bluuebunny/crossref_metadata_2025 huggingface dataset:
Spindle pole body components are reorganized during fission yeast meiosis
Authors: Ohta Midori , Sato Masamitsu , Yamamoto Masayuki
Published: March 2012

During meiosis, the centrosome/spindle pole body (SPB) must be regulated in a manner distinct from that of mitosis to achieve a specialized cell division that will produce gametes. In this paper, we demonstrate that several SPB components are localized to SPBs in a meiosis-specific manner in the fission yeast Schizosaccharomyces pombe. SPB components, such as Cut12, Pcp1, and Spo15, which stay on the SPB during the mitotic cell cycle, disassociate from the SPB during meiotic prophase and then return to the SPB immediately before the onset of meiosis I. Interestingly, the polo kinase Plo1, which normally localizes to the SPB during mitosis, is excluded from them in meiotic prophase, when meiosis-specific, horse-tail nuclear movement occurs. We found that exclusion of Plo1 during this period was essential to properly remodel SPBs, because artificial targeting of Plo1 to SPBs resulted in an overduplication of SPBs. We also found that the centrin Cdc31 was required for meiotic SPB remodeling. Thus Plo1 and a centrin play central roles in the meiotic SPB remodeling, which is essential for generating the proper number of meiotic SPBs and, thereby provide unique characteristics to meiotic divisions.
MDWeb and MDMoby: an integrated web-based platform for molecular dynamics simulations
Authors: Hospital Adam , Andrio Pau , Fenollosa Carles , Cicin-Sain Damjan , Orozco Modesto , Gelpí Josep Lluís
Published: March 2012

Summary: MDWeb and MDMoby constitute a web-based platform to help access to molecular dynamics (MD) in the standard and high-throughput regime. The platform provides tools to prepare systems from PDB structures mimicking the procedures followed by human experts. It provides inputs and can send simulations for three of the most popular MD packages (Amber, NAMD and Gromacs). Tools for analysis of trajectories, either provided by the user or retrieved from our MoDEL database (http://mmb.pcb.ub.es/MoDEL) are also incorporated. The platform has two ways of access, a set of web-services based on the BioMoby framework (MDMoby), programmatically accessible and a web portal (MDWeb).

Availability:  http://mmb.irbbarcelona.org/MDWeb; additional information and methodology details can be found at the web site (http://mmb.irbbarcelona.org/MDWeb/help.php)

Contact:  gelpi@ub.edu; modesto.orozco@irbbarcelona.org

Supplementary information:  Supplementary data are available at Bioinformatics online.
Executive Summary: IDSA Clinical Practice Guideline for Acute Bacterial Rhinosinusitis in Children and Adults
Authors: Chow Anthony W. , Benninger Michael S. , Brook Itzhak , Brozek Jan L. , Goldstein Ellie J. C. , Hicks Lauri A. , Pankey George A. , Seleznick Mitchel , Volturo Gregory , Wald Ellen R. , File Thomas M.
Published: March 2012

Evidence-based guidelines for the diagnosis and initial management of suspected acute bacterial rhinosinusitis in adults and children were prepared by a multidisciplinary expert panel of the Infectious Diseases Society of America comprising clinicians and investigators representing internal medicine, pediatrics, emergency medicine, otolaryngology, public health, epidemiology, and adult and pediatric infectious disease specialties. Recommendations for diagnosis, laboratory investigation, and empiric antimicrobial and adjunctive therapy were developed.
Atrioventricular nodal ablation in atrial fibrillation: a meta‐analysis of biventricular vs. right ventricular pacing mode
Authors: Chatterjee Neal A. , Upadhyay Gaurav A. , Ellenbogen Kenneth A. , Hayes David L. , Singh Jagmeet P.
Published: March 2012

Aims

For patients with refractory atrial fibrillation (AF) undergoing atrioventricular nodal ablation (AVNA), initial single‐chamber right ventricular (RV)‐only pacing is standard. Given the deleterious effects of chronic RV‐only pacing, the impact of an initial biventricular (BiV) pacing strategy post‐ablation is of interest.

Methods and results

We conducted a meta‐analysis to determine the effect of BiV vs. RV‐only pacing in patients undergoing AVNA for refractory atrial fibrillation. A search of multiple electronic databases identified 921 reports, which included four randomized controlled trials (n = 534). Mean New York Heart Association (NYHA) class was 2.3 and mean left ventricular ejection fraction (LVEF) was 44%. When compared with RV‐only pacing, BiV pacing was not associated with reduced mortality [risk ratio 0.85, 95% confidence interval (CI) 0.40–1.82, P = 0.68]. In three studies comprised of patients with left ventricular systolic dysfunction (mean EF 41 ± 3%), BiV pacing demonstrated a non‐significant reduction in cardiac mortality (risk ratio 0.59, 95% CI 0.25–1.39; P = 0.23). Compared with RV‐only pacing, BiV pacing was associated with significant improvement in symptoms [Minnesota Living with Heart Failure Questionnaire (MLWHFQ) 2.72 points fewer, 95% CI 1.45–3.99] and increased LVEF (+2.6%, 95% CI 1.69–3.44), but no significant change in 6 min walk distance (6MWD) (5.02 ms more, 95% CI −1.56 to 11.59; P = 0.13).

Conclusions

In patients with refractory AF undergoing AVNA, BiV pacing was not associated with significantly improved survival when compared with RV‐only pacing. A modest, but significant improvement in structural and functional response to BiV pacing was observed.
Krill space: a comparative assessment of mesoscale structuring in polar and temperate marine ecosystems
Authors: Santora Jarrod A. , Sydeman William J. , Schroeder Isaac D. , Reiss Christian S. , Wells Brian K. , Field John C. , Cossio Anthony M. , Loeb Valerie J.
Published: March 2012

Santora, J. A., Sydeman, W. J., Schroeder, I. D., Reiss, C. S., Wells, B. K., Field, J. C, Cossio, A. M., and Loeb, V. J. 2012. Krill space: a comparative assessment of mesoscale structuring in polar and temperate marine ecosystems. – ICES Journal of Marine Science, 69: . The spatial organization, mesoscale variability, and habitat associations of krill within portions of the Antarctic Peninsula and California Current marine ecosystems are compared. Using a decade of acoustic observations and remotely sensed oceanography (2000–2009), the hypothesis that mesoscale spatial organization of krill in both systems closely relates to geospatial variability of the shelf break and is non-linearly related to geostrophic flow and positively related to chlorophyll a (Chl a) is tested. Directional-dependence analysis to measure spatial variability of krill is used along with spatially explicit generalized additive models to quantify and compare the spatial relationships among krill and habitat characteristics in both systems. The results suggest the following aspects of krill spatial organization: (i) areas of dense aggregation, i.e. hot spots, are present in both systems and are orientated in the direction of the shelf break, (ii) moderate levels of eddy kinetic energy seem to concentrate krill in favourable habitats and lessen the likelihood of advection away from the system, and (iii) variable responses to surface Chl a concentration suggest that real-time Chl a values may not be useful as a global predictor of important krill habitat. The results provide valuable reference points for marine spatial management of krill and for refining ecosystem and foodweb models.
Cardiac-specific knockout of ETA receptor mitigates low ambient temperature-induced cardiac hypertrophy and contractile dysfunction
Authors: Zhang Yingmei , Li Linlin , Hua Yinan , Nunn Jennifer M. , Dong Feng , Yanagisawa Masashi , Ren Jun
Published: March 2012

Cold exposure is associated with oxidative stress and cardiac dysfunction. The endothelin (ET) system, which plays a key role in myocardial homeostasis, may participate in cold exposure-induced cardiovascular dysfunction. This study was designed to examine the role of ET-1 in cold stress-induced cardiac geometric and contractile responses. Wild-type (WT) and ETA receptor knockout (ETAKO) mice were assigned to normal or cold exposure (4°C) environment for 2 and 5 weeks prior to evaluation of cardiac geometry, contractile, and intracellular Ca2+ properties. Levels of the temperature sensor transient receptor potential vanilloid (TRPV1), mitochondrial proteins for biogenesis and oxidative phosphorylation, including UCP2, HSP90, and PGC1α were evaluated. Cold stress triggered cardiac hypertrophy, depressed myocardial contractile capacity, including fractional shortening, peak shortening, and maximal velocity of shortening/relengthening, reduced intracellular Ca2+ release, prolonged intracellular Ca2+ decay and relengthening duration, generation of ROS and superoxide, as well as apoptosis, the effects of which were blunted by ETAKO. Western blotting revealed downregulated TRPV1 and PGC1α as well as upregulated UCP2 and activation of GSK3β, GATA4, and CREB in cold-stressed WT mouse hearts, which were obliterated by ETAKO. Levels of HSP90, an essential regulator for thermotolerance, were unchanged. The TRPV1 agonist SA13353 attenuated whereas TRPV1 antagonist capsazepine mimicked cold stress- or ET-1-induced cardiac anomalies. The GSK3β inhibitor SB216763 ablated cold stress-induced cardiac contractile (but not remodeling) changes and ET-1-induced TRPV1 downregulation. These data suggest that ETAKO protects against cold exposure-induced cardiac remodeling and dysfunction mediated through TRPV1 and mitochondrial function.
Molecular Mapping of the Major Resistance Quantitative Trait Locus qHS2.09 with Simple Sequence Repeat and Single Nucleotide Polymorphism Markers in Maize
Authors: Weng Jianfeng , Liu Xianjun , Wang Zhenhua , Wang Jianjun , Zhang Lin , Hao Zhuanfang , Xie Chuanxiao , Li Mingshun , Zhang Degui , Bai Li , Liu Changlin , Zhang Shihuang , Li Xinhai
Published: March 2012

The major quantitative trait locus (QTL) qHS2.09 plays an important role in resistance to head smut during maize breeding and production. In this study, a near-isogenic line (NIL), L34, which harbors the major QTL qHS2.09 in bin 2.09, was developed using a resistant donor ‘Mo17’ in a susceptible genetic background ‘Huangzao4’. Using 18,683 genome-wide polymorphic loci, this major QTL was finely mapped into an interval of ≈1.10 Mb, flanked by single nucleotide polymorphism (SNP) markers PZE-102187307 and PZE-102188421. Moreover, the favorable allele from ‘Mo17’ for SNP PZE-102187611 in this interval that was most significantly associated with resistance to head smut (P = 1.88 E-10) and accounted for 39.7 to 44.4% of the phenotypic variance in an association panel consisting of 80 inbred lines. With combined linkage and association mapping, this major QTL was finally located between SNP PZE-102187486 and PZE-102188421 with an interval of ≈1.00 Mb. Based on the pedigrees of ‘Mo17’ and its derivatives widely used in temperate maize breeding programs, the favorable haplotype from ‘Mo17’ is shown to be the main source of resistance to head smut in these lines. Therefore, the SNPs closely linked to the major QTL qHS2.09, detected in both linkage and association mapping, and could be useful for marker-assisted selection in maize breeding programs.
Active Emergence from Propofol General Anesthesia Is Induced by Methylphenidate
Authors: Chemali Jessica J. , Van Dort Christa J. , Brown Emery N. , Solt Ken
Published: March 2012

Background

A recent study showed that methylphenidate induces emergence from isoflurane general anesthesia. Isoflurane and propofol are general anesthetics that may have distinct molecular mechanisms of action. The objective of this study was to test the hypothesis that methylphenidate actively induces emergence from propofol general anesthesia.

Methods

Using adult rats, the effect of methylphenidate on time to emergence after a single bolus of propofol was determined. The ability of methylphenidate to restore righting during a continuous target-controlled infusion (TCI) of propofol was also tested. In a separate group of rats, a TCI of propofol was established and spectral analysis was performed on electroencephalogram recordings taken before and after methylphenidate administration.

Results

Methylphenidate decreased median time to emergence after a single dose of propofol from 735 s (95% CI: 598-897 s, n = 6) to 448 s (95% CI: 371-495 s, n = 6). The difference was statistically significant (P = 0.0051). During continuous propofol anesthesia with a median final target plasma concentration of 4.0 μg/ml (95% CI: 3.2-4.6, n = 6), none of the rats exhibited purposeful movements after injection of normal saline. After methylphenidate, however, all six rats promptly exhibited arousal and had restoration of righting with a median time of 82 s (95% CI: 30-166 s). Spectral analysis of electroencephalogram data demonstrated a shift in peak power from δ (less than 4 Hz) to θ (4-8 Hz) and β (12-30 Hz) after administration of methylphenidate, indicating arousal in 4/4 rats.

Conclusions

Methylphenidate decreases time to emergence after a single dose of propofol, and induces emergence during continuous propofol anesthesia in rats. Further study is warranted to test the hypothesis that methylphenidate induces emergence from propofol general anesthesia in humans.
Hexanucleotide motifs mediate recruitment of the RNA elimination machinery to silent meiotic genes
Authors: Yamashita Akira , Shichino Yuichi , Tanaka Hirotsugu , Hiriart Edwige , Touat-Todeschini Leila , Vavasseur Aurélia , Ding Da-Qiao , Hiraoka Yasushi , Verdel André , Yamamoto Masayuki
Published: March 2012

The selective elimination system blocks the accumulation of meiosis-specific mRNAs during the mitotic cell cycle in fission yeast. These mRNAs harbour a region, the determinant of selective removal (DSR), which is recognized by a YTH-family RNA-binding protein, Mmi1. Mmi1 directs target transcripts to destruction in association with nuclear exosomes. Hence, the interaction between DSR and Mmi1 is crucial to discriminate mitosis from meiosis. Here, we show that Mmi1 interacts with repeats of the hexanucleotide U(U/C)AAAC that are enriched in the DSR. Disruption of this ‘DSR core motif’ in a target mRNA inhibits its elimination. Tandem repeats of the motif can function as an artificial DSR. Mmi1 binds to it
in vitro
. Thus, a core motif cluster is responsible for the DSR activity. Furthermore, certain variant hexanucleotide motifs can augment the function of the DSR core motif. Notably, meiRNA, which composes the nuclear Mei2 dot required to suppress Mmi1 activity during meiosis, carries numerous copies of the core/augmenting motifs on its tail and is indeed degraded by the Mmi1/exosome system, indicating its likely role as decoy bait for Mmi1.
Type-specific interaction between human papillomavirus type 58 E2 protein and E7 protein inhibits E7-mediated oncogenicity
Authors: Wang Xin , Qi Mei , Yu Xiuping , Yuan Yan , Zhao Weiming
Published: March 2012

Human papillomavirus type 58 (HPV-58) is a very common HPV type in eastern Asia. Little is known about its biology and tumorigenesis. In this study, HPV-58 E2 protein (58E2) was found to interact with E7 protein (58E7), and the hinge domain of 58E2 was shown to be responsible for binding to the 58E7 protein. Interestingly, the E2–E7 interaction appears to be HPV type-specific, as we found that the HPV-16 E2 could not bind to the 58E7 protein, and neither did 58E2 interact with HPV-16 E7. The biological consequence(s) of the E2–E7 interaction in HPV-58, especially in viral tumorigenesis, was investigated. Results showed that, through interacting with 58E7, 58E2 prevented E7-induced retinoblastoma protein (pRb) degradation and prolonged the half-life of pRb in cells. Additionally, 58E2 abrogated 58E7-induced cell proliferation. These observations collectively suggest that direct interaction with 58E7 is another mechanism for 58E2 to inhibit 58E7-associated carcinogenesis in addition to regulating expression of the 58E7 gene.
Phosphoproteomic Analysis of Seed Maturation in Arabidopsis, Rapeseed, and Soybean
Authors: Meyer Louis J. , Gao Jianjiong , Xu Dong , Thelen Jay J.
Published: March 2012

To characterize protein phosphorylation in developing seed, a large-scale, mass spectrometry-based phosphoproteomic study was performed on whole seeds at five sequential stages of development in soybean (Glycine max), rapeseed (Brassica napus), and Arabidopsis (Arabidopsis thaliana). Phosphopeptides were enriched from 0.5 mg of total peptides using a combined strategy of immobilized metal affinity and metal oxide affinity chromatography. Enriched phosphopeptides were analyzed by Orbitrap tandem mass spectrometry and mass spectra mined against cognate genome or cDNA databases in both forward and randomized orientations, the latter to calculate false discovery rate. We identified a total of 2,001 phosphopeptides containing 1,026 unambiguous phosphorylation sites from 956 proteins, with an average false discovery rate of 0.78% for the entire study. The entire data set was uploaded into the Plant Protein Phosphorylation Database (www.p3db.org), including all meta-data and annotated spectra. The Plant Protein Phosphorylation Database is a portal for all plant phosphorylation data and allows for homology-based querying of experimentally determined phosphosites. Comparisons with other large-scale phosphoproteomic studies determined that 652 of the phosphoproteins are novel to this study. The unique proteins fall into several Gene Ontology categories, some of which are overrepresented in our study as well as other large-scale phosphoproteomic studies, including metabolic process and RNA binding; other categories are only overrepresented in our study, like embryonic development. This investigation shows the importance of analyzing multiple plants and plant organs to comprehensively map the complete plant phosphoproteome.
Quantitative Phosphoproteome Profiling of Iron-Deficient Arabidopsis Roots
Authors: Lan Ping , Li Wenfeng , Wen Tuan-Nan , Schmidt Wolfgang
Published: March 2012

Iron (Fe) is an essential mineral nutrient for plants, but often it is not available in sufficient quantities to sustain optimal growth. To gain insights into adaptive processes to low Fe availability at the posttranslational level, we conducted a quantitative analysis of Fe deficiency-induced changes in the phosphoproteome profile of Arabidopsis (Arabidopsis thaliana) roots. Isobaric tags for relative and absolute quantitation-labeled phosphopeptides were analyzed by liquid chromatography-tandem mass spectrometry on an LTQ-Orbitrap with collision-induced dissociation and high-energy collision dissociation capabilities. Using a combination of titanium dioxide and immobilized metal affinity chromatography to enrich phosphopeptides, we extracted 849 uniquely identified phosphopeptides corresponding to 425 proteins and identified several not previously described phosphorylation motifs. A subset of 45 phosphoproteins was defined as being significantly changed in abundance upon Fe deficiency. Kinase motifs in Fe-responsive proteins matched to protein kinase A/calcium calmodulin-dependent kinase II, casein kinase II, and proline-directed kinase, indicating a possible critical function of these kinase classes in Fe homeostasis. To validate our analysis, we conducted site-directed mutagenesis on IAA-CONJUGATE-RESISTANT4 (IAR4), a protein putatively functioning in auxin homeostasis. iar4 mutants showed compromised root hair formation and developed shorter primary roots. Changing serine-296 in IAR4 to alanine resulted in a phenotype intermediate between mutant and wild type, whereas acidic substitution to aspartate to mimic phosphorylation was either lethal or caused an extreme dwarf phenotype, supporting the critical importance of this residue in Fe homeostasis. Our analyses further disclose substantial changes in the abundance of phosphoproteins involved in primary carbohydrate metabolism upon Fe deficiency, complementing the picture derived from previous proteomic and transcriptomic profiling studies.
(4Z)-4-Benzylidene-2-phenyl-1,3-oxazol-5(4H)-one
Authors: Asiri Abdullah M. , Faidallah Hassan M. , Sobahi Tariq R. , Ng Seik Weng , Tiekink Edward R. T.
Published: March 2012

In the title compound, C17H13NO2, the benzene ring is twisted slightly out of the plane of the oxazole ring to which it is attached [dihedral angle = 7.98 (8)°]. Similarly, there is a twist [dihedral angle = 5.50 (8)°] between the oxazole and phenyl rings that are linkedviathe C=C bond [1.348 (2) Å]; the conformation about the latter isZ. In the crystal, the presence of C—H...O, C—H...π and π–π interactions [centroid–centroid distance = 3.5259 (9) Å] link the molecules into a three-dimensional architecture.
Life history characteristics of a lightly exploited stock of Squalus suckleyi
Authors: Tribuzio C. A. , Kruse G. H.
Published: March 2012

The purpose of this study was to examine the basic life history of a lightly exploited stock of Squalus suckleyi in the Gulf of Alaska to establish a baseline for future comparison and to provide critical information for stock assessments. Average total length (total length extended) of females (87·7 cm) was significantly larger (t‐test, t = −12·57, d.f. = 1533, P < 0·01) than males (80·3 cm); size at 50% maturity (74·5 and 97·3 cm, males and females, respectively) and age at 50% maturity (21 and 36 years, respectively) were also significantly different between the sexes (i.e. bootstrapped 95% c.i. did not overlap). Total average fecundity was 8·5 pups per female, and individual fecundity was a linear function of either length or whole mass. The best estimate of instantaneous natural mortality was 0·097. The delayed age of maturity, low natural mortality and low rates of reproduction imply that only very low rates of fishing mortality are sustainable. Finally, this paper provides the first reported evidence that a small percentage of the adult females may undergo an extended resting period between pregnancies of ≥1 years.
The NADPH oxidase‐mediated production of hydrogen peroxide (H2O2) and resistance to oxidative stress in the necrotrophic pathogen Alternaria alternata of citrus
Authors: YANG SIWY LING , CHUNG KUANG‐REN
Published: March 2012

It has become increasingly apparent that the production of reactive oxygen species (ROS) by the NADPH oxidase (Nox) complex is vital for cellular differentiation and signalling in fungi. We cloned and characterized an AaNoxA gene of the necrotrophic fungus Alternaria alternata, which encodes a polypeptide analogous to mammalian gp91phox and fungal Noxs implicated in the generation of ROS. Genetic analysis confirmed that AaNoxA is responsible for the production of ROS. Moreover, deletion of AaNoxA in A. alternata resulted in an elevated hypersensitivity to hydrogen peroxide (H2O2), menadione, potassium superoxide (KO2), diamide and many ROS‐generating compounds. The results implicate the involvement of AaNoxA in cellular resistance to ROS stress. The impaired phenotypes strongly resemble those previously seen for the ap1 null mutant defective in a YAP1‐like transcriptional regulator and for the hog1 mutant defective in a HOG1‐like mitogen‐activated protein (MAP) kinase. The noxA null mutant was also hypersensitive to Nox inhibitors, nitric oxide (NO·) donors and NO· synthase inhibitors, implying a role of AaNoxA in the NO· signalling pathway. Expression of AaNoxA was activated by H2O2, menadione, KO2, NO· donors and l‐arginine (a substrate for NO· synthase). AaNoxA may be able to sense and respond to both ROS and nitric oxide. Moreover, AaNoxA is required for normal conidiation and full fungal virulence. AaNoxA promoted the expression of the AaAP1 and AaHOG1 genes in A. alternata. Inactivation of AaNoxA greatly reduced the transcriptional activation of AaAP1 in response to ROS stress. Thus, we conclude that the regulatory functions of AaNoxA conferring ROS resistance are modulated partially through the activation of the YAP1‐ and HOG1 MAP kinase‐mediated signalling pathways.
Prenatal exposure to acid‐suppressive drugs and the risk of childhood asthma: a population‐based Danish cohort study
Authors: Andersen A. B. T. , Erichsen R. , Farkas D. K. , Mehnert F. , Ehrenstein V. , Sørensen H. T.
Published: March 2012

Background

Proton pump inhibitors (PPIs) may activate the immune system and cause asthma.

Aim

To investigate the association of prenatal exposure to PPIs and histamine 2‐receptor antagonists (H2RAs) with risk of asthma.

Methods

In this cohort study, 197 060 singletons born between 1996 and 2008 in northern Denmark were followed until the end of 2009. Data were obtained through Danish medical registries. Asthma in offspring was defined as at least two prescriptions of both a β‐agonist and an inhaled glucocorticoid and/or a hospital diagnosis of asthma during the follow‐up. Cox proportional‐hazard regression was used to compute incidence rate ratios, adjusting for covariates.

Results

A total of 2238 (1.1%) children were prenatally exposed to PPIs and 24 506 (12.4%) children developed asthma during follow‐up (median follow‐up = 6.8 years). The adjusted IRR (aIRR) of asthma associated with prenatal exposure to PPIs was 1.41 (95% confidence interval (CI): 1.27–1.56), compared with those unexposed. The association did not vary by trimester of exposure, and prenatal exposure to H2RAs was associated with similar increase in risk. The aIRR for maternal PPI and H2RA use in the year after, but not during pregnancy was 1.32 (95% CI: 1.20–1.46) and 1.13 (0.93–1.36), respectively, compared with non‐use during and in the year after pregnancy.

Conclusions

Prenatal exposure to both PPIs and H2RAs was associated with an increased risk of asthma in our study. Because the observed association is not drug specific and also observed for maternal postnatal use it may be explained by a ‘class effect’ or maternal underlying condition.
Chronic Granulocytic Leukaemia with Ph1 Negative Cells in Bone Marrow and a Ten Year Remission after Busulphan Hypoplasia
Authors: Finney R. , McDonald G. A. , Baikie A. G. , Douglas A. S.
Published: March 2012

Summary. Following busulphan‐induced bone marrow insufficiency a patient with chronic granulocytic leukaemia has had a remission lasting 10 yr. During this time repeated chromosome studies on bone marrow have shown the persistence of a majority of Ph1 negative cells. The relationship of this finding to the unusually long remission is discussed.
Uptake of 57Co Vitamin B12 by Human Haemopoietic Cells in Vitro
Authors: Wickramasinghe S. N. , Carmel R.
Published: March 2012

Summary. Uptake of 57Co‐B12 by haemopoietic cells was studied in short‐term cultures of human bone marrow, using autoradiography and scintillation counting. Autoradiographs from vitamin B12 deficient marrow cultures showed that neutrophil myelocytes, metamyelocytes and mature leucocytes took up the vitamin. No labelling was detected in the eosinophil leucocyte series, in megakaryocytes or in polychromatic megaloblasts. In the erythropoietic series, uptake was seen in some basophilic megaloblasts but only in the most severely megaloblastic marrow, providing direct confirmation that immature erythroblasts take up vitamin B12 to a much greater extent than the more mature erythroblasts. Cells from normoblastic marrow showed no labelling except for one instance in which supraphysiological amounts of 57Co‐B12 were used, when uptake by myelopoietic cells occurred. Scintillation counting of marrow suspensions confirmed the greater uptake by vitamin B12 deficient than by normoblastic cells. Uptake by vitamin B12 deficient cells required serum, but there was no difference between vitamin B12 deficient serum and normal serum.
A Study of the Inheritance and Properties of an Electrophoretic Variant of NADH‐Methaemoglobin Reductase Associated with Congenital Methaemoglobinaemia
Authors: West C. A.
Published: March 2012

Summary. Further investigation on the patient previously reported and on his family are described. It is shown that in this patient the disease is the result of a doubly heterozygous state in which both an electrophoretically slow enzyme variant (ma) and small amounts of electrophoretically normal NADH‐methaemoglobin reductase are present. Electrophoretic and kinetic studies showed that the abnormal enzyme variant ma possessed a significantly reduced capacity for binding NADH compared with the normal enzyme, which was found to consist of two distinct components when studied in an electrophoretic system incorporating NADH. The variant ma appeared to consist of only the minor of these components.

The mother of the patient, and 13 other family members were identified as heterozygotes after electrophoretic analysis of haemoglobin free red cell extracts. The assay of red cell NADH‐methaemoglobin reductase in all the electrophoretically confirmed heterozygotes demonstrated the considerable overlap of their enzyme levels with the normal range, and therefore the inadvisability of utilizing NADH‐methaemoglobin reductase level alone as the criterion of the heterozygous state.
Haemoglobin Biosynthesis during in Vitro Maturation of the Rat Reticulocyte
Authors: Heywood J. D. , Ganzoni A. , Hillman R. S.
Published: March 2012

Summary. The relationship of changes in cellular iron uptake, haem and globin synthesis in the maturing reticulocyte was studied during in vivo maturation of rat reticulocytes produced after phlebotomy. Cellular iron uptake and haem synthesis declined at a more rapid rate than did globin synthesis. During maturation there was a uniform loss of all ribosomal classes and [14C]leucine incorporation studies indicated a decreased time for polypeptide chain synthesis per polysome. These observations support the postulate that globin synthesis is controlled by the availability of haem, the latter in turn being dependent on the availability of iron. The following sequence of events in the maturing reticulocyte is suggested: first, there is a loss of the capacity of the reticulocyte to take up iron leading to cessation of haem synthesis. Depletion of available haem then results in either an accumulation of globin, which by a feedback mechanism suppresses further globin synthesis, or an activation of reticulocyte ribonuclease which breaks down the polyribosome‐mRNA complex, making further protein synthesis impossible.
Phosphotyrosine phosphatase activity and haematologic changes in Down's syndrome patients
Authors: Vergnes H. , Brisson‐Lougarre A. , Limouzy P. , Dray C. , Grozdea J.
Published: March 2012

Summary. Assays of neutrophil phosphotyrosine phosphatase activity and determination of haematological parameters were performed on 12 trisomic 21 probands without any clinical or biological symptom of other evolutive disease. Haematological studies showed the two main classical abnormalities: the existence of a macrocytosis and an enhanced lymphocyte count. Of interest are the very reduced rates of phosphotyrosine phosphatase activity found in granulocytes from these patients. This defect in protein phosphatase can be considered as an additional enzymatic change extending the list of modified factors recognized at molecular and cellular levels in subjects whose risk of leukaemia is significantly increased.
Recurrent granulocytic aplasia as clinical presentation of a persistent parvovirus B19 infection
Authors: Pont Jörg , Puchhammer‐Stöckl Elisabeth , Chott Andreas , Popow‐Kraupp Therese , Kienzer Heinz , Postner Gerhard , Honetz Norbert
Published: March 2012

Summary. We report a case of persistent infection with human parvovirus B19 (PVB19), manifesting clinically as recurrent agranulocytosis and in bone marrow biopsy as recurrent pure granulocytic aplasia. Persistence of parvovirus infection was documented by the presence of PVB19 DNA and anti‐PVB19‐IgM antibodies in the serum for a period of 19 months. Granulocytic aplasia occurred only when anti‐PVB19‐IgG antibodies were not detectable in the serum and granulopoiesis showed immediate recovery with high dose intravenous immunoglobulin treatment. This case report suggests that the erythroid precursor cell may not be the only target cell of PVB19 infection. We suggest testing for active parvovirus infection in cases of aplasia of any lineage of the haematopoietic system.
Mutations of the P53 gene in acute myeloid leukaemia
Authors: Fenaux Pierre , Preudhomme Claude , Quiquandon Isabelle , Jonveaux Philippe , Laï Jean Luc , Vanrumbeke Mickael , Loucheux‐Lefebvre Marie Henriette , Bauters Francis , Berger Roland , Kerckaert Jean Pierre
Published: March 2012

Summary. In a previous report we found point mutations in exons 5–8 of the P53 gene in five of 46 patients with acute myeloid leukaemia (AML), with a predominance of mutations in the 10 patients with 17p monosomy. In this report we extended our findings studying such mutations in 66 unselected additional cases of AML, using polymerase chain reaction single strand conformation polymorphism (SSCP) analysis and nucleotide sequencing. Three of the 66 new cases had a point mutation, leading to a change in one encoded amino acid. Thus, eight of the 112 AML studied had P53 mutations in exons 5–8, suggesting that the incidence of P53 mutation is relatively low in AML. A predominance of mutations in exon 8 (5/8) was found. Six of the eight patients with mutations were older than 60 years of age, and all eight cases had a short survival. All seven mutated cases karyotyped showed complex cytogenetic findings, especially monosomy 5 and/or 7, thus questioning the pathogenic importance of P53 mutations in a context of multiple genetic abnormalities. However, five of them also had 17p monosomy, and in the remaining two cases SSCP and sequence analysis also suggested loss of the normal P53 allele. This supported a role for the P53 gene mutations in leukaemogenesis in the relatively small number of AML patients in whom they were found, through loss of tumour suppressive activity of both normal P53 alleles, as reported in solid tumours.
Increase in 2′,5′‐oligoadenylate synthetase caused by deoxycoformycin in hairy cell leukaemia
Authors: Ganeshaguru K. , De Mel W. C. P. , Sissolak G. , Catovsky D. , Dearden C. E. , Mehta A. B. , Hoffbrand A. V.
Published: March 2012

Summary. 2′,5′‐oligoadenylate synthetase (2–50AS) has been studied in peripheral blood mononuclear cells from nine patients with hairy cell leukaemia (HCL) receiving therapy with the adenosine deaminase inhibitor deoxycoformycin (dCF) or alpha interferon (α‐IFN). 2–50AS mRNA was assayed by dot‐blot hybridization. Increase of 2–50AS mRNA level was seen in six patients with HCL treated with dCF and in one patient treated with α‐IFN who responded to therapy. A patient with a variant form of HCL treated with dCF and the second patient treated with α‐IFN did not show an increase of 2–50AS mRNA and neither responded to therapy. The 15 other patients with T or B‐chronic lymphoblastic leukaemia (CLL), T‐acute lymphoblastic leukaemia (ALL), adult T‐cell leukaemia lymphoma (ATLL), non‐Hodgkins lymphoma (NHL), Sezary and T or B‐prolymphocytic leukaemia (PLL) treated with dCF did not show an increase in 2–50AS, though four patients, all with T‐cell tumours, responded clinically. 2–50AS activity is known to be stimulated by α‐IFN and recent work suggests that this rise in 2–50AS may result in increased cleavage of mRNA for tumour necrosis factor (TNF) and other cytokines on which autocrine growth and proliferation of the tumour cells are dependent. By analogy, we suggest that one mechanism of action of dCF in hairy cell leukaemia may be to break down an autocrine growth loop for TNF or other cytokines. An alternative explanation for these observations is that cytokines released from hairy cells in the bone marrow killed by dCF induce a rise in 2–50AS in circulating leucocytes.
Promoter mutations producing mild β‐thalassaemia in the Italian population
Authors: Meloni Alessandra , Rosatelli M. Cristina , Faà Valeria , Sardu Raffaela , Saba Luisella , Murru Stefania , Sciarratta Giuseppina V. , Baldi Maurizia , Tannoia Nunzia , Vitucci Antonio , Cao Antonio
Published: March 2012

Summary. In this study we have investigated the molecular basis for a mild form of β‐thalassaemia in three patients of Italian descent. In two, belonging to different families and affected by a mild and late‐presenting form of thalassaemia major, direct sequencing of amplified DNA detected a C→T substitution at position −87 of the β‐globin gene in the compound heterozygous state either with codon 39 nonsense mutation or β+IVSI, nt 110 mutation. The −87 (C→T) mutation has been previously described, in combination with the β+IVSI, nt 110 mutation, in a single patient with thalassaemia intermedia. Both our patients showed a more severe phenotype as compared to that resulting from compound heterozygosity for a severe β‐thalassaemia mutation and another promoter mutation (−87, C→G) at the same position. In the third patient with the thalassaemia intermedia phenotype, we detected a novel promoter mutation, consisting in a C→A substitution at position −86, in combination with the codon 39 nonsense mutation. The results of this study indicate that different nucleotide substitutions affecting the proximal CACCC box of the β‐globin gene in combination with severe β‐thalassaemia, produce a mild form of thalassaemia ranging in severity from thalassaemia intermedia to late‐presenting thalassaemia major.
Elliptocytosis‐associated spectrin Rouen (β220/218) has a truncated but still phosphorylatable β chain
Authors: Lecomte M. C. , Gautero H. , Bournier O. , Galand C. , Lahary A. , Vannier J. P. , Garbarz M. , Delaunay J. , Tchernia G. , Boivin P. , Dhermy D.
Published: March 2012

Summary. Spectrin Rouen (β220/218) is a novel variant, carrying a shortened β chain with an apparent molecular weight of 218 kDa. It was detected in a French family. All affected members suffered from haemolytic hereditary elliptocytosis. As other shortened β chain variants described before, the βRouen chain is truncated at its carboxyl terminus. Spectrin Rouen is associated with a defect in spectrin dimer self‐association and with an abnormally high amount of the αI 74 kDa peptide following partial tryptic digestion. Dimer reconstitution experiments from normal and abnormal purified Sp subunits indicated that the increased αI 74 kDa fragment is induced by the altered β chain. However, spectrin Rouen is different from other mutants with a truncated β chain in several respects: its amount is low (< 10%) and the spectrin dimer self‐associated defect is mild. Critically, the βRouen chain has retained the ability of undergoing phosphorylation, even though it is modified in its C‐terminal region. These results, compared to those obtained with β220/214 spectrin Le Puy and β220/216 spectrin Nice, allowed better localization of the β chain sites that can be phosphorylated by a membrane‐bound casein kinase.
Immunological pathways in virus‐induced COPD exacerbations: a role for IL‐15
Authors: Zdrenghea Mihnea T. , Mallia Patrick , Johnston Sebastian L.
Published: March 2012

Eur J Clin Invest 2012; 42 (9): 1010–1015

Background  Chronic obstructive pulmonary disease (COPD) is characterized by high levels of antiviral type 1 cytokine interferon‐γ and activated CD8+ T cells. COPD exacerbations are the major cause of morbidity and mortality, have a prolonged and intense effect on quality of life and may result in accelerated loss of lung function. Respiratory virus infections, frequently within a state of colonization by bacteria, are the major cause of COPD exacerbations, and there is also evidence of virus latency in ‘stable’ disease, suggesting that latent infection might be a cause of chronic inflammation in COPD.

Design  This is an update of current literature concerning the role of interleukin‐15 and major histocompatibility complex class I‐related chain A and B molecules in type 1 immune responses, particularly to respiratory virus infections, which are the main cause of COPD exacerbations. We also present data from our own group suggesting a role for interleukin‐15 in virus‐induced COPD exacerbations.

Results  Type 1 cytokine interleukin‐15 is produced by resident airway cells (epithelial cells and macrophages) in response to virus infection and bacteria. Virus infections modulate major histocompatibility complex class I‐related chain A and B molecules in respiratory epithelial cells.

Conclusions  Interleukin‐15 could play a major role in the airway inflammation in COPD directly, via its own receptors, by amplifying the type 1 immune responses and decreasing apoptosis or indirectly, via modulating molecules associated with cytotoxic activity of natural killer and CD8+ T cells, such as major histocompatibility complex class I‐related chain A and B.
Localization and characterization of cracks in clay‐rocks using frequency and time‐domain induced polarization
Authors: Okay G. , Cosenza P. , Ghorbani A. , Camerlynck C. , Cabrera J. , Florsch N. , Revil A.
Published: March 2012

Induced polarization (IP) is a geophysical method that is potentially sensitive to the presence of cracks in porous rocks and therefore to damage. We performed time‐domain and frequency domain IP measurements at the Tournemire Underground Research Laboratory (URL, Aveyron, France) in areas where different types of cracks are observed. These cracks correspond to both tectonic fractures and new cracks associated with stress release and desiccation resulting from the excavation of a gallery. These measurements were performed both in eastern and northern galleries of the test site. The eastern gallery was excavated in 1996 while the northern gallery was excavated recently in 2008. This gives us the opportunity to study the electrical characteristics of the excavation damaged zone surrounding the galleries with respect to the age of the excavation. Longitudinal profiles were performed along the floor of the galleries with 48 Cu/CuSO4 electrodes separated by a distance of 20 cm. Chargeability and resistivity were inverted using a Gauss‐Newton iterative approach assuming an isotropic heterogeneous clay‐rock material. The resulting IP tomograms show a correlation between high values of chargeability and the presence of calcite‐filled tectonic fractures. X‐ray analysis indicates that the presence of pyrite in these fractures is a potential source of the observed IP signals. The cracks associated with the mechanical damage of the formation exhibit low values of chargeability, on the same order of magnitude than the chargeability of the clay‐rock matrix and are therefore hardly observable. A smaller IP response associated with the presence of these cracks is observed in the older gallery and this observation is qualitatively related to the desaturation process associated with these cracks. In a specific area of one of the galleries, the presence of calcareous nodules is observed to be an important source of anomalous chargeability. This signature seems to be associated with the presence of pyrite.
Aberrant cytokeratin 7 expression of centrilobular hepatocytes: a clinicopathological study
Authors: Matsukuma Susumu , Takeo Hiroaki , Kono Takako , Nagata Yuiko , Sato Kimiya
Published: March 2012

Matsukuma S, Takeo H, Kono T, Nagata Y & Sato K  (2012) Histopathology 61, 857–862

Aberrant cytokeratin 7 expression of centrilobular hepatocytes: a clinicopathological study

Aims:  This study has attempted to elucidate the clinicopathological features of aberrant cytokeratin 7 (CK7) expression by centrilobular hepatocytes.

Methods and results:  A total of 113 liver biopsy specimens from patients with common non‐neoplastic liver diseases, including hepatitis B or C, non‐alcoholic steatohepatitis, alcoholic liver disease and other diseases were examined. In 56 specimens (49.6%), CK7‐positive centrilobular hepatocytes (CK7 + CHs) were identified and sometimes showed binuclear features. CK7 + CHs were associated with patients’ older age (P = 0.004), higher serum levels of aspartate aminotransferase (P = 0.016) and γ‐glutamyltransferase (P = 0.006), centrilobular fibrosis (P < 0.001), prominent thickening of hepatocytic plates (P < 0.001) and higher scores of total and periportal CK7‐positive hepatocytes (both P < 0.001), but were not correlated with gender, steatosis, serum levels of total bilirubin or alanine aminotransferase. In 55 cases of hepatitis B and hepatitis C only, CK7 + CHs were related to a higher stage of fibrosis (P = 0.006).

Conclusion:  CK7 + CHs occur relatively frequently in non‐neoplastic liver disease, associated with centrilobular scarring and the presence of CK7‐positive periportal hepatocytes, and appear to be a non‐specific phenomenon with respect aetiology of underlying disease. CK7 + CHs may represent age‐dependent activation of hepatic progenitor cells or a regenerative phenomenon of hepatocytes themselves, both of which might contribute to liver regeneration.
Long‐term use of HU210 adversely affects spermatogenesis in rats by modulating the endocannabinoid system
Authors: M Lewis S. E. , Paro R. , Borriello L. , Simon L. , Robinson L. , Dincer Z , Riedel G. , Battista N. , Maccarrone M.
Published: March 2012

Recent societal acceptance of cannabinoids as recreational and therapeutic drugs has posed a potential hazard to male reproductive health. Mammals have a highly sophisticated endogenous cannabinoid (ECS) system that regulates male (and female) reproduction and exo‐cannabinoids may influence it adversely. Therefore it is imperative to determine their effects on male reproduction so that men can make informed choices as to their use. Here, an animal model was used to administer HU210, a synthetic analogue of Δ9‐tetrahydrocannabinol (THC) and potent cannabinoid receptor (CB) agonist to determine its effects on reproductive organ weights, spermatogenesis, testicular histology and sperm motility. Its effects on the physiological endocannabinoid system were also investigated. Spermatogenesis was markedly impaired with reductions in total sperm count after 2 weeks of exposure. Spermatogenic efficiency was depleted, and Sertoli cell number decreased as exposure time increased with seminiferous tubules showing germ cell depletion developing into atrophy in some cases. Sperm motility was also adversely affected with marked reductions from 2 weeks on. HU210 also acted on the sperm’s endocannabinoid system. Long‐term use of exo‐cannabinoids has adverse effects on both spermatogenesis and sperm function. These findings highlight the urgent need for studies evaluating the fertility potential of male recreational drug users. HU210, a selective agonist for CB1 and CB2 cannabinoid receptors impairs spermatogenesis and sperm motility and deregulates the endocannabinoid system
Systems model of physician professionalism in practice
Authors: Kitch Barrett T , DesRoches Catherine , Lesser Cara , Cunningham Amy , Campbell Eric G
Published: March 2012

Rationale  This article proposes a systems level conceptualization of physician professionalism that is embedded in and results from the characteristics of the organizations in which doctors work such as hospitals, group practices and physician organizations.

Aims and objectives  The goal of this study was to develop and test the systems model of professionalism.

Methods  In total, 25 interviews were conducted in Minneapolis and Miami. Job titles of the subjects included hospital presidents, medical directors, chairs of hospital departments, quality and safety directors, chief of quality improvement and practising physicians. The data from the interviews were coded and then sorted by members of the study team into major and minor themes.

Results  Virtually, all of the subjects were readily able to confirm aspects of the model by providing real‐life examples of factors at the practice, hospital and market levels that they believed strongly influenced the extent to which physicians adhere, or fail to adhere, to the professional norms.

Conclusions  The systems model of professionalism was consistent with the views and experiences of physicians and administrators in two different geographic regions of the USA. If born out by further research, this model has implications for interventions aimed at improving professionalism as well as for professionalism as a field of study.