bluuebunny/crossref_metadata_2025 huggingface dataset:
Ubiquilin-1 regulates amyloid precursor protein maturation and degradation by stimulating K63-linked polyubiquitination of lysine 688
Authors: El Ayadi Amina , Stieren Emily S. , Barral José M. , Boehning Darren
Published: July 2012

The pathogenesis of Alzheimer’s disease (AD) is associated with proteolytic processing of the amyloid precursor protein (APP) to an amyloidogenic peptide termed Aβ. Although mutations in APP and the secretase enzymes that mediate its processing are known to result in familial forms of AD, the mechanisms underlying the more common sporadic forms of the disease are still unclear. Evidence suggests that the susceptibility of APP to amyloidogenic processing is related to its intracellular localization, and that secretase-independent degradation may prevent the formation of cytotoxic peptide fragments. Recently, single nucleotide polymorphisms in the
UBQLN1
gene have been linked to late-onset AD, and its protein product, ubiquilin-1, may regulate the maturation of full-length APP. Here we show that ubiquilin-1 inhibits the maturation of APP by sequestering it in the early secretory pathway, primarily within the Golgi apparatus. This sequestration significantly delayed the proteolytic processing of APP by secretases and the proteasome. These effects were mediated by ubiquilin-1–stimulated K63-linked polyubiquitination of lysine 688 in the APP intracellular domain. Our results reveal the mechanistic basis by which ubiquilin-1 regulates APP maturation, with important consequences for the pathogenesis of late-onset AD.
Gender, social norms, and survival in maritime disasters
Authors: Elinder Mikael , Erixson Oscar
Published: July 2012

Since the sinking of the
Titanic
, there has been a widespread belief that the social norm of “women and children first” (WCF) gives women a survival advantage over men in maritime disasters, and that captains and crew members give priority to passengers. We analyze a database of 18 maritime disasters spanning three centuries, covering the fate of over 15,000 individuals of more than 30 nationalities. Our results provide a unique picture of maritime disasters. Women have a distinct survival disadvantage compared with men. Captains and crew survive at a significantly higher rate than passengers. We also find that: the captain has the power to enforce normative behavior; there seems to be no association between duration of a disaster and the impact of social norms; women fare no better when they constitute a small share of the ship’s complement; the length of the voyage before the disaster appears to have no impact on women’s relative survival rate; the sex gap in survival rates has declined since World War I; and women have a larger disadvantage in British shipwrecks. Taken together, our findings show that human behavior in life-and-death situations is best captured by the expression “every man for himself.”
Multicopper oxidase-1 is a ferroxidase essential for iron homeostasis in
Drosophila melanogaster
Authors: Lang Minglin , Braun Caroline L. , Kanost Michael R. , Gorman Maureen J.
Published: July 2012

Multicopper ferroxidases catalyze the oxidation of ferrous iron to ferric iron. In yeast and algae, they participate in cellular uptake of iron; in mammals, they facilitate cellular efflux. The mechanisms of iron metabolism in insects are still poorly understood, and insect multicopper ferroxidases have not been identified. In this paper, we present evidence that
Drosophila melanogaster
multicopper oxidase-1 (MCO1) is a functional ferroxidase. We identified candidate iron-binding residues in the MCO1 sequence and found that purified recombinant MCO1 oxidizes ferrous iron. An association between MCO1 function and iron homeostasis was confirmed by two observations: RNAi-mediated knockdown of MCO1 resulted in decreased iron accumulation in midguts and whole insects, and weak knockdown increased the longevity of flies fed a toxic concentration of iron. Strong knockdown of MCO1 resulted in pupal lethality, indicating that
MCO1
is an essential gene. Immunohistochemistry experiments demonstrated that MCO1 is located on the basal surfaces of the digestive system and Malpighian tubules. We propose that MCO1 oxidizes ferrous iron in the hemolymph and that the resulting ferric iron is bound by transferrin or melanotransferrin, leading to iron storage, iron withholding from pathogens, regulation of oxidative stress, and/or epithelial maturation. These proposed functions are distinct from those of other known ferroxidases. Given that MCO1 orthologues are present in all insect genomes analyzed to date, this discovery is an important step toward understanding iron metabolism in insects.
Optogenetic control of phosphoinositide metabolism
Authors: Idevall-Hagren Olof , Dickson Eamonn J. , Hille Bertil , Toomre Derek K. , De Camilli Pietro
Published: July 2012

Phosphoinositides (PIs) are lipid components of cell membranes that regulate a wide variety of cellular functions. Here we exploited the blue light-induced dimerization between two plant proteins, cryptochrome 2 (CRY2) and the transcription factor CIBN, to control plasma membrane PI levels rapidly, locally, and reversibly. The inositol 5-phosphatase domain of OCRL (5-ptase
OCRL
), which acts on PI(4,5)P
2
and PI(3,4,5)P
3
, was fused to the photolyase homology region domain of CRY2, and the CRY2-binding domain, CIBN, was fused to plasma membrane-targeting motifs. Blue-light illumination (458–488 nm) of mammalian cells expressing these constructs resulted in nearly instantaneous recruitment of 5-ptase
OCRL
to the plasma membrane, where it caused rapid (within seconds) and reversible (within minutes) dephosphorylation of its targets as revealed by diverse cellular assays: dissociation of PI(4,5)P
2
and PI(3,4,5)P
3
biosensors, disappearance of endocytic clathrin-coated pits, nearly complete inhibition of KCNQ2/3 channel currents, and loss of membrane ruffling. Focal illumination resulted in local and transient 5-ptase
OCRL
recruitment and PI(4,5)P
2
dephosphorylation, causing not only local collapse and retraction of the cell edge or process but also compensatory accumulation of the PI(4,5)P
2
biosensor and membrane ruffling at the opposite side of the cells. Using the same approach for the recruitment of PI3K, local PI(3,4,5)P
3
synthesis and membrane ruffling could be induced, with corresponding loss of ruffling distally to the illuminated region. This technique provides a powerful tool for dissecting with high spatial–temporal kinetics the cellular functions of various PIs and reversibly controlling the functions of downstream effectors of these signaling lipids.
Pathological crystallization of human immunoglobulins
Authors: Wang Ying , Lomakin Aleksey , Hideshima Teru , Laubach Jacob P. , Ogun Olutayo , Richardson Paul G. , Munshi Nikhil C. , Anderson Kenneth C. , Benedek George B.
Published: July 2012

Condensation of Igs has been observed in pharmaceutical formulations and in vivo in cases of cryoglobulinemia. We report a study of monoclonal IgG cryoglobulins overexpressed by two patients with multiple myeloma. These cryoglobulins form crystals, and we measured their solubility lines. Depending on the supersaturation, we observed a variety of condensate morphologies consistent with those reported in clinical investigations. Remarkably, the crystallization can occur at quite low concentrations. This suggests that, even within the regular immune response to infections, cryoprecipitation of Ig can be possible.
Excessive wave reflections on admission predict post‐discharge events in patients hospitalized due to acute heart failure
Authors: Sung Shih‐Hsien , Yu Wen‐Chung , Cheng Hao‐Min , Lee Ching‐Wei , Lin Mei‐Mei , Chuang Shao‐Yuan , Chen Chen‐Huan
Published: July 2012

Aims

The role of wave reflections in the pathogenesis of acute heart failure syndrome (AHFS) remains unclear. The present study investigated the long‐term prognostic values of the carotid augmentation index (cAI), carotid augmented pressure (cAP), amplitude of the reflected pressure wave from a decomposed carotid pressure wave (Pb), and carotid pulse pressure (PP) on admission in patients hospitalized due to AHFS.

Methods and results

A total of 120 patients (72 ± 14 years, 83.3% men) hospitalized due to AHFS (55.8% with systolic heart failure) were enrolled. Measures of cAI, cAP, Pb, carotid PP, and carotid–femoral pulse wave velocity (cf‐PWV) by tonometry and thoracic fluid content (TFC) by impedance cardiography were obtained within 24 h of admission. N‐terminal pro brain natriuretic peptide (NT‐proBNP) levels were determined before discharge. Patients were followed up for a median of 601 days, accruing 66 adverse events including re‐hospitalization for heart failure, non‐fatal myocardial infarction, non‐fatal stroke, and death. In univariate Cox analysis, all measures significantly predicted post‐discharge events (all P < 0.05). In multivariate analysis, cAP [hazard ratio per SD and 95% confidence interval: 1.32 (1.051–1.67), P = 0.017], Pb [1.44 (1.13–1.84), P = 0.004] and carotid PP [1.35 (1.05–1.73), P = 0.019], but not cAI, TFC, or cf‐PWV, significantly independently predicted events with adjustments for age, estimated glomerular filtration rate, haemoglobin, and NT‐proBNP.

Conclusion

On‐admission measures of wave reflection magnitude, including cAP, Pb, and carotid PP, may be useful for predicting long‐term outcomes in AHFS patients. The results support a major role for wave reflection in the pathogenesis of AHFS.
Internationally Adopted Children from Non-European Countries: General Development during the First Two Years in the Adoptive Family
Authors: Dalen Monica , Theie Steinar
Published: July 2012

Internationally adopted children are often delayed in their development and demonstrate more behaviour problems than nonadopted children due to adverse preadoption circumstances. This is especially true for children adopted from Eastern European countries. Few studies have focused on children adopted from non-European countries. This paper presents results from an ongoing longitudinal study of 119 internationally adopted children from non-European countries during their first two years in Norway. Several scales measuring different aspects of the children’s development are included in the study: communication and gross motor development, temperamental characteristics, and behaviour problems. The results show that internationally adopted children are delayed in their general development when they first arrive in their adoptive families. After two years the children have made significant progress in development. However, they still lag behind in communication and motor skills compared to non-adopted children. The temperamental characteristics seem very stable from time of adoption until two years after adoption. The children demonstrate a low frequency of behaviour problems. However, the behaviour problems have changed during the two years. At time of adoption they show more nonphysically challenging behaviour while after two years their physically challenging behaviour has increased.
Ureteral Reimplantation with Psoas Bladder Hitch in Adults: A Contemporary Series with Long-Term Followup
Authors: Manassero Francesca , Mogorovich Andrea , Fiorini Girolamo , Di Paola Giuseppe , De Maria Maurizio , Selli Cesare
Published: July 2012

We retrospectively evaluated our experience with ureteral reimplantation and psoas bladder hitch to restore urinary tract continuity in patients with lower ureteral defects, since long-term data on the outcomes of this procedure have been relatively scarce in the last two decades. The procedure was performed in 24 patients (7 male, 17 female) with a mean age of 54.6 years. The mean ureteral defect length was 4.8 cm (range 3–10), the ureterovesical anastomosis was performed with simplified split-cuff technique in 18 patients, submucosal tunnel in 2, and direct anastomosis without antireflux technique in 2. Mean followup was 53 months (range 12–125), and there were no reinterventions. Postoperative renal imaging was normal in 22 cases (91.6%) and revealed decreased kidney size in 2, 3 patients presented intermittent flank pain, and 5 had sporadic episodes of lower tract UTI but no one pyelonephritis. Psoas hitch ureteral reimplantation can be successfully used for bridging defects of the lower ureter up to 10 cm in length in difficult clinical situations. It is relatively simple to perform, compared to other procedures of ureteral reconstruction, and it provides adequate protection of the upper urinary tract.
Evaluation of the Effectiveness of a Positive Youth Development Program for Secondary Students in Macau
Authors: Luk Andrew L. , Leong K. M. , Au Annah M. L.
Published: July 2012

A well-tested comprehensive Chinese positive youth development program (Project P.A.T.H.S.) developed in Hong Kong has been modified and adapted for use in Macau. This program aims to help adolescent school children develop positively and to be better prepared for their future. The present study investigated the effectiveness of the Tier 1 Program of “P.A.T.H.S.” for Secondary 2 students of two pilot schools. Since there were “repeating” and “transferring” students joining the program, the effectiveness of the program on these particular groups of participants was also examined. The subjective outcome evaluations including participants' perceptions of the program, program instructors, benefits from the program, and overall satisfaction were positive. Although the longitudinal data from the objective outcome evaluation did not show any notable improvement, the overall effect of the program was found to be positive to the new comers in the junior secondary years. The existing evaluation findings suggest that the Secondary 2 program is especially effective to those newly joining the program. In view of the paucity of youth studies in Macau, the present study can contribute to evidence-based youth work and provide baseline data for the program to be evaluated in the Secondary 3 periods in the future.
Identification of Xylem Occlusions Occurring in CutClematis(ClematisL., fam.RanunculaceaeJuss.) Stems during Their Vase Life
Authors: Jedrzejuk Agata , Rochala Julia , Zakrzewski Jacek , Rabiza-Świder Julita
Published: July 2012

During the vase life of cut stems obstruction of xylem vessels occurs due to microbial growth, formation of tyloses, deposition of materials in the lumen of xylem vessels and the presence of air emboli in the vascular system. Such obstructions may restrict water uptake and its transport towards upwards thus lowering their ornamental value and longevity of cut flowers.Clematisis a very attractive plant material which may be used as cut flower in floral compositions. Nothing is known about the histochemical or cytological nature of xylem blockages occurring in cut stems of this plant. This study shows that inclematis, tyloses are the main source of occlusions, although bacteria and some amorphic substances may also appear inside the vessels. A preservative composed of 200 mg dm−38-HQC (8-hydroxyquinolin citrate) and 2% sucrose arrested bacterial development and the growth of tyloses. This information can be helpful in the development of new treatments to improve keeping qualities of cutclematisstems.
Antisense Reduction of NADP-Malic Enzyme in Flaveria bidentis Reduces Flow of CO2 through the C4 Cycle
Authors: Pengelly Jasper J.L. , Tan Jackie , Furbank Robert T. , von Caemmerer Susanne
Published: July 2012

An antisense construct targeting the C4 isoform of NADP-malic enzyme (ME), the primary enzyme decarboxylating malate in bundle sheath cells to supply CO2 to Rubisco, was used to transform the dicot Flaveria bidentis. Transgenic plants (α-NADP-ME) exhibited a 34% to 75% reduction in NADP-ME activity relative to the wild type with no visible growth phenotype. We characterized the effect of reducing NADP-ME on photosynthesis by measuring in vitro photosynthetic enzyme activity, gas exchange, and real-time carbon isotope discrimination (Ɗ). In α-NADP-ME plants with less than 40% of wild-type NADP-ME activity, CO2 assimilation rates at high intercellular CO2 were significantly reduced, whereas the in vitro activities of both phosphoenolpyruvate carboxylase and Rubisco were increased. Ɗ measured concurrently with gas exchange in these plants showed a lower Ɗ and thus a lower calculated leakiness of CO2 (the ratio of CO2 leak rate from the bundle sheath to the rate of CO2 supply). Comparative measurements on antisense Rubisco small subunit F. bidentis plants showed the opposite effect of increased Ɗ and leakiness. We use these measurements to estimate the C4 cycle rate, bundle sheath leak rate, and bundle sheath CO2 concentration. The comparison of α-NADP-ME and antisense Rubisco small subunit demonstrates that the coordination of the C3 and C4 cycles that exist during environmental perturbations by light and CO2 can be disrupted through transgenic manipulations. Furthermore, our results suggest that the efficiency of the C4 pathway could potentially be improved through a reduction in C4 cycle activity or increased C3 cycle activity.
Binary salt of a palladium(II) complex with (phosphonomethyl)phosphonic (medronic) acid comprising `handbell-like' [Pd{μ-CH2(PO3)2}]3units
Authors: Babaryk Artem A. , Kozachkova Alexandra N. , Tsaryk Natalia V. , Dudko Anatolij V. , Pekhnyo Vasily I.
Published: July 2012

The asymmetric unit of the title compound, dipotassium bis[hexaaquanickel(II)] tris(μ2-methylenediphosphonato)tripalladium(II) hexahydrate, K2[Ni(H2O)6]2[Pd3{CH2(PO3)2}3]·6H2O, consists of half a {[Pd{CH2(PO3)2}]3}6−anion [one Pd atom (4e) and a methylene C atom (4e) occupy positions on a twofold axis] in a rare `handbell-like' arrangement, with K+and [Ni(H2O)6]2+cations to form the neutral complex, completed by three solvent water molecules. The {[Pd{CH2(PO3)2}]3}6−units exhibit close Pd...Pd separations of 3.0469 (4) Å and are packedviaintermolecular C—H...Pd hydrogen bonds. The [KO9] and [NiO6] units are assembled into sheets coplanar with (011) and stacked along the [100] direction. Within these sheets there are [K4Ni4O8] and [K2Ni2O4] loops. Successive alternation of the sheets and [Pd{CH2(PO3)2}]3units parallel to [001] produces the three-dimensional packing, which is also supported by a dense network of hydrogen bonds involving the solvent water molecules.
Pseudopolymorphs of chelidamic acid and its dimethyl ester
Authors: Tutughamiarso Maya , Pisternick Thorsten , Egert Ernst
Published: July 2012

Different tautomeric and zwitterionic forms of chelidamic acid (4-hydroxypyridine-2,6-dicarboxylic acid) are present in the crystal structures of chelidamic acid methanol monosolvate, C7H5NO5·CH4O, (Ia), dimethylammonium chelidamate (dimethylammonium 6-carboxy-4-hydroxypyridine-2-carboxylate), C2H8N+·C7H4NO5−, (Ib), and chelidamic acid dimethyl sulfoxide monosolvate, C7H5NO5·C2H6OS, (Ic). While the zwitterionic pyridinium carboxylate in (Ia) can be explained from the pKavalues, a (partially) deprotonated hydroxy group in the presence of a neutral carboxy group, as observed in (Ib) and (Ic), is unexpected. In (Ib), there are two formula units in the asymmetric unit with the chelidamic acid entities connected by a symmetric O—H...O hydrogen bond. Also, crystals of chelidamic acid dimethyl ester (dimethyl 4-hydroxypyridine-2,6-dicarboxylate) were obtained as a monohydrate, C9H9NO5·H2O, (IIa), and as a solvent-free modification, in which both ester molecules adopt the hydroxypyridine form. In (IIa), the solvent water molecule stabilizes the synperiplanar conformation of both carbonyl O atoms with respect to the pyridine N atom by two O—H...O hydrogen bonds, whereas an antiperiplanar arrangement is observed in the water-free structure. A database study andab initioenergy calculations help to compare the stabilities of the various ester conformations.
1,1′-Methylenedipyridinium tetrachloridocuprate(II) and bis[tetrachloridoaurate(III)] hybrid salts by X-ray powder diffraction
Authors: Al-Ktaifani Mahmoud , Rukiah Mwaffak
Published: July 2012

In order to explore the potential propensity of the 1,1′-methylenedipyridinium dication to form organic–inorganic hybrid ionic compounds by reaction with the appropriate halide metal salt, the organic–inorganic hybrid salts 1,1′-methylenedipyridinium tetrachloridocuprate(II), (C11H12N2)[CuCl4], (I), and 1,1′-methylenedipyridinium bis[tetrachloridoaurate(III)], (C11H12N2)[AuCl4]2, (II), were obtained by treatment of 1,1′-methylenedipyridinium dichloride with CuCl2and Na[AuCl4], respectively. Both hybrid salts were isolated as pure compounds, fully characterized by multinuclear NMR spectroscopy and their molecular structures confirmed by powder X-ray diffraction studies. The crystal structures consist of discrete 1,1′-methylenedipyridinium dications and [CuCl4]2−and [AuCl4]−anions for (I) and (II), respectively. As expected, the dications form a butterfly shape; the CuIIcentre of [CuCl4]2−has a distorted tetrahedral configuration and the AuIIIcentre of [AuCl4]−shows a square-planar coordination. The ionic species of (I) and the dication of (II) each have twofold axial symmetry, while the two [AuCl4]−anions are located on a mirror-plane site. Both crystal structures are stabilized by intermolecular C—H...Cl hydrogen bonds and also by Cl...π interactions. It is noteworthy that, while the average intermolecular centroid–centroid pyridinium ring distance in (I) is 3.643 (8) Å, giving strong evidence for noncovalent π–π ring interactions, for (II), the shortest centroid–centroid distance between pyridinium rings of 5.502 (9) Å is too long for any significant π–π ring interactions, which might be due to the bulk of the two [AuCl4]−anions.
The weakly coordinating perchlorate group in bis(N,N′-dimethylethylenediamine-κ2N,N′)bis(perchlorato-κO)copper(II) studied at 100, 250 and 400 K
Authors: Schnitzler Silvia , Şerb Mihaela-Diana , Englert Ulli
Published: July 2012

The crystal structure of the title compound, [Cu(ClO4)2(C4H12N2)2], (I), is reported at 100, 250 and 400 K. The CuIIcation in this complex is coordinated in a distorted octahedral mode characteristic of Jahn–Teller systems. The coordination of the perchlorate ligandsvialonger, and presumably weaker, axial Cu—O distances varies significantly as a function of temperature. One of the Cu—O distances increases between 100 and 250 K, and one of the Cu—O—Cl angles expands between 250 and 400 K. At all temperatures, the complex forms a two-dimensional N—H...O hydrogen-bond network in the (001) plane.
Structural Basis of the Allosteric Inhibitor Interaction on the HIV‐1 Reverse Transcriptase RNase H Domain
Authors: Christen Martin T. , Menon Lakshmi , Myshakina Nataliya S. , Ahn Jinwoo , Parniak Michael A. , Ishima Rieko
Published: July 2012

HIV‐1 reverse transcriptase (RT) has been an attractive target for the development of antiretroviral agents. Although this enzyme is bi‐functional, having both DNA polymerase and ribonuclease H (RNH) activities, there is no clinically approved inhibitor of the RNH activity. Here, we characterize the structural basis and molecular interaction of an allosteric site inhibitor, BHMP07, with the wild‐type (WT) RNH fragment. Solution NMR experiments for inhibitor titration on WT RNH showed relatively wide chemical shift perturbations, suggesting a long‐range conformational effect on the inhibitor interaction. Comparisons of the inhibitor‐induced NMR chemical shift changes of RNH with those of RNH dimer, in the presence and absence of Mg2+, were performed to determine and verify the interaction site. The NMR results, with assistance of molecular docking, indicate that BHMP07 preferentially binds to a site that is located between the RNH active site and the region encompassing helices B and D (the ‘substrate‐handle region’). The interaction site is consistent with the previous proposed site, identified using a chimeric RNH (p15‐EC) [Gong et al. (2011) Chem Biol Drug Des 77, 39–47], but with slight differences that reflect the characteristics of the amino acid sequences in p15‐EC compared to the WT RNH.
Standardization of Gleason grading among 337 European pathologists
Authors: Egevad Lars , Ahmad Amar S , Algaba Ferran , Berney Daniel M , Boccon‐Gibod Liliane , Compérat Eva , Evans Andrew J , Griffiths David , Grobholz Rainer , Kristiansen Glen , Langner Cord , Lopez‐Beltran Antonio , Montironi Rodolfo , Moss Sue , Oliveira Pedro , Vainer Ben , Varma Murali , Camparo Philippe
Published: July 2012

Aims:  The 2005 International Society of Urological Pathology (ISUP) modification of Gleason grading recommended that the highest grade should always be included in the Gleason score (GS) in prostate biopsies. We analysed the impact of this recommendation on reporting of GS 6 versus 7.

Methods and results:  Fifteen expert uropathologists reached two‐thirds consensus on 15 prostate biopsies with GS 6–7 cancer. Eighty‐five microphotographs were graded by 337 of 617 members of the European Network of Uropathology (ENUP), representing 19 countries. There was agreement between expert and majority member GS in 12 of 15 cases, while members upgraded in three cases. Among members and the expert consensus, a GS >6 was assigned by 64.5% and 60%, respectively. Mean member GS was higher than consensus GS in nine of 15 cases. A Gleason pattern (GP) 5 was reported by 0.3–5.6% in 10 cases. Agreement between consensus and member GS was 58.2–89.3% (mean 71.4%) in GS 6 cases and 46.3–63.8% (mean 56.4%) in GS 7 cases (P = 0.009).

Conclusions:  While undergrading of prostate cancer used to be prevalent, some now tend to overgrade. Minimum diagnostic criteria for GP 4 and 5 in biopsies need to be better defined. Image libraries reviewed by experts may be useful for standardization.
Bayesian model of Hamilton Depression Rating Score (HDRS) with memantine augmentation in bipolar depression
Authors: Stevens Jasper , Bies Robert R. , Shekhar Anantha , Anand Amit
Published: July 2012

Aim

Presynaptic and post‐synaptic glutamatergic modulation is associated with antidepressant activity that takes several weeks to reach a maximal full effect. Limiting mood elevating effects after single drug administration may be the result of compensatory synaptic processes. Therefore, using augmentation treatment with agents having presynaptic and post‐synaptic effects on the glutamatergic system, this study aims to evaluate the effect of augmentation therapy on the rate of change in mood elevation in patients with bipolar depression.

Methods

In a pilot study, 29 outpatients with bipolar depression on a stable lamotrigine dose regimen received placebo or memantine pills daily (titrated up by 5 mg week–1 to 20 mg) in a randomized, double‐blind, parallel group, 8 week study. Patients were evaluated weekly using the 17‐item Hamilton Depression Rating Score (HDRS) and all data were analyzed simultaneously. Linear, exponential, maximal effect, Gompertz and inverse Bateman functions were evaluated using a Bayesian approach population pharmacodynamic model framework. In these models, differences in parameters were examined across the memantine and placebo augmentation groups.

Results

A Gompertz function with a treatment switch on the parameter describing the speed of HDRS decline (γ, 95% confidence interval [CI]) best described the data (γmemantine = 1.8, 95% CI 0.9, 3.6), γplacebo = 1.2, 95% CI 0.5, 3.5)). Between subject variability was identified on baseline HDRS (2.9, 95% CI 1.5, 4.4) and amplitude of score improvement (4.3, 95% CI 2.7, 6.5).

Conclusions

This pharmacodynamic approach identified an increased speed of response after memantine augmentation, compared with placebo augmentation in bipolar depression patients.
Dose titration of BAF312 attenuates the initial heart rate reducing effect in healthy subjects
Authors: Legangneux Eric , Gardin Anne , Johns Donald
Published: July 2012

Aim

Previous studies have shown transient decreases in heart rate (HR) following administration of sphingosine 1‐phosphate (S1P) receptor modulators including BAF312. This study was conducted to determine whether dose titration of BAF312 reduces or eliminates these effects.

Methods

Fifty‐six healthy subjects were randomized 1:1:1:1 to receive BAF312 in one of two dose titration (DT) regimens (DT1 and DT2: 0.25–10 mg over 9–10 days), no titration (10 mg starting dose) or placebo. Pharmacodynamic and pharmacokinetic parameters were assessed.

Results

Neither DT1 nor DT2 resulted in clinically significant bradycardia or atrioventricular conduction effects. Both titration regimens showed a favourable difference on each of days 1–12 vs. the non‐titration regimen on day 1 for HR effects (P < 0.0001). On day 1, the geometric mean ratio of the fraction from the previous day in minimum daily HR between DT1 and non‐titration was 1.18 (95% confidence interval [CI] 1.13, 1.23) and 1.14 (95% CI 1.09, 1.18) for DT2 (both P < 0.05) with significant differences noted through to day 12. Non‐titration HRs showed considerable separation from placebo throughout the study. There was no statistically significant reduction in HR vs. placebo on day 1 in either titration regimen. On days 3–7 subjects in DT1 and DT2 experienced minor reductions in HR vs. placebo (approximately 5 beats min−1; P ≤ 0.0001). From days 9–12, HRs in both titration regimens were comparable with placebo.

Conclusion

Both titration regimens effectively attenuated the initial bradyarrhythmia observed on day 1 of treatment with BAF312 10 mg.
Statins and risk of treated incident diabetes in a primary care population
Authors: Zaharan Nur Lisa , Williams David , Bennett Kathleen
Published: July 2012

Aims

(i) To examine the incidence of new onset treated diabetes in patients treated with different types of statins and (ii) the relationship between the duration and dose of statins and the subsequent development of new onset treated diabetes.

Methods

A retrospective cohort study was performed using the Irish Health Services Executive Primary Care Reimbursement Services national pharmacy claims database. Individuals who received any medicines were identified from January 2001 to January 2009 (n = 1 235 671). Patients newly treated with statins from 1 January 2002 to 31 December 2007 were identified (n = 239 628). Cases were identified as individuals newly treated with antidiabetic medication (n = 38 503). Adjusted hazards ratios (HR) with 95% confidence intervals (CI) were calculated to examine the association between statins (any vs. none) and time to new onset treated diabetes using Cox proportional hazard regression. The dose and duration response relationship between statins and new onset treated diabetes was examined using restricted spline functions to assess the linearity of the relationship.

Results

Statin use was associated with an increased risk of new onset treated diabetes (HR = 1.18, 95% CI 1.15, 1.22). Increased risk of new onset treated diabetes was found with rosuvastatin (HR = 1.41, 95% CI 1.31, 1.52), atorvastatin (HR = 1.23, 95% CI 1.19, 1.27) and simvastatin (HR = 1.15, 95% CI 1.05, 1.25). There were statistically significant overall dose and duration effects for all statins, excepting fluvastatin, which only demonstrated a duration effect.

Conclusion

An increased risk of new onset treated diabetes was found in those treated with statins showing significant duration and dose effect. Further study is required to confirm this association.
Modulation of vaccine response by concomitant probiotic administration
Authors: Maidens Catherine , Childs Caroline , Przemska Agnieszka , Dayel Iman Bin , Yaqoob Parveen
Published: July 2012

Evidence suggests that probiotic bacteria modulate both innate and adaptive immunity in the host, and in some situations can result in reduced severity of common illnesses, such as acute rotavirus infection and respiratory infections. Responses to vaccination are increasingly being used to provide high quality information on the immunomodulatory effects of dietary components in humans. The present review focuses on the effect of probiotic administration upon vaccination response. The majority of studies investigating the impact of probiotics on responses to vaccination have been conducted in healthy adults, and at best they show modest effects of probiotics on serum or salivary IgA titres. Studies in infants and in elderly subjects are very limited, and it is too early to draw any firm conclusions regarding the potential for probiotics to act as adjuvants in vaccination. Although some studies are comparable in terms of duration of the intervention, age and characteristics of the subjects, most differ in terms of the probiotic selected. Further well designed, randomized, placebo‐controlled studies are needed to understand fully the immunomodulatory properties of probiotics, whether the effects exerted are strain‐dependent and age‐dependent and their clinical relevance in enhancing immune protection following vaccination.
Bead-size directed distribution of Pseudomonas aeruginosa results in distinct inflammatory response in a mouse model of chronic lung infection
Authors: Christophersen L J , Trøstrup H , Malling Damlund D S , Bjarnsholt T , Thomsen K , Jensen P Ø , Hougen H P , Høiby N , Moser C
Published: July 2012

Chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients is characterized by biofilms, tolerant to antibiotics and host responses. Instead, immune responses contribute to the tissue damage. However, this may depend on localization of infection in the upper conductive or in the peripheral respiratory zone. To study this we produced two distinct sizes of small alginate beads (SB) and large beads (LB) containing P. aeruginosa. In total, 175 BALB/c mice were infected with either SB or LB. At day 1 the quantitative bacteriology was higher in the SB group compared to the LB group (P < 0·003). For all time-points smaller biofilms were identified by Alcian blue staining in the SB group (P < 0·003). Similarly, the area of the airways in which biofilms were identified were smaller (P < 0·0001). A shift from exclusively endobronchial to both parenchymal and endobronchial localization of inflammation from day 1 to days 2/3 (P < 0·05), as well as a faster resolution of inflammation at days 5/6, was observed in the SB group (P < 0·03). Finally, both the polymorphonuclear neutrophil leucocyte (PMN) mobilizer granulocyte colony-stimulating factor (G-CSF) and chemoattractant macrophage inflammatory protein-2 (MIP-2) were increased at day 1 in the SB group (P < 0·0001). In conclusion, we have established a model enabling studies of host responses in different pulmonary zones. An effective recognition of and a more pronounced host response to infection in the peripheral zones, indicating that increased lung damage was demonstrated. Therefore, treatment of the chronic P. aeruginosa lung infection should be directed primarily at the peripheral lung zone by combined intravenous and inhalation antibiotic treatment.
Growth and production of Pacific ocean perch (Sebastes alutus) in nursery habitats of the Gulf of Alaska
Authors: ROOPER CHRISTOPHER N. , BOLDT JENNIFER L. , BATTEN SONIA , GBURSKI CHRISTOPHER
Published: July 2012

Nursery areas for juvenile fishes are often important for determining recruitment in marine populations by providing habitats that can maximize growth and thereby minimize mortality. Pacific ocean perch (POP, Sebastes alutus) have an extended juvenile period where they inhabit rocky nursery habitats. We examined POP nursery areas to link growth potential to recruitment. Juvenile POP were captured from nursery areas in 2004 and 2008, and estimated growth rates ranged from −0.19 to 0.60 g day−1 based on differences in size between June and August. Predicted growth rates from a bioenergetics model ranged from 0.05 to 0.49 g day−1 and were not significantly different than observed. Substrate preferences and the distribution of their preferred habitats were utilized to predict the extent of juvenile POP nursery habitat in the Gulf of Alaska. Based on densities of fish observed on underwater video transects and the spatial extent of nursery areas, we predicted 278 and 290 million juvenile POP were produced in 2004 and 2008. Growth potential for juvenile POP was reconstructed using the bioenergetics model, spring zooplankton bloom timing and duration and bottom water temperature for 1982–2008. When a single outlying recruitment year in 1986 was removed, growth potential experienced by juvenile POP in nursery areas was significantly correlated to the recruitment time‐series from the stock assessment, explaining ∼30% of the variability. This research highlights the potential to predict recruitment using habitat‐based methods and provides a potential mechanism for explaining some of the POP recruitment variability observed for this population.
Distribution of the Vasotocin Subtype Four Receptor (VT4R) in the Anterior Pituitary Gland of the Chicken, Gallus gallus, and its Possible Role in the Avian Stress Response
Authors: Selvam R. , Jurkevich A. , Kang S. W. , Mikhailova M. V. , Cornett L. E. , Kuenzel W. J.
Published: July 2012

The neurohormone arginine vasotocin (AVT) in non mammalian vertebrates is homologous to arginine vasopressin (AVP) in mammals. Its actions are mediated via G protein‐coupled receptors that belong to the vasotocin/mesotocin family. Because of the known regulatory effects of nonapeptide hormones on anterior pituitary functions, receptor subtypes in that family have been proposed to be located in anterior pituitary cells. Recently, an avian vasotocin receptor subtype designated VT4R has been cloned, which shares 69% sequence homology with a human vasopressin receptor, the V1aR. In the present study, a polyclonal antibody to the VT4R was developed and validated to confirm its specificity to the VT4R. The antibody was used to test the hypothesis that the VT4R is present in the avian anterior pituitary and is specifically associated with certain cell types, where its expression is modulated by acute stress. Western blotting of membrane protein extracts from pituitary tissue, the use of HeLa cells transfected with the VT4R and peptide competition assays all confirmed the specificity of the antibody to the VT4R. Dual‐labelling immunofluorescence microscopy was utilised to identify pituitary cell types that contained immunoreactive VT4R. The receptor was found to be widely distributed throughout the cephalic lobe but not in the caudal lobe of the anterior pituitary. Immunoreactive VT4R was associated with corticotrophs. Approximately 89% of immunolabelled corticotrophs were shown to contain the VT4R. The immunoreactive VT4R was not found in gonadotrophs, somatotrophs or lactotrophs. To determine a possible functional role of the VT4R and previously characterised VT2R, gene expression levels in the anterior pituitary were determined after acute immobilisation stress by quantitative reverse transcriptase‐polymerase chain reaction. The results showed a significant increase in plasma corticosterone levels (three‐ to four‐fold), a significant reduction of VT4R mRNA and an increase of VT2R mRNA (P < 0.05) in acutely immobilised chicks compared to controls. The data suggest a role of the VT4R in the avian stress response.
Over‐expression of a conserved RNA‐binding motif (RRM) domain (csRRM2) improves components of Brassica napus yield by regulating cell size
Authors: Qi Weiwei , Zhang Fengqi , Sun Fan , Huang Yongjuan , Guan Rongzhan , Yang Jinshui , Luo Xiaojin
Published: July 2012

With 4 figures and 1 table

Oilseed rape (Brassica napus L.) is the second most important oilseed crop in the world, and greater production of rape oil is required to satisfy the growing demand for it. We previously found that the cell size and yield of rice (Oryza sativa) and cotton can be increased by over‐expression of the RNA‐binding domains (RRMs) of the flowering control locus A (FCA) protein. We also found that B. napus FCA‐RRM2 shares a high level of sequence similarity with the RRM2 domains of other plants. We isolated B. napus FCA‐RRM2 from variety No.1 ‘Nannongyou’ of Brassica napus. Transformation experiments demonstrated that over‐expression of B. napus FCA‐RRM2 increases plant size, organ size, cell size, plant productivity and oil content in transgenic rape plants by down‐regulating the cell‐cycle‐related gene cyclin‐B2‐1, a known activator of cyclin‐dependent kinase 1 at the G2/M boundary. These results provide a practical approach for the genetic improvement of B. napus and possibly provide a model for investigating cell size regulation.
N‐3 polyunsaturated fatty acid attenuates cholesterol gallstones by suppressing mucin production with a high cholesterol diet in mice
Authors: Kim Ja Kyung , Cho Soo Min , Kang So Hee , Kim Eunjung , Yi Hee , Yun Eun Sun , Lee Dong Goo , Cho Hee Jung , Paik Yong Han , Choi Yang Kyu , Haam Seung Joo , Shin Ho Chul , Lee Dong Ki
Published: July 2012

Background and Aim

The increasing prevalence of cholesterol gallstone (CG) disease has become an economic burden to the healthcare system. Ursodeoxycholic acid (UDCA) is the only established medical agent used to dissolve gallstones. In investigating novel therapeutics for CG, we assessed the preventive effects of n‐3 polyunsaturated fatty acids (n‐3PUFA) on the formation of CG induced by feeding a lithogenic diet (LD) containing high cholesterol levels to mice.

Methods

Mice were divided into the following six groups: (A) regular diet (RD); (B) RD+n‐3PUFA; (C) LD; (D) LD+n‐3PUFA; (E) LD+UDCA; (F) LD+n‐3PUFA+UDCA. After RD/LD feeding for 2 weeks, n‐3PUFA or UDCA was administered orally and the diet maintained for 8 weeks. The levels of phospholipids and cholesterol in bile, CG formation, gallbladder wall thickness, MUC gene expression in gallbladder were analyzed.

Results

No stone or sludge was evident in the RD groups (Groups A, B). Mice in the n‐3PUFA treatment (Groups D, F) showed significantly lower stone formation than the other LD groups (Groups C, E). The combination treatment of n‐3PUFA and UDCA suppressed stone formation more than mono‐therapy with n‐3PUFA or UDCA. Bile phospholipid levels were significantly elevated in the Group F. Hypertrophy of the gallbladder wall was evident in mice fed LD. MUC 2, 5AC, 5B and 6 mRNA expression levels were significantly elevated in the LD‐fed group, and this was suppressed by n‐3PUFA with or without UDCA.

Conclusions

N‐3PUFA attenuated gallstone formation in mouse, through increasing the levels of bile phospholipids and suppressing bile mucin formation.
Potential for statins in the chemoprevention and management of hepatocellular carcinoma
Authors: Lonardo Amedeo , Loria Paola
Published: July 2012

Hepatocellular carcinoma (HCC) is a common, treatment‐resistant malignancy with a complex molecular pathogenesis. Statins are a widely used class of cholesterol‐lowering drugs with potential anticancer activity.

We reviewed the evidence for a role of statins in primary and secondary chemoprevention of HCC and slowing the course of otherwise incurable primary or recurrent disease. A literature search (key words: Statins, hepatocellular carcinoma) conducted to this end, retrieved 119 references. Here we summarize the history, mechanism of action and cardiovascular use of statins and highlight that statins can affect several pathways implicated in the development of HCC. In vitro and animal studies provide strong evidence for a favorable effect of statins on HCC. However, evidence in humans is conflicting. We discuss in full detail the methodological strengths and pitfalls of published data including three cohort studies suggesting that the use of statins may protect from the development of HCC and of a single trial reporting increased survival in those with advanced HCC randomized to receive statins. A remarkably hepato‐safe class of drugs acting on both hepatocyte and endothelial cells, statins also have potentially beneficial effects in lowering portal hypertension. In conclusion, there is strong experimental evidence that statins are beneficial in chemopreventing and slowing the growth of HCC. However, randomized controlled trials are necessary in order to investigate the role of statins in the chemoprevention of HCC and in slowing the course of otherwise incurable disease in humans.
Investigation and management of hepatic incidentalomas
Authors: Fergusson James
Published: July 2012

With the widespread use of medical imaging has come the detection of incidental liver lesions that are, by and large, asymptomatic prior to their discovery. These lesions may become a source of anxiety and often require further investigation to reassure the patient of their usually benign nature. Use of contemporary hepatobiliary imaging and simple laboratory tests often allow a definite diagnosis to be made without resorting to exhaustive investigation or inappropriate surgery. The goal of this paper is to review the clinical features and imaging characteristics of common and important liver incidentalomas, their natural course, complications, and indications for surgical or other intervention.
Alteration of the timing of self‐initiated but not reactive saccades by electrical stimulation in the supplementary eye field
Authors: Kunimatsu Jun , Tanaka Masaki
Published: July 2012

Although we can generate movements whenever we feel like doing so, the way in which neuronal signals regulate the timing of self‐initiated movements remains elusive. There is evidence that the dorsomedial frontal cortex, including the supplementary eye field (SEF), is involved in the self‐triggering of movements. Because the gradual evolution of cortical activity over the dorsomedial frontal cortex is known to reflect the temporal prediction of an upcoming event, we postulated that the timing of self‐initiated movements is regulated by the time course of neuronal activity in the SEF. To test the causal role, we applied electrical microstimulation to the SEF when monkeys prepared for memory‐guided saccades. Stimulation delayed the initiation of saccades when animals were required to make saccades 1200 ± 300 ms following the cue (self‐timed task), but not when they generated memory‐guided saccades in response to the offset of the fixation point (conventional task). As well as the increment in median saccade latencies, stimulation at ∼24% of sites also increased the occurrence of early erroneous saccades. Saccades facilitated by stimulation were always directed toward the cue, even when the cue was located away from the movement field. In contrast, stimulation to the frontal eye fields during saccade preparation exerted no effects in either task. These results suggest that the preparatory signals in the SEF may play a causal role in regulating the timing rather than the direction of self‐initiated saccades.