The association between type D personality,and depression and anxiety ten years after PCI

Objective

There are indications that type D personality and depression are associated in patients treated with percutaneous coronary intervention (PCI). However, at present it is unclear whether this relationship holds in the long term. This study’s aim was to investigate the association between type D personality at 6 months post-PCI (baseline), and depression at 10-year follow-up. A secondary aim was to test the association between type D personality at baseline and anxiety at 10-year follow-up.

Methods

A cohort of surviving consecutive patients (N = 534) who underwent PCI between October 2001 and October 2002. Patients completed the type D personality scale (DS14) measuring type D personality at baseline, and the Hospital Anxiety and Depression Scale (HADS) measuring anxiety and depression at baseline and at 10 years post-PCI.

Results

At baseline, the prevalence of type D personality was 25?% (135/534). Type D personality patients were more often depressed (42?%) than non-type D personality patients (9?%). Response rate of anxiety and depression questionnaires at 10 years was 75?%. At 10-year follow-up, 31?% of type D personality patients were depressed versus 13?% of non-type D personality patients. After adjustments, baseline type D personality remained independently associated with depression at 10 years (OR = 3.69; 95?% CI [1.89–7.19]). Type D showed a similar association with anxiety at 10 years, albeit somewhat lower (OR = 2.72; 95?% CI [1.31–5.63]).

Conclusions

PCI patients with type D personality had a 3.69-fold increased risk for depression and a 2.72-fold increased risk for anxiety at 10 years of follow-up.

     

Calcineurin ensures a link between the DNA replication checkpoint and microtubule-dependent polarized growth

Microtubules are central to eukaryotic cell morphogenesis. Microtubule plus-end tracking proteins (+TIPs) transport polarity factors to the cell cortex, thereby playing a key role in both microtubule dynamics and cell polarity. However, the signalling pathway linking +TIPs to cell polarity control remains elusive. Here we show that the fission yeast checkpoint kinase Cds1 (Chk2 homologue) delays the transition of growth polarity from monopolar to bipolar (termed NETO; new-end take-off). The +TIPs CLIP170 homologue Tip1 and kinesin Tea2 are responsible for this delay, which is accompanied by a reduction in microtubule dynamics at the cell tip. Remarkably, microtubule stabilization occurs asymmetrically, prominently at the non-growing cell end, which induces abnormal accumulation of the polarity factor Tea1. Importantly, NETO delay requires activation of calcineurin, which is carried out by Cds1, resulting in Tip1 dephosphorylation. Thus, our study establishes a critical link between calcineurin and checkpoint-dependent cell morphogenesis.     

Anticooperative Nearest-Neighbor Interactions between Residues in Unfolded Peptides and Proteins

Growing evidence suggests that the conformational distributions of amino acid residues in unfolded peptides and proteins depend on the nature of the nearest neighbors. To explore whether the underlying interactions would lead to a breakdown of the isolated pair hypothesis of the classical random coil model, we further analyzed the conformational propensities that were recently obtained for the two guest residues (x,y) of GxyG tetrapeptides. We constructed a statistical thermodynamics model that allows for cooperative as well as for anticooperative interactions between adjacent residues adopting either a polyproline II or a β-strand conformation. Our analysis reveals that the nearest-neighbor interactions between most of the central residues in the investigated GxyG peptides are anticooperative. Interaction Gibbs energies are rather large at high temperatures (350 K), at which point many proteins undergo thermal unfolding. At room temperature, these interaction energies are less pronounced. We used the obtained interaction parameter in a Zimm-Bragg/Ising-type approach to calculate the temperature dependence of the ultraviolet circular dichroism (CD) of the MAX3 peptide, which is predominantly built by KV repeats. The agreement between simulation and experimental data was found to be satisfactory. Finally, we analyzed the temperature dependence of the CD and ³J(H^NH^α) parameters of the amyloid β_1–9 fragment. The results of this analysis and a more qualitative consideration of the temperature dependence of denatured proteins probed by CD spectroscopy further corroborate the dominance of anticooperative nearest-neighbor interactions. Generally, our results show that unfolded peptides—and most likely also proteins—exhibit some similarity with antiferromagnetic systems.     

Crosstalk between Arg 1175 methylation and Tyr 1173 phosphorylation negatively modulates EGFR-mediated ERK activation

Epidermal growth factor receptor (EGFR) can undergo post-translational modifications, including phosphorylation, glycosylation and ubiquitylation, leading to diverse physiological consequences and modulation of its biological activity. There is increasing evidence that methylation may parallel other post-translational modifications in the regulation of various biological processes. It is still not known, however, whether EGFR is regulated by this post-translational event. Here, we show that EGFR Arg?1175 is methylated by an arginine methyltransferase, PRMT5. Arg?1175 methylation positively modulates EGF-induced EGFR trans-autophosphorylation at Tyr?1173, which governs ERK activation. Abolishment of Arg?1175 methylation enhances EGF-stimulated ERK activation by reducing SHP1 recruitment to EGFR, resulting in augmented cell proliferation, migration and invasion of EGFR-expressing cells. Therefore, we propose a model in which the regulatory crosstalk between PRMT5-mediated Arg?1175 methylation and EGF-induced Tyr?1173 phosphorylation attenuates EGFR-mediated ERK activation.     

In vitro evaluation of single- and multi-strain probiotics: Inter-species inhibition between probiotic strains, and inhibition of pathogens

Many studies comparing the effects of single- and multi-strain probiotics on pathogen inhibition compare treatments with different concentrations. They also do not examine the possibility of inhibition between probiotic strains with a mixture. We tested the ability of 14 single-species probiotics to inhibit each other using a cross-streak assay, and agar spot test. We then tested the ability of 15 single-species probiotics and 5 probiotic mixtures to inhibit Clostridium difficile, Escherichia coli and S. typhimurium, using the agar spot test. Testing was done with mixtures created in two ways: one group contained component species incubated together, the other group of mixtures was made using component species which had been incubated separately, equalised to equal optical density, and then mixed in equal volumes. Inhibition was observed for all combinations of probiotics, suggesting that when used as such there may be inhibition between probiotics, potentially reducing efficacy of the mixture. Significant inter-species variation was seen against each pathogen. When single species were tested against mixtures, the multi-species preparations displayed significantly (p < 0.05 or less) greater inhibition of pathogens in 12 out of 24 cases. Despite evidence that probiotic species will inhibit each other when incubated together in vitro, in many cases a probiotic mixture was more effective at inhibiting pathogens than its component species when tested at approximately equal concentrations of biomass. This suggests that using a probiotic mixture might be more effective at reducing gastrointestinal infections, and that creating a mixture using species with different effects against different pathogens may have a broader spectrum of action that a single provided by a single strain.     

The paradoxical relationship between ligamentum flavum hypertrophy and developmental lumbar spinal stenosis

Background

Ligamentum flavum (LF) hypertrophy is a common cause of lumbar spinal stenosis and is thought to be degeneration-driven. Developmental spinal stenosis (DSS) is characterized by pre-existing narrowed spinal canals and is likely a developmental problem that occurs in childhood. In these cases, the LF may demonstrate different characteristics as compared to degeneration-driven stenosis. Thus, this study aimed to investigate the relationship between histological changes of LF and canal size.

Methods

Patients who had surgical decompression for lumbar spinal stenosis were prospectively recruited and divided into three groups (critical DSS, relative DSS and non-DSS) based on previously defined anteroposterior bony spinal canal diameter measurements on MRI. The degree of disc degeneration and LF thickness were also measured from L1 to S1. Surgical LF specimens were retrieved for histological assessment of fibrotic grade and area of fibrosis.

Results

A total of 19 females and 15 males (110 LF specimens) with an overall mean age of 65.9 years (SD?±?9.8 years) were recruited. DSS was found to have a significant negative correlation (p?<?0.001) with LF thickness, its fibrotic grade and area of fibrosis (%). Non-DSS exhibited a significant positive relationship with the degree of LF fibrosis. Disc degeneration and LF thickness had no correlation with LF histology.

Conclusions

Our study is the first to definitively note that degeneration is the cause of LF fibrosis in non-DSS patients; however, in contrast, an inverse relationship exists between canal size and LF fibrosis in DSS patients, suggesting a different pathomechanism. Hence, despite a similar degree of LF thickness, DSS patients have LF with less fibrosis compared with non-DSS patients. Further investigation of the cause of LF changes in DSS is necessary to understand this relationship.

     

Recurrent Implantation Failure-update overview on etiology,diagnosis, treatment and future directions

Recurrent implantation failure (RIF) refers to cases in which women have had three failed in vitro fertilization (IVF) attempts with good quality embryos. The definition should also take advanced maternal age and embryo stage into consideration. The failure of embryo implantation can be a consequence of uterine, male, or embryo factors, or the specific type of IVF protocol. These cases should be investigated to determine the most likely etiologies of the condition, as this is a complex problem with several variables. There are multiple risk factors for recurrent implantation failure including advanced maternal age, smoking status of both parents, elevated body mass index, and stress levels. Immunological factors such as cytokine levels and presence of specific autoantibodies should be examined, as well as any infectious organisms in the uterus leading to chronic endometritis. Uterine pathologies such as polyps and myomas as well as congenital anatomical anomalies should be ruled out. Sperm analysis, pre-implantation genetic screening and endometrial receptivity should be considered and evaluated, and IVF protocols should be tailored to specific patients or patient populations. Treatment approaches should be directed toward individual patient cases. In addition, we suggest considering a new initial step in approach to patients with RIF, individualized planned activities to activate the brain's reward system in attempt to improve immunological balance in the body.     

Evolutionary Behaviour,Trade-Offs and Cyclic and Chaotic Population Dynamics

Many studies of the evolution of life-history traits assume that the underlying population dynamical attractor is stable point equilibrium. However, evolutionary outcomes can change significantly in different circumstances. We present an analysis based on adaptive dynamics of a discrete-time demographic model involving a trade-off whose shape is also an important determinant of evolutionary behaviour. We derive an explicit expression for the fitness in the cyclic region and consequently present an adaptive dynamic analysis which is algebraic. We do this fully in the region of 2-cycles and (using a symbolic package) almost fully for 4-cycles. Simulations illustrate and verify our results. With equilibrium population dynamics, trade-offs with accelerating costs produce a continuously stable strategy (CSS) whereas trade-offs with decelerating costs produce a non-ES repellor. The transition to 2-cycles produces a discontinuous change: the appearance of an intermediate region in which branching points occur. The size of this region decreases as we move through the region of 2-cycles. There is a further discontinuous fall in the size of the branching region during the transition to 4-cycles. We extend our results numerically and with simulations to higher-period cycles and chaos. Simulations show that chaotic population dynamics can evolve from equilibrium and vice-versa.     

Medical Product Development, Innovation, and Life-Cycle Regulation: The Challenges for Biostatistics

The article provides a perspective on the challenges for biostatistics as well as on contributions that biostatisticians are making and can make to medical product development and regulation and what the future might be in these areas. The current environment in the United States for pharmaceutical development and regulation is discussed along with the expectations that the public has for how medical products should contribute to public heath. The globalization of research and the use of study designs that incorporate multi-regional populations present new challenges for design and inference. The emerging interest in and development of the science of safety assessment and quantitative approaches to risk evaluation is considered. Guidance development, especially in the area of clinical trials design, continues to be one of the needs that FDA is asked to meet. Guidance development is proceeding for non-inferiority study designs, adaptive designs, multiple endpoints in clinical trials, and missing outcome data in clinical trials. Biostatisticians will be asked and challenged to take on leadership roles in new areas such as personalized medicine, biomarker and genomics, development of new tools for visual display of clinical data, quality assurance and monitoring in clinical trials.     

GSM 900 MHz radiation inhibits ants' association between food sites and encountered cues

The kinetics of the acquisition and loss of the use of olfactory and visual cues were previously obtained in six experimental colonies of the ant Myrmica sabuleti meinert 1861, under normal conditions. In the present work, the same experiments were conducted on six other naive identical colonies of M. sabuleti, under electromagnetic radiation similar to those surrounding GSM and communication masts. In this situation, no association between food and either olfactory or visual cues occurred. After a recovery period, the ants were able to make such an association but never reached the expected score. Such ants having acquired a weaker olfactory or visual score and still undergoing olfactory or visual training were again submitted to electromagnetic waves. Not only did they lose all that they had memorized, but also they lost it in a few hours instead of in a few days (as under normal conditions when no longer trained). They kept no visual memory at all (instead of keeping 10% of it as they normally do). The impact of GSM 900?MHz radiation was greater on the visual memory than on the olfactory one. These communication waves may have such a disastrous impact on a wide range of insects using olfactory and/or visual memory, i.e., on bees.     

Serological identification and molecular characterization of B (A) 02 subtype in patients and blood donors from Eastern China

This study was designed to identify the rare?type?ABO?blood?groups, B(A) 02, from Eastern China. Three samples with discordant serological results during routine blood type identification and four samples from one sample’ family were selected. All of them were detected by serological method. The exon 6 and 7 of the ABO genes were amplified by PCR and sequenced. They were typed as AsubB by serology and as BO by genotype. In AsubB samples, nt 700C>G mutation was detected in B gene, which was previously defined as B(A)02 alleles. In these seven samples, six showed B(A)02/O01 and one showed B(A)02/O02.B(A)02 allele was found to be more common in this study than B(A)04 which is considered to be more frequent than B(A)02. The careful identification of rare blood types is important for the safety of clinical blood transfusion.     

Antarctic, Sub-Antarctic and cold temperate echinoid database

This database includes spatial data of Antarctic, Sub-Antarctic and cold temperate echinoid distribution (Echinodermata: Echinoidea) collected during many oceanographic campaigns led in the Southern Hemisphere from 1872 to 2010. The dataset lists occurrence data of echinoid distribution south of 35°S latitude, together with information on taxonomy (from species to genus level), sampling sources (cruise ID, sampling dates, ship names) and sampling sites (geographic coordinates and depth). Echinoid occurrence data were compiled from the Antarctic Echinoid Database (David et al. 2005a), which integrates records from oceanographic cruises led in the Southern Ocean until 2003. This database has been upgraded to take into account data from oceanographic cruises led after 2003. The dataset now reaches a total of 6160 occurrence data that have been checked for systematics reliability and consistency. It constitutes today the most complete database on Antarctic and Sub-Antarctic echinoids.     

In vitro radioprotection studies of organoselenium compounds: differences between mono- and diselenides

Organoselenium compounds belonging to the class of monoselenides, such as selenomethionine (SeM) and methylselenocysteine (MSeCys) and diselenides including selenocystine (SeCys) and selenopropionic acid (SePA), were examined for their comparative radioprotective effects using in vitro models. Effects of these compounds on the inhibition of γ-radiation induced lipid peroxidation in liposomes, protein carbonylation in bovine serum albumin (BSA) and strand breaks in pBR322 plasmid DNA, assessed, respectively, by the formation of thiobarbituric acid reactive substances, formation of 2,2′-dinitrophenyl hydrazine (DNPH) carbonyl complex and horizontal gel electrophoresis, were used to compare their radioprotective ability. The IC₅₀ values for SeCys, SePA, SeM and MSeCys for lipid peroxidation were 27 ± 1, 33 ± 2, 200 ± 8 and 163 ± 4 μM, respectively, and the values for inhibition of protein carbonylation were >200, 300 ± 6, 464 ± 8 and 436 ± 3 μM, respectively. Inhibition of DNA strand break formation was tested at 200 μM for all the compounds and SePA and SeCys exhibited a protective effect on DNA, while SeM and MSeCys did not lead to any protection. The in vitro cytotoxicity studies in normal and tumor cells revealed that MSeCys and SeM were not cytotoxic to lymphocytes and EL4 tumor cells at the concentrations employed. In contrast, SeCys was toxic, with a higher effect on tumor cells than lymphocytes. Our studies suggest that the non-toxic diselenides like SePA should be explored as protective agents against γ-irradiation induced damage.     

Physical Interactions between Mcm10, DNA, and DNA Polymerase ��

Mcm10 is an essential eukaryotic protein required for the initiation and elongation phases of chromosomal replication. Specifically, Mcm10 is required for the association of several replication proteins, including DNA polymerase α (pol α), with chromatin. We showed previously that the internal (ID) and C-terminal (CTD) domains of Mcm10 physically interact with both single-stranded (ss) DNA and the catalytic p180 subunit of pol α. However, the mechanism by which Mcm10 interacts with pol α on and off DNA is unclear. As a first step toward understanding the structural details for these critical intermolecular interactions, x-ray crystallography and NMR spectroscopy were used to map the binary interfaces between Mcm10-ID, ssDNA, and p180. The crystal structure of an Mcm10-ID·ssDNA complex confirmed and extended our previous evidence that ssDNA binds within the oligonucleotide/oligosaccharide binding-fold cleft of Mcm10-ID. We show using NMR chemical shift perturbation and fluorescence spectroscopy that p180 also binds to the OB-fold and that ssDNA and p180 compete for binding to this motif. In addition, we map a minimal Mcm10 binding site on p180 to a small region within the p180 N-terminal domain (residues 286–310). These findings, together with data for DNA and p180 binding to an Mcm10 construct that contains both the ID and CTD, provide the first mechanistic insight into how Mcm10 might use a handoff mechanism to load and stabilize pol α within the replication fork.To maintain their genomic integrity, cells must ensure complete and accurate DNA replication once per cell cycle. Consequently, DNA replication is a highly regulated and orchestrated series of molecular events. Multiprotein complexes assembled at origins of replication lead to assembly of additional proteins that unwind chromosomal DNA and synthesize nascent strands. The first event is the formation of a pre-replicative complex, which is composed of the origin recognition complex, Cdc6, Cdt1, and Mcm2–7 (for review, see Ref. 1). Initiation of replication at the onset of S-phase involves the activity of cyclin- and Dbf4-dependent kinases concurrent with recruitment of key factors to the origin. Among these, Mcm10 (2, 3) is recruited in early S-phase and is required for loading of Cdc45 (4). Mcm2–7, Cdc45, and the GINS complex form the replicative helicase (5–8). Origin unwinding is followed by loading of RPA,³ And-1/Ctf4, and pol α onto ssDNA (9–12). In addition, recruitment of Sld2, Sld3, and Dpb11/TopBP1 are essential for replication initiation (13, 14), and association of topoisomerase I, proliferating cellular nuclear antigen (PCNA), replication factor C, and the replicative DNA polymerases δ and ϵ completes the replisome (for review, see Ref. 15).Mcm10 is exclusive to eukaryotes and is essential to both initiation and elongation phases of chromosomal DNA replication (6, 8, 16). Mutations in Mcm10 in yeast result in stalled replication, cell cycle arrest, and cell death (2, 3, 17–19). These defects can be explained by the number of genetic and physical interactions between Mcm10 and many essential replication proteins, including origin recognition complex, Mcm2–7, and PCNA (3, 12, 20–24). In addition, Mcm10 has been shown to stimulate the phosphorylation of Mcm2–7 by Dbf4-dependent kinase in vitro (25). Thus, Mcm10 is an integral component of the replication machinery.Importantly, Mcm10 physically interacts with and stabilizes pol α and helps to maintain its association with chromatin (16, 26, 27). This is a critical interaction during replication because pol α is the only enzyme in eukaryotic cells that is capable of initiating DNA synthesis de novo. Indeed, Mcm10 stimulates the polymerase activity of pol α in vitro (28), and interestingly, the fission yeast Mcm10, but not Xenopus Mcm10, has been shown to exhibit primase activity (29, 30). Mcm10 is composed of three domains, the N-terminal (NTD), internal (ID), and C-terminal (CTD) domains (29). The NTD is presumably an oligomerization domain, whereas the ID and CTD both interact with DNA and pol α (29). The CTD is not found in yeast, whereas the ID is highly conserved among all eukaryotes. The crystal structure of Mcm10-ID showed that this domain is composed of an oligonucleotide/oligosaccharide binding (OB)-fold and a zinc finger motif, which form a unified DNA binding platform (31). An Hsp10-like motif important for the interaction with pol α has been identified in the sequence of Saccharomyces cerevisiae Mcm10-ID (16, 26).DNA pol α-primase is composed of four subunits: p180, p68, p58, and p48. The p180 subunit possesses the catalytic DNA polymerase activity, and disruption of this gene is lethal (32, 33). p58 and p48 form the DNA-dependent RNA polymerase (primase) activity (34, 35), whereas the p68 subunit has no known catalytic activity but serves a regulatory role (36, 37). Pol α plays an essential role in lagging strand synthesis by first creating short (7–12 nucleotide) RNA primers followed by DNA extension. At the critical length of ∼30 nucleotides, replication factor C binds to the nascent strand to displace pol α and loads PCNA with pols δ and ϵ (for review, see Ref. 38).The interaction between Mcm10 and pol α has led to the suggestion that Mcm10 may help recruit the polymerase to the emerging replisome. However, the molecular details of this interaction and the mechanism by which Mcm10 may recruit and stabilize the pol α complex on DNA has not been investigated. Presented here is the high resolution structure of the conserved Mcm10-ID bound to ssDNA together with NMR chemical shift perturbation competition data for pol α binding in the presence of ssDNA. Collectively, these data demonstrate a shared binding site for DNA and pol α in the OB-fold cleft of Mcm10-ID, with a preference for ssDNA over pol α. In addition, we have mapped the Mcm10-ID binding site on pol α to a 24-residue segment of the N-terminal domain of p180. Based on these results, we propose Mcm10 helps to recruit pol α to origins of replication by a molecular hand-off mechanism.