A multivariate mixed linear model for meta-analysis.

A multivariate mixed-effects approach for meta-analysis is presented. The approach (a) incorporates as outcomes multiple effect sizes per study; (b) allows different studies to have different subsets of effect sizes; and (c) treats each study's effect sizes as random realizations from a population of possible effect sizes. Application is illustrated via reanalysis of data from studies assessing the effects of coaching on verbal and mathematical subtests of the Scholastic Aptitude Test. Covariance components are estimated via restricted maximum likelihood (REML); inferences about regression coefficients and specific study effect sizes are based on their joint conditional distribution given the REML covariance component estimates. The approach can be implemented via now-standard software for unbalanced hierarchical data. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Resumption of mitosis during post-thaw culture: a key parameter in selecting the right embryos for transfer

A new oxidative pathway for the degradation of caffeine(1,3,7-Trimethylxanthine, I) by a mixed culture consisting of strains belonging to the genera Klebsiella and Rhodococcus is presented. The mixed culture does not initiate degradation by N-demethylation either complete or partial, but instead carries out oxidation at the C-8 position resulting in the formation of 1,3,7-trimethyluric acid (TMU, II) which further gets degraded to 3,6,8-trimethylallantoin (TMA, III). Both TMU and TMA are hitherto not shown to be formed in the microbial system. Further degradation of TMA (III) by caffeine grown cells yields dimethylurea (VII) as one of the metabolites. Oxygen uptake studies indicated that caffeine(I) grown cells oxidized TMU(II), TMA (III), glyoxalic acid (VI), dimethylurea(VII), and monomethylurea(V), but not monomethyl and dimethyluric acids. The mixed culture does not accept theophylline(1,3-dimethylxanthine), theobromine(3,7-dimethylxanthine), and paraxanthine(1,7-dimethylxanthine) as the carbon source.     

On the Possibility of Observing Third Sound on 3He

This paper focuses on the hydrodynamics of third sound on a superfluid ³ He film. We solve the hydrodynamical equations in the limit of thick films with weak interaction with the substrate. The surface tension at the free interface is shown to have a large effect on the third sound velocity and on the attenuation for frequencies larger than 1Hz. In the case of a diffusely scattering substrate a ripplon-like dispersion relation is found for this frequency range.     

The role of perspective in the accessibility of goals during reading.

An implicit assumption of several causal reasoning models is that readers adopt the goals of a narrative's protagonist during text comprehension. In apparent violation of this assumption, readers participating in Experiment 1 of the present study drew inferences relevant to a protagonist's goal even when that goal was already satisfied from the perspective of the protagonist. In Experiments 2 and 3, participants were explicitly asked to view the text situation from the point of view of the protagonist. In this case, the goals of the reader and the protagonist should be the same. In these experiments, participants focused on the goals of the protagonist only when those goals had not been satisfied from the perspective of the protagonist. These results are discussed in terms of reader- and character-based perspectives and in terms of text characteristics that cue perspective taking. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Combined differentiating therapy for myelodysplastic syndromes: a phase II study

An in vitro synergism between different inducers of AML cell differentiation has been previously observed. Therefore, we treated 53 myelodysplastic (MDS) patients with a low dose combination of cis-retinoic acid (cRA, 20-40 mg/day) and 1,25 alpha (OH)2 cholecalciferol [(OH)2D3, 1-1.5 micrograms/day] +/- intermittent 6-thioguanine (30 mg/m2/day). The latter was reserved for patients with bone marrow (BM) blast excess (> or = 5%). The treatment was well tolerated, without major toxicity. Among 25 patients with BM blasts less than 5%, we observed one complete, eight partial and four minor responses (response rate 52%) with a median response duration of 8 months (2 +/- 24). Median survival, which did not correlate with response, is projected at 76 months. Thirty-one patients with BM blast excess (> or = 5%), including three of the previous group who progressed to refractory anemia with excess of blasts (RAEB), were treated with the three-drug protocol. One complete, 12 partial and six minor responses were obtained (response rate 61%) with a median response duration of 6 months (2-29+). A significant difference in survival (P < 0.005) was observed between the 19 responders (median 25 months) and the 12 non-responders (median 9 months). A reduction in the transfusion need was observed in 41% of the transfusion-dependent patients with blast excess and in 53% of those without blast excess. Therefore, combined differentiating therapy seems more effective than previously reported single agent treatments and should be considered for a larger randomized study to assess its actual impact on survival of MDS patients.     

Lactococcus lactis and stress

It is now generally recognized that cell growth conditions in nature are often suboptimal compared to controlled conditions provided in the laboratory. Natural stresses like starvation and acidity are generated by cell growth itself. Other stresses like temperature or osmotic shock, or oxygen, are imposed by the environment. It is now clear that defense mechanisms to withstand different stresses must be present in all organisms. The exploration of stress responses in lactic acid bacteria has just begun. Several stress response genes have been revealed through homologies with known genes in other organisms. While stress response genes appear to be highly conserved, however, their regulation may not be. Thus, search of the regulation of stress response in lactic acid bacteria may reveal new regulatory circuits. The first part of this report addresses the available information on stress response in Lactococcus lactis. Acid stress response may be particularly important in lactic acid bacteria, whose growth and transition to stationary phase is accompanied by the production of lactic acid, which results in acidification of the media, arrest of cell multiplication, and possible cell death. The second part of this report will focus on progress made in acid stress response, particularly in L. lactis and on factors which may affect its regulation. Acid tolerance is presently under study in L. lactis. Our results with strain MG1363 show that it survives a lethal challenge at pH 4.0 if adapted briefly (5 to 15 minutes) at a pH between 4.5 and 6.5. Adaptation requires protein synthesis, indicating that acid conditions induce expression of newly synthesized genes. These results show that L. lactis possesses an inducible response to acid stress in exponential phase. To identify possible regulatory genes involved in acid stress response, we determined low pH conditions in which MG1363 is unable to grow, and selected at 37 degrees C for transposition insertional mutants which were able to survive. About thirty mutants resistant to low pH conditions were characterized. The interrupted genes were identified by sequence homology with known genes. One insertion interrupts ahrC, the putative regulator of arginine metabolism; possibly, increased arginine catabolism in the mutant produces metabolites which increase the pH. Several other mutations putatively map at some step in the pathway of (p)ppGpp synthesis. Our results suggest that the stringent response pathway, which is involved in starvation and stationary phase survival, may also be implicated in acid pH tolerance.     

Differentiation of smooth muscle cells from undifferentiated cells of chicken gizzard occurs on the layer of fibroblast-like cells

Conflicting results have been reported in literature about the influence of beta-adrenergic stimulation on the fast cardiac sodium current (INa+). To elucidate these mechanisms in multicellular preparations we used the loose-patch-clamp technique to evaluate the effect of the beta-adrenergic agonist isoproterenol 1-1000 nmol/l. Isoproterenol enhanced INa+ at all membrane potentials by elevation of the maximal available INa+ . Only at the high concentration of 1 micromol/l was INa+ slightly depressed after depolarizing conditioning clamps. The most marked increase of the maximal available INa+ was 30+/-9% after application of 100 nmol/l isoproterenol. To learn about the mechanisms in view of sodium channel modulation we combined isoproterenol with the sodium channel blocker lidocaine (47 micromol/l). Under these circumstances the effects of both drugs were completely independent. This investigation shows clearly that low concentrations of isoproterenol increase INa+ in multicellular preparations by a gating-independent mechanism.     

Anomalies of the tracheobronchial tree in patients with esophageal atresia

Bone marrow examination revealed a lipid-laden histiocytosis in seven patients undergoing long-term total parenteral nutrition necessitated by extensive short-bowel surgical resection. Clinical abnormalities occurred during this treatment which required bone marrow examination. These included hepatosplenomegaly and peripheral blood cytopenia; the median time to the detection of these abnormalities was 64 months. The most striking change within the bone marrow was the presence of many pigment-laden histiocytes which had the typical morphology of sea-blue histiocytes seen in the so-called idiopathic sea-blue histiocyte syndrome. The occurrence of sea-blue histiocytosis in the bone marrow in association with long-term parenteral nutrition for short-bowel syndrome has not, to our knowledge, been reported previously and should now be considered in the differential diagnosis of bone marrow sea-blue histiocytosis.     

Antisense oligonucleotide inhibition of hepatitis C virus gene expression in transformed hepatocytes

Genetic and biochemical studies have provided convincing evidence that the 5' noncoding region (5' NCR) of hepatitis C virus (HCV) is highly conserved among viral isolates worldwide and that translation of HCV is directed by an internal ribosome entry site (IRES) located within the 5' NCR. We have investigated inhibition of HCV gene expression using antisense oligonucleotides complementary to the 5' NCR, translation initiation codon, and core protein coding sequences. Oligonucleotides were evaluated for activity after treatment of a human hepatocyte cell line expressing the HCV 5' NCR, core protein coding sequences, and the majority of the envelope gene (E1). More than 50 oligonucleotides were evaluated for inhibition of HCV RNA and protein expression. Two oligonucleotides, ISIS 6095, targeted to a stem-loop structure within the 5' NCR known to be important for IRES function, and ISIS 6547, targeted to sequences spanning the AUG used for initiation of HCV polyprotein translation, were found to be the most effective at inhibiting HCV gene expression. ISIS 6095 and 6547 caused concentration-dependent reductions in HCV RNA and protein levels, with 50% inhibitory concentrations of 0.1 to 0.2 microM. Reduction of RNA levels, and subsequently protein levels, by these phosphorothioate oligonucleotides was consistent with RNase H cleavage of RNA at the site of oligonucleotide hybridization. Chemically modified HCV antisense phosphodiester oligonucleotides were designed and evaluated for inhibition of core protein expression to identify oligonucleotides and HCV target sequences that do not require RNase H activity to inhibit expression. A uniformly modified 2'-methoxyethoxy phosphodiester antisense oligonucleotide complementary to the initiator AUG reduced HCV core protein levels as effectively as phosphorothioate oligonucleotide ISIS 6095 but without reducing HCV RNA levels. Results of our studies show that HCV gene expression is reduced by antisense oligonucleotides and demonstrate that it is feasible to design antisense oligonucleotide inhibitors of translation that do not require RNase H activation. The data demonstrate that chemically modified antisense oligonucleotides can be used as tools to identify important regulatory sequences and/or structures important for efficient translation of HCV.