Concomitant administration of zoster and pneumococcal vaccines in adults ≥60 years old. This study evaluated safety & immunogenicity of ZOSTAVAX® (zoster vaccine: ZV) administered concomitantly versus nonconcomitantly with PNEUMOVAX® 23 (pneumococcal vaccine: PPV23). This randomized, double-blind, placebo-controlled study enrolled 473 subjects ≥60 years old in 1:1 ratio to receive ZV & PPV23 concomitantly (Day 1) or nonconcomitantly (PPV23 Day 1, ZV Week 4). Blood samples obtained for pneumococcal polysaccharide (PnPs) antibody (Ab) testing by enzyme-linked immunosorbent assay (ELISA) and varicella-zoster virus (VZV) Ab testing by glycoprotein ELISA. Subjects followed for adverse experiences (AEs) for 28 days postvaccination. Mean baseline VZV geometric mean titers (GMT) in nonconcomitant group were lower than concomitant group. Four weeks postvaccination with ZV, VZV Ab response in concomitant group was not similar to nonconcomitant group; estimated VZV GMT ratio [concomitant/nonconcomitant] was 0.70 (95% CI, 0.61-0.80). VZV Ab response was acceptable in concomitant group; estimated geometric mean foldrise (GMFR) from baseline was 1.9 (95% CI, 1.7-2.1). PnPs serotype-specific Ab responses were similar in both groups. All 6 reported serious AEs were deemed not related to study vaccine. Postvaccination of ZV, incidence of injection-site AEs was similar in both groups; clinical AEs were numerically but not significantly higher in nonconcomitant group. In summary, VZV GMT Ab response induced by ZV administered concomitantly with PPV23 was inferior to that induced nonconcomitantly. These results indicate that, to avoid a potential decrease in ZV immunogenicity, ZV & PPV23 should not be given concomitantly. Concomitant administration did not affect response to PPV23 serotypes tested. When administered concomitantly, ZV & PPV23 vaccines were generally well tolerated.


Anti-tau oligomers passive vaccination for the treatment of Alzheimer disease. The aggregation and accumulation of the microtubule-associated protein (Tau) is a pathological hallmark of Alzheimer's disease (AD) and many neurodegenerative diseases. Despite the poor correlation between neurofirillary tangles (NFTs) and disease progression, and evidence showing, that neuronal loss in AD actually precedes NFTs formation research until recently focused on them and other large meta-stable inclusions composed of aggregated hyperphosphorylated tau protein. Lately, the significance and toxicity of NFTs has been challenged and new aggregated tau entity has emerged as the true pathogenic species in tauopathies and a possible mediator of Aβ toxicity in AD. Tau intermediate aggregate (tau oligomers; aggregates of an intermediate that is between monomers and NFTs in size) can cause neurodegeneration and memory impairment in the absence of Aβ. This exciting body of evidence includes results from human brain samples, transgenic mouse and cell-based studies. Despite extensive efforts to develop a safe and efficacious vaccine for AD using Aβ peptide as an immunogen in active vaccination approaches or anti Aβ antibodies for passive vaccination, success has been modest. Nonetheless, these studies have produced a wealth of fundamental knowledge that has potential to application to the development of a tau-based immunotherapy. Herein, I discuss the evidence supporting the critical role of tau oligomers in AD, the potential and challenges for targeting them by immunotherapy as a novel approach for AD treatment.


Simplified β-amyloid peptides for safer Alzheimer's vaccines development. Over the past few years, new ways of fighting Alzheimer's disease have emerged based on stimulating the immunitary defence system of the patients. To avoid toxicity and autoimmune response related to the Aβ[1-42] peptide immunotherapy, in the last decade a large number of works aimed at identifying new classes of safe Aβ derivatives by modifying the full length β-amyloid form. In strict agreement with the purposes of the sequence-simplification technology, Aβ[1-16], Aβ[13-28] and Aβ[25-42] fragments were selected in order to retain the major immunogenic sites of the Aβ[1-42] peptide, and corresponding simplified forms were designed and synthesized. All glycinated Aβ derivatives showed immunogenic and antigenic properties similar to the parent Aβ[1-42] peptide, and raised antibodies were all able to cross-recognize both Aβ[1-42] and Aβ[1-40] synthetic structures. All Aβ simplified forms showed reduced fibrillogenic and inflammatory properties. In particular, the Aβ[13-28]+G form failed to induce IFN-γ production thus suggesting that this molecule could represent a good candidate for potentially safer AD vaccine therapy.


AFFITOME® technology in neurodegenerative diseases: the doubling advantage. Neurodegenerative diseases are still an area of unmet medical need. This is in contrast to our increasing knowledge on their pathology (e.g., Alzheimer's- (AD), Parkinson's (PD) disease). They are driven by the cerebral accumulation and aggregation of specific proteins (e.g., β-amyloid and hyperphosphorylated tau in the case of AD) in defined brain regions and, as a consequence, death of neurons. Accordingly, removal of given protein aggregates is expected to modify the course of the respective neurodegenerative disease. This has been convincingly demonstrated in animal models of human diseases. However, not every technology that can be used and proves successful in animal models can be translated to the human situation. As highlighted by recent progress in the field of AD research, specific immunotherapy is a viable option in this regard. Given the fact that the aggregates are composed of self-proteins, immunotherapeutic approaches have to consider the issue of potential autoimmunity. This is especially true in case of vaccines. An innovative solution to this problem is offered by the so called AFFITOME® technology, which relies on the use of "doubles" of native molecules, functionally mimotopes or AFFITOPES® if identified by AFFiRiS, as the antigenic vaccine component.


Effectiveness of Lanzhou lamb rotavirus vaccine against hospitalized gastroenteritis: further analysis and update.


Cell cycle control of cell death in yeast.


Differential regulation of MMP7 in colon cancer cells resistant and sensitive to oxaliplatin-induced cell death. We have previously shown that metalloproteinase 7 (MMP7) expression is increased during the acquisition of resistance to oxaliplatin in colon cancer cells. Now we have analyzed the implication of β-catenin and EGFR pathways in the up-regulation of MMP7 in the oxaliplatin-resistant human colon cancer cell lines RHT29 and RHCT116 p53-/-, derived from the HT29 and HCT116 p53-/- cells, respectively. Oxaliplatin treatment increased EGFR expression and induced its activation in all the cell lines. However, β-catenin mRNA was only upregulated in the HT29 and RHT29 cells, with a marked increase in the nuclear/cytoplasmic β-catenin protein ratio in the oxaliplatin-resistant RHT29 cells. To determine the contribution of β-catenin and EGFR to the expression of MMP7 we performed siRNA experiments. β-catenin abrogation only prevented the induction of MMP7 by oxaliplatin in HT29 and RHT29 cells. Accordingly, viability of oxaliplatin-treated RHT29 cells under β-catenin silencing was decreased. On the other hand, EGFR siRNA induced contradictory effects, decreasing PEA3 and MMP7 expression in control and oxaliplatin-treated RHCT116 p53-/- cells but increasing basal- and oxaliplatin-induced PEA3 and MMP7 in the HT29 and RHT29 cells. Oxaliplatin-induced MMP7 up-regulation is differentially achieved in colon cancer cell lines, as a result of EGFR and β-catenin cross-talk on MMP7 gene transcription. Taken together, our results point out the disparity of effects that β-catenin and EGFR blocking therapeutic strategies may exert on MMP7 expression depending on the cellular context and remark the importance of a better knowledge of MMP7 regulation to improve chemotherapy effectiveness in colon cancer.


p53 and senescence: A little goes a long way.


New insights into 5q- syndrome as a ribosomopathy. Myelodysplastic Syndromes (MDS) are a heterogeneous group of acquired clonal bone marrow disorders, characterised by ineffective hematopoiesis. The mechanisms underlying many of these blood disorders have remained elusive due to the difficulty in pinpointing specific gene mutations or haplo-insufficencies, which can occur within large deleted regions. However, there is an increasing interest in the classification of some of these diseases as ribosomopathies. Indeed, studies have implicated Ribosomal Protein (RP) S14 as a strong candidate for haploinsufficiency in 5q- syndrome, a particular form of MDS. Recently, two novel mouse models have provided evidence for the involvement of both RPS14 and the p53 pathway, and specific miRNAs in 5q- syndrome. In this review we will discuss: 5q- syndrome mouse models, the possible mechanisms underlying this blood disorder with respect to the candidate genes and comparisons with other ribosomopathies and the involvement of the p53 pathway in these diseases.


Aven-uing between nuclear export and cell cycle arrest.


Rarity of AKT1 and AKT3 E17K mutations in squamous cell carcinoma of lung.


Adrenal cortex and micro-RNAs: An update.


Toward the mechanisms preventing merotelic kinetochore-microtubule attachments.


RhoBTB2 (DBC2) comes of age as a multifunctional tumor suppressor.


Histone genes, DNA replication, apoptosis and aging: What are the connections?


Antibacterial autophagy occurs at PI(3)P-enriched domains of the endoplasmic reticulum and requires Rab1 GTPase. Autophagy mediates the degradation of cytoplasmic components in eukaryotic cells and plays a key role in immunity. The mechanism of autophagosome formation is not clear. Here we examined two potential membrane sources for antibacterial autophagy: the ER and mitochondria. DFCP1, a marker of specialized ER domains known as 'omegasomes,' associated with Salmonella-containing autophagosomes via its PtdIns(3)P and ER-binding domains, while a mitochondrial marker (cytochrome b5-GFP) did not. Rab1 also localized to autophagosomes, and its activity was required for autophagosome formation, clearance of protein aggregates and peroxisomes, and autophagy of Salmonella. Overexpression of Rab1 enhanced antibacterial autophagy. The role of Rab1 in antibacterial autophagy was independent of its role in ER-to-Golgi transport. Our data suggest that antibacterial autophagy occurs at omegasomes and reveal that the Rab1 GTPase plays a crucial role in mammalian autophagy.


A quantitative assay for the monitoring of autophagosome accumulation in different phases of the cell cycle. Macroautophagy is a process accompanied by the formation of double-membrane vesicles known as autophagosomes. Although in recently published reviews various methods for the detection of autophagosomes were described, a reliable technique for the automated quantitative evaluation of autophagosome accumulation is still lacking. Here we developed a new assay which is based on the fact that the number of autophagosomes is correlated with the amount of the LC3-II protein, which is specifically associated with autophagosomal membranes. Monitoring of autophagosome: accumulation was performed by extracting the membrane-unbound LC3-I form of the protein from cells, followed by flow cytometric detection of the autophagosomal membrane-associated fraction of LC3-II. This assay could be used for monitoring autophagosomes by flow cytometry utilizing immunostaining with the antibody against the LC3 protein. It is also suitable for analysis of: cells expressing GFP-LC3. We showed that co-staining with propidium iodide allows detection of basal level of autophagosomes in different phases of the cell cycle. Autophagy activators, such as: rapamycin or cell starvation, were able to induce accumulation of autophagosomes in G0/G1, S and G2/M phases. Thus, utilization of this assay simplifies monitoring of autophagosome accumulation induced by different activators or inhibitors of macroautophagy and it is suggested as being useful in the detection of autophagosomes in different phases of the cell cycle.


PUMA-mediated tumor suppression: A tale of two stories. Several recent studies provided evidence that PUMA, a pro-apoptotic member of the BH3-only protein subgroup of the Bcl-2 family, is critical for restricting survival and recovery of different cell types, including those of the hematopoietic system, after γ-irradiation (IR)-triggered DNA damage. According to its pro-apoptotic function downstream of p53, PUMA is considered to act as a tumor suppressor. While this expectation was met in a model of oncogene-driven lymphomagenesis or carcinogen-driven tumor formation in the gut, studies on IR-driven tumor formation revealed surprising new insights into the role of p53-triggered and PUMA-mediated apoptosis in tumorigenesis and stem cell homeostasis.


PIN it on auxin: the role of PIN1 and PAT in tomato development. The growth and development of plants is regulated by several external and internal factors including auxin. Its distribution regulates several developmental processes in plants. Auxin molecules function as mobile signals and are involved in the spatial and temporal coordination of plant morphogenesis and in plant responses to their environment. The intercellular transport of auxin is facilitated by transport proteins and the disruption of polar auxin flow results in various developmental abnormalities. In this review, we discuss the developmental and physiological significance of over-accumulation of PIN1 auxin transport facilitator protein in tomato as seen in the enhanced polar auxin transport pct1-2 mutant.


Chromosomes kiss and tell: Long-range chromosome contacts modulate replication termination.


Repeat-element driven activation of proto-oncogenes in human malignancies. Recent data demonstrated that the aberrant activity of endogenous repetitive elements of the DNA in humans can drive the expression of proto-oncogenes. This article summarizes these results and gives an outlook on the impact of these findings on the pathogenesis and therapy of human cancer.


Identification of novel factors involved in or regulating initiation of DNA replication by a genome-wide phenotypic screen in Saccharomyces cerevisiae. DNA replication in eukaryotic cells is tightly regulated to ensure faithful inheritance of the genetic material. While the replicators, replication origins and many replication-initiation proteins in Saccharomyces cerevisiae have been identified and extensively studied, the detailed mechanism that controls the initiation of DNA replication is still not well understood. It is likely that some factors involved in or regulating the initiation of DNA replication have not been discovered. To identify novel DNA replication-initiation proteins and their regulators, we developed a sensitive and comprehensive phenotypic screen by combining several established genetic strategies including plasmid loss assays with plasmids containing a single versus multiple replication origins and colony color sectoring assays. We isolated dozen of mutants in previously known initiation proteins and identified several novel factors, including Ctf1p Ctf3p, Ctf4p, Ctf18p, Adk1p and Cdc60p, whose mutants lose plasmid containing a single replication origin at high rates but lose plasmid carrying multiple replication origins at lower rates. We also show that overexpression of replication initiation proteins causes synthetic dosage lethality or growth defects in ctf1 and ctf18 mutants and that Ctf1p and Ctf18p physically interact with ORC, Cdt1p and MCM proteins. Furthermore, depletion of both Ctf1p and Ctf18p prevents S phase entry, retards S phase progression, and reduces pre-RC formation during the M-to-G₁ transition. These data suggest that Ctf1p and Ctf18p together play important roles in regulating the initiation of DNA replication.


Two types of autophagy are better than one during hepatocyte oxidative stress.


Cis-interactions between non-coding ribosomal spacers dependent on RNAP-II separate RNAP-I and RNAP-III transcription domains. Ribosome biogenesis requires transcription of structural RNAs. In budding yeast, ribosomal units contain both 35S and 5S RNA genes separated by intergenic spacer sequences (IGS) that are transcribed by RNAP-II. IGS transcripts cause instability by promoting unequal sister chromatid recombination between repeats and are thus rapidly degraded by the exosome. Whether RNAP-II within IGS regions plays any functional role is unknown. Here we demonstrate that the bulk of RNAP-II bound to IGS sites is blocked for elongation and hence remains in a poised or stalled configuration. We describe a novel role for these stalled RNAP-II complexes in the formation of cis-interactions between the IGS of rDNA. We show that this function separates 35S and 5S RNA genes into polymerase-specific chromatin loops and demonstrate that removal of stalled RNAP-II complexes causes displacement of RNAP-III from the 5S gene region and transcriptional downregulation of 5S rRNA by spreading of RNAP-I. We conclude that stalled RNAP-II plays an active role in the cis-organisation of ribosomal repeats providing domains of polymerase specificity in the nucleolar transcription environment.


A novel role for greatwall kinase in recovery from DNA damage. Activation of the DNA damage response (DDR) is critical for genomic integrity and tumor suppression. The occurrence of DNA damage quickly evokes the DDR through ATM/ATR-dependent signal transduction, which promotes DNA repair and activates the checkpoint to halt cell cycle progression. The "turn off" process of the DDR upon satisfaction of DNA repair, also known as "checkpoint recovery", involves deactivation of DDR elements, but the mechanism is poorly understood. Greatwall kinase (Gwl) has been identified as a key element in the G(2)/M transition and helps maintain M phase through inhibition of PP 2A/B55δ, the principal phosphatase for Cdk-phosphorylated substrates. Here we show that Gwl also promotes recovery from DNA damage and is itself directly inhibited by the DNA damage response (DDR). In Xenopus egg extracts, immunodepletion of Gwl increased the DDR to damaged DNA, whereas addition of wild type, but not kinase dead Gwl, inhibited the DDR. The removal of damaged DNA from egg extracts leads to recovery from checkpoint arrest and entry into mitosis, a process impaired by Gwl depletion and enhanced by Gwl overexpression. Moreover, activation of Cdk1 after the removal of damaged DNA is regulated by Gwl. Collectively, these results defines Gwl as a new regulator of the DDR, which plays an important role in recovery from DNA damage.


An in vitro chemoresponse assay defines a subset of colorectal and lung carcinomas responsive to cetuximab. Cetuximab is a chimeric monoclonal antibody for the epidermal growth factor receptor (EGFR) that may provide benefit to select cancer patients; however, identification of the characteristics of those patients who may benefit from its use is not complete. The ChemoFx® drug response marker (DRM) is an in vitro assay that can provide drug response data on tumor specimens before any patient treatment is initiated. We determined the feasibility of using the ChemoFx DRM to test tumor samples for sensitivity to cetuximab. We exposed four non-small cell lung carcinoma (NSCLC) cell lines (H358, H520, HCC827, and H1666) to cetuximab and determined their sensitivity using the ChemoFx DRM and, in parallel, EGFR status using immunocytochemistry, Western blotting, and In-Cell Western (TM) analysis. We used the ChemoFx DRM to determine cetuximab sensitivity of primary NSCLC and colorectal tumor samples. The ChemoFx DRM distinguished between cetuximab-sensitive and -resistant cell lines. Cetuximab sensitivity was not dependent on EGFR mutational status; H358 cells were non-responsive to cetuximab yet contain wild-type EGFR, whereas H1666 cells were intermediately responsive to cetuximab and contain wild-type EGFR. HCC827 (EGFR-mutant) cells were intermediately responsive and, as expected, H520 cells (EGFR-null) were non-responsive to cetuximab. ChemoFx-determined cetuximab sensitivity of primary NSCLC and colorectal tumor samples was 9.0% and 7.5%, respectively. Use of the ChemoFx DRM is feasible for determining cetuximab sensitivity. The ChemoFx-determined cetuximab responses of primary NSCLC and colorectal tumor specimens were similar to published response rates of patients to treatment with cetuximab monotherapy.


Rfc5p regulates alternate RFC complex functions in sister chromatid pairing reactions in budding yeast. Sister chromatid pairing reactions, termed cohesion establishment, occur during S-phase and appear to be regulated by Replication Factor C (RFC) complexes. For instance, RFCs that contain Ctf18p exhibit pro-establishment activities while those that contain Elg1p exhibit anti-establishment activities. It remains unknown whether Ctf18p-RFC and Elg1p-RFC functions are simply opposing or instead reveal complicated and non-parallel regulatory mechanisms. To better understand the nature of these novel pathways, we analyzed the small RFC subunit Rfc5p that is common to both Ctf18p-RFC and Elg1p-RFC. Despite this commonality, the data show that diminished Rfc5p function rescues ctf7/eco1 mutant cell phenotypes, revealing that Rfc5p promotes anti-establishment activities. This rescue is specific to establishment pathways in that rfc5-1 greatly accentuates growth defects when expressed in scc2 (deposition), mcd1/scc1 or smc3 (cohesion maintenance) mutated cells. Our results reveal for the first time a role for small RFC subunits in directing RFC complex functions-in this case towards anti-establishment pathways. We further report that Pds5p exhibits both establishment and anti-establishment functions in cohesion. This duality suggests that categorizations of establishment and anti-establishment activities require further examination.


Shifting senescence into quiescence by turning up p53.


Redundancy and variation in the ubiquitin-mediated proteolytic targeting of a transcription factor. As central components of the intricate networks of eukaryotic gene regulation, transcription factors are frequent targets of ubiquitin-dependent proteolysis. A well-known example is the budding yeast MATα2 (α2) transcriptional repressor, which functions as a master regulator of cell-type determination. Degradation of α2 by the ubiquitin-proteasome system is necessary for a phenotypic switch from one cell type to another. A surprisingly complex set of ubiquitin-protein conjugation mechanisms are involved. One pathway utilizes an integral-membrane ubiquitin ligase (E3) that also functions in endoplasmic reticulum-associated degradation (ERAD). Recently, we showed that a second α2 ubiquitylation pathway uses a heterodimeric E3 that, while able to bind the ubiquitin-like protein SUMO, directly recognizes non-sumoylated α2. Other transcription factors are now also known to be ubiquitylated by multiple mechanisms; as many as a dozen E3s have been implicated in degradation of the human p53 tumor suppressor, for example. We discuss general issues of redundancy and mechanistic variation in protein modification by ubiquitin.


The role of miR-31 and its target gene SATB2 in cancer-associated fibroblasts. It is well established that there is a dynamic relationship between the expanding tumor and the host surrounding tissue. Cancer-associated fibroblasts (CAFs), the most common cellular population found in the tumor microenvironment, supporting tumor growth and dissemination. Here, we set out to determine the factors that may be involved in dramatic alteration of gene expression pattern in CAFs, focusing on microRNA and transcriptional regulators. We established matched pairs of human CAFs isolated from endometrial cancer and normal endometrial fibroblasts. MicroRNA and mRNA analyses identified differential expression of 11 microRNAs, with miR-31 being the most downregulated microRNA in CAFs (p = 0.007). We examined several putative miR-31 target genes identified by microarray analysis and demonstrated that miR-31 directly targets the homeobox gene SATB2, which is responsible for chromatin remodeling and regulation of gene expression, and was significantly elevated in CAFs. The functional relevance of miR-31 and SATB2 were tested in in vitro models of endometrial cancer. Overexpression of miR-31 significantly impaired the ability of CAFs to stimulate tumor cell migration and invasion, without affecting tumor cell proliferation. Genetic manipulation of SATB2 levels in normal fibroblasts or CAFs showed that, reciprocally to miR-31, SATB2 increased tumor cell migration and invasion, while knockdown of endogenous SATB2 in CAFs reversed this phenotype. Introduction of SATB2 into normal fibroblasts stimulated expression of a number of genes involved in cell invasion, migration and scattering. These findings provide new insights into tumor-stroma interaction and document that miR-31 and its target gene SATB2, are involved in regulation of tumor cell motility.


Autophagy in Gaucher disease due to saposin C deficiency. Gaucher disease, due to a deficit of glucosylceramidase or, rarely, of its activator saposin C, is characterized by accumulation of glucosylceramide in the lysosomes of monocyte/macrophage lineage. In our study we demonstrate that saposin C deficiency due to mutations involving a cysteine residue results in increased autophagy. Autophagy was monitored by LC3 analysis and confirmed by electron microscopy; we observed a correlation among saposin C mutation, Gaucher phenotype and increased autophagy.


Reduction of Pten dose leads to neoplastic development in multiple organs of Pten (shRNA) mice. To address the impact of partial reduction of Pten on tumor initiation, we generated PtenshRNA mice, in which PTEN expression was reduced below normal levels in various tissues. PtenshRNA mice frequently developed lymphoid and prostatic hyperplasia, splenomegaly, and sebaceous adenomas. Our observations support the notion that partial reduction of the dose of Pten with shRNA is sufficient to induce neoplastic disease in multiple organ systems.


Regulation of autophagy by extracellular matrix glycoproteins in HeLa cells. Macroautophagy is a major lysosomal degradation pathway for cellular components in eukaryotic cells. Baseline macroautophagy is important for quality control of the cytoplasm in order to avoid the accumulation of cytotoxic products. Its stimulation by various stressful situations, including nutrient starvation, is important in maintaining cell survival. Here we demonstrate that macroautophagy is regulated differently depending on whether HeLa cells adhere to collagen I or collagen IV, proteins typical of connective tissue and basal membrane, respectively. We observed that the basal levels of macroautophagy were higher in cells plated on collagen IV than in cells plated on collagen I or on uncoated substrate. However, the stimulation of macroautophagy by nutrient starvation, as reflected by the buildup of autophagosomes and the increase in the autophagic flux, was higher in cells plated on collagen I than in cells plated on collagen IV. These contrasting results were not due to differences in the starvation-dependent inhibition of mTOR complex 1 signaling. Interestingly, cells plated on collagen IV formed numerous focal adhesions (FAs), whereas fewer FAs were observed in cells plated on the other substrates. This implies that focal adhesion kinase (FAK) was more robustly activated by collagen IV. Silencing the expression of FAK by siRNA in cells plated on collagen IV shifted the autophagic phenotype of these cells to an "uncoated substrate autophagic phenotype" under both basal and starvation-induced conditions. Moreover, cells plated on collagen IV were less dependent on autophagy to survive in the absence of nutrients. We conclude that extracellular matrix components can modulate macroautophagy and mitigate its role in cell survival.


E2F1 regulation by the APC/C.

E2F1 regulation by the APC/C.


MAPK machinery in plants: recognition and response to different stresses through multiple signal transduction pathways. The mitogen-activated protein kinase (MAPK) cascades play diverse roles in intra- and extra-cellular signaling in plants. MAP kinases are the component of kinase modules which transfer information from sensors to responses in eukaryotes including plants. They play a pivotal role in transduction of diverse extracellular stimuli such as biotic and abiotic stresses as well as a range of developmental responses including differentiation, proliferation and death. Several cascades are induced by different biotic and abiotic stress stimuli such as pathogen infections, heavy metal, wounding, high and low temperatures, high salinity, UV radiation, ozone, reactive oxygen species, drought and high or low osmolarity. MAPK signaling has been implicated in biotic stresses and has also been associated with hormonal responses. The cascade is regulated by various mechanisms, including not only transcriptional and translational regulation but through post-transcriptional regulation such as protein-protein interactions. Recent detailed analysis of certain specific MAP kinase pathways have revealed the specificity of the kinases in the cascade, signal transduction patterns, identity of pathway targets and the complexity of the cascade. The latest insights and finding are discussed in this paper in relation to the role of MAPK pathway modules in plant stress signaling.


Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway. In the present study, we report that compound C, an inhibitor of a key intracellular energy sensor AMP-activated protein kinase (AMPK), can induce autophagy in cancer cells. The induction of autophagy in U251 human glioma cell line was demonstrated by acridine orange staining of intracellular acidic vesicles, Beclin 1 induction, p62 decrease and conversion of LC3-I to autophagosome-associated LC3-II in the presence of proteolysis inhibitors. The presence of autophagosome-like vesicles was confirmed by transmission electron microscopy. Compound C-mediated inhibition of AMPK and raptor in U251 cells was associated with paradoxical decrease in phosphorylation of AMPK/raptor-repressed mTOR, a major negative regulator of autophagy, and its downstream target p70S6K. The phosphorylation of an mTOR activator Akt and the PI3K-activating kinase Src was also impaired in compound C-treated cells. The siRNA-mediated AMPK silencing did not reduce the activity of the Akt/mTOR/p70S6K pathway and AMPK activators metformin and AIC AR failed to block compound C-induced autophagy. Autophagy inhibitors bafilomycin and chloroquine significantly increased the cytotoxicity of compound C towards U251 cells, as confirmed by increase in lactate dehydrogenase release, DNA fragmentation and caspase-3 activation. Similar effects of compound C were also observed in C6 rat glioma, L929 mouse fibrosarcoma and B16 mouse melanoma cell lines. Since compound C has previously been reported to suppress AMPK-dependent autophagy in different cell types, our findings suggest that the effects of compound C on autophagy might be dose-, cell type- and/or context-dependent. By demonstrating the ability of compound C to induce autophagic response in cancer cells via AMPK inhibition-independent downregulation of Akt/mTOR pathway, our results warrant caution when using compound C to inhibit AMPK-dependent cellular responses, but also support further exploration of compound C and related molecules as potential anticancer agents.


Chromatin unfolding by Cdt1 regulates MCM loading via opposing functions of HBO1 and HDAC11-geminin. The efficiency of metazoan origins of DNA replication is known to be enhanced by histone acetylation near origins. Although this correlates with increased MCM recruitment, the mechanism by which such acetylation regulates MCM loading is unknown. We show here that Cdt1 induces large-scale chromatin decondensation that is required for MCM recruitment. This process occurs in G₁, is suppressed by Geminin, and requires HBO1 HAT activity and histone H4 modifications. HDAC11, which binds Cdt1 and replication origins during S-phase, potently inhibits Cdt1-induced chromatin unfolding and re-replication, suppresses MCM loading and binds Cdt1 more efficiently in the presence of Geminin. We also demonstrate that chromatin at endogenous origins is more accessible in G₁ relative to S-phase. These results provide evidence that histone acetylation promotes MCM loading via enhanced chromatin accessibility. This process is regulated positively by Cdt1 and HBO1 in G₁ and repressed by Geminin-HDAC11 association with Cdt1 in S-phase, and represents a novel form of replication licensing control.


Identification of a high affinity TAG-72 binding peptide by phage display selection. Phage display was used to select novel peptides that specifically bind the TAG-72 antigen and with properties suitable for imaging TAG-72 positive cancers. After three rounds of selection against TAG-72 and using two different elution conditions including a long elution, the consensus sequences FRERCDKHPQKCTKFL and DPRHCQKRVLPCPAWL were expressed on phages G3-15 and T3-15 respectively. ELISA, fluorescence-activated cell sorting analysis and fluorescence microscopy provided evidence that both phages specifically bound TAG-72 in vitro. Both peptides are stable in 37oC serum. By a cell binding competition assay, the IC50 for T3-15 was measured as 0.29 nM and therefore 36-fold higher affinity than G3-15 at 10.32 nM. The biodistribution in mice carrying LS-174T tumors in one thigh were similar for both 99mTc-peptides at 30 min, but at 90 min the 99mTc-T3-15 peptide accumulated almost three times higher in the tumor. The SPECT/CT images were consistent with the biodistribution results. The f88-4/Cys6 phage library and two different elution conditions were used to identify two new higher affinity binding peptides for the TAG-72 antigen. One, was a single brief elution with pH 2.2 glycine buffer, and the second began with the glycine elution but was followed with a longer elution with Tris buffered saline (TBS) at pH 7.4. The phages that bound TAG-72 were evaluated by fluorescence-activated cell sorting analysis using TAG-72 positive LS-174T cells and confirmed by immunofluorescence imaging. The consensus peptides displayed on the selected phages were synthesized and conjugated with NHS-MAG3 for radiolabeling with 99mTc. The IC50 for TAG-72 binding was evaluated by cell binding competition in vitro while binding affinity was evaluated in vivo by necropsy and SPECT/CT imaging in a tumor mouse model. We have identified a peptide with a sub nanomolar inhibition constant for the TAG-72 antigen that may have application in cancer imaging.


InhibitING entry into S phase and cell cycle progression.


Laminin regulates PI3K basal localization and activation to sustain STAT5 activation. Extracellular matrix (ECM) is a key regulator of tissue morphogenesis and functional differentiation in the mammary gland. We showed recently that laminin-111 (LN1) together with prolactin induces β-casein expression in mammary epithelial cells (MECs) by sustaining STAT5 activation. Others have shown that Rac1 is required for integrin-mediated STAT5 activation, but molecules upstream of Rac1 remain to be elucidated. Here, we show that exposure to three-dimensional (3D) laminin-rich ECM (LrECM) gels changes the localization of phosphoinositide 3-kinase (PI3K) in MECs from diffuse to basal accompanied with the activation of PI3K-Rac1 signaling pathway. We show by co-immunoprecipitation that Rac1 associates with STAT5, and that LrECM treatment enhances this interaction. Blocking PI3K with LY294002 inhibits LrECM-dependent Rac1 activation, attenuates sustained STAT5 phosphorylation and blocks β-casein gene transcription. These results indicate that PI3K is a key mediator of the LN1-induced signaling cascade which controls the activity of transcription factors essential for tissue-specific gene expression.


Important proposals for education-service exchange programs.


Helicase-inactivating mutations as a basis for dominant negative  phenotypes. There is ample evidence from studies of both unicellular and multicellular organisms that helicase-inactivating mutations lead to cellular dysfunction and disease phenotypes. In this review, we will discuss the mechanisms underlying the basis for abnormal phenotypes linked to mutations in genes encoding DNA helicases. Recent evidence demonstrates that a clinically relevant patient missense mutation in Fanconi Anemia Complementation Group J exerts detrimental effects on the biochemical activities of the FANCJ helicase, and these molecular defects are responsible for aberrant genomic stability and a poor DNA damage response. The ability of FANCJ to use the energy from ATP hydrolysis to produce the force required to unwind duplex or G-quadruplex DNA structures or destabilize protein bound to DNA is required for its DNA repair functions in vivo. Strikingly, helicase-inactivating mutations can exert a spectrum of dominant negative phenotypes, indicating that expression of the mutant helicase protein potentially interferes with normal DNA metabolism and has an effect on basic cellular processes such as DNA replication, the DNA damage response and protein trafficking. This review emphasizes that future studies of clinically relevant mutations in helicase genes will be important to understand the molecular pathologies of the associated diseases and their impact on heterozygote carriers.


Would a Flexner Report today focus only on graduate medical education?


The important role of medical licensure in the United States.


Team-based learning: it's here and it WORKS!


Education-for-service is not enough to meet our workforce needs.


Commentary: A delicate balance: weighing the effects of conflict-of-interest rules on intramural research at the National Institutes of Health. In 2005, in response to increasing public concerns about potential conflicts of interest in biomedical research, the Department of Health and Human Services (DHHS) tightened its ethics rules to prohibit National Institutes of Health (NIH) employees from receiving consulting fees from "significantly affected organizations." In response, NIH took steps to implement these regulations and ensure that relationships between intramural NIH researchers and industry could proceed without threatening the integrity of federally funded research. Examples of these steps include creating an ethics advisory committee to review outside activities of NIH scientists and subjecting its researchers to special scrutiny to eliminate any perception of personal profit or conflict of interest. In the authors' experiences, interactions between NIH scientists and industry have continued relatively unaffected by these regulations. The continuing success of the technology transfer program at NIH and the number and types of cooperative research and development agreements with industry are good measures of the extent of productive interactions with industry since the implementation of the 2005 ethics rules. Although recruitment of outstanding scientists to the intramural program has continued, these regulations also have challenged NIH's ability to attract and retain some of the most qualified scientists, who fear they may miss certain opportunities because of the tighter regulations. As DHHS revises the regulations governing oversight of financial conflicts of interest in the extramural community, the authors recognize that the NIH intramural experience may provide valuable lessons about developing and implementing the next generation of financial conflict-of-interest rules.


Commentary: Taking back Year 4: a call to action. In this issue of Academic Medicine, Walling and Merando's literature review on the senior-year curriculum finds a broad consensus that this final year underperforms educationally at many U.S. medical schools, but little agreement on how to improve it. The review challenges us to consider how best to develop this key piece of educational real estate, which is too often frittered away on auditions, interview odysseys, and electives of uncertain educational value. In this commentary, the author approaches this education question from an unorthodox viewpoint, the delivery system and medical workforce perspectives. He proposes taking back major portions of Year 4 from elective clerkships and investing the time in required course work to prepare graduates to practice and lead in a redesigned 21st-century health system, providing superior access and outcomes at sustainable costs. The recommendations draw inspiration from the Institute of Medicine's "Chasm" reports, specifically echoing its 2003 Health Professions Education report that identified five new competencies deemed essential for all 21st-century health professionals. Finally, the author disputes the view that delivery system overhaul lies beyond the purview of educators, pointing to the historical precedent of the greatest medical paradigm shift of all time, the closure of the proprietary medical schools a century ago triggered by Flexner's report. The author closes by calling medical educators to action, to prepare the next generation of physicians to radically redesign health care and lead us out of the present crisis.


Commentary: Are we ready to embrace the rest of the Flexner Report? At the start of the 20th century, Abraham Flexner proposed a number of reforms for medical education in his seminal 1910 report, Medical Education in the United States and Canada. His recommendations were wide ranging, including a strong scientific basis, use of pedagogical methods, and faculty whose principal role is that of educator. Of these, reforms in science education for medicine received the widest attention and revolutionized physicians' intellectual foundations for medical practice. But what of Flexner's other suggested reforms, those skills needed to develop "the educated man" who can meet the "greatly modified ethical responsibility" of modern medical practice? As the 21st century begins, Flexner's ideas on these other subjects he considered critical for physician training are reappearing in the medical education literature. If history is a guide, medical education could be on the cusp of another set of great advances by renewing interest in medical humanities, reevaluating the makeup of medical school teaching faculty, and seeking innovations in pedagogy to facilitate active and integrated learning. The time is ripe to embrace the rest of the Flexner Report.


Commentary: Flexner and Dutch medical education: a misinterpretation? Abraham Flexner's 1910 report, Medical Education in the United States and Canada, was hardly noticed in the Netherlands, and though his 1925 book, Medical Education: A Comparative Study, was extensively discussed in the Dutch Medical Journal, it did not and could not affect medical education in the Netherlands. Until the 1970s, the medical curriculum in the Netherlands consisted of four phases: the propaedeutic year (premedical sciences), two preclinical years, two theoretical clinical years, and one-and-a-half to two years of clerkships. When in the 1970s interest in curriculum innovation arose in the Netherlands, it was based on developments in North America that challenged "Flexnerian" norms in medical education. As hardly anyone in the Netherlands cared to study Flexner's work closely, his name became synonymous with the conventional curriculum just as it had in North America. However, the Dutch conventional curriculum was quite different from the American conventional curriculum, so attributing its origins to Flexner's work was a serious misrepresentation. In this commentary, the author clarifies common misconceptions about the history of Dutch medical education and argues that the curriculum as Flexner saw it differed considerably from the Dutch medical curriculum a century ago.


No debt, better education, and better health care: what's not to like?


The Kansas Medical Student Loan program: a successful tuition-service exchange model.


The University of Chicago REACH program: improving health, decreasing debt.


Community partnerships: alternative means of financing medical school.


Service residencies: a new approach to the medical education-service exchange.


The "Medical Marshall Plan": rebuilding public trust in American medicine.


Return-of-service programs: meeting community and student needs in an ethical manner.


SERVICE: Selecting Educational Residencies with Value, Incentives, Cost, and Effectiveness.


The F. Edward Hébert School of Medicine model: tuition-free medical school in exchange for public service.


The Primary Care Med-ED Plan: reducing medical student indebtedness while expanding primary care.


Write.

Write.


Artist's statement: Transposition.

Artist's statement: Transposition.


2010 Humanism in Medicine Essay Contest: second place: The white coat.


Medicine and the arts. Portrait of Dr. Samuel D. Gross (The Gross Clinic) by Thomas Eakins. Commentary.


AM last page: The health reform law and academic medicine.


Early initiation of antiretroviral therapy and associated reduction in mortality, morbidity and defaulting in a nurse-managed, community cohort in Lesotho. The latest WHO guidelines recommend initiating antiretroviral therapy (ART) at CD4 cell counts less than 350 cells/μl. However, donors and national governments are reluctant to support implementation owing to uncertainty regarding feasibility and relative benefit. Lesotho has supported earlier initiation since 2008. We assessed outcomes comparing early (CD4 cell counts >200 cells/μl) and late (CD4 cell counts ≤200 cells/μl) initiation. We describe survival probability among patients initiating ART at CD4 cell counts 200 or less and more than 200 cells/μl and assess associations between baseline CD4 cell counts and mortality, morbidity, loss to follow-up and hospitalization using Cox regression adjusting for confounders identified a priori. Our analysis included 1177 patients; median age was 38 years and the majority (67%) were women. Median time on ART for the overall cohort was 506 days (interquartile range 396-608). Five hundred and thirty eight patients initiated ART at a CD4 cell count 200 cells/μl or less (interquartile range 54-160) and 639 patients initiated at CD4 cell count more than 200 cells/μl (interquartile range 238-321). In multivariate analysis, we found that patients initiating at CD4 cell count more than 200 cells/μl were 68% less likely to die (adjusted hazard ratio 0.32, 95% confidence interval 0.20-0.50), and 39% less likely to be lost to follow-up (adjusted hazard ratio 0.61, 95% confidence interval 0.43-0.87). Initiating ART at CD4 cell count more than 200 cells/μl was also associated with a 27% reduction in the rate of incident morbidity (adjusted hazard ratio 0.73, 95% confidence interval 0.65-0.82) and a 63% decreased rate of hospitalization (adjusted hazard ratio 0.37, 95% confidence interval 0.19-0.73). Earlier initiation is feasible in a low resource, high HIV prevalence setting, and provides important benefits in terms of reduced mortality, morbidity, retention and hospitalization. Donors should fully support the implementation of the latest WHO recommendations.


Antiretroviral treatment is a behavioural intervention: but why?


Raltegravir-induced cerebellar ataxia.

Raltegravir-induced cerebellar ataxia.


The role of the health system in HIV treatment-as-prevention.


HIV-positive child with epidermodysplasia verruciformis-like lesions and homozygous mutation in TMC6.


Seroreversion in vertically HIV-1-infected children treated early and efficiently: rule or exception?


Families are veterans, too.

Families are veterans, too.


A failure to rescue ourselves.

A failure to rescue ourselves.


Material safety data sheets.

Material safety data sheets.


Serving the patient.

Serving the patient.


Cover conundrum.

Cover conundrum.


Where does the waste go?

Where does the waste go?


Rectal cancer rates rising in patients under 40.


Working conditions at magnet hospitals.

Working conditions at magnet hospitals.


Cutting the pediatric insulin error rate.


Calcium supplements may increase heart disease risk.


Managing dysphagia through diet modifications. Dysphagia can lead to malnutrition, dehydration, aspiration pneumonia, and even death. The condition has diverse causes and symptoms vary widely. Nurses are likely to encounter patients with dysphagia in various settings, including acute care medical units, rehabilitation centers, and skilled nursing facilities. Dietary modification--altering the consistency of foods and liquids--is a fundamental aspect of dysphagia management. This article describes normal and impaired swallowing, discusses several types and levels of dietary modification, and offers readers a concise list of nursing considerations.


Chemotherapy drugs put health care workers at risk.


Caring for families with deployment stress.


Evidence-based practice, step by step: Critical appraisal of the evidence: part III. This is the seventh article in a series from the Arizona State University College of Nursing and Health Innovation's Center for the Advancement of Evidence-Based Practice. Evidence-based practice (EBP) is a problem-solving approach to the delivery of health care that integrates the best evidence from studies and patient care data with clinician expertise and patient preferences and values. When delivered in a context of caring and in a supportive organizational culture, the highest quality of care and best patient outcomes can be achieved. The purpose of this series is to give nurses the knowledge and skills they need to implement EBP consistently, one step at a time. Articles will appear every two months to allow you time to incorporate information as you work toward implementing EBP at your institution. Also, we've scheduled "Chat with the Authors" calls every few months to provide a direct line to the experts to help you resolve questions. See details below.


Preparing for a year on the battlefield.


RSS for the uninitiated.

RSS for the uninitiated.


Safe intrahospital transport of non-ICU patients. The Pennsylvania Patient Safety Reporting System is a confidential, statewide Internet reporting system to which all Pennsylvania hospitals, outpatient-surgery facilities, and birthing centers, as well as some abortion facilities, must file information on medical errors.Safety Monitor is a column from Pennsylvania's Patient Safety Authority, the authority that informs nurses on issues that can affect patient safety and presents strategies they can easily integrate into practice. For more information on the authority, visit www.patientsafetyauthority.org. For the original article discussed in this column or for other articles on patient safety, click on "Patient Safety Advisories" and then "Advisory Library" in the left-hand navigation menu.


Goodbye Cherry Ames.

Goodbye Cherry Ames.


The human carotid body: expression of oxygen sensing and signaling genes of relevance for anesthesia. Hypoxia is a common cause of adverse events in the postoperative period, where respiratory depression due to residual effects of drugs used in anesthesia is an important underlying factor. General anesthetics and neuromuscular blocking agents reduce the human ventilatory response to hypoxia. Although the carotid body (CB) is the major oxygen sensor in humans, critical oxygen sensing and signaling pathways have been investigated only in animals so far. Thus, the aim of this study was to characterize the expression of key genes and localization of their products involved in the human oxygen sensing and signaling pathways with a focus on receptor systems and ion channels of relevance in anesthesia. Six CBs were removed unilaterally from patients undergoing radical neck dissection. The gene expression and cell-specific protein localization in the CBs were investigated with DNA microarrays, real-time polymerase chain reaction, and immunohistochemistry. We found gene expression of the oxygen-sensing pathway, heme oxygenase 2, and the K channels TASK (TWIK-related acid sensitive K channel)-1 and BK (large-conductance potassium channel). In addition, we show the expression of critical receptor subunits such as γ-aminobutyric acid A (α2, β3, and γ2), nicotinic acetylcholine receptors (α3, α7, and β2), purinoceptors (A2A and P2X2), and the dopamine D2 receptor. In unique samples of the human CB, we here demonstrate presence of critical proteins in the oxygen-sensing and signaling cascade. Our findings demonstrate similarities to, but also important differences from, established animal models. In addition, our work establishes an essential platform for studying the interaction between anesthetic drugs and human CB chemoreception.


Retraction movement of the Frova airway intubation introducer to assist nasotracheal intubation in patients with limited mouth opening.


Neostigmine/glycopyrrolate administered after recovery from neuromuscular block increases upper airway collapsibility by decreasing genioglossus muscle activity in response to negative pharyngeal pressure. Reversal of residual neuromuscular blockade by acetylcholinesterase inhibitors (e.g., neostigmine) improves respiratory function. However, neostigmine may also impair muscle strength. We hypothesized that neostigmine administered after recovery of the train-of-four (TOF) ratio impairs upper airway integrity and genioglossus muscle function. We measured, in 10 healthy male volunteers, epiglottic and nasal mask pressures, genioglossus electromyogram, air flow, respiratory timing, and changes in lung volume before, during (TOF ratio: 0.5), and after recovery of the TOF ratio to unity, and after administration of neostigmine 0.03 mg/kg IV (with glycopyrrolate 0.0075 mg/kg). Upper airway critical closing pressure (Pcrit) was calculated from flow-limited breaths during random pharyngeal negative pressure challenges. Pcrit increased significantly after administration of neostigmine/glycopyrrolate compared with both TOF recovery (mean ± SD, by 27 ± 21%; P = 0.02) and baseline (by 38 ± 17%; P = 0.002). In parallel, phasic genioglossus activity evoked by negative pharyngeal pressure decreased (by 37 ± 29%, P = 0.005) compared with recovery, almost to a level observed at a TOF ratio of 0.5. Lung volume, respiratory timing, tidal volume, and minute ventilation remained unchanged after neostigmine/glycopyrrolate injection. Neostigmine/glycopyrrolate, when administered after recovery from neuromuscular block, increases upper airway collapsibility and impairs genioglossus muscle activation in response to negative pharyngeal pressure. Reversal with acetylcholinesterase inhibitors may be undesirable in the absence of neuromuscular blockade.


Identification of PD-1 as a unique marker for failing immune reconstitution in HIV-1-infected patients on treatment. PD-1 expression on T cells correlates with T-cell exhaustion and disease progression in HIV-infected patients. Previous studies have shown that combinational antiretroviral therapy induced viral suppression results in immune restoration and reduced PD-1 expression. However, a significant number of patients fail to restore CD4 T cells despite suppression of HIV replication below limit of quantification. In this study, we have analyzed PD-1 expression on CD4 and CD8 T cells in patients with poor immune reconstitution despite successful highly active antiretroviral therapy. We found that T cells of such patients express significantly higher levels of PD-1 than patients who had normal recovery of CD4 cells after treatment. In contrast, failing immune reconstitution was not associated with the expression of activation markers, indicating that PD-1 is a unique marker for failing immune reconstitution despite viral suppression. Furthermore, we show that T cells from patients with poor immune recovery differ from T cells of elderly in respect of their marker profile. PD-1 expression negatively correlated with individual CD4 cell counts, and PD-1 expressing T cells were more prone to programmed death ligand-mediated inhibition of T-cell proliferation, indicating that PD-1-mediated T-cell suppression may have a role in impaired immune reconstitution in HIV patients.


Structural, functional, and molecular alterations produced by aldosterone plus salt in rat heart: association with enhanced serum and glucocorticoid-regulated kinase-1 expression. We aimed to evaluate the structural, functional, inflammatory, and oxidative alterations, as well as serum and glucocorticoid-regulated kinase-1 (SGK-1) expression, produced in rat heart by aldosterone + salt administration. Fibrosis mediators such as connective tissue growth factor, matrix metalloproteinase 2, and tissue inhibitor of metalloproteinases 2 were also evaluated. Treatment with spironolactone was evaluated to prove mineralocorticoid mediation. Male Wistar rats received aldosterone (1 mg[middle dot]kg-1[middle dot]d-1) + 1% NaCl for 3 weeks. Half of the animals were treated with spironolactone (200 mg[middle dot]kg-1[middle dot]d-1). Systolic and diastolic blood pressures, left ventricle (LV) systolic pressure, and LV end-diastolic pressure were elevated (P < 0.05) in aldosterone + salt-treated rats. In aldosterone + salt-treated rats, -dP/dt decreased (P < 0.05), but +dP/dt was similar in all groups. Spironolactone normalized (P < 0.05) systolic blood pressure, diastolic blood pressure, LV systolic pressure, LV end-diastolic pressure, and -dP/dt. Relative heart weight, collagen content, messenger RNA expression of transforming growth factor beta, connective tissue growth factor, matrix metalloproteinase 2, tissue inhibitor of metalloproteinases 2, tumor necrosis factor alpha, interleukin-1[beta], p22phox, endothelial nitric oxide synhtase, and SGK-1 were increased (P < 0.05) in aldosterone + salt-treated rats, being reduced by spironolactone (P < 0.05). SGK-1 might be a key mediator in the structural, functional, and molecular cardiac alterations induced by aldosterone + salt in rats. All the observed changes and mediators are related with the activation of mineralocorticoid receptors.


Intracerebroventricular leptin administration differentially alters cardiac energy metabolism in mice fed a low-fat and high-fat diet. Leptin directly acts on peripheral tissues and alters energy metabolism in obese mice. It also has acute beneficial effects on these tissues via its hypothalamic action. However, it is not clear what effect chronic intracerebroventrical (ICV) leptin administration has on cardiac energy metabolism. We examined the effects of chronic ICV leptin on glucose and fatty acid metabolism in isolated working hearts from high-fat-fed and low-fat-fed mice. Mice were fed a high-fat (60% calories from fat) or low-fat (10% calories from fat) diet for 8 weeks before ICV leptin (5 [mu]g/d) for 7 days. In low-fat-fed mice, leptin increased glucose oxidation rates in isolated working hearts when compared with control [203 +/- 21 vs. 793 +/- 93 nmol[middle dot](g dry weight)-1[middle dot]min-1]. In high-fat-fed mice leptin inhibited fatty acid oxidation [476 +/- 73 vs. 251 +/- 38 nmol[middle dot](g[middle dot]dry[middle dot]wt)-1[middle dot]min-1]. The increase in glucose oxidation in low-fat-fed mice was accompanied by increased pyruvate dehydrogenase activity. In high-fat-fed mice, leptin increased cardiac malonyl coenzyme A levels, secondary to a decrease in malonyl coenzyme A decarboxylase expression. These results suggest that ICV leptin alters cardiac energy metabolism opposite to its peripheral effects and that these effects differ depending on energy substrate supply to the mice.


HIV-related stigma, social norms, and HIV testing in Soweto and Vulindlela, South Africa: National Institutes of Mental Health Project Accept (HPTN 043). HIV testing is necessary to curb the increasing epidemic. However, HIV-related stigma and perceptions of low likelihood of societal HIV testing may reduce testing rates. This study aimed to explore this association in South Africa, where HIV rates are extraordinarily high. Data were taken from the Soweto and Vulindlela, South African sites of Project Accept, a multinational HIV prevention trial. Self-reported HIV testing, stigma, and social norms items were used to study the relationship between HIV testing, stigma, and perceptions about societal testing rates. The stigma items were broken into 3 factors: negative attitudes, negative perceptions about people living with HIV, and perceptions of fair treatment for people living with HIV (equity). Results from a univariate logistic regression suggest that history of HIV testing was associated with decreased negative attitudes about people living with HIV/AIDS, increased perceptions that people living with HIV/AIDS experience discrimination, and increased perceptions that people with HIV should be treated equitably. Results from a multivariate logistic regression confirm these effects and suggest that these differences vary according to sex and age. Compared with people who had never tested for HIV, those who had previously tested were more likely to believe that the majority of people have tested for HIV. Data suggest that interventions designed to increase HIV testing in South Africa should address stigma and perceptions of societal testing.


Hemodynamic actions of corticotropin-releasing hormone and proopiomelanocortin derivatives in septic patients. Proopiomelanocortin (POMC) derivatives and mRNA of POMC have been detected in cardiomyocytes and vascular smooth muscle cells. Increased plasma levels of POMC derivatives have been found in septic patients during cardiovascular deregulation; therefore, we evaluated whether corticotroph-type (ACTH, β-endorphin, β-lipotropin) or melanotroph-type (α-melanocyte-stimulating hormone and N-acetyl-β-END) POMC derivatives have influences on patients' hemodynamics during sepsis. Seventeen septic patients were monitored by pulmonary artery catheter and corticotropin-releasing hormone (CRH) tests were performed by intravenous administration of 100 μg CRH. Before, 15, 30, 45, and 60 minutes after CRH administration, hemodynamic variables were measured, and plasma concentrations of POMC derivatives were determined. After CRH administration, heart rate, cardiac index, and stroke index increased, and the systemic vascular resistance index decreased; moreover, a correlation between ACTH concentration and stroke index as well as an inverse correlation between (α-melanocyte-stimulating hormone concentration and systemic vascular resistance index was observed. CRH and ACTH may have opposite effects on the blood pressure (mean arterial pressure). Immediately after CRH injection mean arterial pressure decreased. ACTH (in contrast to β-endorphin or β-lipotropin), released into the cardiovascular compartment 15 minutes after CRH injection, might have raised mean arterial pressure as compatible with the correlation between ACTH levels and stroke index. (α-melanocyte-stimulating hormone appears to have a vasodilative effect during sepsis.


Hemodynamic and metabolic effects of para- versus intraaortic counterpulsatile circulation supports. Despite the success of intraaortic balloon counterpulsation, data on physiologic indices and optimal inflation/deflation timing control of chronic counterpulsation devices are unclear. This study explored the acute hemodynamic and metabolic efficacy of a novel 40-ml stroke volume paraaortic blood pump (PABP) versus a standard intraaortic balloon pump (IABP). Acute porcine model was used with eight pigs randomly divided into PABP (n = 4) and IABP (n = 4) groups. Hemodynamic and metabolic measurements were obtained with and without mechanical assistance. In one pig, the inflation/deflation control was adjusted to different settings, with corresponding performance indices measured. The PABP significantly improved classical counterpulsation indices (p ≤ 0.05) and achieved an average beneficial effect on these indices 1.5-3.5 times greater than that of the IABP. Classical metabolic indices (tension time index and endocardial viability ratio [EVR]), and indices new to chronic counterpulsation research (coronary perfusion, left ventricular stroke work (SW), and a newly derived EVR) were also used in assessment. Both IABP assistance and PABP assistance improved these physiologic indices, with a trend toward PABP superiority in reducing left ventricular SW (p = 0.08). An optimal PABP deflation timing occurs during systole (25 milliseconds after the R-wave) and can minimize coronary regurgitation.


The effect of St John's Wort on the pharmacodynamic response of clopidogrel in hyporesponsive volunteers and patients: increased platelet inhibition by enhancement of CYP3A4 metabolic activity. Clopidogrel is metabolically activated by cytochrome P450 (CYP) isoenzymes. We evaluated whether St. John's wort (SJW), a CYP2C19 and CYP3A4 inducer, enhances the pharmacodynamic response of clopidogrel. Volunteers (n = 45) were screened for clopidogrel hyporesponsiveness after a 300-mg load. After a 7-day washout, hyporesponders (n = 10) received 14 days of SJW (300 mg 3 times a day) followed by a second 300-mg clopidogrel. Platelet aggregation was measured at 0, 2, 4, and 6 hours postloading; hepatic CYP3A4 activity was simultaneously determined at 0 and 4 hours by the erythromycin breath test. A prospective, randomized, double-blind pilot study was conducted in postcoronary stent patients (n = 85) on clopidogrel 75 mg/d screened for clopidogrel hyporesponsiveness. Hyporesponders (n = 20) were randomized to SJW (n = 10) or placebo (n = 10); platelet aggregation was measured before and after 14 days of therapy. In volunteers, SJW decreased platelet aggregation (59% ± 14% vs. 40% ± 15% at 2 hours, P = 0.02; 56% ± 10% vs. 44% ± 13% at 4 hours, P < 0.03; and 55% ± 14% vs. 37% ± 14% at 6 hours, P = 0.01) and increased CYP3A4 activity (2.1% ± 0.4% CO2 exhaled per hour before vs. 2.9% ± 0.6% CO2 exhaled per hour after SJW, P = 0.002). In patients, SJW decreased platelet reactivity (226 ± 39 vs. 185 ± 49 P2Y12 reactivity units, P = 0.0002) and increased platelet inhibition (23% ± 11% vs. 41% ± 16%, P = 0.002). SJW may be a future therapeutic option to increase CYP metabolic activity and antiplatelet effect of clopidogrel in hyporesponders.


Electrophysiological properties of HBI-3000: a new antiarrhythmic agent with multiple-channel blocking properties in human ventricular myocytes. HBI-3000 (sulcardine sulfate) has been shown to suppress various ventricular arrhythmias in animal models. The electrophysiological properties of HBI-3000 were investigated using standard microelectrode and patch-clamp techniques in single human ventricular myocytes. HBI-3000 led to concentration-dependent suppression of dofetilide-induced early afterdepolarizations in single nonfailing human ventricular myocytes and early afterdepolarizations seen in failing ventricular myocytes. The concentration-dependent prolongation of action potential duration (APD) by HBI-3000 was bell shaped with maximum response occurring around 10 μM. Interestingly, HBI-3000 at the concentration of 10 μM modestly prolonged the APD at all 3 basic cycle lengths. The slope of APD-cycle length curve of HBI-3000 was only slightly steeper than that of control (88.8 ± 7.7 ms/s vs. 78.9 ± 5.2 ms/s in control, n = 8, P > 0.05). HBI-3000 only showed a minimal use-dependent prolongation of the APD in human ventricular myocytes. HBI-3000 inhibited fast sodium current (INa-F), late sodium channel (INa-L), L-type calcium current (ICa-L), and rapidly activating delayed rectifier K current (IKr) in single human ventricular myocytes. The estimated half-maximal inhibitory concentration values of INa-F, INa-L, ICa-L, and IKr were 48.3 ± 3.8, 16.5 ± 1.4, 32.2 ± 2.9, and 22.7 ± 2.5 μM, respectively. The ion channel profile and electrophysiological properties of HBI-3000 are similar to those of ranolazine and chronic amiodarone (reduced INa-F, INa-L, ICa-L, and IKr). HBI-3000 may be a promising antiarrhythmic agent with low proarrhythmic risk.


Elite sprinting: are athletes individually step-frequency or step-length reliant? The aim of this study was to investigate the step characteristics among the very best 100-m sprinters in the world to understand whether the elite athletes are individually more reliant on step frequency (SF) or step length (SL). A total of 52 male elite-level 100-m races were recorded from publicly available television broadcasts, with 11 analyzed athletes performing in 10 or more races. For each run of each athlete, the average SF and SL over the whole 100-m distance was analyzed. To determine any SF or SL reliance for an individual athlete, the 90% confidence interval (CI) for the difference between the SF-time versus SL-time relationships was derived using a criterion nonparametric bootstrapping technique. Athletes performed these races with various combinations of SF and SL reliance. Athlete A10 yielded the highest positive CI difference (SL reliance), with a value of 1.05 (CI = 0.50-1.53). The largest negative difference (SF reliance) occurred for athlete A11 as -0.60, with the CI range of -1.20 to 0.03. Previous studies have generally identified only one of these variables to be the main reason for faster running velocities. However, this study showed that there is a large variation of performance patterns among the elite athletes and, overall, SF or SL reliance is a highly individual occurrence. It is proposed that athletes should take this reliance into account in their training, with SF-reliant athletes needing to keep their neural system ready for fast leg turnover and SL-reliant athletes requiring more concentration on maintaining strength levels.


Role of microRNAs in cardiac preconditioning. Preconditioning (PC) of the heart by sublethal ischemia, mild heat shock, or hypoxia has evolved as a powerful experimental tool to discover novel signaling mechanisms in cardioprotection. The ultimate goal is to determine novel therapeutic targets for potential application in humans to protect the heart against ischemia-related injuries. In recent years, there has been a tremendous interest in understanding the role of small noncoding RNAs, microRNAs (miRs), in cardiovascular diseases. miRs have been recognized as regulators of gene expression by destabilization and translational inhibition of target messenger RNAs. Studies have shown that several miRs, including miR-1, miR-133, miR-21, miR-126, miR-320, miR-92a, and miR-199a, are regulated after preconditioning and play an active role in protecting the heart against ischemia/reperfusion injury. These miRs also drive the synthesis of important cardioprotective proteins including heat shock protein (HSP)-70, endothelial nitric oxide synthase, inducible nitric oxide synthase, HSP-20, Sirt1, and hypoxia-inducible factor 1a. We believe that identification and targeted delivery of miR(s) in the heart could have an immense therapeutic potential in reducing myocardial infarction in patients suffering from heart disease.


Body mass, training, menses, and bone in adolescent runners: a 3-yr follow-up. Endurance runners with low bone mass during adolescence may risk attaining a low peak bone mineral density (BMD) in adulthood. Alternatively, they may mature late and undergo delayed bone mineral accumulation. The purpose of this study was to evaluate 40 adolescent runners (aged 15.9 ± 0.2 yr) at two time points, approximately 3 yr apart, to assess bone mass status and identify variables associated with bone mass change. Follow-up measures included a questionnaire to assess menstrual status, training, and sports participation history, height and weight, and a dual-energy x-ray absorptiometry scan to assess total body, total hip, and lumbar spine BMD, bone mineral content (BMC), BMD z-score, and body composition. We used -1 and -2 BMD z-score cutoffs to categorize runners with low bone mass. Eighty-seven percent of girls with low BMD at baseline had low BMD at the follow-up. Girls with low compared with normal baseline BMD had lower follow-up adjusted total body (2220.4 ± 65.8 vs 2793.1 ± 68.2 g, P < 0.001), total hip (27.0 ± 1 vs 33.9 ± 1.0 g, P < 0.05), and lumbar spine (47.8 ± 2.0 vs 66.3 ± 2.2 g, P < 0.001) BMC values. Variables related to 3-yr training volume, menstrual function, age, developmental stage, and change in body mass explained 29%-54% of the variability in BMC change. The majority of adolescent runners with low BMD at baseline had low BMD after a 3-yr follow-up. Our observations suggest that "catch-up" accrual may be difficult and, thus, emphasize the importance of gaining adequate bone mineral during the early adolescent years.


Effects of whole-body vibration training on different devices on bone mineral density. Whole-body vibration (WBV) is a new nonpharmacological approach to counteract osteoporosis. However, the specific vibration protocol to most effectively reduce osteoporotic risk has not been reported. In the ELVIS II (Erlangen Longitudinal Vibration Study II) trial, we determined the effect of different WBV devices on bone mineral density (BMD) and neuromuscular performance. A total of 108 postmenopausal women (65.8 ± 3.5 yr) were randomly allocated to 1) rotational vibration training (RVT), i.e., 12.5 Hz, 12 mm, three sessions per week, for 15 min, including dynamic squat exercises; 2) vertical vibration training (VVT), i.e., 35 Hz, 1.7 mm, as above; and 3) a wellness control group (CG), i.e., two blocks of 10 low-intensity gymnastics sessions. BMD was measured at the hip and lumbar spine at baseline and after 12 months of training using dual-energy x-ray absorptiomety. Maximum isometric leg extension strength and leg power were determined using force plates. A BMD gain at the lumbar spine was observed in both vibration VT groups (RVT = +0.7% ± 2.2%, VVT = +0.5% ± 2.0%), which was significant compared with the CG value (-0.4% ± 2.0%) for RVT (P = 0.04) and borderline nonsignificant for VVT (P = 0.08). In the neck region, no significant treatment effect occurred. Neck BMD values tended to increase in both VT groups (RVT = +0.3% ± 2.7%, VVT = +1.1% ± 3.4%) and remained stable in CG (-0.0% ± 2.1%).Both VT groups gained maximum leg strength (RVT = +27% ± 22%, VVT = +24% ± 34%) compared with CG (+6% ± 20%, P = 0.000), whereas power measurements did not reach the level of significance (P = 0.1). WBV training is effective for reducing the risk for osteoporosis by increasing lumbar BMD and leg strength.


Hormonal responses to resistance exercise during different menstrual cycle states. To investigate the effect of menstrual cycle states on ovarian and anabolic hormonal responses to acute resistance exercise in young women. Eight healthy women (eumenorrhea; EM) and eight women with menstrual disorders including oligomenorrhea and amenorrhea (OAM) participated in this study. The EM group performed acute resistance exercises during the early follicular (EF) and midluteal (ML) phases, and the OAM group performed the same exercises. All subjects performed three sets each of lat pull-downs, leg curls, bench presses, leg extensions, and squats at 75%-80% of one-repetition maximum with a 1-min rest between sets. Blood samples were obtained before exercise, immediately after, 30 min after, and 60 min after the exercise. In the EM group, resting serum levels of estradiol and progesterone in the ML phase were higher than those in the EF phase and higher than those in the OAM group. Serum estradiol and progesterone in the ML phase increased after the exercise but did not change in the EF phase or in the OAM group. In contrast, resting levels of testosterone in the OAM group were higher than those in both the ML and EF phases of the EM group. After the exercise, serum growth hormone increased in both the ML and EF phases but did not change in the OAM group. The responses of anabolic hormones to acute resistance exercise are different among the menstrual cycle states in young women. Women with menstrual disturbances with low estradiol and progesterone serum levels have an attenuated anabolic hormone response to acute resistance exercise, suggesting that menstrual disorders accompanying low ovarian hormone levels may affect exercise-induced change in anabolic hormones in women.


Effectiveness of sulfur-containing antioxidants in delaying skeletal muscle fatigue. Reactions involving thiol biochemistry seem to play a crucial role in skeletal muscle fatigue. N-acetylcysteine amide (NACA) and L-ergothioneine (ERGO) are thiol-based antioxidants available for human use that have not been evaluated for effects on muscle fatigue. To test the hypothesis that NACA and ERGO delay skeletal muscle fatigue. We exposed mouse diaphragm fiber bundles to buffer (CTRL), NACA, ERGO, or N-acetylcysteine (NAC; positive control). Treatments were performed in vitro using 10 mM for 60 min at 37 °C. After treatment, we determined the muscle force-frequency and fatigue characteristics. The force-frequency relationship was shifted to the left by ERGO and to the right by NACA compared with CTRL and NAC. Maximal tetanic force was similar among groups. The total force-time integral (FTI; N · s · cm) during the fatigue trial was decreased by NACA (420 ± 35, P < 0.05), unaffected by ERGO (657 ± 53), and increased by NAC (P < 0.05) compared with CTRL (581 ± 54). The rate of contraction (dF/dtMAX) during the fatigue trial was not affected by any of the treatments tested. NAC, but not NACA or ERGO, delayed the slowing of muscle relaxation (dF/dtMIN) during fatigue. In summary, NACA and ERGO did not delay skeletal muscle fatigue in vitro. We conclude that these antioxidants are unlikely to improve human exercise performance.


Pelvic reconstruction with mesh for advanced pelvic organ prolapse: a new economic surgical method. The aim of this study was to introduce a new pelvic reconstructive surgical operation with use of specially designed puncture needles and precut mesh. In addition, the anatomic results and the safety of this reconstructive approach were evaluated. Ninety-nine women who were older than 60 years with stage III or IV prolapse according to pelvic organ prolapse quantification (POP-Q) underwent the modified pelvic reconstructive surgical operation. Follow-up was more than 1 year. The objective and subjective results were measured by POP-Q and quality-of-life questionnaires, respectively. Complications were also observed both in the surgical operation and in the follow-up examination. No severe intraoperative complications were observed. POP-Q measurements of Ba, Bp, and C taken 1 year postoperatively were significantly improved compared with those at baseline (P < 0.001), but eight women (8.1%) showed recurrence. A significant improvement in quality-of-life scores was observed (P < 0.001). The incidence rate of mesh exposure and the de novo urgent incontinence rates were 2% and 12%, respectively. This new pelvic reconstructive surgical operation is a cost-effective and safe method and is easy to perform.


Relationship of television time with accelerometer-derived sedentary time: NHANES. To examine the relationship of self-reported television (TV) viewing time with accelerometer-derived total sedentary time and to determine whether it differs by subgroup. Using data for adults (≥20 yr) from the 2003-2004 and 2005-2006 nationally representative US National Health and Nutrition Examination Surveys (NHANES; n=5738), linear regression models examined the associations of categories of self-reported TV viewing time (<1, 1, 2, 3, 4, and >5 h·d) with accelerometer-derived sedentary time (<100 counts per minute; h·d). Spearman ρ assessed the correlation between participants' rankings on the two measures. Analyses were stratified by gender, age, race/ethnicity, and, in the 2003-2004 NHANES cycle, by work status among working-aged adults (20-65 yr, n=2069). TV viewing time was significantly associated with sedentary time, with positive associations for all gender, age, race/ethnicity groups, and for those not working or working part-time, but not for those in full-time work. However, correlations between rankings of the measures were only "fair" overall (ρ=0.22) and were similar for all gender and racial/ethnic groups and for those of mid- and older age but not for those of younger age (20-39 yr, ρ=0.05). In the working-aged subgroup, there was also a fair correlation between the measures for those not working (ρ=0.22) but no significant correlation for those in part-time (ρ=0.14) or full-time work (ρ=0.03). Associations of TV viewing time with accelerometer-derived total sedentary time were statistically significant, but correlations were of only fair magnitude, and the strength of the relationship was not consistent across all population subgroups. These findings suggest that TV viewing time has an influence on overall sedentary time at a population level; however, measurement of sedentary time in other domains is also important.


Overexpression of piccolo C2A domain induces depression-like behavior in mice. Piccolo is one of the components of the active zone at chemical synapses and regulates the transport of synaptic vesicles. The piccolo C2A domain is an important calcium sensor and binds with phosphatidylinositol or synaptotagmin-1. Recently, clinical studies suggested that a single nucleotide polymorphism in the piccolo C2A domain might be a causal risk factor for major depression. To clarify the association of piccolo with depression, we produced a transgenic mouse overexpressing the C2A domain of piccolo, and investigated the behavior of these mice. The mice exhibited depression-like behavior in both forced swim and tail suspension tests, suggesting that piccolo might regulate the depressive behavior.


The relationship between respiratory viral loads and diagnosis in children presenting to a pediatric hospital emergency department. respiratory viral infections account for a considerable proportion of pediatric emergency room visits. Illnesses range in severity from mild upper respiratory tract infections to serious lower respiratory tract infections (LRTI). The relationship between viral load and specific viruses to clinical diagnosis made by physicians in this setting is poorly understood. we applied a real-time, quantitative polymerase chain reaction (qPCR) panel for 13 common respiratory viruses to 195 frozen, archival nasopharyngeal aspirate specimens obtained from symptomatic children ≤ 4 months of age presenting to the emergency room. Mean total viral load and number of viruses per archival nasopharyngeal aspirate specimen were compared between LRTI (n = 70) and non-LRTI (1 or more of upper respiratory tract infection, fever, or cough) (n = 125), as were yield and concordance of qPCR results to viral culture/direct fluorescence assay (DFA). children with LRTI had significantly increased total viral load and harbored more viruses than the non-LRTI group. Respiratory syncytial virus-A and -B were significantly associated with LRTI, and parainfluenza virus-1 with non-LRTI. Individual loads of parainfluenza virus-2 and human rhinovirus were increased in LRTI versus non-LRTI. Quantitative PCR yielded more viruses (including coinfections, where a "dominant virus" was typically identified) than viral culture/DFA and documented nucleic acid from pathogens not tested by culture/DFA including human rhinovirus; coronaviruses -OC43, -229E, and -NL63; and metapneumovirus. in symptomatic children presenting to the emergency room, total viral load is related to clinical diagnosis; specific viruses are associated with particular clinical diagnoses, and qPCR has a higher yield than other viral diagnostic methods.


Altered gentamicin serum concentrations in obese pediatric patients. We performed a retrospective case-cohort study of 50 obese pediatric patients aged 2 to 18 years who received scheduled gentamicin therapy, with serum peak and trough concentrations measured. Obese pediatric patients had significantly higher gentamicin serum peak and trough concentrations despite receiving significantly lower mg/kg of actual body weight doses of gentamicin.


Safety and immunogenicity of a booster dose of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine coadministered with DTPw-HBV/Hib and poliovirus vaccines. The safety and reactogenicity profiles of the 10-valent pneumococcal conjugate vaccine, PHiD-CV, and 7vCRM were comparable within the Philippines and Poland when coadministered as a booster dose with DTPw-HBV/Hib and poliovirus vaccines to toddlers primed with the same vaccines. Robust immune responses for all 10 vaccine pneumococcal serotypes and protein D following PHiD-CV booster vaccination were indicative of effective priming.


2010 Dietary Guidelines. Updated recommendations put focus on obesity.


New criteria proposes using pain, symptoms to diagnose fibromyalgia.


Women who eat healthy diets may lower risk of cataracts.


Radon. Protect yourself from an invisible threat.


Mayo Clinic office visit. Raynaud's disease. An interview with Kevin Moder, M.D.


Interval training. Boost your fitness in quick bursts.


Are older people more sensitive to cold weather?


Does trigeminal neuralgia always get worse over time?


New once-daily, long-acting inhaled β₂-agonist: what role will it play in the treatment of chronic obstructive pulmonary disease?


Subclinical organ damage in perimenopausal women with essential hypertension. Hypertension and its complications are more common in postmenopausal women than before menopause. However, whether this is due to the effect of age or menopause is still unknown. The aim of the study was to assess the effect of menopause on blood pressure (BP), left ventricular and vascular structure and function, as well as kidney function in perimenopausal women. The study involved 192 women aged 40 to 60 years (mean age, 51.73 ±1.82 years), including 152 with newly diagnosed essential hypertension and 40 normotensive controls matched for age. In all subjects, 24-hour BP monitoring was performed. Echocardiographic examination with the assessment of left ventricular mass (LVM) and systolic and diastolic function,as well as carotid ultrasound with the measurement of intima-media thickness (IMT) in the common carotid artery were performed. Carotid-femoral pulse wave velocity (PWV) was measured. Glomerular filtration rate (eGFR) was calculated and urinary albumin-creatinine ratio (UACR) was measured. The study group was divided according to hypertension and menopausal status into 4 subgroups: normotensive premenopausal, normotensive postmenopausal, hypertensive premenopausal, and hypertensive postmenopausal women. Menopause did not affect BP or LVM. Differences in LVM between pre- and postmenopausal women were dependent on age and the body mass index. Hypertensive postmenopausal compared with hypertensive premenopausal women had significantly higher IMT (0.72 ±0.34 mm vs. 0.59 ±0.30 mm, P = 0.001) and a lower ratio of early to late mitral inflow velocity (E/A, 1.04 ±0.32 vs. 1.32 ±0.33, P = 0.01). PWV was higher in hypertensives compared to controls (9.7 ±1.6 m/s vs. 8.4 ±1.2 m/s, P = 0.001), without differences between premenopausal and postmenopausal women. Menopause did not affect eGFR and UACR either in the hypertensive or normotensive group. Left ventricular diastolic function and carotid IMT are independently associated with menopausal status in both normo- and hypertensive women. Menopause per se did not affect BP in the examined group.


N-acetylcysteine fails to prevent renal dysfunction and oxidative stress after noniodine contrast media administration during percutaneous coronary interventions. Oxidative stress is believed to have a role in contrast-induced nephropathy. Based on this assumption, several known antioxidants have been studied to assess their effect on nephropathy, especially N-acetylcysteine (NAC). However, its usefulness has yet to be confirmed. We aimed to assess whether NAC has any protective effect on contrast-induced renal dysfunction, and whether NAC affects the parameters of oxidative stress in serum and urine. Sixty patients with coronary artery disease, who presented for an elective percutaneous coronary intervention (PCI), were randomized into 2 groups in an age- and gender-matched fashion: one group received 600 mg intravenous NAC and the other did not. Before and 24 hours after the procedure, blood and urine samples were obtained to assess total oxidant capacity (TOC), total antioxidant capacity (TAC), oxidative stress index (OSI), and renal function. Twenty-four hours after PCI, TOC and OSI levels were significantly increased and TAC levels significantly decreased, both in serum and urine. However, we did not observe any differences in oxidative parameters between patients who received NAC and those who did not. Multivariate analyses identified no protective effect of NAC on renal function, and no effect on oxidative parameters in either serum or urine. In this first clinical study that determined TOC and TAC levels in both serum and urine after exposure to contrast media, NAC was not found to affect oxidant parameters or protect against contrast nephropathy, at least in patients without the risk factors for nephropathy, such as diabetes mellitus or baseline renal or cardiac dysfunction.


Association between glycemic control and the level of knowledge and disease awareness in type 2 diabetic patients. Diabetes-related complications may be prevented if good metabolic control is achieved. In addition to drug therapy, patient education may facilitate better glycemic control. The aim of the study was to assess the relationship between glycemic control and effective diabetes education using the knowledge and awareness (KA) questionnaire in type 2 diabetic patients. Moreover, the effect of age, duration of diabetes, sex, body mass index (BMI), and education level on glycemic control was assessed cross-sectionally. The study included 164 patients with type 2 diabetes. The KA questionnaire, adapted for Turkish population, was distributed among patients after establishing whether they received diabetes education. Associations between the questionnaire scores and glycated hemoglobin (HbA(1c)), fasting blood glucose (FBG), and BMI were assessed. A significant negative correlation was observed between KA scores and HbA(1c) and FBG levels. Sixty-three patients had received diabetes education. These patients had higher KA scores compared with the remaining group (24.0 ±4.0 vs. 16.8 ±5.37, respectively; P <0.0001) and lower HbA1c levels (6.5% vs. 8.5%, respectively; P <0.0001). In type 2 diabetic patients, the higher the KA score, the more efficient glycemic control can be achieved. Patients who require diabetes education can be identified by using questionnaires that determine their KA level and by using HbA(1c) tests.


Aspirin chemoprevention of gastrointestinal cancer in the next decade. A review of the evidence. Together, gastrointestinal (GI) cancers now account for 25% of neoplastic deaths in the West. In Poland, GI cancer rates are likely to increase further as westernization progresses. Given that conventional cancer therapies have made only modest reductions in cancer mortality, there is a great interest in chemoprevention to prevent or slow malignant transformation from premalignant lesions. The financial pressures in the immediate future require even more stringent criteria for chemopreventive agents - they must be cheap but also safe and efficacious. In this regard, several reviews have indicated that aspirin possesses many favorable qualities for chemoprevention. Furthermore, meta-analyses indicate that aspirin may decrease cancer by approximately 30%. Several large clinical trials are underway, including AspECT (Aspirin and Esomeprazole Chemoprevention Trial) that aims not only to prevent cancer but also decrease the gastric side effects by combining aspirin with potent acid-suppressing drugs. In conclusion, whether aspirin will be the world's first proven chemopreventive agent is currently unknown but the evidence looks hopeful.


Progression of retinopathy in persons with type 2 diabetes: new data, same conclusions? The ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial was designed primarily to examine the effects of intensive glycemic control on cardiovascular events in persons with type 2 diabetes who were, for additional reasons, at high risk for such events. The trial also examined effects on the same endpoints of intervention on blood pressure and on serum lipids. The study intervention on glycemic control was stopped early because of the effects of this intervention on mortality. The trial provided important data on the effects of the various interventions on diabetic retinopathy, confirming the importance of intensive glycemic control in diminishing the progression of retinopathy. In addition, it provided evidence of a protective effect of fenofibrate treatment on the same retinopathy endpoint. However, the apparent paradoxical effects of intensive glycemic control on macrovascular and microvascular disease suggests caution in the care of persons with type 2 diabetes who are judged to be at high risk for cardiovascular events.


How should we treat tuberculosis in adult patients with chronic kidney disease? Key messages from the British Thoracic Society Guidelines. This review highlights the key messages from the 2010 British Thoracic Society Guidelines on the management of Mycobacterium tuberculosis infection and disease in adult patients with chronic kidney disease. These guidelines were developed in response to many requests for advice from respiratory and infectious diseases physicians who treat patients with tuberculosis, as there was very little information available to help clinicians manage the disease in this population of often very sick patients. Renal units in the United Kingdom were prescribing variable chemoprophylaxis regimens that frequently had no basis in evidence, and drug doses used to treat tuberculosis were often inappropriate because of clinicians' natural concern about poisoning a patient with little or no renal function. The guidelines address these issues together with when and how to screen for latent infection and the different needs of patients with renal impairment, those needing dialysis and those with a transplanted kidney. It became very clear in compiling these guidelines that there is a shortage of both background information on rates of tuberculosis in such patients in countries with low background prevalence, and good randomized controlled trials of treatment regimens. Wherever possible, the recommendations made are evidence-based, but this was not always available. This review gives a summary of those recommendations and reiterates some of the important messages; in particular, tuberculosis should be managed with the full involvement of the chest or infectious diseases physician who is the local lead for this important infection.


Integrated care for patients with advanced chronic obstructive pulmonary disease: a new approach to organization. Chronic obstructive pulmonary disease (COPD) affects approximately 10% of the population aged above 40 years. In advanced COPD (forced expiratory volume in 1 second <50% of the predicted value), patients suffer from severe pulmonary symptoms including dyspnea, chronic cough, poor exercise tolerance, which are commonly associated with systemic disorders, such as osteoporosis, loss of fat-free body mass, fatigue, anxiety, and depression. Moreover, patients with advanced COPD experience annually an average of 2 to 3 episodes of exacerbations requiring hospitalization. We present here a model of integrated care based on the cooperation between medical staff, social workers, volunteers and patients and their families. The essential components of this model are intensive education, treatment supervision, and support in self-management as well as coping with the disease and its consequences. It is expected that these measures will result in a decreased number of exacerbations requiring hospitalization, improved disease course, and better quality of life.


The antimicrobial and phagocytic defense mechanisms of the terrestrial gastropod Lehmannia nyctelia against Escherichia coli and Staphylococcus aureus. Gastropods are significant vectors of human infectious diseases and are exposed to a wide range of soil parasites and micro-organisms. To defend against infection, we hypothesized that the slug produces both soluble and cellular defense mechanisms. In the gastropod Lehmannia nyctelia, soluble antimicrobial activity was measured by disk diffusion assay and phagocytosis was measured by in vitro and in vivo uptake of fluorescent Escherichia coli bioparticles. In disk diffusion assays we failed to observe either methanol or dimethylsulfoxide soluble material in the slug secretions and tissues. However, isolation of the slug skin cells demonstrated phagocytic morphology in vitro when exposed to Escherichia coli and Staphylococcus aureus and internalization of fluorescent Escherichia coli bioparticles. Further, examination of histological sections of a slug exposed to fluorescent Escherichia coli bioparticles revealed a subset of skin cells which had cytoplasmic accumulations of the bioparticles. These data suggest that the Lehmannia nyctelia skin contains active phagocytic cells that may affect the set of parasites and microbes for which slugs can serve as vectors of disease.


Identification of a µ opiate receptor signaling mechanism in human placenta. Previous studies report that genes in the morphine biosynthetic pathway have been found in placental tissue. Prior researchers have shown that kappa opioid receptors are present in human placenta. We determined if a µ opiate receptor was present and which subtype was expressed in human placenta. We also sought to demonstrate a functional µ opiate receptor in human placenta. Polymerase chain reactions as well as DNA sequencing were performed to identify the µ opiate receptor subtypes present in human placenta. The functionality of the receptor was demonstrated by real time amperometric measurements of morphine induced NO release. The µ4 opiate receptor sequence was present as well as the µ1 opioid receptor transcript. The addition of morphine to placental tissue resulted in immediate nitric oxide release and this effect was blocked by naloxone. In the present study, an intact morphine signaling system has been demonstrated in human placenta. Morphine signaling in human placenta probably functions to regulate the immune, vascular, and endocrine functions of this organ via NO.