and zinc; and negatively associated with calcium, salts, percent potassium, and cation exchange capacity (CEC). Marketable (medium or larger sized bulbs) yield was negatively associated with phosphorus and percent potassium, and positively associated with salts, calcium, and CEC. Results from this project could contribute to the development of a risk index to predict potential risk from Iris yellow spot virus and its onion thrips vector.

Accepted for publication 6 July 2010. Published 20 August 2010.
Potassium Phosphite Mixed with Other Fungicides Reduces Yield Loss to Downy Mildew on Collard
Authors: Keinath Anthony P.
Published: August 2010

Downy mildew of collard occurs frequently in the southeastern United States, and fungicides have become an essential part of economical control strategies for the disease. Fungicides were evaluated in 2007 and 2008 either alone or combined with a reduced rate (2 pt/acre) of potassium phosphite. Two formulations of potassium phosphite also were tested alone at the full rate (4 pt/acre). Presidio, Presidio plus Pro-Phyt (2007) or K-Phite (2008), K-Phite, Amistar plus ProPhyt, and Aliette reduced downy mildew severity at the final rating and also reduced AUDPC over the two years. Presidio plus potassium phosphite and Amistar plus ProPhyt increased the weight of healthy leaves and stems over the water control and also increased economic return calculated after fungicide and other production costs were subtracted from the crop value. The yields with Ranman, Sonata, and Presidio applied in combination with potassium phosphite were 16% greater than with the fungicides applied alone. Potassium phosphite may be useful in a tank-mix with other fungicides applied to collard to prevent yield loss to downy mildew.

Accepted for publication 7 July 2010. Published 23 August 2010.
Occurrences of Soybean Viruses, Fungal Diseases, and Pests in Illinois Soybean Rust Sentinel Plots
Authors: Hobbs Houston A. , Herman Theresa K. , Slaminko Tara L. , Wang Yi , Nguyen Binh T. , McCoppin Nancy K. , Domier Leslie L. , Hartman Glen L.
Published: August 2010

After soybean rust was confirmed in soybean in the USA, sentinel plots were established in 26 states to monitor its spread. Funding for establishing, sampling, and monitoring the plots came from the USDA, national, regional, and state soybean commodity boards, and state departments of agriculture, extension services, and universities. The presence of sentinel plots for soybean rust monitoring provided the potential for reducing the time and expense of extensive statewide travel for collection of soybean leaf samples for monitoring the incidence of other foliar diseases of soybean in Illinois.

Accepted for publication 27 July 2010. Published 27 August 2010.
Fungicide Resistance Management Guidelines for the Control of Tomato Diseases in the Mid-Atlantic and Northeast Regions of the United States
Authors: Wyenandt Christian A. , Rideout Steven L. , Gugino Beth K. , McGrath Margaret T. , Everts Kathryne L. , Mulrooney Robert P.
Published: August 2010

Foliar diseases and fruit rots occur routinely on tomato, an important crop grown throughout the Mid-Atlantic and Northeast regions of the United States where it is produced for both fresh-market and processing. To enable these tomato growers to more effectively manage economically important diseases, a fungicide resistance management table has been developed which promotes the importance of understanding FRAC (Fungicide Resistance Action Committee) codes and provides an integrated pest management tool for tomato growers which will allow them to develop season-long disease control programs with an emphasis on fungicide resistance management.

Accepted for publication 19 July 2010. Published 27 August 2010.
Survey of Fusarium spp. Associated with Fruit Rot of Pumpkin in Ohio
Authors: Wyenandt Christian A. , Riedel Richard M. , Rhodes Landon H. , Bennett Mark A. , Nameth Steven G. P.
Published: August 2010

From 2000 to 2002 commercial pumpkin (Cucurbita pepo) fields in Ohio were surveyed for Fusarium fruit rot. From six counties in 2000, 2001, and 2002, a total of 43 isolates from eight farms, 84 isolates from nine farms, and 40 isolates from six farms were collected, respectively. Fusarium solani f. sp. cucurbitae race 1 was the most commonly isolated Fusarium species from infected pumpkin fruit in Ohio. Other Fusaria isolated from infected fruit included F. oxysporum, F. graminearum, and F. acuminatum. A survey of infected pumpkin fruit in the field and inoculation studies of mature, healthy pumpkin cultivar Magic Lantern in the laboratory resulted in three types of fruit rot symptoms. Type 1, caused by F. oxysporum and F. acuminatum, resulted in a slow-expanding rot just below the rind surface of the infected fruit. Type 2, caused by F. graminearum, resulted in an expanding, slightly sunken, irregular rot of the rind surface. Type 3, caused by F. solani resulted in expanding, circular sunken lesions on the fruit surface bearing white to tan sporodochia. This is the first report of F. solani f. sp. cucurbitae race 1, F. oxysporum, F. acuminatum, and F. graminearum causing fruit rot of pumpkin in Ohio.

Accepted for publication 26 July 2010. Published 27 August 2010.
Impact of translational selection on codon usage bias in the archaeon
Methanococcus maripaludis
Authors: Emery Laura R. , Sharp Paul M.
Published: September 2010

Patterns of codon usage have been extensively studied among Bacteria and Eukaryotes, but there has been little investigation of species from the third domain of life, the Archaea. Here, we examine the nature of codon usage bias in a methanogenic archaeon,
Methanococcus maripaludis
. Genome-wide patterns of codon usage are dominated by a strong A + T bias, presumably largely reflecting mutation patterns. Nevertheless, there is variation among genes in the use of a subset of putatively translationally optimal codons, which is strongly correlated with gene expression level. In comparison with Bacteria such as
Escherichia coli
, the strength of selected codon usage bias in highly expressed genes in
M. maripaludis
seems surprisingly high given its moderate growth rate. However, the pattern of selected codon usage differs between
M. maripaludis
and
E. coli
: in the archaeon, strongly selected codon usage bias is largely restricted to twofold degenerate amino acids (AAs). Weaker bias among the codons for fourfold degenerate AAs is consistent with the small number of tRNA genes in the
M. maripaludis
genome.
Group decisions and individual differences: route fidelity predicts flight leadership in homing pigeons (
Columba livia
)
Authors: Freeman Robin , Mann Richard , Guilford Tim , Biro Dora
Published: September 2010

How social-living animals make collective decisions is currently the subject of intense scientific interest, with increasing focus on the role of individual variation within the group. Previously, we demonstrated that during paired flight in homing pigeons, a fully transitive leadership hierarchy emerges as birds are forced to choose between their own and their partner's habitual routes. This stable hierarchy suggests a role for individual differences mediating leadership decisions within homing pigeon pairs. What these differences are, however, has remained elusive. Using novel quantitative techniques to analyse habitual route structure, we show here that leadership can be predicted from prior route-following fidelity. Birds that are more faithful to their own route when homing alone are more likely to emerge as leaders when homing socially. We discuss how this fidelity may relate to the leadership phenomenon, and propose that leadership may emerge from the interplay between individual route confidence and the dynamics of paired flight.
Is evolutionary history repeatedly rewritten in light of new fossil discoveries?
Authors: Tarver J. E. , Donoghue P. C. J. , Benton M. J.
Published: September 2010

Mass media and popular science journals commonly report that new fossil discoveries have ‘rewritten evolutionary history’. Is this merely journalistic hyperbole or is our sampling of systematic diversity so limited that attempts to derive evolutionary history from these datasets are premature? We use two exemplars—catarrhine primates (Old World monkeys and apes) and non-avian dinosaurs—to investigate how the maturity of datasets can be assessed. Both groups have been intensively studied over the past 200 years and so should represent pinnacles in our knowledge of vertebrate systematic diversity. We test the maturity of these datasets by assessing the completeness of their fossil records, their susceptibility to changes in macroevolutionary hypotheses and the balance of their phylogenies through study time. Catarrhines have shown prolonged stability, with discoveries of new species being evenly distributed across the phylogeny, and thus have had little impact on our understanding of their fossil record, diversification and evolution. The reverse is true for dinosaurs, where the addition of new species has been non-random and, consequentially, their fossil record, tree shape and our understanding of their diversification is rapidly changing. The conclusions derived from these analyses are relevant more generally: the maturity of systematic datasets can and should be assessed before they are exploited to derive grand macroevolutionary hypotheses.
Mothers matter! Maternal support, dominance status and mating success in male bonobos (Pan paniscus)
Authors: Surbeck Martin , Mundry Roger , Hohmann Gottfried
Published: September 2010

Variation in male mating success is often related to rank differences. Males who are unable to monopolize oestrous females alone may engage in coalitions, thus enhancing their mating success. While studies on chimpanzees and dolphins suggest that coalitions are independent of kinship, information from female philopatric species shows the importance of kin support, especially from mothers, on the reproductive success of females. Therefore, one might expect a similar effect on sons in male philopatric species. We evaluate mating success determinants in male bonobos using data from nine male individuals from a wild population. Results reveal a steep, linear male dominance hierarchy and a positive correlation between dominance status and mating success. In addition to rank, the presence of mothers enhances the mating success of sons and reduces the proportion of matings by the highest ranking male. Mothers and sons have high association rates and mothers provide agonistic aid to sons in conflicts with other males. As bonobos are male-philopatric and adult females occupy high dominance status, maternal support extends into adulthood and females have the leverage to intervene in male conflicts. The absence of female support to unrelated males suggests that mothers gain indirect fitness benefits by supporting their sons.
Timing of the maturation transition in haddock Melanogrammus aeglefinus
Authors: Tobin D. , Wright P. J. , O'Sullivan M.
Published: August 2010

The timing of maturation in haddock Melanogrammus aeglefinus was examined using changes in gonad development, follicle stimulating hormone β (FSH‐β) transcript expression profile, growth and condition of 1 year old females held under a common environment between the summer and winter solstices. The circumnuclear ring, cortical alveolus and vitellogenic oocyte stages were first observed in August, October and November, respectively. FSH‐β transcript levels did not change significantly until September but increased markedly thereafter in maturing fish. A combined analysis of the mean oocyte diameter of the leading cohort, histological staging and FSH‐β transcript profile provided evidence of a commitment to maturation by October or November. Contrary to that previously proposed for gadoid species, histological analysis of field‐caught immature M. aeglefinus during the spawning season indicated that cortical alveolar, rather than circumnuclear ring, stage oocytes provided definitive evidence of maturation. A decrease in relative liver size following the summer solstice suggested a possible link between energy status and maturation.
Experimental and field evidence of behavioural habitat selection by juvenile Atlantic Acipenser oxyrinchus oxyrinchus and shortnose Acipenser brevirostrum sturgeons
Authors: Niklitschek E. J. , Secor D. H.
Published: August 2010

The present work reports behavioural responses by young‐of‐the‐year (21–30 cm) Atlantic sturgeon Acipenser oxyrinchus oxyrinchus and shortnose sturgeon Acipenser brevirostrum to nine binary combinations of dissolved oxygen saturation (40, 70 and 100%), temperature (12, 20 and 28°C) and salinity (1, 8 and 15). Both species showed no acclimation effects and similar discrimination and avoidance reactions to hypoxia (40% oxygen saturation), selecting higher dissolved oxygen choices in 71% of the tests. Acipenser oxyrinchus oxyrinchus and A. brevirostrum showed a similar preference for 20°C (>64% incidence), but differed in their responses to extreme temperature choices. Acipenser brevirostrum showed a significant avoidance behaviour to the 12°C but not to the 28°C choice. In contrast, A. o. oxyrinchus showed similar preference for 12 and 20°C, but avoided the 28°C choice in 71% of the tests where this temperature was included (P < 0·01). No significant preferences were observed among salinity choices, except between salinities 1 and 8, where A. o. oxyrinchus showed a significant preference for salinity 8. Behavioural responses matched expectations from bioenergetics in both species and were also consistent with the distribution of juvenile A. o. oxyrinchus capture locations in the Chesapeake Bay.
Epigenetic alteration of the NF‐κB‐inducing kinase (NIK) gene is involved in enhanced NIK expression in basal‐like breast cancer
Authors: Yamamoto Mizuki , Ito Taku , Shimizu Takafumi , Ishida Takaomi , Semba Kentaro , Watanabe Shinya , Yamaguchi Noritaka , Inoue Jun‐ichiro
Published: August 2010

Basal‐like breast cancers are triple‐negative (estrogen receptor negative, progesterone receptor negative, erythroblastic leukemia viral oncogene homolog 2 (ERBB2) negative) tumors with an aggressive clinical behavior that lacks effective molecular targets for therapy. We reported previously that the basal‐like subtype cell lines display high constitutive nuclear factor (NF)‐κB activation, whose inhibition in the basal‐like subtypes suppressed their proliferation. Moreover, NF‐κB‐inducing kinase (NIK) is involved in the constitutive NF‐κB activation. Here, we report that enhanced NIK expression, which is exclusively observed in the basal‐like subtype rather than the luminal‐like subtype or non‐tumorigenic mammary epithelial cells, is caused by epigenetic alteration of the NIK gene. The stability of NIK mRNA and transcriptional activity driven by the NIK promoter are similar in the basal‐like and luminal‐like subtypes. However, histone H3 acetylation levels were up‐regulated in the basal‐like subtype. Furthermore, treatment of the luminal‐like subtype with a histone deacetylase inhibitor, valproic acid, significantly increased NIK expression. Although DNA methylation of the NIK locus was not detected, NIK expression also increased when the luminal‐like subtype was treated with 5‐azacytidine, which inhibits histone H3‐Lys‐9 dimethylation in addition to DNA methylation. Taken together, these results suggest that the closed chromatin structure mediated by histone H3 methylation and deacetylation suppresses NIK expression in the luminal‐like subtype, whereas disruption of these suppression mechanisms leads to enhanced NIK expression and the constitutive NF‐κB activation in the basal‐like subtype. Thus, NIK and genes induced by the NIK‐mediated constitutive NF‐κB activation could be therapeutic targets of basal‐like breast cancer. (Cancer Sci 2010; 101: 2391–2397)
Prospective evaluation of pharmacokinetically guided dosing of carboplatin in Japanese patients with cancer
Authors: Shimokata Tomoya , Ando Yuichi , Yasuda Yoshinari , Hamada Akinobu , Kawada Kenji , Saito Hideyuki , Matsuo Seiichi , Kondo Masashi , Imaizumi Kazuyoshi , Hasegawa Yoshinori
Published: August 2010

The Calvert formula, that is, carboplatin dose (mg) = target area under the concentration versus time curve (AUC) × (glomerular filtration rate [GFR] + 25), has not been validated in Japanese subjects in whom the GFR was accurately measured. The purpose of this study is to evaluate the validity of this formula for Japanese patients with cancer and modify it for this population. The GFR was measured on the basis of inulin clearance, which is considered to reflect the accurate GFR. Inulin clearance was measured in 28 patients with cancer. The adjusted 24‐h creatinine clearance (24‐h Ccr) was unbiased (mean prediction error [MPE] ± SE = −2.3 ± 4.5%) and acceptably precise (root mean squared error = 23.7%) for GFR assessment. The pharmacokinetics of carboplatin were analyzed in 21 patients with a GFR of 17.2–91.4 mL/min. The original Calvert formula overestimated carboplatin clearance, resulting in an MPE of 14.3%. When we revised the Calvert formula for Japanese patients by substituting a non‐renal clearance of 15 for 25, that is, dose = target AUC × (GFR + 15), the MPE decreased to −0.1% (P < 0.001). We conclude that the adjusted 24‐h Ccr is acceptably precise for GFR assessment, and the non‐renal clearance of carboplatin is suggested to be lower in Japanese patients with cancer than in their Western counterparts. (Cancer Sci 2010; 101: 2601–2605)
Effectiveness of a mood management component as an adjunct to a telephone counselling smoking cessation intervention for smokers with a past major depression: a pragmatic randomized controlled trial
Authors: Van Der Meer Regina M. , Willemsen Marc C. , Smit Filip , Cuijpers Pim , Schippers Gerard M.
Published: August 2010

Aims  To assess whether the addition of a mood management component to telephone counselling produces higher abstinence rates in smokers with past major depression and helps to prevent recurrence of depressive symptoms.

Design  Pragmatic randomized controlled trial with two conditions, with follow‐up at 6 and 12 months. The control intervention consisted of eight sessions of proactive telephone counselling. The mood management intervention was an integration of the control intervention with a mood management component. This component consisted of a self‐help mood management manual, two more preparatory proactive telephone counselling sessions and supplementary homework assignments and advice.

Setting  Dutch national smoking cessation quitline.

Participants  A total of 485 daily smokers with past major depression, according to the DSM‐IV.

Measurements  The primary outcome measure was prolonged abstinence and secondary outcome measures were 7‐day point prevalence abstinence and depressive symptoms.

Findings  The mood management intervention resulted in significantly higher prolonged abstinence rates at 6‐ and 12‐month follow‐up (30.5% and 23.9% in experimental condition, 22.3% and 14.0% in the control condition). The odds ratios were 1.60 (95% CI 1.06–2.42) and 1.96 (95% CI 1.22–3.14) for both follow‐ups. The mood management intervention did not seem to prevent recurrence of depressive symptoms.

Conclusions  Adding a mood management component to telephone counselling for smoking cessation in smokers with a past major depression increases cessation rates without necessarily reducing depressive symptoms.
Prevalence of the metabolic syndrome in men and women with alcohol dependence: results from a cross‐sectional study during behavioural treatment in a controlled environment
Authors: Kahl Kai G. , Greggersen Wiebke , Schweiger Ulrich , Cordes Joachim , Correll Christoph U. , Ristow Jessica , Burow Juliane , Findel Corinna , Stoll Anne , Balijepalli Chakrapani , Göres Laura , Lösch Christian , Hillemacher Thomas , Bleich Stefan , Moebus Susanne
Published: August 2010

Aims  Prevalence of metabolic syndrome (MetS) in men and women who use alcohol has been inconsistent in the literature. The aim of this study is to compare the prevalence of MetS in patients with a diagnosis of alcohol dependence who are currently abstinent in a controlled environment, and in control subjects followed in primary care from a similar region in Northern Germany.

Design  Cross‐sectional study.

Setting  In‐patient cognitive behavioural therapy.

Participants  One hundred and ninety‐seven men and women with alcohol dependence during behavioural treatment in a controlled environment were compared to 1158 subjects from primary care from a similar region in northern Germany.

Measurements  We used the American Heart Association/National Heart, Lung and Blood Institute (AHA/NHBLI) criteria to determine the rate of MetS and each single criterion of MetS in both groups.

Findings  The prevalence of MetS was almost twice as high in men and women with alcohol dependence compared to control subjects (30.6% versus 17.0%). With respect to the single criteria, elevations were found for fasting glucose and blood pressure in both genders and for triglycerides in women only. High density lipoprotein (HDL)‐cholesterol was higher in men and women with alcohol dependence.

Conclusions  Our results demonstrate an increased rate of MetS, increased blood pressure and dysregulation of glucose and lipid metabolism in alcohol‐dependent patients. Whether high HDL‐cholesterol has cardioprotective effects in this context remain doubtful.
A comparison of four international surveys of tobacco dependence treatment provision: implications for monitoring the Framework Convention on Tobacco Control
Authors: Bitton Asaf , Raw Martin , Richards Ann , McNeill Ann , Rigotti Nancy A.
Published: August 2010

Aims  Article 14 of the Framework Convention on Tobacco Control (FCTC) requires countries to implement systems to provide tobacco dependence treatment. We report on global efforts to monitor the implementation of Article 14, and compare the surveys used in this effort.

Design  Cross‐sectional comparison of agreement (concordance and discordance) among the four main surveys used to monitor tobacco dependence treatment provision.

Setting  Four global surveys of tobacco treatment provision.

Participants  The four surveys were Raw et al. (2009), the Framework Convention Alliance (FCA) Monitor, World Health Organization (WHO) MPOWER survey and the FCTC Party Reports.

Measurements  Concordance as measured by percentage providing the same answers, as well as kappa statistic of inter‐rater agreement.

Findings  The four surveys used to monitor Article 14 implementation vary widely in countries sampled, questions asked, respondent characteristics and survey design. The four surveys generally show a moderate to high concordance (kappa > 0.60) with each other across most survey pairs and most domains, except for the MPOWER and FCTC Party governmental surveys (63% overall concordance, kappa = 0.26). This concordance was lower than any other survey pair examined. Government respondents to the WHO MPOWER and FCTC Party Report surveys provided answers to the same question domains with relatively poorer concordance than those from surveys of non‐governmental or mixed governmental/non‐governmental sources.

Conclusions  Current surveys of tobacco dependence treatment provision are in general agreement with each other except for the two official government surveys that rely on governmental respondents. We believe that this points to the continued need for independent non‐governmental monitoring of FCTC protocol implementation.
Addiction Research Centres and the Nurturing of Creativity The Norwegian Centre for Addiction Research (SERAF)
Authors: Bramness Jørgen G. , Clausen Thomas , Duckert Fanny , Ravndal Edle , Waal Helge
Published: August 2010

The Norwegian Centre for Addiction Research (SERAF) at the University of Oslo is a newly established, clinical addiction research centre. It is located at the Oslo University Hospital and has a major focus on opioid dependency, investigating Norwegian opioid maintenance treatment (OMT), with special interest in OMT during pregnancy, mortality, morbidity and criminality before, during and after OMT and alternatives to OMT, such as the use of naltrexone implants. The well‐developed health registries of Norway are core assets that also allow the opportunity for other types of substance abuse research. This research includes health services, abuse of prescription drugs and drugs of abuse in connection with traffic. The centre also focuses upon comorbidity, investigating the usefulness and limitations of psychometric instruments, drug abuse in different psychiatric treatment settings and internet‐based interventions for hazardous alcohol consumption.
The microenvironment differentially impairs passive and active immunotherapy in chronic lymphocytic leukaemia – CXCR4 antagonists as potential adjuvants for monoclonal antibodies
Authors: Buchner Maike , Brantner Philipp , Stickel Natalie , Prinz Gabriele , Burger Meike , Bär Constance , Dierks Christine , Pfeifer Dietmar , Ott Ariane , Mertelsmann Roland , Gribben John G. , Veelken Hendrik , Zirlik Katja
Published: August 2010

Direct contact with stromal cells protects chronic lymphocytic leukaemia (CLL) B cells from chemotherapy‐induced apoptosis in vitro. Blockade of CXCR4 signalling antagonizes stroma‐mediated interactions and restores CLL chemosensitivity. In vivo, administration of CXCR4 antagonists effectively mobilizes haematopoietic progenitor cells. Therefore, combinations of CXCR4 blockade and cytoreductive treatment with selective activity on CLL cells may avoid potential haematotoxicity. Hence, we tested CXCR4 antagonists in the context of passive and active immunotherapeutic approaches. We evaluated how efficiently rituximab, alemtuzumab and cytotoxic T cells killed CLL cells cocultured with stromal cells in the presence and absence of a CXCR4 antagonist. Stromal cell contact attenuated rituximab‐ and alemtuzumab‐induced complement‐dependent cytotoxicity of CLL cells. Addition of CXCR4 antagonists abrogated the protective effect of stroma. In contrast, stromal cells did not impair antibody‐dependent cell‐mediated cytotoxicity and cytotoxicity induced by activated T cells. Destruction of microtubules in CLL target cells restored the protective effect of stroma coculture for CLL cells during Natural Killer cell attack by preventing mitochondrial relocalization towards the immunological synapse. Our data identify the combination of CXCR4 antagonists with passive ‐ but not active ‐ immunotherapy as a promising potential treatment concept in CLL.
Primary central nervous system lymphoma in the elderly: a multicentre retrospective analysis
Authors: Schuurmans Mascha , Bromberg Jacoline E. C. , Doorduijn Jeanette , Poortmans Philip , Taphoorn Martin J. B. , Seute Tatjana , Enting Roelien , Van Imhoff Gustaaf , Van Norden Yvette , Van Den Bent Martin J.
Published: August 2010

Elderly patients with primary central nervous ystem lymphoma (PCNSL) do not tolerate treatment with combined radio‐chemotherapy well because of leuco‐encephalopathy; they are usually treated initially with chemotherapy or radiotherapy alone. Little is known about the efficacy and toxicity of these treatments outside clinical studies. This study was a retrospective analysis of all patients aged 60 years or over who were admitted with PCNSL to one of five Dutch centers between 1998 and 2007. A total of 74 patients were identified. Twenty‐nine were treated with radiotherapy only (Group A), in 36 the intended treatment was chemotherapy alone (Group B), and nine were planned to receive chemotherapy followed by radiotherapy (Group C). Median overall survival was 20 months; 4 months in patients with a Karnofsky performance status (KPS) <70, 25 months in patients with a KPS ≥ 70 (P < 0·001). Treatment modality was not an independent prognostic factor. Forty patients were treated with methotrexate 3 g/m2: there were two toxic deaths. Ten patients discontinued chemotherapy because of toxicity. Delayed encephalopathy was reported in 10 patients. In conclusion, community hospitals still frequently utilize whole brain radiotherapy in elderly PCNSL patients, though a majority tolerates chemotherapy well. Performance status was the most important variable determining prognosis. Short and long term toxicities must be weighed against possible clinical benefits of each treatment, making treatment decisions a highly individualized process.
Upfront VIP‐reinforced‐ABVD (VIP‐rABVD) is not superior to CHOP/21 in newly diagnosed peripheral T cell lymphoma. Results of the randomized phase III trial GOELAMS‐LTP95
Authors: Simon Audrey , Peoch Michel , Casassus Philippe , Deconinck Eric , Colombat Philippe , Desablens Bernard , Tournilhac Olivier , Eghbali Houchingue , Foussard Charles , Jaubert Jerome , Vilque Jean Pierre , Rossi Jean François , Lucas Virginie , Delwail Vincent , Thyss Antoine , Maloisel Frederic , Milpied Noel , Le Gouill Steven , Lamy Thierry , Gressin Rémy
Published: August 2010

Peripheral T‐Cell lymphomas (PTCL) are relatively rare diseases but appear to be highly aggressive and display worse remission and survival rates than B‐cell lymphomas. Despite unsatisfactory results with the cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) regimen, it remains the reference front‐line therapy in these diseases, but has not been challenged in phase III trials. The Groupe Ouest Est d’Etude des Leucémies et Autres Maladies du Sang (GOELAMS) devised an alternative therapeutic schedule including etoposide, ifosfamide, cisplatin alternating with doxorubicin, bleomycin, vinblastine, dacarbazine (VIP‐reinforced‐ABVD; VIP‐rABVD) and compared it to CHOP/21 as front‐line treatment in non‐cutaneous PTCL. All newly diagnosed patients were eligible. The primary objective was to improve the 2‐year event‐free survival (EFS) rate. Secondary objectives were to compare the response rate, overall survival, and toxicities as well as identify prognostic factors. Eighty‐eight patients were identified between 1996 and 2002. Both arms were well balanced for patients’ characteristics in terms of histological and clinical presentation. No significant difference was observed between the two arms in terms of 2‐year EFS. Anaplastic large cell lymphoma type and Ann Arbor stage I–II were identified as two independent favourable prognostic factors influencing survival. VIP‐rABVD was not superior to CHOP/21 in terms of EFS as first‐line treatment of PTCL, confirming that CHOP/21 remains the reference regimen in these lymphomas.
The impact of bleeding history, von Willebrand factor and PFA–100® on the diagnosis of type 1 von Willebrand disease: results from the European study MCMDM‐1VWD
Authors: Castaman Giancarlo , Tosetto Alberto , Goodeve Anne , Federici Augusto B. , Lethagen Stefan , Budde Ulrich , Batlle Javier , Meyer Dominique , Mazurier Claudine , Goudemand Jenny , Eikenboom Jeroen , Schneppenheim Reinhard , Ingerslev Jorgen , Habart David , Hill Frank , Peake Ian , Rodeghiero Francesco
Published: August 2010

The relationships between the Platelet Function Analyzer (PFA)‐100 and von Willebrand factor (VWF) levels and bleeding score (BS) were evaluated within a multicentre project on Molecular and Clinical Markers for the Diagnosis and Management of type 1 von Willebrand disease (MCMDM‐1VWD). PFA‐100 closure time, either with epinephrine (EPI) or adenosine diphosphate (ADP)‐cartridges, was measured in 107 index cases, 105 affected and 71 unaffected family members, and 79 healthy controls. By regression analysis VWF levels were strongly related to both closure times, with a non‐linear progression. In a multiple stepwise regression model, age‐ and sex‐adjusted PFA‐100 ADP and VWF ristocetin cofactor activity (VWF:RCo) were independently associated with BS. Most of the variation of BS was predicted by PFA‐100 ADP and VWF:RCo alone. In the subgroup of patients with subtle abnormalities of the multimeric pattern, VWF was invariably reduced and closure time prolonged in almost all of them. Neither PFA‐100 ADP nor EPI closure times appeared to significantly improve the diagnostic capability of VWF antigen (VWF:Ag) measurement. Thus, in an unselected population a normal PFA‐100 would be useful to exclude VWD, but whether it could replace the more specific VWF assay in patients with significant mucocutaneous bleeding symptoms remains to be investigated prospectively.
Common occurrence of monoclonal B‐cell lymphocytosis among members of high‐risk CLL families
Authors: Goldin Lynn R. , Lanasa Mark C. , Slager Susan L. , Cerhan James R. , Vachon Celine M. , Strom Sara S. , Camp Nicola J. , Spector Logan G. , Leis Jose F. , Morrison Vicki A. , Glenn Martha , Rabe Kari G. , Achenbach Sara J. , Algood Sallie D. , Abbasi Fatima , Fontaine Laura , Yau Michelle , Rassenti Laura Z. , Kay Neil E. , Call Timothy G. , Hanson Curtis A. , Weinberg J. Brice , Marti Gerald E. , Caporaso Neil E.
Published: August 2010

Monoclonal B‐cell lymphocytosis (MBL) is an asymptomatic haematological condition characterized by low absolute levels of B‐cell clones with a surface immunophenotype similar to that of chronic lymphocytic leukaemia (CLL). In the general population, MBL increases with age with a prevalence of 5–9% in individuals over age 60 years. It has been reported to be higher among first‐degree relatives from CLL families. We report results of multi‐parameter flow cytometry among 505 first‐degree relatives with no personal history of lymphoproliferative disease from 140 families having at least two cases of CLL. Seventeen percent of relatives had MBL. Age was the most important determinant where the probability for developing MBL by age 90 years was 61%. MBL clustered in certain families but clustering was independent of the number of known CLL cases in a family. As is the case with CLL, males had a significantly higher risk for MBL than did females (P = 0·04). MBL patients had significantly higher mean absolute lymphocyte counts (2·4 × 109/l) and B‐cell counts (0·53 × 109/l) than those with a normal B‐cell immuno‐phenotype. Our findings show that MBL occurs at a very high rate in high risk CLL families. Both the age and gender distribution of MBL are parallel to CLL, implying a shared inherited risk.
The novel Hsp‐90 inhibitor SNX7081 is significantly more potent than 17‐AAG against primary CLL cells and a range of haematological cell lines, irrespective of lesions in the TP53 pathway
Authors: Best O. Giles , Singh Nisha , Forsyth Cecily , Mulligan Stephen P.
Published: August 2010

Inhibitors of heat‐shockprotein 90 (Hsp90) have been proposed as a novel therapeutic option for Chronic Lymphocytic Leukaemia (CLL), particularly as their mechanism of action appears independent of mutations of ATM or TP53. We investigated the activity of a novel Hsp90 inhibitor, SNX7081, against a panel of eight haematological cell lines and 23 CLL patient samples. SNX7081 displayed significant effects on cell cycle distribution, apoptotic rate and levels of ZAP‐70 in the cell lines and in the patient samples, irrespective of TP53 status. Our findings suggest SNX7081 may represent a promising therapeutic option for aggressive CLL.
Genetic variability of TMPRSS6 and its association with iron deficiency anaemia
Authors: Delbini Paola , Vaja Valentina , Graziadei Giovanna , Duca Lorena , Nava Isabella , Refaldi Chiara , Cappellini Maria D.
Published: August 2010

Transmembrane Protease, Serine 6 (TMPRSS6) has an important role in iron homeostasis and its mutations, performed in TMPRSS6‐deficient mice, have been recently associated with iron‐refractory iron deficiency anaemia (IRIDA). Several variants of TMPRSS6 have been already identified; however the role of polymorphisms and TMPRSS6 haplotypes, causing iron deficiency anaemia, have not yet been investigated. This study sequenced the TMPRSS6 gene in 16 subjects with IRIDA phenotype and identified 27 DNA polymorphisms. Eight single nucleotide polymorphisms and four haplotypes were significantly associated with iron‐refractory anaemia (P < 0·001). Our preliminary results suggest a possible association between specific haplotypes of TMPRSS6 and IRIDA.
What’s new in acne? An analysis of systematic reviews published in 2009–2010
Authors: Smith E. V. , Grindlay D. J. C. , Williams H. C.
Published: August 2010

This review highlights clinically important findings about acne treatment identified in nine systematic reviews published or indexed in the period March 2009 to February 2010. A systematic review of dietary influences on acne suggested that a possible role of dietary factors in acne cannot be dismissed, as the studies to date have not been sufficiently large or robust. Another review looked at benzoyl peroxide, which may be enjoying a comeback because of increasing bacterial resistance to antibiotics, and suggested that there was a lack of evidence that stronger preparations were more effective than weaker ones. The same team also carried out a systematic review addressing the question of whether topical retinoids cause an initial worsening of acne. They found no evidence to suggest initial worsening of acne severity, although there was evidence of skin irritation that typically settled by 8–12 weeks. A review of oral isotretinoin and psychiatric side-effects reinforced a possible link between the two, although it pointed out that the better-quality primary studies were still inconclusive. An updated Cochrane Review confirmed the efficacy of combined oral contraceptives (COCs) in reducing acne lesion counts. It also found that the evidence to support COCs containing cyproterone acetate over others was very limited. Another Cochrane Review failed to show any benefit of spironolactone for acne, based on limited studies. Three reviews examined laser and light therapies, and found some evidence of superiority only for blue or blue/red light treatment over placebo light, but a general absence of comparisons against other acne treatments. Photodynamic therapy had consistent benefits over placebo but was associated with significant side-effects and was not shown to be better than topical adapalene.
Cutaneous adverse drug reactions in a hospital-based Chinese population
Authors: Huang H.-Y. , Luo X.-Q. , Chan L.-S. , Cao Z.-H. , Sun X.-F. , Xu J.-H.
Published: August 2010

Background. Cutaneous adverse drug reactions (CADRs) are common skin adverse reactions associated with drugs.

Aim. To assess recent trends in CADRs and the drugs associated with them, using data from the past 5 years in the largest single database available on a hospital-based population in China.

Methods. All clinical records of inpatients admitted with a diagnosis of CADR to the Dermatology Ward, Huashan Hospital from January 2004 to December 2008 were retrospectively studied.

Results. In the 734 patients, the three most common types of CADRs were nonsevere reactions, erythema multiforme (EM)-like eruptions (n = 255), urticaria (n = 192) and exanthematous reactions (n = 159), followed by three severe reactions: Stevens–Johnson syndrome (n = 58), toxic epidermal necrolysis (n = 29) and exfoliative dermatitis (n = 22). The most common single drug associated with the development of all drug eruptions was allopurinol, followed by amoxicillin, cephalosporins, antiepileptic agents and antipyretic/analgesic agents. However, the most common single drugs associated with severe reactions were antiepileptic agents, followed by allopurinol, antipyretic/analgesic agents and cephalosporins. In contrast to patients with nonsevere reactions, patients with severe reactions were more likely to be male (P < 0.001) and to have a greater mean age of onset (P < 0.001), a longer latency period (P < 0.001) and a longer duration of hospitalization (P < 0.001).

Conclusion. In contrast to previous studies, we found allopurinol to be the most common single drug associated with CADRs followed by antibiotics (amoxicillin and cephalosporins), and antiepileptic, especially carbamazepine. A higher incidence of EM-like eruptions and urticaria was also seen.
Dermatology referrals in an East Asian tertiary hospital: a need for inpatient medical dermatology
Authors: Tay L. K. , Lee H. Y. , Thirumoorthy T. , Pang S. M.
Published: August 2010

Background. Within hospitals, there is a need for dermatological expertise, as hospitalized patients have a wider spectrum of severe and serious dermatological conditions, associated with significant morbidity.

Aim. To characterize the patient profile and referral pattern of inpatient dermatology consultations, and to evaluate the diagnostic accuracy of non-dermatologists.

Methods. This was a retrospective study reviewing all inpatient referrals for dermatology consultations during a 1-year period from July 2005 to June 2006 (inclusive), at the largest multi-disciplinary tertiary hospital in Singapore.

Results. Of the 731 referrals made for dermatology consultations, 26.9% of patients had ≥ 3 important underlying comorbidities. Eczema/dermatitis (33.1%; n = 242) and cutaneous infections (23.4%; n = 171) accounted for over half of the dermatological consultations, followed by cutaneous adverse drug reactions (12.3%; n = 90). The provisional diagnoses of the referring doctors agreed with the final diagnoses confirmed by dermatologists in only 30.2% of all referrals; incorrect diagnoses were made in 35.2% of cases, and no provisional diagnoses were made in the remaining 34.6% of cases. Most misdiagnosed skin diseases were in fact common dermatoses (such as eczemas, cutaneous infections, drug rash) that required only standard treatment.

Conclusion. Our study reiterates the importance of inpatient medical dermatology in terms of both service and education. There should be continual efforts to ensure that dermatologists have the highest level of training and experience in medical dermatology, to provide collaborative optimum care for hospitalized patients with dermatological diseases.
Down-regulation of p38 mitogen-activated protein kinase activation and proinflammatory cytokine production by mitogen-activated protein kinase inhibitors in inflammatory bowel disease
Authors: Docena G , Rovedatti L , Kruidenier L , Fanning Á , Leakey N A B , Knowles C H , Lee K , Shanahan F , Nally K , McLean P G , Di Sabatino A , MacDonald T T
Published: September 2010

Crohn's disease and ulcerative colitis are inflammatory bowel diseases (IBD) characterized by chronic relapsing mucosal inflammation. Tumour necrosis factor (TNF)-α, a known agonist of the mitogen-activated protein kinase (MAPK) pathway, is a key cytokine in this process. We aimed first to determine whether p38 MAPK is activated in IBD inflamed mucosa, and then studied the effect of four different p38α inhibitory compounds on MAPK phosphorylation and secretion of proinflammatory cytokines by IBD lamina propria mononuclear cells (LPMCs) and organ culture biopsies. In vivo phospho-p38α and p38α expression was evaluated by immunoblotting on intestinal biopsies from inflamed areas of patients affected by Crohn's disease and ulcerative colitis, and from normal mucosa of sex- and age-matched control subjects. Both mucosal biopsies and isolated LPMCs were incubated with four different p38α selective inhibitory drugs. TNF-α, interleukin (IL)-1β and IL-6 were measured in the organ and cell culture supernatants by enzyme-linked immunosorbent assay. We found higher levels of phospho-p38α in the inflamed mucosa of IBD patients in comparison to controls. All the p38α inhibitory drugs inhibited p38α phosphorylation and secretion of TNF-α, IL-1β and IL-6 from IBD LPMCs and biopsies. Activated p38α MAPK is up-regulated in the inflamed mucosa of patients with IBD. Additionally, all the p38α selective inhibitory drugs significantly down-regulated the activation of the MAPK pathway and the secretion of proinflammatory cytokines.