A Novel Virus-Like Particle Based Vaccine Platform Displaying the Placental Malaria Antigen VAR2CSA.

PubMed

Thrane, Susan; Janitzek, Christoph M; Agerbæk, Mette Ø; Ditlev, Sisse B; Resende, Mafalda; Nielsen, Morten A; Theander, Thor G; Salanti, Ali; Sander, Adam F

2015-01-01

Placental malaria caused by Plasmodium falciparum is a major cause of mortality and severe morbidity. Clinical testing of a soluble protein-based vaccine containing the parasite ligand, VAR2CSA, has been initiated. VAR2CSA binds to the human receptor chondroitin sulphate A (CSA) and is responsible for sequestration of Plasmodium falciparum infected erythrocytes in the placenta. It is imperative that a vaccine against malaria in pregnancy, if administered to women before they become pregnant, can induce a strong and long lasting immune response. While most soluble protein-based vaccines have failed during clinical testing, virus-like particle (VLP) based vaccines (e.g., the licensed human papillomavirus vaccines) have demonstrated high efficacy, suggesting that the spatial assembly of the vaccine antigen is a critical parameter for inducing an optimal long-lasting protective immune response. We have developed a VLP vaccine display platform by identifying regions of the HPV16 L1 coat protein where a biotin acceptor site (AviTagTM) can be inserted without compromising VLP-assembly. Subsequent biotinylation of Avi-L1 VLPs allow us to anchor monovalent streptavidin (mSA)-fused proteins to the biotin, thereby obtaining a dense and repetitive VLP-display of the vaccine antigen. The mSA-VAR2CSA antigen was delivered on the Avi-L1 VLP platform and tested in C57BL/6 mice in comparison to two soluble protein-based vaccines consisting of naked VAR2CSA and mSA-VAR2CSA. The mSA-VAR2CSA Avi-L1 VLP and soluble mSA-VAR2CSA vaccines induced higher antibody titers than the soluble naked VAR2CSA vaccine after three immunizations. The VAR2CSA Avi-L1 VLP vaccine induced statistically significantly higher endpoint titres compared to the soluble mSA-VAR2CSA vaccine, after 1st and 2nd immunization; however, this difference was not statistically significant after 3rd immunization. Importantly, the VLP-VAR2CSA induced antibodies were functional in inhibiting the binding of parasites to CSA. This study demonstrates that the described Avi-L1 VLP-platform may serve as a versatile system for facilitating optimal VLP-display of large and complex vaccine antigens.

Identification of a Major Dimorphic Region in the Functionally Critical N-Terminal ID1 Domain of VAR2CSA

PubMed Central

Doritchamou, Justin; Sabbagh, Audrey; Jespersen, Jakob S.; Renard, Emmanuelle; Salanti, Ali; Nielsen, Morten A.; Deloron, Philippe; Tuikue Ndam, Nicaise

2015-01-01

The VAR2CSA protein of Plasmodium falciparum is transported to and expressed on the infected erythrocyte surface where it plays a key role in placental malaria (PM). It is the current leading candidate for a vaccine to prevent PM. However, the antigenic polymorphism integral to VAR2CSA poses a challenge for vaccine development. Based on detailed analysis of polymorphisms in the sequence of its ligand-binding N-terminal region, currently the main focus for vaccine development, we assessed var2csa from parasite isolates infecting pregnant women. The results reveal for the first time the presence of a major dimorphic region in the functionally critical N-terminal ID1 domain. Parasite isolates expressing VAR2CSA with particular motifs present within this domain are associated with gravidity- and parasite density-related effects. These observations are of particular interest in guiding efforts with respect to optimization of the VAR2CSA-based vaccines currently under development. PMID:26393516

Structure of the DBL3X-DBL4ε region of the VAR2CSA placental malaria vaccine candidate: insight into DBL domain interactions

PubMed Central

Gangnard, Stéphane; Lewit-Bentley, Anita; Dechavanne, Sébastien; Srivastava, Anand; Amirat, Faroudja; Bentley, Graham A.; Gamain, Benoît

2015-01-01

The human malaria parasite, Plasmodium falciparum, is able to evade spleen-mediated clearing from blood stream by sequestering in peripheral organs. This is due to the adhesive properties conferred by the P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) family exported by the parasite to the surface of infected erythrocytes. Expression of the VAR2CSA variant of PfEMP1 leads to pregnancy-associated malaria, which occurs when infected erythrocytes massively sequester in the placenta by binding to low-sulfated Chondroitin Sulfate A (CSA) present in the intervillous spaces. VAR2CSA is a 350 kDa protein that carries six Duffy-Binding Like (DBL) domains, one Cysteine-rich Inter-Domain Regions (CIDR) and several inter-domain regions. In the present paper, we report for the first time the crystal structure at 2.9 Å of a VAR2CSA double domain, DBL3X-DBL4ε, from the FCR3 strain. DBL3X and DBL4ε share a large contact interface formed by residues that are invariant or highly conserved in VAR2CSA variants, which suggests that these two central DBL domains (DBL3X-DBL4ε) contribute significantly to the structuring of the functional VAR2CSA extracellular region. We have also examined the antigenicity of peptides corresponding to exposed loop regions of the DBL4ε structure. PMID:26450557

VAR2CSA signatures of high Plasmodium falciparum parasitemia in the placenta.

PubMed

Rovira-Vallbona, Eduard; Monteiro, Isadora; Bardají, Azucena; Serra-Casas, Elisa; Neafsey, Daniel E; Quelhas, Diana; Valim, Clarissa; Alonso, Pedro; Dobaño, Carlota; Ordi, Jaume; Menéndez, Clara; Mayor, Alfredo

2013-01-01

Plasmodium falciparum infected erythrocytes (IE) accumulate in the placenta through the interaction between Duffy-binding like (DBL) domains of parasite-encoded ligand VAR2CSA and chondroitin sulphate-A (CSA) receptor. Polymorphisms in these domains, including DBL2X and DBL3X, may affect their antigenicity or CSA-binding affinity, eventually increasing parasitemia and its adverse effects on pregnancy outcomes. A total of 373 DBL2X and 328 DBL3X sequences were obtained from transcripts of 20 placental isolates infecting Mozambican women, resulting in 176 DBL2X and 191 DBL3X unique sequences at the protein level. Sequence alignments were divided in segments containing combinations of correlated polymorphisms and the association of segment sequences with placental parasite density was tested using Bonferroni corrected regression models, taking into consideration the weight of each sequence in the infection. Three DBL2X and three DBL3X segments contained signatures of high parasite density (P<0.003) that were highly prevalent in the parasite population (49-91%). Identified regions included a flexible loop that contributes to DBL3X-CSA interaction and two DBL3X motifs with evidence of positive natural selection. Limited antibody responses against signatures of high parasite density among malaria-exposed pregnant women could not explain the increased placental parasitemia. These results suggest that a higher binding efficiency to CSA rather than reduced antigenicity might provide a biological advantage to parasites with high parasite density signatures in VAR2CSA. Sequences contributing to high parasitemia may be critical for the functional characterization of VAR2CSA and the development of tools against placental malaria.

Antibody levels to recombinant VAR2CSA domains vary with Plasmodium falciparum parasitaemia, gestational age, and gravidity, but do not predict pregnancy outcomes.

PubMed

Fried, Michal; Kurtis, Jonathan D; Swihart, Bruce; Morrison, Robert; Pond-Tor, Sunthorn; Barry, Amadou; Sidibe, Youssoufa; Keita, Sekouba; Mahamar, Almahamoudou; Andemel, Naissem; Attaher, Oumar; Dembele, Adama B; Cisse, Kadidia B; Diarra, Bacary S; Kanoute, Moussa B; Narum, David L; Dicko, Alassane; Duffy, Patrick E

2018-03-09

Maternal malaria is a tropical scourge associated with poor pregnancy outcomes. Women become resistant to Plasmodium falciparum pregnancy malaria as they acquire antibodies to the variant surface antigen VAR2CSA, a leading vaccine candidate. Because malaria infection may increase VAR2CSA antibody levels and thereby confound analyses of immune protection, gravidity-dependent changes in antibody levels during and after infection, and the effect of VAR2CSA antibodies on pregnancy outcomes were evaluated. Pregnant women enrolled in a longitudinal cohort study of mother-infant pairs in Ouelessebougou, Mali provided plasma samples at enrollment, gestational week 30-32, and delivery. Antibody levels to VAR2CSA domains were measured using a multiplex bead-based assay. Antibody levels to VAR2CSA were higher in multigravidae than primigravidae. Malaria infection was associated with increased antibody levels to VAR2CSA domains. In primigravidae but not in secundigravidae or multigravidae, antibodies levels sharply declined after an infection. A relationship between any VAR2CSA antibody specificity and protection from adverse pregnancy outcomes was not detected. During malaria infection, primigravidae acquire short-lived antibodies. The lack of an association between VAR2CSA domain antibody reactivity and improved pregnancy outcomes suggests that the recombinant proteins may not present native epitopes targeted by protective antibodies.

Overproduction, purification and crystallization of a chondroitin sulfate A-binding DBL domain from a Plasmodium falciparum var2csa-encoded PfEMP1 protein

DOE Office of Scientific and Technical Information (OSTI.GOV)

Higgins, Matthew K., E-mail: mkh20@cam.ac.uk

A chondroitin sulfate A-binding DBL important in placental malaria has been overproduced, purified and crystallized. Diffraction data were collected to 1.9 Å resolution. The PfEMP1 proteins of the malaria parasite Plasmodium falciparum are inserted into the membrane of infected red blood cells, where they mediate adhesion to a variety of human receptors. The DBL domains of the var2csa-encoded PfEMP1 protein play a critical role in malaria of pregnancy, tethering infected cells to the surface of the placenta through interactions with the glycosaminoglycan carbohydrate chondroitin sulfate A (CSA). A CSA-binding DBL domain has been overproduced in a bacterial expression system, purifiedmore » and crystallized. Native data sets extending to 1.9 Å resolution have been collected and phasing is under way.« less

Lack of gender-specific antibody recognition of products from domains of a var gene implicated in pregnancy-associated Plasmodium falciparum malaria.

PubMed

Jensen, Anja T R; Zornig, Hanne D; Buhmann, Caecilie; Salanti, Ali; Koram, Kwadwo A; Riley, Eleanor M; Theander, Thor G; Hviid, Lars; Staalsoe, Trine

2003-07-01

Gender-specific and parity-dependent acquired antibody recognition is characteristic of variant surface antigens (VSA) expressed by chondroitin sulfate A (CSA)-adherent Plasmodium falciparum involved in pregnancy-associated malaria (PAM). However, antibody recognition of recombinant products of a specific VSA gene (2O2var1) implicated in PAM and transcribed by a CSA-adhering parasite line did not have these characteristics. Furthermore, we could not demonstrate preferential transcription of 2O2var1 in the CSA-adhering line versus the unselected, parental isolate. Our data call for circumspection regarding the molecular identity of the parasite ligand mediating adhesion to CSA in PAM.

High Levels of Antibodies to Multiple Domains and Strains of VAR2CSA Correlate with the Absence of Placental Malaria in Cameroonian Women Living in an Area of High Plasmodium falciparum Transmission

PubMed Central

Tutterrow, Yeung L.; Avril, Marion; Singh, Kavita; Long, Carole A.; Leke, Robert J.; Sama, Grace; Salanti, Ali; Smith, Joseph D.; Leke, Rose G. F.

2012-01-01

Placental malaria, caused by sequestration of Plasmodium falciparum-infected erythrocytes in the placenta, is associated with increased risk of maternal morbidity and poor birth outcomes. The parasite antigen VAR2CSA (variant surface antigen 2-chondroitin sulfate A) is expressed on infected erythrocytes and mediates binding to chondroitin sulfate A, initiating inflammation and disrupting homeostasis at the maternal-fetal interface. Although antibodies can prevent sequestration, it is unclear whether parasite clearance is due to antibodies to a single Duffy binding-like (DBL) domain or to an extensive repertoire of antibodies to multiple DBL domains and allelic variants. Accordingly, plasma samples collected longitudinally from pregnant women were screened for naturally acquired antibodies against an extensive panel of VAR2CSA proteins, including 2 to 3 allelic variants for each of 5 different DBL domains. Analyses were performed on plasma samples collected from 3 to 9 months of pregnancy from women living in areas in Cameroon with high and low malaria transmission. The results demonstrate that high antibody levels to multiple VAR2CSA domains, rather than a single domain, were associated with the absence of placental malaria when antibodies were present from early in the second trimester until term. Absence of placental malaria was associated with increasing antibody breadth to different DBL domains and allelic variants in multigravid women. Furthermore, the antibody responses of women in the lower-transmission site had both lower magnitude and lesser breadth than those in the high-transmission site. These data suggest that immunity to placental malaria results from high antibody levels to multiple VAR2CSA domains and allelic variants and that antibody breadth is influenced by malaria transmission intensity. PMID:22331427

Comparison of functional assays used in the clinical development of a placental malaria vaccine.

PubMed

Pehrson, Caroline; Heno, Kristine K; Adams, Yvonne; Resende, Mafalda; Mathiesen, Line; Soegaard, Max; de Jongh, Willem A; Theander, Thor G; Salanti, Ali; Nielsen, Morten A

2017-01-23

Malaria in pregnancy is associated with significant morbidity in pregnant women and their offspring. Plasmodium falciparum infected erythrocytes (IE) express VAR2CSA that mediates binding to chondroitin sulphate A (CSA) in the placenta. Two VAR2CSA-based vaccines for placental malaria are in clinical development. The purpose of this study was to evaluate the robustness and comparability of binding inhibition assays used in the clinical development of placental malaria vaccines. The ability of sera from animals immunised with different VAR2CSA constructs to inhibit IE binding to CSA was investigated in three in vitro assays using 96-well plates, petri dishes, capillary flow and an ex vivo placental perfusion assay. The inter-assay variation was not uniform between assays and ranged from above ten-fold in the flow assay to two-fold in the perfusion assay. The intra-assay variation was highest in the petri dish assay. A positive correlation between IE binding avidity and the level of binding after antibody inhibition in the petri dish assay indicate that high avidity IE binding is more difficult to inhibit. The highest binding inhibition sensitivity was found in the 96-well and petri dish assays compared to the flow and perfusion assays where binding inhibition required higher antibody titers. The inhibitory capacity of antibodies is not easily translated between assays and the high sensitivity of the 96-well and petri dish assays stresses the need for comparing serial dilutions of serum. Furthermore, IE binding avidity must be in the same range when comparing data from different days. There was an overall concordance in the capacity of antibody-mediated inhibition, when comparing the in vitro assays with the perfusion assay, which more closely represents in vivo conditions. Importantly the ID1-ID2a protein in a liposomal formulation, currently in a phase I trial, effectively induced antibodies that inhibited IE adhesion in placental tissue. Copyright © 2016. Published by Elsevier Ltd.

Placenta-specific drug delivery by trophoblast-targeted nanoparticles in mice

PubMed Central

Zhang, Baozhen; Tan, Lunbo; Yu, Yan; Wang, Baobei; Chen, Zhilong; Han, Jinyu; Li, Mengxia; Chen, Jie; Xiao, Tianxia; Ambati, Balamurali K; Cai, Lintao; Yang, Qing; Nayak, Nihar R; Zhang, Jian; Fan, Xiujun

2018-01-01

Rationale: The availability of therapeutics to treat pregnancy complications is severely lacking, mainly due to the risk of harm to the fetus. In placental malaria, Plasmodium falciparum-infected erythrocytes (IEs) accumulate in the placenta by adhering to chondroitin sulfate A (CSA) on the surfaces of trophoblasts. Based on this principle, we have developed a method for targeted delivery of payloads to the placenta using a synthetic placental CSA-binding peptide (plCSA-BP) derived from VAR2CSA, a CSA-binding protein expressed on IEs. Methods: A biotinylated plCSA-BP was used to examine the specificity of plCSA-BP binding to mouse and human placental tissue in tissue sections in vitro. Different nanoparticles, including plCSA-BP-conjugated nanoparticles loaded with indocyanine green (plCSA-INPs) or methotrexate (plCSA-MNPs), were administered intravenously to pregnant mice to test their efficiency at drug delivery to the placenta in vivo. The tissue distribution and localization of the plCSA-INPs were monitored in live animals using an IVIS imaging system. The effect of plCSA-MNPs on fetal and placental development and pregnancy outcome were examined using a small-animal high-frequency ultrasound (HFUS) imaging system, and the concentrations of methotrexate in fetal and placental tissues were measured using high-performance liquid chromatography (HPLC). Results: plCSA-BP binds specifically to trophoblasts and not to other cell types in the placenta or to CSA-expressing cells in other tissues. Moreover, we found that intravenously administered plCSA-INPs accumulate in the mouse placenta, and ex vivo analysis of the fetuses and placentas confirmed placenta-specific delivery of these nanoparticles. We also demonstrate successful delivery of methotrexate specifically to placental cells by plCSA-BP-conjugated nanoparticles, resulting in dramatic impairment of placental and fetal development. Importantly, plCSA-MNPs treatment had no apparent adverse effects on maternal tissues. Conclusion: These results demonstrate that plCSA-BP-guided nanoparticles could be used for the targeted delivery of payloads to the placenta and serve as a novel placenta-specific drug delivery option. PMID:29774074

Differential recognition of P. falciparum VAR2CSA domains by naturally acquired antibodies in pregnant women from a malaria endemic area.

PubMed

Brolin, Kim J M; Persson, Kristina E M; Wahlgren, Mats; Rogerson, Stephen J; Chen, Qijun

2010-02-16

Plasmodium falciparum infected red blood cells (iRBC) express variant surface antigens (VSA) of which VAR2CSA is involved in placental sequestration and causes pregnancy-associated malaria (PAM). Primigravidae are most susceptible to PAM whereas antibodies associated with protection are often present at higher levels in multigravid women. However, HIV co-infection with malaria has been shown to alter this parity-dependent acquisition of immunity, with more severe symptoms as well as more malaria episodes in HIV positive women versus HIV negative women of a similar parity. Using VAR2CSA DBL-domains expressed on the surface of CHO-745 cells we quantified levels of DBL-domain specific IgG in sera from pregnant Malawian women by flow cytometry. Dissociations constants of DBL5epsilon specific antibodies were determined using a surface plasmon resonance technique, as an indication of antibody affinities. VAR2CSA DBL5epsilon was recognized in a gender and parity-dependent manner with anti-DBL5epsilon IgG correlating significantly with IgG levels to VSA-PAM on the iRBC surface. HIV positive women had lower levels of anti-DBL5epsilon IgG than HIV negative women of similar parity. In primigravidae, antibodies in HIV positive women also showed significantly lower affinity to VAR2CSA DBL5epsilon. Pregnant women from a malaria-endemic area had increased levels of anti-DBL5epsilon IgG by parity, indicating this domain of VAR2CSA to be a promising vaccine candidate against PAM. However, it is important to consider co-infection with HIV, as this seems to change the properties of antibody response against malaria. Understanding the characteristics of antibody response against VAR2CSA is undoubtedly imperative in order to design a functional and efficient vaccine against PAM.

Functional Antibodies against VAR2CSA in Nonpregnant Populations from Colombia Exposed to Plasmodium falciparum and Plasmodium vivax

PubMed Central

Doritchamou, Justin; Arango, Eliana M.; Cabrera, Ana; Arroyo, Maria Isabel; Kain, Kevin C.; Ndam, Nicaise Tuikue; Maestre, Amanda

2014-01-01

In pregnancy, parity-dependent immunity is observed in response to placental infection with Plasmodium falciparum. Antibodies recognize the surface antigen, VAR2CSA, expressed on infected red blood cells and inhibit cytoadherence to the placental tissue. In most settings of malaria endemicity, antibodies against VAR2CSA are predominantly observed in multigravid women and infrequently in men, children, and nulligravid women. However, in Colombia, we detected antibodies against multiple constructs of VAR2CSA among men and children with acute P. falciparum and Plasmodium vivax infection. The majority of men and children (>60%) had high levels of IgGs against three recombinant domains of VAR2CSA: DBL5ε, DBL3X, and ID1-ID2. Surprisingly, these antibodies were observed only in pregnant women, men, and children exposed either to P. falciparum or to P. vivax. Moreover, the anti-VAR2CSA antibodies are of high avidity and efficiently inhibit adherence of infected red blood cells to chondroitin sulfate A in vitro, suggesting that they are specific and functional. These unexpected results suggest that there may be genotypic or phenotypic differences in the parasites of this region or in the host response to either P. falciparum or P. vivax infection outside pregnancy. These findings may hold significant clinical relevance to the pathophysiology and outcome of malaria infections in this region. PMID:24686068

Multiplexing detection of IgG against Plasmodium falciparum pregnancy-specific antigens

PubMed Central

Fonseca, Ana Maria; Quinto, Llorenç; Jiménez, Alfons; González, Raquel; Bardají, Azucena; Maculuve, Sonia; Dobaño, Carlota; Rupérez, Maria; Vala, Anifa; Aponte, John J.; Sevene, Esperanza; Macete, Eusebio; Menéndez, Clara

2017-01-01

Background Pregnant women exposed to Plasmodium falciparum generate antibodies against VAR2CSA, the parasite protein that mediates adhesion of infected erythrocytes to the placenta. There is a need of high-throughput tools to determine the fine specificity of these antibodies that can be used to identify immune correlates of protection and exposure. Here we aimed at developing a multiplex-immunoassay to detect antibodies against VAR2CSA antigens. Methods and findings We constructed two multiplex-bead arrays, one composed of 3 VAR2CSA recombinant-domains (DBL3X, DBL5Ɛ and DBL6Ɛ) and another composed of 46 new peptides covering VAR2CSA conserved and semi-conserved regions. IgG reactivity was similar in multiplexed and singleplexed determinations (Pearson correlation, protein array: R2 = 0.99 and peptide array: R2 = 0.87). IgG recognition of 25 out of 46 peptides and all recombinant-domains was higher in pregnant Mozambican women (n = 106) than in Mozambican men (n = 102) and Spanish individuals (n = 101; p<0.05). Agreement of IgG levels detected in cryopreserved plasma and in elutions from dried blood spots was good after exclusion of inappropriate filter papers. Under heterogeneous levels of exposure to malaria, similar seropositivity cutoffs were obtained using finite mixture models applied to antibodies measured on pregnant Mozambican women and average of antibodies measured on pregnant Spanish women never exposed to malaria. The application of the multiplex-bead array developed here, allowed the assessment of higher IgG levels and seroprevalences against VAR2CSA-derived antigens in women pregnant during 2003–2005 than during 2010–2012, in accordance with the levels of malaria transmission reported for these years in Mozambique. Conclusions The multiplex bead-based immunoassay to detect antibodies against selected 25 VAR2CSA new-peptides and recombinant-domains was successfully implemented. Analysis of field samples showed that responses were specific among pregnant women and dependent on the level of exposure to malaria. This platform provides a high-throughput approach to investigating correlates of protection and identifying serological markers of exposure for malaria in pregnancy. PMID:28715465

Murine Model for Preclinical Studies of Var2CSA-Mediated Pathology Associated with Malaria in Pregnancy

PubMed Central

Dechavanne, Sebastien; Sousa, Patrícia M.; Barateiro, André; Cunha, Sónia F.; Nunes-Silva, Sofia; Lima, Flávia A.; Murillo, Oscar; Marinho, Claudio R. F.; Gangnard, Stephane; Srivastava, Anand; Braks, Joanna A.; Janse, Chris J.; Gamain, Benoit; Penha-Gonçalves, Carlos

2016-01-01

Plasmodium falciparum infection during pregnancy leads to abortions, stillbirth, low birth weight, and maternal mortality. Infected erythrocytes (IEs) accumulate in the placenta by adhering to chondroitin sulfate A (CSA) via var2CSA protein exposed on the P. falciparum IE membrane. Plasmodium berghei IE infection in pregnant BALB/c mice is a model for severe placental malaria (PM). Here, we describe a transgenic P. berghei parasite expressing the full-length var2CSA extracellular region (domains DBL1X to DBL6ε) fused to a P. berghei exported protein (EMAP1) and characterize a var2CSA-based mouse model of PM. BALB/c mice were infected at midgestation with different doses of P. berghei-var2CSA (P. berghei-VAR) or P. berghei wild-type IEs. Infection with 104 P. berghei-VAR IEs induced a higher incidence of stillbirth and lower fetal weight than P. berghei. At doses of 105 and 106 IEs, P. berghei-VAR-infected mice showed increased maternal mortality during pregnancy and fetal loss, respectively. Parasite loads in infected placentas were similar between parasite lines despite differences in maternal outcomes. Fetal weight loss normalized for parasitemia was higher in P. berghei-VAR-infected mice than in P. berghei-infected mice. In vitro assays showed that higher numbers of P. berghei-VAR IEs than P. berghei IEs adhered to placental tissue. Immunization of mice with P. berghei-VAR elicited IgG antibodies reactive to DBL1-6 recombinant protein, indicating that the topology of immunogenic epitopes is maintained between DBL1-6–EMAP1 on P. berghei-VAR and recombinant DBL1-6 (recDBL1-6). Our data suggested that impairments in pregnancy caused by P. berghei-VAR infection were attributable to var2CSA expression. This model provides a tool for preclinical evaluation of protection against PM induced by approaches that target var2CSA. PMID:27045035

Targeting Common but Complex Proteoglycans on Breast Cancer Cells and Stem Cells Using Evolutionary Refined Malaria Proteins

DTIC Science & Technology

2014-09-01

protein VAR2CSA. We have extensive data demonstrating that this protein specifically targets sulfated chondroitin sulfate A proteoglycans present on all... chondroitin sulfate A on circulating tumor cells using a evolutionary refined malaria protein B) National Annual PhD meeting in Oncology, March 26-27...malaria protein VAR2CSA when sulfated on carbon 4 of the CS backbone. We have identified CSPG4 as a major protein in breast cancer cells, but also a

B-Cell Responses to Pregnancy-Restricted and -Unrestricted Plasmodium falciparum Erythrocyte Membrane Protein 1 Antigens in Ghanaian Women Naturally Exposed to Malaria Parasites

PubMed Central

Ampomah, Paulina; Stevenson, Liz; Ofori, Michael F.; Barfod, Lea

2014-01-01

Protective immunity to Plasmodium falciparum malaria acquired after natural exposure is largely antibody mediated. IgG-specific P. falciparum EMP1 (PfEMP1) proteins on the infected erythrocyte surface are particularly important. The transient antibody responses and the slowly acquired protective immunity probably reflect the clonal antigenic variation and allelic polymorphism of PfEMP1. However, it is likely that other immune-evasive mechanisms are also involved, such as interference with formation and maintenance of immunological memory. We measured PfEMP1-specific antibody levels by enzyme-linked immunosorbent assay (ELISA) and memory B-cell frequencies by enzyme-linked immunosorbent spot (ELISPOT) assay in a cohort of P. falciparum-exposed nonpregnant Ghanaian women. The antigens used were a VAR2CSA-type PfEMP1 (IT4VAR04) with expression restricted to parasites infecting the placenta, as well as two commonly recognized PfEMP1 proteins (HB3VAR06 and IT4VAR60) implicated in rosetting and not pregnancy restricted. This enabled, for the first time, a direct comparison in the same individuals of immune responses specific for a clinically important parasite antigen expressed only during well-defined periods (pregnancy) to responses specific for comparable antigens expressed independent of pregnancy. Our data indicate that PfEMP1-specific B-cell memory is adequately acquired even when antigen exposure is infrequent (e.g., VAR2CSA-type PfEMP1). Furthermore, immunological memory specific for VAR2CSA-type PfEMP1 can be maintained for many years without antigen reexposure and after circulating antigen-specific IgG has disappeared. The study provides evidence that natural exposure to P. falciparum leads to formation of durable B-cell immunity to clinically important PfEMP1 antigens. This has encouraging implications for current efforts to develop PfEMP1-based vaccines. PMID:24566620

CRISPR/Cas9 Genome Editing Reveals That the Intron Is Not Essential for var2csa Gene Activation or Silencing in Plasmodium falciparum.

PubMed

Bryant, Jessica M; Regnault, Clément; Scheidig-Benatar, Christine; Baumgarten, Sebastian; Guizetti, Julien; Scherf, Artur

2017-07-11

Plasmodium falciparum relies on monoallelic expression of 1 of 60 var virulence genes for antigenic variation and host immune evasion. Each var gene contains a conserved intron which has been implicated in previous studies in both activation and repression of transcription via several epigenetic mechanisms, including interaction with the var promoter, production of long noncoding RNAs (lncRNAs), and localization to repressive perinuclear sites. However, functional studies have relied primarily on artificial expression constructs. Using the recently developed P. falciparum clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system, we directly deleted the var2csa P. falciparum 3D7_1200600 (Pf3D7_1200600) endogenous intron, resulting in an intronless var gene in a natural, marker-free chromosomal context. Deletion of the var2csa intron resulted in an upregulation of transcription of the var2csa gene in ring-stage parasites and subsequent expression of the PfEMP1 protein in late-stage parasites. Intron deletion did not affect the normal temporal regulation and subsequent transcriptional silencing of the var gene in trophozoites but did result in increased rates of var gene switching in some mutant clones. Transcriptional repression of the intronless var2csa gene could be achieved via long-term culture or panning with the CD36 receptor, after which reactivation was possible with chondroitin sulfate A (CSA) panning. These data suggest that the var2csa intron is not required for silencing or activation in ring-stage parasites but point to a subtle role in regulation of switching within the var gene family. IMPORTANCE Plasmodium falciparum is the most virulent species of malaria parasite, causing high rates of morbidity and mortality in those infected. Chronic infection depends on an immune evasion mechanism termed antigenic variation, which in turn relies on monoallelic expression of 1 of ~60 var genes. Understanding antigenic variation and the transcriptional regulation of monoallelic expression is important for developing drugs and/or vaccines. The var gene family encodes the antigenic surface proteins that decorate infected erythrocytes. Until recently, studying the underlying genetic elements that regulate monoallelic expression in P. falciparum was difficult, and most studies relied on artificial systems such as episomal reporter genes. Our study was the first to use CRISPR/Cas9 genome editing for the functional study of an important, conserved genetic element of var genes-the intron-in an endogenous, episome-free manner. Our findings shed light on the role of the var gene intron in transcriptional regulation of monoallelic expression. Copyright © 2017 Bryant et al.

Oncofetal Chondroitin Sulfate Glycosaminoglycans Are Key Players in Integrin Signaling and Tumor Cell Motility.

PubMed

Clausen, Thomas Mandel; Pereira, Marina Ayres; Al Nakouzi, Nader; Oo, Htoo Zarni; Agerbæk, Mette Ø; Lee, Sherry; Ørum-Madsen, Maj Sofie; Kristensen, Anders Riis; El-Naggar, Amal; Grandgenett, Paul M; Grem, Jean L; Hollingsworth, Michael A; Holst, Peter J; Theander, Thor; Sorensen, Poul H; Daugaard, Mads; Salanti, Ali

2016-12-01

Many tumors express proteoglycans modified with oncofetal chondroitin sulfate glycosaminoglycan chains (ofCS), which are normally restricted to the placenta. However, the role of ofCS in cancer is largely unknown. The function of ofCS in cancer was analyzed using the recombinant ofCS-binding VAR2CSA protein (rVAR2) derived from the malaria parasite, Plasmodium falciparum We demonstrate that ofCS plays a key role in tumor cell motility by affecting canonical integrin signaling pathways. Binding of rVAR2 to tumor cells inhibited the interaction of cells with extracellular matrix (ECM) components, which correlated with decreased phosphorylation of Src kinase. Moreover, rVAR2 binding decreased migration, invasion, and anchorage-independent growth of tumor cells in vitro Mass spectrometry of ofCS-modified proteoglycan complexes affinity purified from tumor cell lines on rVAR2 columns revealed an overrepresentation of proteins involved in cell motility and integrin signaling, such as integrin-β1 (ITGB1) and integrin-α4 (ITGA4). Saturating concentrations of rVAR2 inhibited downstream integrin signaling, which was mimicked by knockdown of the core chondroitin sulfate synthesis enzymes β-1,3-glucuronyltransferase 1 (B3GAT1) and chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1). The ofCS modification was highly expressed in both human and murine metastatic lesions in situ and preincubation or early intravenous treatment of tumor cells with rVAR2 inhibited seeding and spreading of tumor cells in mice. This was associated with a significant increase in survival of the animals. These data functionally link ofCS modifications with cancer cell motility and further highlights ofCS as a novel therapeutic cancer target. The cancer-specific expression of ofCS aids in metastatic phenotypes and is a candidate target for therapy. Mol Cancer Res; 14(12); 1288-99. ©2016 AACR. ©2016 American Association for Cancer Research.

Targeted Disruption of a Ring-infected Erythrocyte Surface Antigen (RESA)-like Export Protein Gene in Plasmodium falciparum Confers Stable Chondroitin 4-Sulfate Cytoadherence Capacity*

PubMed Central

Goel, Suchi; Muthusamy, Arivalagan; Miao, Jun; Cui, Liwang; Salanti, Ali; Winzeler, Elizabeth A.; Gowda, D. Channe

2014-01-01

The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family proteins mediate the adherence of infected erythrocytes to microvascular endothelia of various organs, including the placenta, thereby contributing to cerebral, placental, and other severe malaria pathogenesis. Several parasite proteins, including KAHRP and PfEMP3, play important roles in the cytoadherence by mediating the clustering of PfEMP1 in rigid knoblike structures on the infected erythrocyte surface. The lack of a subtelomeric region of chromosome 2 that contains kahrp and pfemp3 causes reduced cytoadherence. In this study, microarray transcriptome analysis showed that the absence of a gene cluster, comprising kahrp, pfemp3, and four other genes, results in the loss of parasitized erythrocytes adhering to chondroitin 4-sulfate (C4S). The role of one of these genes, PF3D7_0201600/PFB0080c, which encodes PHISTb (Plasmodium helical interspersed subtelomeric b) domain-containing RESA-like protein 1 expressed on the infected erythrocyte surface, was investigated. Disruption of PFB0080c resulted in increased var2csa transcription and VAR2CSA surface expression, leading to higher C4S-binding capacity of infected erythrocytes. Further, PFB0080c-knock-out parasites stably maintained the C4S adherence through many generations of growth. Although the majority of PFB0080c-knock-out parasites bound to C4S even after culturing for 6 months, a minor population bound to both C4S and CD36. These results strongly suggest that the loss of PFB0080c markedly compromises the var gene switching process, leading to a marked reduction in the switching rate and additional PfEMP1 expression by a minor population of parasites. PFB0080c interacts with VAR2CSA and modulates knob-associated Hsp40 expression. Thus, PFB0080c may regulate VAR2CSA expression through these processes. Overall, we conclude that PFB0080c regulates PfEMP1 expression and the parasite's cytoadherence. PMID:25342752

Molecular mechanisms of immunosuppression by cyclosporins.

PubMed

Zenke, G; Baumann, G; Wenger, R; Hiestand, P; Quesniaux, V; Andersen, E; Schreier, M H

1993-06-23

Despite the successful clinical application of the immunosuppressive drug cyclosporin A (CsA, Sandimmun), its precise mechanism of action in the process of T cell activation remains elusive. CsA binds to the high-affinity cytosolic receptor cyclophilin whose peptidyl-prolyl cis-trans isomerase activity is inhibited upon binding. The linkage of this effect with the inhibition of the T cell receptor-mediated signal transduction pathway, which leads to a suppression of lymphokine gene transcription, is still unclear. We analyzed the relationship between cyclophilin-binding and immunosuppressive activity (e.g., effect on IL-2 transcription) of cyclosporin derivatives in vitro. The results show that binding to cyclophilin is required, but not sufficient for immunosuppression. Cyclosporin analogues which completely lack immunosuppressive activity but fully retained their cyclophilin-binding capacity antagonize the immunosuppressive activity of CsA. These derivatives inhibit the isomerase activity of cyclophilin, which clearly demonstrates that inhibition of the cyclophilin isomerase activity does not lead to immunosuppression. In analogy to the other immunosuppressants of microbial origin, FK-506 and rapamycin, a specific structure of the "effector" domain of CsA, which is unrelated to the cyclophilin-binding domain, determines the biological activity. In the nucleus, CsA interferes with the DNA-binding of inducible transcription factors to their respective DNA motifs within lymphokine promoters by affecting intracellular translocation of transcription factor subunits.

The immunosuppressives FK 506 and cyclosporin A inhibit the generation of protein factors binding to the two purine boxes of the interleukin 2 enhancer.

PubMed Central

Brabletz, T; Pietrowski, I; Serfling, E

1991-01-01

Like Cyclosporin A (CsA), the macrolide FK 506 is a potent immunosuppressive that inhibits early steps of T cell activation, including the synthesis of Interleukin 2 (II-2) and numerous other lymphokines. The block of II-2 synthesis occurs at the transcriptional level. At concentrations that block T cell activation, FK 506 and CsA inhibit the proto-enhancer activity of Purine boxes of the II-2 promoter and the generation of lymphocyte-specific factors binding to the Purine boxes. Under the same conditions, the DNA binding of other II-2 enhancer factors remains unaffected by both compounds. These results support the view that FK 506 and CsA, which both inhibit the activity of peptidylprolyl cis/trans isomerases, suppress T cell activation by a similar, if not identical mechanism. Images PMID:1707162

The immunosuppressives FK 506 and cyclosporin A inhibit the generation of protein factors binding to the two purine boxes of the interleukin 2 enhancer.

PubMed

Brabletz, T; Pietrowski, I; Serfling, E

1991-01-11

Like Cyclosporin A (CsA), the macrolide FK 506 is a potent immunosuppressive that inhibits early steps of T cell activation, including the synthesis of Interleukin 2 (II-2) and numerous other lymphokines. The block of II-2 synthesis occurs at the transcriptional level. At concentrations that block T cell activation, FK 506 and CsA inhibit the proto-enhancer activity of Purine boxes of the II-2 promoter and the generation of lymphocyte-specific factors binding to the Purine boxes. Under the same conditions, the DNA binding of other II-2 enhancer factors remains unaffected by both compounds. These results support the view that FK 506 and CsA, which both inhibit the activity of peptidylprolyl cis/trans isomerases, suppress T cell activation by a similar, if not identical mechanism.

Voltage stability index based optimal placement of static VAR compensator and sizing using Cuckoo search algorithm

NASA Astrophysics Data System (ADS)

Venkateswara Rao, B.; Kumar, G. V. Nagesh; Chowdary, D. Deepak; Bharathi, M. Aruna; Patra, Stutee

2017-07-01

This paper furnish the new Metaheuristic algorithm called Cuckoo Search Algorithm (CSA) for solving optimal power flow (OPF) problem with minimization of real power generation cost. The CSA is found to be the most efficient algorithm for solving single objective optimal power flow problems. The CSA performance is tested on IEEE 57 bus test system with real power generation cost minimization as objective function. Static VAR Compensator (SVC) is one of the best shunt connected device in the Flexible Alternating Current Transmission System (FACTS) family. It has capable of controlling the voltage magnitudes of buses by injecting the reactive power to system. In this paper SVC is integrated in CSA based Optimal Power Flow to optimize the real power generation cost. SVC is used to improve the voltage profile of the system. CSA gives better results as compared to genetic algorithm (GA) in both without and with SVC conditions.

Molecular mechanisms of immunosuppression.

PubMed

Baumann, G; Zenke, G; Wenger, R; Hiestand, P; Quesniaux, V; Andersen, E; Schreier, M H

1992-04-01

The immunosuppressive drug cyclosporin A (CsA, Sandimmun, SIM) is currently being evaluated in a variety of autoimmune disorders with some remarkable successes. Despite the wide empiric application of CsA, the precise mechanism of action of this drug remains elusive. To identify the molecular mode of action of CsA in the process of T cell activation, we have compared the biological profile of cyclophilin-binding cyclosporin analogues (CBCA), which lack immunosuppressive properties, with CsA. We have found that CsA binding to its intracellular receptor (cyclophilin) is required but not sufficient for immunosuppression. Moreover, inhibition of the peptidyl-prolyl cis-trans isomerase activity of cyclophilin does not seem to be relevant for the inhibitory effects of CsA. In analogy to the immunosuppressants FK506 and rapamycin, a specific structure at the 'effector' domain of the CsA molecule different from the immunophilin 'binding' domain determines the biological activity. Overall, a significant understanding of the structure-activity relationship of CsA has emerged. This will have a major impact on the identification of the precise mechanism of action of CsA and its side effects in the process of immunosuppression.

Targeting Common but Complex Proteoglycans on Breast Cancer Cells and Stem Cells Using Evolutionary Refined Malaria Proteins

DTIC Science & Technology

2014-09-01

chondroitin sulfate A proteoglycans present on all tested breast cancer cells and the vast majority of tested tissue biopsies. Using pull down assays...Invited, Daugaard. C) 2014. Gordon research conference, July 6-11; Targeting of cancer-specific chondroitin sulfate on circulating tumor cells using...now successfully identified a number of proteoglycans that interact with the recombinant malaria protein VAR2CSA when sulfated on carbon 4 of the CS

Cyclophilin B mediates cyclosporin A incorporation in human blood T-lymphocytes through the specific binding of complexed drug to the cell surface.

PubMed

Allain, F; Denys, A; Spik, G

1996-07-15

Cyclophilin B (CyPB) is a cyclosporin A (CsA)-binding protein located within intracellular vesicles and released in biological fluids. We recently reported the specific binding of this protein to T-cell surface receptor which is internalized even in the presence of CsA. These results suggest that CyPB might target the drug to lymphocytes and consequently modify its activity. To verify this hypothesis, we have first investigated the binding capacity and internalization of the CsA-CyPB complex in human peripheral blood T-lymphocytes and secondly compared the inhibitory effect of both free and CyPB-complexed CsA on the CD3-induced activation and proliferation of T-cells. Here, we present evidence that both the CsA-CyPB complex and free CyPB bind to the T-lymphocyte surface, with similar values of Kd and number of sites. At 37 degrees C, the complex is internalized but, in contrast to the protein, the drug is accumulated within the cell. Moreover, CyPB receptors are internalized together with the ligand and rapidly recycled to the cell surface. Finally, we demonstrate that CyPB-complexed CsA remains as efficient as uncomplexed CsA and that CyPB enhances the immunosuppressive activity of the drug. Taken together, our results support the hypothesis that surface CyPB receptors may be related to the selective and variable action of CsA, through specific binding and targeting of the CyPB-CsA complex to peripheral blood T-lymphocytes.

Identification and characterization of a cyclosporin binding cyclophilin from Staphylococcus aureus Newman

PubMed Central

Polley, Soumitra; Seal, Soham; Mahapa, Avisek; Jana, Biswanath; Biswas, Anindya; Mandal, Sukhendu; Sinha, Debabrata; Sau, Keya; Sau, Subrata

2017-01-01

Cyclophilins, a class of peptidyl-prolyl cis-trans isomerase (PPIase) enzymes, are inhibited by cyclosporin A (CsA), an immunosuppressive drug. Staphylococcus aureus Newman, a pathogenic bacterium, carries a gene for encoding a putative cyclophilin (SaCyp). SaCyp shows significant homology with other cyclophilins at the sequence level. A three-dimensional model structure of SaCyp harbors a binding site for CsA. To verify whether SaCyp possesses both the PPIase activity and the CsA binding ability, we have purified and investigated a recombinant SaCyp (rCyp) using various in vitro tools. Our RNase T1 refolding assay indicates that rCyp has a substantial extent of PPIase activity. rCyp that exists as a monomer in the aqueous solution is truly a cyclophilin as its catalytic activity specifically shows sensitivity to CsA. rCyp appears to bind CsA with a reasonably high affinity. Additional investigations reveal that binding of CsA to rCyp alters its structure and shape to some extent. Both rCyp and rCyp-CsA are unfolded via the formation of at least one intermediate in the presence of guanidine hydrochloride. Unfolding study also indicates that there is substantial extent of thermodynamic stabilization of rCyp in the presence of CsA as well. The data suggest that rCyp may be exploited to screen the new antimicrobial agents in the future. PMID:28584448

Towards the Rational Design of a Candidate Vaccine against Pregnancy Associated Malaria: Conserved Sequences of the DBL6ε Domain of VAR2CSA

PubMed Central

Badaut, Cyril; Bertin, Gwladys; Rustico, Tatiana; Fievet, Nadine; Massougbodji, Achille; Gaye, Alioune; Deloron, Philippe

2010-01-01

Background Placental malaria is a disease linked to the sequestration of Plasmodium falciparum infected red blood cells (IRBC) in the placenta, leading to reduced materno-fetal exchanges and to local inflammation. One of the virulence factors of P. falciparum involved in cytoadherence to chondroitin sulfate A, its placental receptor, is the adhesive protein VAR2CSA. Its localisation on the surface of IRBC makes it accessible to the immune system. VAR2CSA contains six DBL domains. The DBL6ε domain is the most variable. High variability constitutes a means for the parasite to evade the host immune response. The DBL6ε domain could constitute a very attractive basis for a vaccine candidate but its reported variability necessitates, for antigenic characterisations, identifying and classifying commonalities across isolates. Methodology/Principal Findings Local alignment analysis of the DBL6ε domain had revealed that it is not as variable as previously described. Variability is concentrated in seven regions present on the surface of the DBL6ε domain. The main goal of our work is to classify and group variable sequences that will simplify further research to determine dominant epitopes. Firstly, variable sequences were grouped following their average percent pairwise identity (APPI). Groups comprising many variable sequences sharing low variability were found. Secondly, ELISA experiments following the IgG recognition of a recombinant DBL6ε domain, and of peptides mimicking its seven variable blocks, allowed to determine an APPI cut-off and to isolate groups represented by a single consensus sequence. Conclusions/Significance A new sequence approach is used to compare variable regions in sequences that have extensive segmental gene relationship. Using this approach, the VAR2CSA DBL6 domain is composed of 7 variable blocks with limited polymorphism. Each variable block is composed of a limited number of consensus types. Based on peptide based ELISA, variable blocks with 85% or greater sequence identity are expected to be recognized equally well by antibody and can be considered the same consensus type. Therefore, the analysis of the antibody response against the classified small number of sequences should be helpful to determine epitopes. PMID:20585655

Kinetics of B cell responses to Plasmodium falciparum erythrocyte membrane protein 1 in Ghanaian women naturally exposed to malaria parasites.

PubMed

Ampomah, Paulina; Stevenson, Liz; Ofori, Michael F; Barfod, Lea; Hviid, Lars

2014-06-01

Naturally acquired protective immunity to Plasmodium falciparum malaria takes years to develop. It relies mainly on Abs, particularly IgG specific for Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) proteins on the infected erythrocyte surface. It is only partially understood why acquisition of clinical protection takes years to develop, but it probably involves a range of immune-evasive parasite features, not least of which are PfEMP1 polymorphism and clonal variation. Parasite-induced subversion of immunological memory and expansion of "atypical" memory B cells may also contribute. In this first, to our knowledge, longitudinal study of its kind, we measured B cell subset composition, as well as PfEMP1-specific Ab levels and memory B cell frequencies, in Ghanaian women followed from early pregnancy up to 1 y after delivery. Cell phenotypes and Ag-specific B cell function were assessed three times during and after pregnancy. Levels of IgG specific for pregnancy-restricted, VAR2CSA-type PfEMP1 increased markedly during pregnancy and declined after delivery, whereas IgG levels specific for two PfEMP1 proteins not restricted to pregnancy did not. Changes in VAR2CSA-specific memory B cell frequencies showed typical primary memory induction among primigravidae and recall expansion among multigravidae, followed by contraction postpartum in all. No systematic changes in the frequencies of memory B cells specific for the two other PfEMP1 proteins were identified. The B cell subset analysis confirmed earlier reports of high atypical memory B cell frequencies among residents of P. falciparum-endemic areas, and indicated an additional effect of pregnancy. Our study provides new knowledge regarding immunity to P. falciparum malaria and underpins efforts to develop PfEMP1-based vaccines against this disease. Copyright © 2014 by The American Association of Immunologists, Inc.

The dependence of chemokine–glycosaminoglycan interactions on chemokine oligomerization

PubMed Central

Dyer, Douglas P; Salanga, Catherina L; Volkman, Brian F; Kawamura, Tetsuya; Handel, Tracy M

2016-01-01

Both chemokine oligomerization and binding to glycosaminoglycans (GAGs) are required for their function in cell recruitment. Interactions with GAGs facilitate the formation of chemokine gradients, which provide directional cues for migrating cells. In contrast, chemokine oligomerization is thought to contribute to the affinity of GAG interactions by providing a more extensive binding surface than single subunits alone. However, the importance of chemokine oligomerization to GAG binding has not been extensively quantified. Additionally, the ability of chemokines to form different oligomers has been suggested to impart specificity to GAG interactions, but most studies have been limited to heparin. In this study, several differentially oligomerizing chemokines (CCL2, CCL3, CCL5, CCL7, CXCL4, CXCL8, CXCL11 and CXCL12) and select oligomerization-deficient mutants were systematically characterized by surface plasmon resonance to determine their relative affinities for heparin, heparan sulfate (HS) and chondroitin sulfate-A (CS-A). Wild-type chemokines demonstrated a hierarchy of binding affinities for heparin and HS that was markedly dependent on oligomerization. These results were corroborated by their relative propensity to accumulate on cells and the critical role of oligomerization in cell presentation. CS-A was found to exhibit greater chemokine selectivity than heparin or HS, as it only bound a subset of chemokines; moreover, binding to CS-A was ablated with oligomerization-deficient mutants. Overall, this study definitively demonstrates the importance of oligomerization for chemokine–GAG interactions, and demonstrates diversity in the affinity and specificity of different chemokines for GAGs. These data support the idea that GAG interactions provide a mechanism for fine-tuning chemokine function. PMID:26582609

Long-term tensile bond strength of differently cemented nanocomposite CAD/CAM crowns on dentin abutment.

PubMed

Stawarczyk, Bogna; Stich, Nicola; Eichberger, Marlis; Edelhoff, Daniel; Roos, Malgorzata; Gernet, Wolfgang; Keul, Christine

2014-03-01

To test the tensile bond strength of luted composite computer aided design/computer aided manufacturing (CAD/CAM) crowns after use of different adhesive systems combined with different resin composite cements on dentin abutments. Human molars (n=200) were embedded in acrylic resin, prepared in a standardized manner and divided into 20 groups (n=10). The crowns were treated as follows: (i) Monobond Plus/Heliobond (MH), (ii) Ambarino P60 (AM), (iii) Visio.link (VL), (iv) VP connect (VP), and (v) non-treated as control groups (CG) and luted with Variolink II (VAR) or Clearfil SA Cement (CSA). Tensile bond strength (TBS) was measured initially (24h water, 37°C) and after aging (5000 thermal cycles, 5/55°C). The failure types were evaluated after debonding. TBS values were analyzed using three-way and one-way ANOVA, followed by post hoc Scheffé-test, and two-sample Student's t-tests. Among VAR and after aging, CG presented significantly higher TBS (p=0.007) than groups treated with MH, AM and VP. Other groups showed no impact of pre-treatment. A decrease of TBS values after thermal aging was observed within CSA: CG (p=0.002), MH (p<0.001), VL (p<0.001), AM (p=0.002), VP (p<0.001) and within VAR: MH (p=0.002) and AM (p=0.014). Groups cemented with VAR showed significantly higher TBS then groups cemented with CSA: non-aged groups: CG (p<0.001), and after thermal aging: CG (p=0.003), MH (p<0.001), VL (p=0.005), VP (p=0.010). According to the study results nano-composite CAD/CAM crowns should be cemented with VAR. Pre-treatment is not necessary if the tested resin composite cements are used. Copyright © 2013 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Antigenic variation in malaria: in situ switching, relaxed and mutually exclusive transcription of var genes during intra-erythrocytic development in Plasmodium falciparum.

PubMed Central

Scherf, A; Hernandez-Rivas, R; Buffet, P; Bottius, E; Benatar, C; Pouvelle, B; Gysin, J; Lanzer, M

1998-01-01

Members of the Plasmodium falciparum var gene family encode clonally variant adhesins, which play an important role in the pathogenicity of tropical malaria. Here we employ a selective panning protocol to generate isogenic P.falciparum populations with defined adhesive phenotypes for CD36, ICAM-1 and CSA, expressing single and distinct var gene variants. This technique has established the framework for examining var gene expression, its regulation and switching. It was found that var gene switching occurs in situ. Ubiquitous transcription of all var gene variants appears to occur in early ring stages. However, var gene expression is tightly regulated in trophozoites and is exerted through a silencing mechanism. Transcriptional control is mutually exclusive in parasites that express defined adhesive phenotypes. In situ var gene switching is apparently mediated at the level of transcriptional initiation, as demonstrated by nuclear run-on analyses. Our results suggest that an epigenetic mechanism(s) is involved in var gene regulation. PMID:9736619

Distribution of cyclophilin B-binding sites in the subsets of human peripheral blood lymphocytes.

PubMed

Denys, A; Allain, F; Foxwell, B; Spik, G

1997-08-01

Cyclophilin B (CyPB) is a cyclosporin A (CsA)-binding protein, mainly associated with the secretory pathway and released in biological fluids. We have recently demonstrated that both free CyPB and CyPB-CsA complex specifically bind to peripheral blood T lymphocytes and are internalized. These results suggest that CyPB might promote the targeting of the drug into sensitive cells. Peripheral blood lymphocytes are subdivided in several populations according to their biological functions and sensitivity to CsA. We have investigated the binding of CyPB to these different subsets using a CyPB derivatized by fluorescein through its single cysteine which retains its binding properties. We have confirmed that only T cells were involved in the interaction with CyPB. The ligand binding was found to be heterogeneously distributed on the different T-cell subsets and surface-bound CyPB was mainly associated with the CD4-positive cells. No significant difference was noted between the CD45RA and CD45RO subsets, demonstrating that CyPB-binding sites were equally distributed between native and memory T cells. CD3 stimulation of T lymphocytes led to a decrease in the CyPB-binding capacity, that may be explained by a down-regulation of the CyPB-receptor expression upon T-cell activation. Finally, we demonstrated that CyPB-receptor-positive cells, isolated on CyPB sulphydryl-coupled affinity matrices, are more sensitive to CyPB-complexed CsA than mixed peripheral blood lymphocytes, suggesting that CyPB potentiates CsA activity through the binding of the complex. Taken together, our results demonstrate that CyPB-binding sites are mainly associated with resting cells of the helper T lymphocyte, and that CyPB might modulate the distribution of CsA through the drug targeting to sensitive cells.

A putative carbohydrate-binding domain of the lactose-binding Cytisus sessilifolius anti-H(O) lectin has a similar amino acid sequence to that of the L-fucose-binding Ulex europaeus anti-H(O) lectin.

PubMed

Konami, Y; Yamamoto, K; Osawa, T; Irimura, T

1995-04-01

The complete amino acid sequence of a lactose-binding Cytisus sessilifolius anti-H(O) lectin II (CSA-II) was determined using a protein sequencer. After digestion of CSA-II with endoproteinase Lys-C or Asp-N, the resulting peptides were purified by reversed-phase high performance liquid chromatography (HPLC) and then subjected to sequence analysis. Comparison of the complete amino acid sequence of CSA-II with the sequences of other leguminous seed lectins revealed regions of extensive homology. The amino acid sequence of a putative carbohydrate-binding domain of CSA-II was found to be similar to those of several anti-H(O) leguminous lectins, especially to that of the L-fucose-binding Ulex europaeus lectin I (UEA-I).

Involvement of two classes of binding sites in the interactions of cyclophilin B with peripheral blood T-lymphocytes.

PubMed

Denys, A; Allain, F; Carpentier, M; Spik, G

1998-12-15

Cyclophilin B (CyPB) is a cyclosporin A (CsA)-binding protein, mainly associated with the secretory pathway, and is released in biological fluids. We recently reported that CyPB specifically binds to T-lymphocytes and promotes enhanced incorporation of CsA. The interactions with cellular binding sites involved, at least in part, the specific N-terminal extension of the protein. In this study, we intended to specify further the nature of the CyPB-binding sites on peripheral blood T-lymphocytes. We first provide evidence that the CyPB binding to heparin-Sepharose is prevented by soluble sulphated glycosaminoglycans (GAG), raising the interesting possibility that such interactions may occur on the T-cell surface. We then characterized CyPB binding to T-cell surface GAG and found that these interactions involved the N-terminal extension of CyPB, but not its conserved CsA-binding domain. In addition, we determined the presence of a second CyPB binding site, which we termed a type I site, in contrast with type II for GAG interactions. The two binding sites exhibit a similar affinity but the expression of the type I site was 3-fold lower. The conclusion that CyPB binding to the type I site is distinct from the interactions with GAG was based on the findings that it was (1) resistant to NaCl wash and GAG-degrading enzyme treatments, (2) reduced in the presence of CsA or cyclophilin C, and (3) unmodified in the presence of either the N-terminal peptide of CyPB or protamine. Finally, we showed that the type I binding sites were involved in an endocytosis process, supporting the hypothesis that they may correspond to a functional receptor for CyPB.

Immunophilin ligands demonstrate common features of signal transduction leading to exocytosis or transcription.

PubMed Central

Hultsch, T; Albers, M W; Schreiber, S L; Hohman, R J

1991-01-01

Investigations of the actions and interactions of the immunophilin ligands FK506, cyclosporin A (CsA), rapamycin, and 506BD suggest that complexes of FK506 with an FK506-binding protein or of CsA with a cyclophilin (CsA-binding protein) inhibit the T-cell receptor-mediated signal transduction that results in the transcription of interleukin 2. Now we report an identical spectrum of activities of FK506, CsA, rapamycin, and 506BD on IgE receptor-mediated signal transduction that results in exocytosis of secretory granules from the rat basophilic leukemia cell line RBL-2H3, a mast cell model. Both FK506 and CsA inhibit receptor-mediated exocytosis (CsA IC50 = 200 nM; FK506 IC50 = 2 nM) without affecting early receptor-associated events (hydrolysis of phosphatidylinositol, synthesis and release of eicosanoids, uptake of Ca2+). In contrast, rapamycin and 506BD, which share common structural elements with FK506, by themselves have no effect on IgE receptor-mediated exocytosis. Both compounds, however, prevent inhibition by FK506 but not by CsA. Affinity chromatography with FK506, CsA, and rapamycin matrices indicates that the same set of immunophilins present in RBL-2H3 cells have been found in Jurkat T cells and calf thymus; however, the relative amounts of these proteins differ in the two cell types. These results suggest the existence of a common step in cytoplasmic signaling in T cells and mast cells that may be part of a general signaling mechanism. Images PMID:1712484

Enhancing the effect of secreted cyclophilin B on immunosuppressive activity of cyclosporine.

PubMed

Denys, A; Allain, F; Masy, E; Dessaint, J P; Spik, G

1998-04-27

Cyclophilin B (CyPB) is a cyclosporine (CsA)-binding protein, located within intracellular vesicles and secreted in biological fluids. In previous works, we reported that CyPB specifically interacts with the T-cell membrane and potentiates the ability of CsA to inhibit CD3-induced proliferation of T lymphocytes. CyPB levels were measured in plasma from healthy donors and transplant patients. The role of extracellular CyPB on the distribution and activity of CsA was investigated first by studies on the uptake of free and CyPB-complexed drug by blood cells, and second by studies on the inhibitory effects of these two compounds on the CD3-induced proliferation of peripheral blood mononuclear cells. A significant increase in plasma CyPB level was observed for CsA-treated patients (13+/-6.4 nM, n=42) in comparison with untreated donors (4.3+/-2.1 nM, n=34). In vitro, extracellular CyPB dose dependently modified CsA distribution between plasma, erythrocyte, and lymphocyte contents, by both retaining the complexed drug extracellularly and promoting its specific accumulation within peripheral blood mononuclear cells. Moreover, the enhanced ability of CyPB-complexed CsA to suppress CD3-induced T-cell proliferation was preserved in the presence of other blood cells, implying specific targeting of the drug to sensitive cells. Furthermore, although a large interindividual variability of sensitivity to the drug was confirmed for 18 individuals, we found that CyPB potentiated the activity of CsA in restoring a high sensitivity to the immunosuppressant. These results suggest that plasma CyPB may contribute to the acceptance and the good maintenance of organ transplantation by enhancing the immunosuppressive activity of CsA through a receptor-mediated incorporation of CyPB-complexed CsA within peripheral blood lymphocytes.

High occupancy of sigma-1 receptors in the human brain after single oral administration of fluvoxamine: a positron emission tomography study using [11C]SA4503.

PubMed

Ishikawa, Masatomo; Ishiwata, Kiichi; Ishii, Kenji; Kimura, Yuichi; Sakata, Muneyuki; Naganawa, Mika; Oda, Keiichi; Miyatake, Ryousuke; Fujisaki, Mihisa; Shimizu, Eiji; Shirayama, Yukihiko; Iyo, Masaomi; Hashimoto, Kenji

2007-10-15

Sigma-1 receptors might be implicated in the pathophysiology of psychiatric diseases, as well as in the mechanisms of action of some selective serotonin reuptake inhibitors (SSRIs). Among the several SSRIs, fluvoxamine has the highest affinity for sigma-1 receptors (Ki = 36 nM), whereas paroxetine shows low affinity (Ki = 1893 nM). The present study was undertaken to examine whether fluvoxamine binds to sigma-1 receptors in living human brain. A dynamic positron emission tomography (PET) data acquisition using the selective sigma-1 receptor ligand [(11)C]SA4503 was performed with arterial blood sampling to evaluate quantitatively the binding of [(11)C]SA4503 to sigma-1 receptors in 15 healthy male volunteers. Each subject had two PET scans before and after randomly receiving a single dose of either fluvoxamine (50, 100, 150, or 200 mg) or paroxetine (20 mg). The binding potential of [(11)C]SA4503 in 9 regions of the brain was calculated by a 2-tissue 3-compartment model. In addition, we examined the effects of functional polymorphisms of the sigma-1 receptor (SIGMAR1) gene on the binding potential of [(11)C]SA4503. Fluvoxamine bound to sigma-1 receptors in all brain regions in a dose-dependent manner, whereas paroxetine did not bind to sigma-1 receptors. However, there was no association between the SIGMAR1 gene polymorphism GC-241-240TT and binding potential. The study demonstrated that fluvoxamine bound to sigma-1 receptors in living human brain at therapeutic doses. These findings suggest that sigma-1 receptors may play an important role in the mechanism of action of fluvoxamine.

Receptor-mediated transcytosis of cyclophilin B through the blood-brain barrier.

PubMed

Carpentier, M; Descamps, L; Allain, F; Denys, A; Durieux, S; Fenart, L; Kieda, C; Cecchelli, R; Spik, G

1999-07-01

Cyclophilin B (CyPB) is a cyclosporin A (CsA)-binding protein mainly located in intracellular vesicles and secreted in biological fluids. In previous works, we demonstrated that CyPB interacts with T lymphocytes and enhances in vitro cellular incorporation and activity of CsA. In addition to its immunosuppressive activity, CsA is able to promote regeneration of damaged peripheral nerves. However, the crossing of the drug from plasma to neural tissue is restricted by the relative impermeability of the blood-brain barrier. To know whether CyPB might also participate in the delivery of CsA into the brain, we have analyzed the interactions of CyPB with brain capillary endothelial cells. First, we demonstrated that CyPB binds to two types of binding sites present at the surface of capillary endothelial cells from various species of tissues. The first type of binding sites (K(D) = 300 nM; number of sites = 3 x 10(6)) is related to interactions with negatively charged compounds such as proteoglycans. The second type of binding sites, approximately 50,000 per cell, exhibits a higher affinity for CyPB (K(D) = 15 nM) and is involved in an endocytosis process, indicating it might correspond to a functional receptor. Finally, the use of an in vitro model of blood-brain barrier allowed us to demonstrate that CyPB is transcytosed by a receptor-mediated pathway (flux = 16.5 fmol/cm2/h). In these conditions, CyPB did not significantly modify the passage of CsA, indicating that it is unlikely to provide a pathway for CsA brain delivery.

Structural and Functional Characterization of an Archaeal Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated Complex for Antiviral Defense (CASCADE)*

PubMed Central

Lintner, Nathanael G.; Kerou, Melina; Brumfield, Susan K.; Graham, Shirley; Liu, Huanting; Naismith, James H.; Sdano, Matthew; Peng, Nan; She, Qunxin; Copié, Valérie; Young, Mark J.; White, Malcolm F.; Lawrence, C. Martin

2011-01-01

In response to viral infection, many prokaryotes incorporate fragments of virus-derived DNA into loci called clustered regularly interspaced short palindromic repeats (CRISPRs). The loci are then transcribed, and the processed CRISPR transcripts are used to target invading viral DNA and RNA. The Escherichia coli “CRISPR-associated complex for antiviral defense” (CASCADE) is central in targeting invading DNA. Here we report the structural and functional characterization of an archaeal CASCADE (aCASCADE) from Sulfolobus solfataricus. Tagged Csa2 (Cas7) expressed in S. solfataricus co-purifies with Cas5a-, Cas6-, Csa5-, and Cas6-processed CRISPR-RNA (crRNA). Csa2, the dominant protein in aCASCADE, forms a stable complex with Cas5a. Transmission electron microscopy reveals a helical complex of variable length, perhaps due to substoichiometric amounts of other CASCADE components. A recombinant Csa2-Cas5a complex is sufficient to bind crRNA and complementary ssDNA. The structure of Csa2 reveals a crescent-shaped structure unexpectedly composed of a modified RNA-recognition motif and two additional domains present as insertions in the RNA-recognition motif. Conserved residues indicate potential crRNA- and target DNA-binding sites, and the H160A variant shows significantly reduced affinity for crRNA. We propose a general subunit architecture for CASCADE in other bacteria and Archaea. PMID:21507944

Structural and functional characterization of an archaeal clustered regularly interspaced short palindromic repeat (CRISPR)-associated complex for antiviral defense (CASCADE).

PubMed

Lintner, Nathanael G; Kerou, Melina; Brumfield, Susan K; Graham, Shirley; Liu, Huanting; Naismith, James H; Sdano, Matthew; Peng, Nan; She, Qunxin; Copié, Valérie; Young, Mark J; White, Malcolm F; Lawrence, C Martin

2011-06-17

In response to viral infection, many prokaryotes incorporate fragments of virus-derived DNA into loci called clustered regularly interspaced short palindromic repeats (CRISPRs). The loci are then transcribed, and the processed CRISPR transcripts are used to target invading viral DNA and RNA. The Escherichia coli "CRISPR-associated complex for antiviral defense" (CASCADE) is central in targeting invading DNA. Here we report the structural and functional characterization of an archaeal CASCADE (aCASCADE) from Sulfolobus solfataricus. Tagged Csa2 (Cas7) expressed in S. solfataricus co-purifies with Cas5a-, Cas6-, Csa5-, and Cas6-processed CRISPR-RNA (crRNA). Csa2, the dominant protein in aCASCADE, forms a stable complex with Cas5a. Transmission electron microscopy reveals a helical complex of variable length, perhaps due to substoichiometric amounts of other CASCADE components. A recombinant Csa2-Cas5a complex is sufficient to bind crRNA and complementary ssDNA. The structure of Csa2 reveals a crescent-shaped structure unexpectedly composed of a modified RNA-recognition motif and two additional domains present as insertions in the RNA-recognition motif. Conserved residues indicate potential crRNA- and target DNA-binding sites, and the H160A variant shows significantly reduced affinity for crRNA. We propose a general subunit architecture for CASCADE in other bacteria and Archaea.

Biceps-Related Physical Findings Are Useful to Prevent Misdiagnosis of Cervical Spondylotic Amyotrophy as a Rotator Cuff Tear.

PubMed

Iwata, Eiichiro; Shigematsu, Hideki; Inoue, Kazuya; Egawa, Takuya; Tanaka, Masato; Okuda, Akinori; Morimoto, Yasuhiko; Masuda, Keisuke; Yamamoto, Yusuke; Sakamoto, Yoshihiro; Koizumi, Munehisa; Tanaka, Yasuhito

2018-02-01

Case-control study. The aim of the present study was to identify physical findings useful for differentiating between cervical spondylotic amyotrophy (CSA) and rotator cuff tears to prevent the misdiagnosis of CSA as a rotator cuff tear. CSA and rotator cuff tears are often confused among patients presenting with difficulty in shoulder elevation. Twenty-five patients with CSA and 27 with rotator cuff tears were enrolled. We included five physical findings specific to CSA that were observed in both CSA and rotator cuff tear patients. The findings were as follows: (1) weakness of the deltoid muscle, (2) weakness of the biceps muscle, (3) atrophy of the deltoid muscle, (4) atrophy of the biceps muscle, and (5) swallow-tail sign (assessment of the posterior fibers of the deltoid). Among 25 CSA patients, 10 (40.0%) were misdiagnosed with a rotator cuff tear on initial diagnosis. The sensitivity and specificity of each physical finding were as follows: (1) deltoid weakness (sensitivity, 92.0%; specificity, 55.6%), (2) biceps weakness (sensitivity, 80.0%; specificity, 100%), (3) deltoid atrophy (sensitivity, 96.0%; specificity, 77.8%), (4) biceps atrophy (sensitivity, 88.8%; specificity, 92.6%), and (5) swallow-tail sign (sensitivity, 56.0%; specificity, 74.1%). There were statistically significant differences in each physical finding. CSA is likely to be misdiagnosed as a rotator cuff tear; however, weakness and atrophy of the biceps are useful findings for differentiating between CSA and rotator cuff tears to prevent misdiagnosis.

Despite irreversible binding, PET tracer [11C]-SA5845 is suitable for imaging of drug competition at sigma receptors-the cases of ketamine and haloperidol.

PubMed

Kortekaas, Rudie; Maguire, R Paul; van Waarde, Aren; Leenders, Klaus L; Elsinga, Philip H

2008-07-01

Many psychotropic compounds bind to sigma receptors and several new sigma ligands are in development for psychiatric indications such as anxiety, attention deficit hyperactivity disorder, depression and psychosis. Of special interest for drug development are tomographic methods that can quantify the binding of promising sigma ligands in a regional manner. Here we present the development of such a method and the first evaluation of sigma ligand [11C]-SA5845 in a primate. Extensive pharmacokinetic modeling was done on tissue curves and a heart lumen curve. The effects of pretreatment and challenge with haloperidol were studied as well as those of pretreatment with +/- -ketamine. The tracer had a plasma half-life of 77+/-1.7min and was rapidly taken up by all brain areas. The binding pattern was consistent with binding to sigma receptors and compartment modeling showed there was considerable specific binding that was irreversible. We therefore calculated the net influx rate, Ki, with the Gjedde-Patlak linearization, as a measure of free receptors. As expected, Ki was very sensitive to the presence of competing ligands - -ketamine and/or haloperidol. Summarizing, the tracer is well suited for visualizing sigma receptors in the brain and moreover, the presented method is able to quantify, on a regional basis, specific binding of unlabeled ligands to sigma receptors.

Cytoadherence of Plasmodium falciparum to intercellular adhesion molecule 1 and chondroitin-4-sulfate expressed by the syncytiotrophoblast in the human placenta.

PubMed Central

Maubert, B; Guilbert, L J; Deloron, P

1997-01-01

Late stages of Plasmodium falciparum-infected erythrocytes (IRBCs) frequently sequester in the placentas of pregnant women, a phenomenon associated with low birth weight of the offspring. To investigate the physiological mechanism of this sequestration, we developed an in vitro assay for studying the cytoadherence of IRBCs to cultured term human trophoblasts. The capacity for binding to the syncytiotrophoblast varied greatly among P. falciparum isolates and was mediated by intercellular adhesion molecule 1 (ICAM-1), as binding was totally inhibited by 84H10, a monoclonal antibody specific for ICAM-1. Binding of the P. falciparum line RP5 to the syncytiotrophoblast involves chondroitin-4-sulfate (CSA), as this binding was dramatically impaired by addition of free CSA to the binding medium or by preincubation of the syncytiotrophoblast with chondroitinase ABC. ICAM-1 and CSA were visualized on the syncytiotrophoblast by immunofluorescence, while CD36, E-selectin, and vascular cell adhesion molecule 1 were not expressed even on tumor necrosis factor alpha (TNF-alpha)-stimulated syncytiotrophoblast tissue, and monoclonal antibodies against these cell adhesion molecules did not inhibit cytoadherence. ICAM-1 expression and cytoadherence of wild isolates was upregulated by TNF-alpha, a cytokine that can be secreted by the numerous mononuclear phagocytes present in malaria-infected placentas. These results suggest that cytoadherence may be involved in the placental sequestration and broaden the understanding of the physiopathology of the malaria-infected placenta. PMID:9119459

Targeting Common but Complex Proteoglycans on Breast Cancer Cells and Stem Cells Using Evolutionary Refined Malaria Proteins

DTIC Science & Technology

2017-10-01

heart of C57BL/6 mice resulted in aggressive bone metastasis with an overall penetrance of 50%–60% 1(Fig. 7J). The bone metastases invaded into...metastases, while all control-treated mice died with metastatic disease (p = 0.0196) 1(Fig. 7L). Indeed, the VAR2CSA drug conjugate-treatment 6...CS- conjugated and 15 have been directly associated with human malignant disease (Table S5). To investigate the inter-tumor diversity in expression

CRISPR-Cas type I-A Cascade complex couples viral infection surveillance to host transcriptional regulation in the dependence of Csa3b

PubMed Central

He, Fei; Vestergaard, Gisle; Peng, Wenfang; She, Qunxin

2017-01-01

Abstract CRISPR-Cas (clustered regularly interspaced short palindromic repeats and the associated genes) constitute adaptive immune systems in bacteria and archaea and they provide sequence specific immunity against foreign nucleic acids. CRISPR-Cas systems are activated by viral infection. However, little is known about how CRISPR-Cas systems are activated in response to viral infection or how their expression is controlled in the absence of viral infection. Here, we demonstrate that both the transcriptional regulator Csa3b, and the type I-A interference complex Cascade, are required to transcriptionally repress the interference gene cassette in the archaeon Sulfolobus. Csa3b binds to two palindromic repeat sites in the promoter region of the cassette and facilitates binding of the Cascade to the promoter region. Upon viral infection, loading of Cascade complexes onto crRNA-matching protospacers leads to relief of the transcriptional repression. Our data demonstrate a mechanism coupling CRISPR-Cas surveillance of protospacers to transcriptional regulation of the interference gene cassette thereby allowing a fast response to viral infection. PMID:27980065

Sequence analysis of DBL2β domain of vargene of Indonesian Plasmodium falciparum

NASA Astrophysics Data System (ADS)

Sulistyaningsih, E.; Romadhon, B. D.; Palupi, I.; Hidayah, F.; Dewi, R.; Prasetyo, A.

2018-03-01

Malaria is a major health problem in tropical countries including Indonesia. The most deadly agent is Plasmodium falciparum. In P. falciparum infection, PfEMP1 is supposed to play an important role in the pathogenesis of malaria. PfEMP1 is encoded by var gene family, it is a polymorphic protein where the extra-cellular portion contains of three distinct binding domains: Duffy binding-like (DBL), Cysteine-rich interdomain regions (CIDR) and C2. PfEMP1 varies in domain composition and binding specificity. The study explored the characteristic of Indonesian DBL2β-var genes and investigated its role to the malaria outcome. Twenty blood samples from clinically mild to severe malaria patients in Jember, East Java were collected for DNA extraction. Diagnosis was confirmed by Giemsa-stained thick blood smear. PCR was conducted using specific primer targeting on the full-length of DBL2ß and resulted approximately single band of 1,7 kb in a sample. This band was observed only from severe malaria sample. Sequence analysis directly from PCR product showed 74-99% similarities with previous sequences in Gene Bank. In conclusion, the DBL2β domain of vargene of Indonesian isolates was 1603 nucleotides in length and there was a possible association of the existence of DBL2β domain with the severity of malaria outcome.

Cyclosporin A and its analogs inhibit hepatitis B virus entry into cultured hepatocytes through targeting a membrane transporter, sodium taurocholate cotransporting polypeptide (NTCP)

PubMed Central

Watashi, Koichi; Sluder, Ann; Daito, Takuji; Matsunaga, Satoko; Ryo, Akihide; Nagamori, Shushi; Iwamoto, Masashi; Nakajima, Syo; Tsukuda, Senko; Borroto-Esoda, Katyna; Sugiyama, Masaya; Tanaka, Yasuhito; Kanai, Yoshikatsu; Kusuhara, Hiroyuki; Mizokami, Masashi; Wakita, Takaji

2014-01-01

Chronic hepatitis B virus (HBV) infection is a major public health problem worldwide. Although nucleos(t)ide analogs inhibiting viral reverse transcriptase are clinically available as anti-HBV agents, emergence of drug-resistant viruses highlights the need for new anti-HBV agents interfering with other targets. Here we report that cyclosporin A (CsA) can inhibit HBV entry into cultured hepatocytes. The anti-HBV effect of CsA was independent of binding to cyclophilin and calcineurin. Rather, blockade of HBV infection correlated with the ability to inhibit the transporter activity of sodium taurocholate cotransporting polypeptide (NTCP). We also found that HBV infection-susceptible cells, differentiated HepaRG cells and primary human hepatocytes expressed NTCP, while nonsusceptible cell lines did not. A series of compounds targeting NTCP could inhibit HBV infection. CsA inhibited the binding between NTCP and large envelope protein in vitro. Evaluation of CsA analogs identified a compound with higher anti-HBV potency, having a median inhibitory concentration <0.2 μM. Conclusion: This study provides a proof of concept for the novel strategy to identify anti-HBV agents by targeting the candidate HBV receptor, NTCP, using CsA as a structural platform. (Hepatology 2014;59:1726–1737) PMID:24375637

Keratinocyte secretion of cyclophilin B via the constitutive pathway is regulated through its cyclosporin-binding site.

PubMed

Fearon, Paula; Lonsdale-Eccles, Ann A; Ross, O Kehinde; Todd, Carole; Sinha, Aparna; Allain, Fabrice; Reynolds, Nick J

2011-05-01

Cyclophilin B (CypB) is an endoplasmic reticulum (ER)-resident member of the cyclophilin family of proteins that bind cyclosporin A (CsA). We report that as in other cell types, CypB trafficked from the ER and was secreted by keratinocytes into the media in response to CsA. Concentrations as low as 1 pM of CsA induced secretion of CypB. Using brefeldin A, we showed that CypB is secreted from keratinocytes via the constitutive secretory pathway. We defined that substitution of tryptophan residue 128 in the CsA-binding site of CypB with alanine resulted in dissociation of CypB(W128A)-green fluorescent protein (GFP) from the ER. Photobleaching studies revealed a significant reduction in the diffusible mobility of CypB(W128A)-GFP compared with CypB(WT)-GFP, consistent with redistribution of CypB(W128A)-GFP into secretory vesicles disconnected from the ER/Golgi network. Furthermore, CsA significantly decreased the mobility of CypB(WT)-GFP but not CypB(W128A)-GFP. These studies demonstrate that therapeutically relevant concentrations of CsA regulate secretion of CypB by keratinocytes, and that a key residue within the CsA-binding site of CypB controls retention of CypB within the ER and regulates entry into the secretory pathway. As keratinocytes express CypB receptors (CD147) and CypB exhibits chemotactic properties, these data have implications for the therapeutic effects of CsA in inflammatory skin disease.

Keratinocyte Secretion of Cyclophilin B via the Constitutive Pathway Is Regulated through Its Cyclosporin-Binding Site

PubMed Central

Fearon, Paula; Lonsdale-Eccles, Ann A; Ross, O Kehinde; Todd, Carole; Sinha, Aparna; Allain, Fabrice; Reynolds, Nick J

2011-01-01

Cyclophilin B (CypB) is an endoplasmic reticulum (ER)-resident member of the cyclophilin family of proteins that bind cyclosporin A (CsA). We report that as in other cell types, CypB trafficked from the ER and was secreted by keratinocytes into the media in response to CsA. Concentrations as low as 1 p of CsA induced secretion of CypB. Using brefeldin A, we showed that CypB is secreted from keratinocytes via the constitutive secretory pathway. We defined that substitution of tryptophan residue 128 in the CsA-binding site of CypB with alanine resulted in dissociation of CypBW128A-green fluorescent protein (GFP) from the ER. Photobleaching studies revealed a significant reduction in the diffusible mobility of CypBW128A-GFP compared with CypBWT-GFP, consistent with redistribution of CypBW128A-GFP into secretory vesicles disconnected from the ER/Golgi network. Furthermore, CsA significantly decreased the mobility of CypBWT-GFP but not CypBW128A-GFP. These studies demonstrate that therapeutically relevant concentrations of CsA regulate secretion of CypB by keratinocytes, and that a key residue within the CsA-binding site of CypB controls retention of CypB within the ER and regulates entry into the secretory pathway. As keratinocytes express CypB receptors (CD147) and CypB exhibits chemotactic properties, these data have implications for the therapeutic effects of CsA in inflammatory skin disease. PMID:21270823

CRISPR-Cas type I-A Cascade complex couples viral infection surveillance to host transcriptional regulation in the dependence of Csa3b.

PubMed

He, Fei; Vestergaard, Gisle; Peng, Wenfang; She, Qunxin; Peng, Xu

2017-02-28

CRISPR-Cas (clustered regularly interspaced short palindromic repeats and the associated genes) constitute adaptive immune systems in bacteria and archaea and they provide sequence specific immunity against foreign nucleic acids. CRISPR-Cas systems are activated by viral infection. However, little is known about how CRISPR-Cas systems are activated in response to viral infection or how their expression is controlled in the absence of viral infection. Here, we demonstrate that both the transcriptional regulator Csa3b, and the type I-A interference complex Cascade, are required to transcriptionally repress the interference gene cassette in the archaeon Sulfolobus. Csa3b binds to two palindromic repeat sites in the promoter region of the cassette and facilitates binding of the Cascade to the promoter region. Upon viral infection, loading of Cascade complexes onto crRNA-matching protospacers leads to relief of the transcriptional repression. Our data demonstrate a mechanism coupling CRISPR-Cas surveillance of protospacers to transcriptional regulation of the interference gene cassette thereby allowing a fast response to viral infection. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Cyclosporin A and its analogs inhibit hepatitis B virus entry into cultured hepatocytes through targeting a membrane transporter, sodium taurocholate cotransporting polypeptide (NTCP).

PubMed

Watashi, Koichi; Sluder, Ann; Daito, Takuji; Matsunaga, Satoko; Ryo, Akihide; Nagamori, Shushi; Iwamoto, Masashi; Nakajima, Syo; Tsukuda, Senko; Borroto-Esoda, Katyna; Sugiyama, Masaya; Tanaka, Yasuhito; Kanai, Yoshikatsu; Kusuhara, Hiroyuki; Mizokami, Masashi; Wakita, Takaji

2014-05-01

Chronic hepatitis B virus (HBV) infection is a major public health problem worldwide. Although nucleos(t)ide analogs inhibiting viral reverse transcriptase are clinically available as anti-HBV agents, emergence of drug-resistant viruses highlights the need for new anti-HBV agents interfering with other targets. Here we report that cyclosporin A (CsA) can inhibit HBV entry into cultured hepatocytes. The anti-HBV effect of CsA was independent of binding to cyclophilin and calcineurin. Rather, blockade of HBV infection correlated with the ability to inhibit the transporter activity of sodium taurocholate cotransporting polypeptide (NTCP). We also found that HBV infection-susceptible cells, differentiated HepaRG cells and primary human hepatocytes expressed NTCP, while nonsusceptible cell lines did not. A series of compounds targeting NTCP could inhibit HBV infection. CsA inhibited the binding between NTCP and large envelope protein in vitro. Evaluation of CsA analogs identified a compound with higher anti-HBV potency, having a median inhibitory concentration <0.2 μM. This study provides a proof of concept for the novel strategy to identify anti-HBV agents by targeting the candidate HBV receptor, NTCP, using CsA as a structural platform. Copyright © 2014 The Authors. Hepatology published by Wiley on behalf of the American Association for the Study of Liver Diseases.

The gene encoding PBP74/CSA/motalin-1, a novel mouse hsp70, maps to mouse chromosome 18

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ohashi, Manabu; Oyanagi, Mitsuru; Kominami, Ryo

1995-11-20

The 70-kDa heat shock proteins (hsp70) function in folding of peptides and the assembly and disassembly of protein complexes. They are encoded by a multigene family comprising both heat-inducible and constitutively expressed genes. Different family members function in different organelles: hsp70 members such as hsp70 and hsc70 are present in the cytoplasm, BiP/GRP78 in the endoplasmic reticulum, and GRP75 in the mitochondria. PBP74/CSA/motalin-1 is a novel mouse hsp70 protein that was identified by three different groups. PBP74 was found to be a peptide-binding protein implicated in antigen processing. CSA is an antigen specific for the CM strain, and motalin-1 ismore » a protein associated with cellular mortality. 10 refs., 1 fig.« less

Diverse Effects of Cyclosporine on Hepatitis C Virus Strain Replication

PubMed Central

Ishii, Naoto; Watashi, Koichi; Hishiki, Takayuki; Goto, Kaku; Inoue, Daisuke; Hijikata, Makoto; Wakita, Takaji; Kato, Nobuyuki; Shimotohno, Kunitada

2006-01-01

Recently, a production system for infectious particles of hepatitis C virus (HCV) utilizing the genotype 2a JFH1 strain has been developed. This strain has a high capacity for replication in the cells. Cyclosporine (CsA) has a suppressive effect on HCV replication. In this report, we characterize the anti-HCV effect of CsA. We observe that the presence of viral structural proteins does not influence the anti-HCV activity of CsA. Among HCV strains, the replication of genotype 1b replicons was strongly suppressed by treatment with CsA. In contrast, JFH1 replication was less sensitive to CsA and its analog, NIM811. Replication of JFH1 did not require the cellular replication cofactor, cyclophilin B (CyPB). CyPB stimulated the RNA binding activity of NS5B in the genotype 1b replicon but not the genotype 2a JFH1 strain. These findings provide an insight into the mechanisms of diversity governing virus-cell interactions and in the sensitivity of these strains to antiviral agents. PMID:16611911

Rosetting Plasmodium falciparum-infected erythrocytes bind to human brain microvascular endothelial cells in vitro, demonstrating a dual adhesion phenotype mediated by distinct P. falciparum erythrocyte membrane protein 1 domains.

PubMed

Adams, Yvonne; Kuhnrae, Pongsak; Higgins, Matthew K; Ghumra, Ashfaq; Rowe, J Alexandra

2014-03-01

Adhesion interactions between Plasmodium falciparum-infected erythrocytes (IE) and human cells underlie the pathology of severe malaria. IE cytoadhere to microvascular endothelium or form rosettes with uninfected erythrocytes to survive in vivo by sequestering IE in the microvasculature and avoiding splenic clearance mechanisms. Both rosetting and cytoadherence are mediated by the parasite-derived IE surface protein family Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). Rosetting and cytoadherence have been widely studied as separate entities; however, the ability of rosetting P. falciparum strains to cytoadhere has received little attention. Here, we show that IE of the IT/R29 strain expressing a rosette-mediating PfEMP1 variant (IT4var09) cytoadhere in vitro to a human brain microvascular endothelial cell line (HBEC-5i). Cytoadherence was inhibited by heparin and by treatment of HBEC-5i with heparinase III, suggesting that the endothelial receptors for IE binding are heparan sulfate proteoglycans. Antibodies to the N-terminal regions of the IT4var09 PfEMP1 variant (NTS-DBL1α and DBL2γ domains) specifically inhibited and reversed cytoadherence down to low concentrations (<10 μg/ml of total IgG). Surface plasmon resonance experiments showed that the NTS-DBLα and DBL2γ domains bind strongly to heparin, with half-maximal binding at a concentration of ∼0.5 μM in both cases. Therefore, cytoadherence of IT/R29 IE is distinct from rosetting, which is primarily mediated by NTS-DBL1α interactions with complement receptor 1. These data show that IT4var09-expressing parasites are capable of dual interactions with both endothelial cells and uninfected erythrocytes via distinct receptor-ligand interactions.

Development of Ultra-Super Sensitive Immunohistochemistry and Its Application to the Etiological Study of Adult T-Cell Leukemia/Lymphoma

PubMed Central

Hasui, Kazuhisa; Wang, Jia; Tanaka, Yuetsu; Izumo, Shuji; Eizuru, Yoshito; Matsuyama, Takami

2012-01-01

Antigen retrieval (AR) and ultra-super sensitive immunohistochemistry (ultra-IHC) have been established for application to archival human pathology specimens. The original ultra-IHC was the ImmunoMax method or the catalyzed signal amplification system (ImmunoMax/CSA method), comprising the streptavidin-biotin complex (sABC) method and catalyzed reporter deposition (CARD) reaction with visualization of its deposition. By introducing procedures to diminish non-specific staining in the original ultra-IHC method, we developed the modified ImmunoMax/CSA method with AR heating sections in an AR solution (heating-AR). The heating-AR and modified ImmunoMax/CSA method visualized expression of the predominantly simple present form of HTLV-1 proviral DNA pX region p40Tax protein (Tax) in adult T-cell leukemia/lymphoma (ATLL) cells in archival pathology specimens in approximately 75% of cases. The simple present form of Tax detected exhibited a close relation with ATLL cell proliferation. We also established a new simplified CSA (nsCSA) system by replacing the sABC method with the secondary antibody- and horse radish peroxidase-labeled polymer reagent method, introducing the pretreatments blocking non-specific binding of secondary antibody reagent, and diminishing the diffusion of deposition in the CARD reaction. Combined with AR treating sections with proteinase K solution (enzymatic-AR), the nsCSA system visualized granular immunostaining of the complex present form of Tax in a small number of ATLL cells in most cases, presenting the possibility of etiological pathological diagnosis of ATLL and suggesting that the complex present form of Tax-positive ATLL cells were young cells derived from ATLL stem cells. The heating-AR and ultra-IHC detected physiological expression of the p53 protein and its probable phosphorylation by Tax in peripheral blood mononuclear cells of peripheral blood tissue specimens from HTLV-1 carriers, as well as physiological and pathological expression of the molecules involved with G1 phase progression and G1–S phase transition (E2F-1, E2F-4, DP-1, and cyclin E) in ATLL and peripheral T-cell lymphoma cells. The ultra-IHC with AR is useful for etiological pathological diagnosis of ATLL since HTLV-1 pathogenicity depends on that of Tax, and can be a useful tool for studies translating advanced molecular biology and pathology to human pathology. PMID:22685351

Diagnostic Cutoff Value for Ultrasonography of the Common Fibular Neuropathy at the Fibular Head

PubMed Central

2016-01-01

Objective To establish the diagnostic cutoff value of ultrasonographic measurement for common fibular neuropathy (CFN) at the fibular head (FH). Methods Twenty patients with electrodiagnostically diagnosed CFN at the FH and 30 healthy controls were included in the study. The cross-sectional area (CSA) of sciatic nerve at mid-thigh level, common fibular nerve at popliteal fossa (PF), and common fibular (CF) nerve at FH were measured. Additionally, the difference of CF nerve CSA at the FH between symptomatic side and asymptomatic side (ΔSx–Asx), the ratio of CF nerve CSA at FH to at PF (FH/PF), and the ratio of CF nerve CSA at the FH symptomatic side to asymptomatic side (Ratio Sx–Asx) were calculated. Results CSA at the FH, FH/PF, ΔSx–Asx, and Ratio Sx–Asx showed significant differences between the patient and control groups. The cutoff value for diagnosing CFN at the FH was 11.7 mm2 for the CSA at the FH (sensitivity 85.0%, specificity 90.0%), 1.70 mm2 for the ΔSx–Asx (sensitivity 83.3%, specificity 97.0%), 1.11 for the FH/PF (sensitivity 47.1%, specificity 93.3%), and 1.24 for the Ratio Sx–Asx (sensitivity 72.2%, specificity 96.7%). Conclusion The ultrasonographic measurement and cutoff value could be a valuable reference in diagnosing CFN at the FH and improving diagnostic reliability and efficacy. PMID:28119836

Placental Malaria Induces Variant-Specific Antibodies of the Cytophilic Subtypes Immunoglobulin G1 (IgG1) and IgG3 That Correlate with Adhesion Inhibitory Activity

PubMed Central

Elliott, Salenna R.; Brennan, Amy K.; Beeson, James G.; Tadesse, Eyob; Molyneux, Malcolm E.; Brown, Graham V.; Rogerson, Stephen J.

2005-01-01

Antibodies targeting variant antigens on the surfaces of chondroitin sulfate A (CSA)-binding malaria-infected erythrocytes have been linked to protection against the complications of malaria in pregnancy. We examined the isotype/subtype profiles of antibodies that bound to variant surface antigens expressed by CSA-adherent Plasmodium falciparum in pregnant Malawian women with and without histologically defined placental malaria. Women in their first pregnancy with placental malaria produced significantly greater amounts of immunoglobulin G1 (IgG1) and IgG3 reactive with surface antigens of malaria-infected erythrocytes than uninfected women of the same gravidity. IgG1 and IgG3 levels in infected and control women in later pregnancies were similar to those in infected women in their first pregnancy. Levels of IgG2 and IgG4 were similarly low in infected and uninfected women of all gravidities. IgM that bound to the surface of CSA-adherent P. falciparum occurred in all groups of women and malaria-naïve controls. There was a significant correlation between IgG1 and IgG3 levels, indicating that women usually produced both subtypes. Levels of IgG1 and IgG3 correlated with the ability of serum or plasma to inhibit parasite adhesion to CSA. Taken together, these data suggest that IgG1 and IgG3 dominate the IgG response to placental-type variant surface antigens. They may function by blocking parasite adhesion to placental CSA, but given their cytophilic nature, they might also opsonize malaria-infected erythrocytes for interaction with Fc receptors on phagocytic cells. PMID:16113309

Variola virus F1L is a Bcl-2-like protein that unlike its vaccinia virus counterpart inhibits apoptosis independent of Bim

PubMed Central

Marshall, B; Puthalakath, H; Caria, S; Chugh, S; Doerflinger, M; Colman, P M; Kvansakul, M

2015-01-01

Subversion of host cell apoptosis is an important survival strategy for viruses to ensure their own proliferation and survival. Certain viruses express proteins homologous in sequence, structure and function to mammalian pro-survival B-cell lymphoma 2 (Bcl-2) proteins, which prevent rapid clearance of infected host cells. In vaccinia virus (VV), the virulence factor F1L was shown to be a potent inhibitor of apoptosis that functions primarily be engaging pro-apoptotic Bim. Variola virus (VAR), the causative agent of smallpox, harbors a homolog of F1L of unknown function. We show that VAR F1L is a potent inhibitor of apoptosis, and unlike all other characterized anti-apoptotic Bcl-2 family members lacks affinity for the Bim Bcl-2 homology 3 (BH3) domain. Instead, VAR F1L engages Bid BH3 as well as Bak and Bax BH3 domains. Unlike its VV homolog, variola F1L only protects against Bax-mediated apoptosis in cellular assays. Crystal structures of variola F1L bound to Bid and Bak BH3 domains reveal that variola F1L forms a domain-swapped Bcl-2 fold, which accommodates Bid and Bak BH3 in the canonical Bcl-2-binding groove, in a manner similar to VV F1L. Despite the observed conservation of structure and sequence, variola F1L inhibits apoptosis using a startlingly different mechanism compared with its VV counterpart. Our results suggest that unlike during VV infection, Bim neutralization may not be required during VAR infection. As molecular determinants for the human-specific tropism of VAR remain essentially unknown, identification of a different mechanism of action and utilization of host factors used by a VAR virulence factor compared with its VV homolog suggest that studying VAR directly may be essential to understand its unique tropism. PMID:25766319

Variola virus F1L is a Bcl-2-like protein that unlike its vaccinia virus counterpart inhibits apoptosis independent of Bim.

PubMed

Marshall, B; Puthalakath, H; Caria, S; Chugh, S; Doerflinger, M; Colman, P M; Kvansakul, M

2015-03-12

Subversion of host cell apoptosis is an important survival strategy for viruses to ensure their own proliferation and survival. Certain viruses express proteins homologous in sequence, structure and function to mammalian pro-survival B-cell lymphoma 2 (Bcl-2) proteins, which prevent rapid clearance of infected host cells. In vaccinia virus (VV), the virulence factor F1L was shown to be a potent inhibitor of apoptosis that functions primarily be engaging pro-apoptotic Bim. Variola virus (VAR), the causative agent of smallpox, harbors a homolog of F1L of unknown function. We show that VAR F1L is a potent inhibitor of apoptosis, and unlike all other characterized anti-apoptotic Bcl-2 family members lacks affinity for the Bim Bcl-2 homology 3 (BH3) domain. Instead, VAR F1L engages Bid BH3 as well as Bak and Bax BH3 domains. Unlike its VV homolog, variola F1L only protects against Bax-mediated apoptosis in cellular assays. Crystal structures of variola F1L bound to Bid and Bak BH3 domains reveal that variola F1L forms a domain-swapped Bcl-2 fold, which accommodates Bid and Bak BH3 in the canonical Bcl-2-binding groove, in a manner similar to VV F1L. Despite the observed conservation of structure and sequence, variola F1L inhibits apoptosis using a startlingly different mechanism compared with its VV counterpart. Our results suggest that unlike during VV infection, Bim neutralization may not be required during VAR infection. As molecular determinants for the human-specific tropism of VAR remain essentially unknown, identification of a different mechanism of action and utilization of host factors used by a VAR virulence factor compared with its VV homolog suggest that studying VAR directly may be essential to understand its unique tropism.

Investigation of Tribological Behavior of a Novel Hybrid Composite Prepared with Al-Coconut Shell Ash Mixed with Graphite

NASA Astrophysics Data System (ADS)

Siva Sankara Raju, R.; Panigrahi, M. K.; Ganguly, R. I.; Srinivasa Rao, G.

2017-08-01

The present investigation develops a next-generation hybrid Al metal matrix composite using coconut shell ash (CSA) and graphite (Gr) reinforcement. Stir-casting is adapted to prepare an Al-1100-based composite. Three other composites of Al-Al2O3, Al-Al2O3-Gr, and Al-CSA are prepared that contain equivalent volume fractions of Al2O3, CSA, and Gr. These assist in comparisons among the three composites and the developed hybrid Al-CSA-Gr composite. The study reveals that the addition of 3 pct Gr improves the specific strength, toughness, and tribological properties. The Al-CSA composite shows better mechanical properties, such as tensile strength and hardness, than the other three composites. Gr addition helps the hybrid Al-CSA-Gr composite to attain better tribological properties with a slightly lower specific strength. Scanning electron microscopy studies of the worn material surfaces corroborate the findings of the abrasion testing. Elemental analyses by energy-dispersive X-ray spectroscopy of the debris from the counter-face of the tribo surface confirm the presence of Al, O, Si, Fe, Mn, and C.

Performance of CHROMagar Selective Medium and Oxacillin Resistance Screening Agar Base for Identifying Staphylococcus aureus and Detecting Methicillin Resistance

PubMed Central

Kluytmans, Jan; Van Griethuysen, Arjanne; Willemse, Piet; Van Keulen, Peter

2002-01-01

Two new selective media, oxacillin resistance screening agar base (ORSAB) and CHROMagar Staph aureus (CSA), were evaluated for identification of Staphylococcus aureus and for screening of methicillin resistance by addition of antimicrobial agents to these media. A well-defined collection consisting of 1,140 staphylococci was used. A total of 624 were S. aureus, of which 358 were methicillin susceptible and 266 were methicillin resistant, and 516 were coagulase-negative staphylococci. The methicillin-resistant S. aureus (MRSA) strains were selected based on the results of phage typing; 247 different types were included in the analysis. For identification of S. aureus, both media performed better after 24 h than after 48 h. The sensitivities at 24 h were comparable (CSA, 98.6%; ORSAB, 97.1%), but the specificity of CSA was significantly higher (CSA, 97.1%; ORSAB, 92.1%). For screening of methicillin resistance, antibiotic supplements were added to both media. The sensitivity was lower after 24 h (CSA, 58.6%; ORSAB, 84.2%) and increased significantly after 48 h (CSA, 77.5%; ORSAB, 91.4%). At both time intervals ORSAB was significantly more sensitive than CSA. However, the specificities of both media were high after 24 h (CSA, 99.1%; ORSAB, 98.3%) and decreased significantly after 48 h of incubation (CSA, 94.7%; ORSAB, 95.5%). In conclusion, for identification of S. aureus, CSA is more accurate than ORSAB because of a significantly higher specificity. For screening of MRSA, ORSAB performs better than CSA, but the usefulness in clinical practice is limited because a significant number of strains are not detected. PMID:12089266

How Much Child Sexual Abuse is “Below the Surface,” and Can We Help Adults Identify it Early?

PubMed Central

Martin, Erin K.; Silverstone, Peter H.

2013-01-01

Child sexual abuse (CSA) occurs frequently in society to children aged between 2 and 17. It is significantly more common in girls than boys, with the peak age for CSA occurring when girls are aged 13–17. Many children experience multiple episodes of CSA, as well as having high rates of other victimizations (such as physical assaults). One of the problems for current research in CSA is different definitions of what this means, and no recent review has clearly differentiated more severe forms of CSA, and how commonly this is disclosed. In general we suggest there are four types of behavior that should be included as CSA, namely (1) non-contact, (2) genital touching, (3) attempted vaginal and anal penetrative acts, and (4) vaginal and anal penetrative acts. Evidence suggests that CSA involving types (2), (3), and (4) is more likely to have significant long-term outcomes, and thus can be considered has having higher-impact. From the research to date approximately 15% of girls aged 2–17 experience higher-impact CSA (with most studies suggesting that between 12 and 18% of girls experience higher-impact CSA). Approximately 6% of boys experience higher-impact CSA (with most studies suggesting that between 5 and 8% experience higher-impact CSA). The data also suggests that in over 95% of cases the CSA is never disclosed to authorities. Thus, CSA is frequent but often not identified, and occurs “below the surface” in the vast majority of higher-impact cases. Helping adults to understand “below the surface” CSA might help them to recognize it early, but there are very few indicators specific to CSA, making this a challenging goal to achieve. Nonetheless, given that CSA frequently occurs with other types of abuse, a training program that focuses on both CSA and other abuse may offer a method to allow both early recognition and prevention by adults in the general population. PMID:23874306

Structure–function characterization of three human antibodies targeting the vaccinia virus adhesion molecule D8

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matho, Michael H.; Schlossman, Andrew; Gilchuk, Iuliia M.

Vaccinia virus (VACV) envelope protein D8 is one of three glycosaminoglycan adhesion molecules and binds to the linear polysaccharide chondroitin sulfate (CS). D8 is also a target for neutralizing antibody responses that are elicited by the smallpox vaccine, which has enabled the first eradication of a human viral pathogen and is a useful model for studying antibody responses. However, to date, VACV epitopes targeted by human antibodies have not been characterized at atomic resolution. Here in this paper, we characterized the binding properties of several human anti-D8 antibodies and determined the crystal structures of three VACV-mAb variants, VACV-66, VACV-138, andmore » VACV-304, separately bound to D8. Although all these antibodies bound D8 with high affinity and were moderately neutralizing in the presence of complement, VACV-138 and VACV-304 also fully blocked D8 binding to CS-A, the low affinity ligand for D8. VACV-138 also abrogated D8 binding to the high-affinity ligand CS-E, but we observed residual CS-E binding was observed in the presence of VACV-304. Analysis of the VACV-138– and VACV-304–binding sites along the CS-binding crevice of D8, combined with different efficiencies of blocking D8 adhesion to CS-A and CS-E allowed us to propose that D8 has a high- and low-affinity CS-binding region within its central crevice. The crevice is amenable to protein engineering to further enhance both specificity and affinity of binding to CS-E. Finally, a wild-type D8 tetramer specifically bound to structures within the developing glomeruli of the kidney, which express CS-E. We propose that through structure-based protein engineering, an improved D8 tetramer could be used as a potential diagnostic tool to detect expression of CS-E, which is a possible biomarker for ovarian cancer.« less

Structure–function characterization of three human antibodies targeting the vaccinia virus adhesion molecule D8

DOE PAGES

Matho, Michael H.; Schlossman, Andrew; Gilchuk, Iuliia M.; ...

2017-11-09

Vaccinia virus (VACV) envelope protein D8 is one of three glycosaminoglycan adhesion molecules and binds to the linear polysaccharide chondroitin sulfate (CS). D8 is also a target for neutralizing antibody responses that are elicited by the smallpox vaccine, which has enabled the first eradication of a human viral pathogen and is a useful model for studying antibody responses. However, to date, VACV epitopes targeted by human antibodies have not been characterized at atomic resolution. Here in this paper, we characterized the binding properties of several human anti-D8 antibodies and determined the crystal structures of three VACV-mAb variants, VACV-66, VACV-138, andmore » VACV-304, separately bound to D8. Although all these antibodies bound D8 with high affinity and were moderately neutralizing in the presence of complement, VACV-138 and VACV-304 also fully blocked D8 binding to CS-A, the low affinity ligand for D8. VACV-138 also abrogated D8 binding to the high-affinity ligand CS-E, but we observed residual CS-E binding was observed in the presence of VACV-304. Analysis of the VACV-138– and VACV-304–binding sites along the CS-binding crevice of D8, combined with different efficiencies of blocking D8 adhesion to CS-A and CS-E allowed us to propose that D8 has a high- and low-affinity CS-binding region within its central crevice. The crevice is amenable to protein engineering to further enhance both specificity and affinity of binding to CS-E. Finally, a wild-type D8 tetramer specifically bound to structures within the developing glomeruli of the kidney, which express CS-E. We propose that through structure-based protein engineering, an improved D8 tetramer could be used as a potential diagnostic tool to detect expression of CS-E, which is a possible biomarker for ovarian cancer.« less

Identification and characterization of intracellular proteins that bind oligonucleotides with phosphorothioate linkages

PubMed Central

Liang, Xue-hai; Sun, Hong; Shen, Wen; Crooke, Stanley T.

2015-01-01

Although the RNase H-dependent mechanism of inhibition of gene expression by chemically modified antisense oligonucleotides (ASOs) has been well characterized, little is known about the interactions between ASOs and intracellular proteins that may alter cellular localization and/or potency of ASOs. Here, we report the identification of 56 intracellular ASO-binding proteins using multi-step affinity selection approaches. Many of the tested proteins had no significant effect on ASO activity; however, some proteins, including La/SSB, NPM1, ANXA2, VARS and PC4, appeared to enhance ASO activities, likely through mechanisms related to subcellular distribution. VARS and ANXA2 co-localized with ASOs in endocytic organelles, and reduction in the level of VARS altered lysosome/ASO localization patterns, implying that these proteins may facilitate ASO release from the endocytic pathway. Depletion of La and NPM1 reduced nuclear ASO levels, suggesting potential roles in ASO nuclear accumulation. On the other hand, Ku70 and Ku80 proteins inhibited ASO activity, most likely by competition with RNase H1 for ASO/RNA duplex binding. Our results demonstrate that phosphorothioate-modified ASOs bind a set of cellular proteins that affect ASO activity via different mechanisms. PMID:25712094

Dynamic CO₂ inhalation: a novel treatment for CSR-CSA associated with CHF.

PubMed

Wan, Zhi Hui; Wen, Fang Jing; Hu, Ke

2013-05-01

Cheyne-Stokes respiration with central sleep apnea (CSR-CSA) is very common in patients with chronic congestive heart failure (CHF). A current concept of the key pathophysiological mechanism leading to CSR-CSA is a fluctuation of PaCO2 below and above the apneic threshold. A number of therapeutic approaches for CSR-CSA have been proposed-all with varying success, some of which include various modes of positive airway pressure among other strategies. However, CO2 oscillations seen in CSR-CSA have yet to be looked at as a specific therapeutic target by current treatments. Previous studies have shown that delivery of constant CO2 is efficacious in eliminating CSR-CSA by raising PaCO2, but there are serious concerns about the potential side effects, such as unwanted elevations in ventilation, work of breathing, and sympathetic nerve activity (SNA), and consequently CO2 inhalation therapy has not been recommended as a routine option for therapy. However, recent new studies into CO2 inhalation therapy have been made that may reshape its role as therapeutic. In this review, we will focus on the recent developments of administration of dynamic CO2 in the management of CSR-CSA in CHF patients.

Proton chemical shift tensors determined by 3D ultrafast MAS double-quantum NMR spectroscopy

NASA Astrophysics Data System (ADS)

Zhang, Rongchun; Mroue, Kamal H.; Ramamoorthy, Ayyalusamy

2015-10-01

Proton NMR spectroscopy in the solid state has recently attracted much attention owing to the significant enhancement in spectral resolution afforded by the remarkable advances in ultrafast magic angle spinning (MAS) capabilities. In particular, proton chemical shift anisotropy (CSA) has become an important tool for obtaining specific insights into inter/intra-molecular hydrogen bonding. However, even at the highest currently feasible spinning frequencies (110-120 kHz), 1H MAS NMR spectra of rigid solids still suffer from poor resolution and severe peak overlap caused by the strong 1H-1H homonuclear dipolar couplings and narrow 1H chemical shift (CS) ranges, which render it difficult to determine the CSA of specific proton sites in the standard CSA/single-quantum (SQ) chemical shift correlation experiment. Herein, we propose a three-dimensional (3D) 1H double-quantum (DQ) chemical shift/CSA/SQ chemical shift correlation experiment to extract the CS tensors of proton sites whose signals are not well resolved along the single-quantum chemical shift dimension. As extracted from the 3D spectrum, the F1/F3 (DQ/SQ) projection provides valuable information about 1H-1H proximities, which might also reveal the hydrogen-bonding connectivities. In addition, the F2/F3 (CSA/SQ) correlation spectrum, which is similar to the regular 2D CSA/SQ correlation experiment, yields chemical shift anisotropic line shapes at different isotropic chemical shifts. More importantly, since the F2/F1 (CSA/DQ) spectrum correlates the CSA with the DQ signal induced by two neighboring proton sites, the CSA spectrum sliced at a specific DQ chemical shift position contains the CSA information of two neighboring spins indicated by the DQ chemical shift. If these two spins have different CS tensors, both tensors can be extracted by numerical fitting. We believe that this robust and elegant single-channel proton-based 3D experiment provides useful atomistic-level structural and dynamical information for a variety of solid systems that possess high proton density.

Proton chemical shift tensors determined by 3D ultrafast MAS double-quantum NMR spectroscopy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Rongchun; Mroue, Kamal H.; Ramamoorthy, Ayyalusamy, E-mail: ramamoor@umich.edu

2015-10-14

Proton NMR spectroscopy in the solid state has recently attracted much attention owing to the significant enhancement in spectral resolution afforded by the remarkable advances in ultrafast magic angle spinning (MAS) capabilities. In particular, proton chemical shift anisotropy (CSA) has become an important tool for obtaining specific insights into inter/intra-molecular hydrogen bonding. However, even at the highest currently feasible spinning frequencies (110–120 kHz), {sup 1}H MAS NMR spectra of rigid solids still suffer from poor resolution and severe peak overlap caused by the strong {sup 1}H–{sup 1}H homonuclear dipolar couplings and narrow {sup 1}H chemical shift (CS) ranges, which rendermore » it difficult to determine the CSA of specific proton sites in the standard CSA/single-quantum (SQ) chemical shift correlation experiment. Herein, we propose a three-dimensional (3D) {sup 1}H double-quantum (DQ) chemical shift/CSA/SQ chemical shift correlation experiment to extract the CS tensors of proton sites whose signals are not well resolved along the single-quantum chemical shift dimension. As extracted from the 3D spectrum, the F1/F3 (DQ/SQ) projection provides valuable information about {sup 1}H–{sup 1}H proximities, which might also reveal the hydrogen-bonding connectivities. In addition, the F2/F3 (CSA/SQ) correlation spectrum, which is similar to the regular 2D CSA/SQ correlation experiment, yields chemical shift anisotropic line shapes at different isotropic chemical shifts. More importantly, since the F2/F1 (CSA/DQ) spectrum correlates the CSA with the DQ signal induced by two neighboring proton sites, the CSA spectrum sliced at a specific DQ chemical shift position contains the CSA information of two neighboring spins indicated by the DQ chemical shift. If these two spins have different CS tensors, both tensors can be extracted by numerical fitting. We believe that this robust and elegant single-channel proton-based 3D experiment provides useful atomistic-level structural and dynamical information for a variety of solid systems that possess high proton density.« less

[Association of childhood sexual abuse and disordered eating in a sample of Mexican adolescents].

PubMed

Unikel-Santoncini, Claudia; Ramos-Lira, Luciana; Juárez-García, Francisco

2011-01-01

To analyze the association between childhood sexual abuse (CSA) and disordered eating (DE). A probabilistic sample of 2,358 female high school students of public schools in the Estado de Mexico was used. DE was more prevalent among CSA sufferers (p < or = 0.05). Preoccupation with gaining weight, binging and restrictive behaviors were associated to CSA (p < or = 0.05). The probability of DE was 7 times higher when the CSA experience had not been revealed and 36 times when CSA happened before 14 years of age. The association between CSA and DE is clear in the sample studied, as well as with some of its specific characteristics, which highlights the need to deepen in this research field and to incorporate the evaluation of CSA and its consequences in adolescents' mental health.

Procarcinogenic effects of cyclosporine A are mediated through the activation of TAK1/TAB1 signaling pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Jianmin; Walsh, Stephanie B.; Verney, Zoe M.

Research highlights: {yields} Organ transplant recipients are highly susceptible to early skin cancer development. {yields} CsA-mediated TGFB1-dependent TAK1/TAB1 signaling augments invasive tumor growth. {yields} CsA enhances accumulation of upstream kinases, ZMP, AMPK and IRAK to activate TAK1. {yields} TAK1 mediates enhanced proliferation and reduced apoptosis via CsA-dependent NF{kappa}B. -- Abstract: Cyclosporine A (CsA) is an immunosuppressive drug commonly used for maintaining chronic immune suppression in organ transplant recipients. It is known that patients receiving CsA manifest increased growth of aggressive non-melanoma skin cancers. However, the underlying mechanism by which CsA augments tumor growth is not fully understood. Here, we showmore » that CsA augments the growth of A431 epidermoid carcinoma xenograft tumors by activating tumor growth factor {beta}-activated kinase1 (TAK1). The activation of TAK1 by CsA occurs at multiple levels by kinases ZMP, AMPK and IRAK. TAK1 forms heterodimeric complexes with TAK binding protein 1 and 2 (TAB1/TAB2) which in term activate nuclear factor {kappa}B (NF{kappa}B) and p38 MAP kinase. Transcriptional activation of NF{kappa}B is evidenced by IKK{beta}-mediated phosphorylation-dependent degradation of I{kappa}B and consequent nuclear translocation of p65. This also leads to enhancement in the expression of its transcriptional target genes cyclin D1, Bcl2 and COX-2. Similarly, activation of p38 leads to enhanced inflammation-related signaling shown by increased phosphorylation of MAPKAPK2 and which in turn phosphorylates its substrate HSP27. Activation of both NF{kappa}B and p38 MAP kinase provide mitogenic stimuli to augment the growth of SCCs.« less

Physical symptoms in very young children assessed for sexual abuse: a mixed method analysis from the ASAC study.

PubMed

Vrolijk-Bosschaart, Thekla F; Brilleslijper-Kater, Sonja N; Widdershoven, Guy A; Teeuw, Arianne Rian H; Verlinden, Eva; Voskes, Yolande; van Duin, Esther M; Verhoeff, Arnoud P; Benninga, Marc A; Lindauer, Ramón J L

2017-10-01

So far, a recognizable pattern of clinical symptoms for child sexual abuse (CSA), especially in young male children, is lacking. To improve early recognition of CSA, we reviewed physical complaints, physical examination, and tests on sexually transmitted infections (STIs) in confirmed victims (predominantly preschool boys) of CSA from the Amsterdam sexual abuse case (ASAC). We retrospectively analyzed the outcomes of the primary assessment using mixed methods: descriptive analysis of physical complaints, physical exams, and STI tests from medical files and a qualitative analysis on expert's interpretations of physical complaints and children's behavior during physical examination. We included 54 confirmed CSA victims, median age 3.2 (0-6) years, 43 boys (80%), and 11 girls (20%). Physical complaints were reported in 50%, of which gastrointestinal and anogenital complaints were most common. None of the children showed CSA-specific genital signs at physical examination. Most prominent finding during physical examination was a deviant behavioral response (anxiety, withdrawal, too outgoing) in 15 children (28%), especially in children who experienced anal/vaginal penetration. Testing for STIs was negative. Physical complaints and physical signs at examinations were non-specific for CSA. Deviant behavioral reactions during physical examination were the most prominent finding. Precise observation of a child's behavior during physical examination is needed. What is known • Child sexual abuse (CSA) affects many children on both the short and the long term but remains unrecognized in most cases. • So far, there is a lack of studies on symptom patterns of CSA in male, preschool children. What is new • None of the children showed CSA-specific findings at physical and anogenital examination; STIs were not found in the confirmed victims of CSA. • The most prominent finding was the deviant behavioral response of the children examined, especially in children who experienced anal/vaginal penetration; therefore, precise observation of a child's behavior during physical examination is a crucial part of the evaluation of suspected CSA.

Immune responses during gestational malaria: a review of the current knowledge and future trend of research.

PubMed

Maestre, Amanda; Carmona-Fonseca, Jaime

2014-04-15

Women pregnant with their first child are susceptible to severe P. falciparum disease from placental malaria because they lack immunity to placenta-specific cytoadherence proteins. In subsequent pregnancies, as immunity against placental parasites is acquired, there is a reduced risk of adverse effects of malaria on the mother and fetus and asymptomatic parasitaemia is common. In the case of vivax malaria, with increasing reports of severe cases in Asia and South America, the effects of infection by this species during pregnancy remain to be elucidated. This review summarized the main aspects involved in the acquisition of specific antimalarial immune responses during pregnancy with emphasis in research carried out in America and Asia, in order to offer a framework of interpretation for studies on pregnant women with malaria which are recently being produced in these regions. The authors conclude that (1) Effective humoral responses during gestational malaria are mainly directed against variant surface antigens codified by genes of the var2Csa family of P. falciparum; (2) Acquisition of immunity against these variant antigens depends on the degree and intensity of transmission, and the chance increases with age and successive pregnancies; (3) Antibody development is guided by specific cellular immune responses in cases of placental and maternal infection, and (4) The study of the significance of acquisition of specific immunity against both P. falciparum and P. vivax in America, should be performed.

Identification and characterization of intracellular proteins that bind oligonucleotides with phosphorothioate linkages.

PubMed

Liang, Xue-hai; Sun, Hong; Shen, Wen; Crooke, Stanley T

2015-03-11

Although the RNase H-dependent mechanism of inhibition of gene expression by chemically modified antisense oligonucleotides (ASOs) has been well characterized, little is known about the interactions between ASOs and intracellular proteins that may alter cellular localization and/or potency of ASOs. Here, we report the identification of 56 intracellular ASO-binding proteins using multi-step affinity selection approaches. Many of the tested proteins had no significant effect on ASO activity; however, some proteins, including La/SSB, NPM1, ANXA2, VARS and PC4, appeared to enhance ASO activities, likely through mechanisms related to subcellular distribution. VARS and ANXA2 co-localized with ASOs in endocytic organelles, and reduction in the level of VARS altered lysosome/ASO localization patterns, implying that these proteins may facilitate ASO release from the endocytic pathway. Depletion of La and NPM1 reduced nuclear ASO levels, suggesting potential roles in ASO nuclear accumulation. On the other hand, Ku70 and Ku80 proteins inhibited ASO activity, most likely by competition with RNase H1 for ASO/RNA duplex binding. Our results demonstrate that phosphorothioate-modified ASOs bind a set of cellular proteins that affect ASO activity via different mechanisms. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adhikary, Suraj; Eichman, Brandt F.

DNA glycosylases specialized for the repair of alkylation damage must identify, with fine specificity, a diverse array of subtle modifications within DNA. The current mechanism involves damage sensing through interrogation of the DNA duplex, followed by more specific recognition of the target base inside the active site pocket. To better understand the physical basis for alkylpurine detection, we determined the crystal structure of Schizosaccharomyces pombe Mag1 (spMag1) in complex with DNA and performed a mutational analysis of spMag1 and the close homologue from Saccharomyces cerevisiae (scMag). Despite strong homology, spMag1 and scMag differ in substrate specificity and cellular alkylation sensitivity,more » although the enzymological basis for their functional differences is unknown. We show that Mag preference for 1,N{sup 6}-ethenoadenine ({var_epsilon}A) is influenced by a minor groove-interrogating residue more than the composition of the nucleobase-binding pocket. Exchanging this residue between Mag proteins swapped their {var_epsilon}A activities, providing evidence that residues outside the extrahelical base-binding pocket have a role in identification of a particular modification in addition to sensing damage.« less

The influence of radiographic viewing perspective and demographics on the Critical Shoulder Angle

PubMed Central

Suter, Thomas; Popp, Ariane Gerber; Zhang, Yue; Zhang, Chong; Tashjian, Robert Z.; Henninger, Heath B.

2014-01-01

Background Accurate assessment of the critical shoulder angle (CSA) is important in clinical evaluation of degenerative rotator cuff tears. This study analyzed the influence of radiographic viewing perspective on the CSA, developed a classification system to identify malpositioned radiographs, and assessed the relationship between the CSA and demographic factors. Methods Glenoid height, width and retroversion were measured on 3D CT reconstructions of 68 cadaver scapulae. A digitally reconstructed radiograph was aligned perpendicular to the scapular plane, and retroversion was corrected to obtain a true antero-posterior (AP) view. In 10 scapulae, incremental anteversion/retroversion and flexion/extension views were generated. The CSA was measured and a clinically applicable classification system was developed to detect views with >2° change in CSA versus true AP. Results The average CSA was 33±4°. Intra- and inter-observer reliability was high (ICC≥0.81) but decreased with increasing viewing angle. Views beyond 5° anteversion, 8° retroversion, 15° flexion and 26° extension resulted in >2° deviation of the CSA compared to true AP. The classification system was capable of detecting aberrant viewing perspectives with sensitivity of 95% and specificity of 53%. Correlations between glenoid size and CSA were small (R≤0.3), and CSA did not vary by gender (p=0.426) or side (p=0.821). Conclusions The CSA was most susceptible to malposition in ante/retroversion. Deviations as little as 5° in anteversion resulted in a CSA >2° from true AP. A new classification system refines the ability to collect true AP radiographs of the scapula. The CSA was unaffected by demographic factors. PMID:25591458

PAPP-A affects tendon structure and mechanical properties.

PubMed

Yang, Tai-Hua; Thoreson, Andrew R; An, Kai-Nan; Zhao, Chunfeng; Conover, Cheryl A; Amadio, Peter C

2015-10-01

Pregnancy-associated plasma protein-A (PAPP-A) serves to increase local insulin-like growth factor (IGF) stimulation of proliferation and differentiation in many tissues through proteolysis of inhibitory IGF-binding proteins. The purpose of this study was to investigate the effects of PAPP-A on tendon structure and mechanical properties. A total of 30 tails from 6-month-old mice were tested with 10 tails in each of following groups: PAPP-A knockout (KO), skeletal-specific PAPP-A overexpressing transgenic (Tg) and wild type (WT). Morphologically, the total tail cross-sectional area (CSA), individual tissue CSAs of bone, muscle and tendon, and fascicle diameter were measured. A fascicle pullout test was performed to assess stiffness and strength of interfascicular structures. Fascicles were mechanically characterized through low and high displacement rate uniaxial tension tests providing modulus at each rate, hysteresis area and stress relaxation ratio. The KO mice had a smaller total tail CSA (p<0.05), fascicle diameter (p<0.05), absolute tendon CSA (p<0.05), fast and slow stiffness (p<0.05 for both) and larger hysteresis area (p<0.05) compared to WT and Tg mice. On the other hand, the Tg mice had a larger fascicle diameter (p<0.05), absolute tendon CSA (p<0.05), higher interfascicular strength and stiffness (p<0.05) and lower fascicular modulus at low displacement rates (p<0.05) compared to WT and KO mice. Tg mice also had larger total tail CSA area (p<0.05) and smaller hysteresis area (p<0.05) than KO mice, and larger normalized tendon CSA (p<0.05) than WT mice. Based on these data, we conclude that PAPP-A affects fascicle structure, thereby affecting tendon phenotype. Copyright © 2015 Elsevier Inc. All rights reserved.

A Flexible Binding Site Architecture Provides New Insights into CcpA Global Regulation in Gram-Positive Bacteria.

PubMed

Yang, Yunpeng; Zhang, Lu; Huang, He; Yang, Chen; Yang, Sheng; Gu, Yang; Jiang, Weihong

2017-01-24

Catabolite control protein A (CcpA) is the master regulator in Gram-positive bacteria that mediates carbon catabolite repression (CCR) and carbon catabolite activation (CCA), two fundamental regulatory mechanisms that enable competitive advantages in carbon catabolism. It is generally regarded that CcpA exerts its regulatory role by binding to a typical 14- to 16-nucleotide (nt) consensus site that is called a catabolite response element (cre) within the target regions. However, here we report a previously unknown noncanonical flexible architecture of the CcpA-binding site in solventogenic clostridia, providing new mechanistic insights into catabolite regulation. This novel CcpA-binding site, named cre var , has a unique architecture that consists of two inverted repeats and an intervening spacer, all of which are variable in nucleotide composition and length, except for a 6-bp core palindromic sequence (TGTAAA/TTTACA). It was found that the length of the intervening spacer of cre var can affect CcpA binding affinity, and moreover, the core palindromic sequence of cre var is the key structure for regulation. Such a variable architecture of cre var shows potential importance for CcpA's diverse and fine regulation. A total of 103 potential cre var sites were discovered in solventogenic Clostridium acetobutylicum, of which 42 sites were picked out for electrophoretic mobility shift assays (EMSAs), and 30 sites were confirmed to be bound by CcpA. These 30 cre var sites are associated with 27 genes involved in many important pathways. Also of significance, the cre var sites are found to be widespread and function in a great number of taxonomically different Gram-positive bacteria, including pathogens, suggesting their global role in Gram-positive bacteria. In Gram-positive bacteria, the global regulator CcpA controls a large number of important physiological and metabolic processes. Although a typical consensus CcpA-binding site, cre, has been identified, it remains poorly explored for the diversity of CcpA-mediated catabolite regulation. Here, we discovered a novel flexible CcpA-binding site architecture (cre var ) that is highly variable in both length and base composition but follows certain principles, providing new insights into how CcpA can differentially recognize a variety of target genes to form a complicated regulatory network. A comprehensive search further revealed the wide distribution of cre var sites in Gram-positive bacteria, indicating it may have a universal function. This finding is the first to characterize such a highly flexible transcription factor-binding site architecture, which would be valuable for deeper understanding of CcpA-mediated global catabolite regulation in bacteria. Copyright © 2017 Yang et al.

In vitro antioxidant properties, DNA damage protective activity, and xanthine oxidase inhibitory effect of cajaninstilbene acid, a stilbene compound derived from pigeon pea [Cajanus cajan (L.) Millsp.] leaves.

PubMed

Wu, Nan; Kong, Yu; Fu, Yujie; Zu, Yuangang; Yang, Zhiwei; Yang, Mei; Peng, Xiao; Efferth, Thomas

2011-01-12

The antioxidant properties, DNA damage protective activities, and xanthine oxidase (XOD) inhibitory effect of cajaninstilbene acid (CSA) derived from pigeon pea leaves were studied in the present work. Compared with resveratrol, CSA showed stronger antioxidant properties, DNA damage protective activity, and XOD inhibition activity. The IC(50) values of CSA for superoxide radical scavenging, hydroxyl radical scavenging, nitric oxide scavenging, reducing power, lipid peroxidation, and XOD inhibition were 19.03, 6.36, 39.65, 20.41, 20.58, and 3.62 μM, respectively. CSA possessed good protective activity from oxidative DNA damage. Furthermore, molecular docking indicated that CSA was more potent than resveratrol or allopurinol to interact with the active site of XOD (calculated free binding energy: -229.71 kcal mol(-1)). On the basis of the results, we conclude that CSA represents a valuable natural antioxidant source and may potentially be applicable in health food industry.

Cardiac surgery-associated acute kidney injury

PubMed Central

Ortega-Loubon, Christian; Fernández-Molina, Manuel; Carrascal-Hinojal, Yolanda; Fulquet-Carreras, Enrique

2016-01-01

Cardiac surgery-associated acute kidney injury (CSA-AKI) is a well-recognized complication resulting with the higher morbid-mortality after cardiac surgery. In its most severe form, it increases the odds ratio of operative mortality 3–8-fold, length of stay in the Intensive Care Unit and hospital, and costs of care. Early diagnosis is critical for an optimal treatment of this complication. Just as the identification and correction of preoperative risk factors, the use of prophylactic measures during and after surgery to optimize renal function is essential to improve postoperative morbidity and mortality of these patients. Cardiopulmonary bypass produces an increased in tubular damage markers. Their measurement may be the most sensitive means of early detection of AKI because serum creatinine changes occur 48 h to 7 days after the original insult. Tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 are most promising as an early diagnostic tool. However, the ideal noninvasive, specific, sensitive, reproducible biomarker for the detection of AKI within 24 h is still not found. This article provides a review of the different perspectives of the CSA-AKI, including pathogenesis, risk factors, diagnosis, biomarkers, classification, postoperative management, and treatment. We searched the electronic databases, MEDLINE, PubMed, EMBASE using search terms relevant including pathogenesis, risk factors, diagnosis, biomarkers, classification, postoperative management, and treatment, in order to provide an exhaustive review of the different perspectives of the CSA-AKI. PMID:27716701

Autobiographical Memory Specificity in Child Sexual Abuse Victims

PubMed Central

Ogle, Christin M.; Block, Stephanie D.; Harris, LaTonya S.; Goodman, Gail S.; Pineda, Annarheen; Timmer, Susan; Urquiza, Anthony; Saywitz, Karen J.

2013-01-01

The present study examined the specificity of autobiographical memory in adolescents and adults with versus without child sexual abuse (CSA) histories. Eighty-five participants, approximately half of whom per age group had experienced CSA, were tested on the Autobiographical Memory Interview. Individual difference measures, including for trauma-related psychopathology, were also administered. Findings revealed developmental differences in the relation between autobiographical memory specificity and CSA. Even with depression statistically controlled, reduced memory specificity in CSA victims relative to controls was observed among adolescents but not among adults. A higher number of Posttraumatic Stress Disorder criteria met predicted more specific childhood memories in participants who reported CSA as their most traumatic life event. These findings contribute to the scientific understanding of childhood trauma and autobiographical memory functioning and underscore the importance of considering the role of age and degree of traumatization within the study of autobiographical memory. PMID:23627947

Structural Basis for the ABO Blood-Group Dependence of Plasmodium falciparum Rosetting

PubMed Central

Hessel, Audrey; Raynal, Bertrand; England, Patrick; Cohen, Jacques H.; Bertrand, Olivier; Peyrard, Thierry; Bentley, Graham A.; Lewit-Bentley, Anita; Mercereau-Puijalon, Odile

2012-01-01

The ABO blood group influences susceptibility to severe Plasmodium falciparum malaria. Recent evidence indicates that the protective effect of group O operates by virtue of reduced rosetting of infected red blood cells (iRBCs) with uninfected RBCs. Rosetting is mediated by a subgroup of PfEMP1 adhesins, with RBC binding being assigned to the N-terminal DBL1α1 domain. Here, we identify the ABO blood group as the main receptor for VarO rosetting, with a marked preference for group A over group B, which in turn is preferred to group O RBCs. We show that recombinant NTS-DBL1α1 and NTS-DBL1α1-CIDR1γ reproduce the VarO-iRBC blood group preference and document direct binding to blood group trisaccharides by surface plasmon resonance. More detailed RBC subgroup analysis showed preferred binding to group A1, weaker binding to groups A2 and B, and least binding to groups Ax and O. The 2.8 Å resolution crystal structure of the PfEMP1-VarO Head region, NTS-DBL1α1-CIDR1γ, reveals extensive contacts between the DBL1α1 and CIDR1γ and shows that the NTS-DBL1α1 hinge region is essential for RBC binding. Computer docking of the blood group trisaccharides and subsequent site-directed mutagenesis localized the RBC-binding site to the face opposite to the heparin-binding site of NTS-DBLα1. RBC binding involves residues that are conserved between rosette-forming PfEMP1 adhesins, opening novel opportunities for intervention against severe malaria. By deciphering the structural basis of blood group preferences in rosetting, we provide a link between ABO blood grouppolymorphisms and rosette-forming adhesins, consistent with the selective role of falciparum malaria on human genetic makeup. PMID:22807674

Cyclosporine a inhibits apoptosis of rat gingival epithelium.

PubMed

Ma, Su; Liu, Peihong; Li, Yanwu; Hou, Lin; Chen, Li; Qin, Chunlin

2014-08-01

The use of cyclosporine A (CsA) induces hyperplasia of the gingival epithelium in a site-specific response manner, but the molecular mechanism via which the lesion occurs is unclear. The present research aims to investigate the site-specific effect of CsA on the apoptosis of gingival epithelium associated with gingival hyperplasia. Forty Wistar rats were divided into CsA-treated and non-treated groups. Paraffin-embedded sections of mandibular first molars were selected for hematoxylin and eosin staining, immunohistochemistry analyses of bcl-2 and caspase-3, and the staining of terminal deoxynucleotidyl transfer-mediated dUTP nick-end labeling (TUNEL). The area of the whole gingival epithelium and the length of rete pegs were measured, and the number of bcl-2- and caspase-3-positive cells in the longest rete peg were counted. The analysis of variance for factorial designs and Fisher least significant difference test for post hoc analysis were used to determine the significance levels. In CsA-treated rats, bcl-2 expression was significantly upregulated, whereas caspase-3 expression was downregulated, along with a reduced number of TUNEL-positive cells. The site-specific distribution of bcl-2 was consistent with the site-specific hyperplasia of the gingival epithelium in CsA-treated rats. CsA inhibited gingival epithelial apoptosis via the mitochondrial pathway and common pathway. The antiapoptotic protein bcl-2 might play a critical role in the pathogenesis of the site-specific hyperplasia of gingival epithelium induced by CsA. There were mechanistic differences in the regulation of apoptosis for cells in the attached gingival epithelium, free gingival epithelium, and junctional epithelium.

Childhood Sexual Abuse in Adolescents Adjudicated for Sexual Offenses: Mental Health Consequences and Sexual Offending Behaviors.

PubMed

Morais, Hugo B; Alexander, Apryl A; Fix, Rebecca L; Burkhart, Barry R

2018-02-01

Most studies on the mental health consequences of childhood sexual abuse (CSA) focus predominantly on CSA survivors who do not commit sexual offenses. The current study examined the effects of CSA on 498 male adolescents adjudicated for sexual offenses who represent the small portion of CSA survivors who engage in sexual offenses. The prevalence of internalizing symptoms, parental attachment difficulties, specific sexual offending behaviors, and risk for sexually offending were compared among participants with and without a history of CSA. Results indicated that participants with a history of CSA were more likely to be diagnosed with major depression and posttraumatic stress disorder than those who did not report a history of CSA. A history of CSA was also positively correlated with risk for sexually offending and with specific offense patterns and consensual sexual behaviors. No significant differences emerged on parental attachment difficulties. These results highlight that adolescents adjudicated for sexual offenses with a history of CSA present with differences in sexual and psychological functioning as well as markedly different offending patterns when compared with those without a CSA history. Clinical implications and future directions are discussed.

Autumnalamide targeted proteins of the immunophilin family.

PubMed

Sánchez, Jon Andoni; Alfonso, Amparo; Thomas, Olivier P; Botana, Luís M

2017-02-01

Previous works with autumnalamide reported that Store Operated Calcium (SOC) channels were blocked through mitochondrial modulation. In the present paper we studied the effect of autumnalamide on ionomycin Ca 2+ fluxes. Thus, autumnalamide did not modify ionomycin-sensitive intracellular pools while the ionomycin-induced Ca 2+ influx was blocked with similar potency whether the incubation was done before or after ionomycin-sensitive pools depletion. Nevertheless, autumnalamide was not able to inhibit ionomycin-induced Ca 2+ influx once the membrane channels were activated. Moreover, the compound efficiently inhibited flufenamic acid (FFA) Ca 2+ release induced in this organelle but no the next influx. Since in previous work the effect of autumnalamide was inhibited by cyclosporine A (CsA), structures that target this drug were studied. Therefore, the affinity of autumnalamide for cyclophilin D (Cyp D) was examined. The K D obtained for Cyp D- autumnalamide was 1.51±1.399. Moreover, the K D for Cyp A- autumnalamide was calculated. The peptide had a similar order of Cyp A binding affinity than CsA (8.08±1.23 and 6.85±1.1μM respectively). After testing autumnalamide-binding capacity for Cyp A, the activity of this compound on Cyp A pathway was tested. Thus, the effect on interleukin (IL)-2 release on activated T-lymphocytes was checked. Autumnalamide was able to reduce IL-2 levels near to T cells in resting conditions. Next, the effect over calcineurin and NFATc1 was also evaluated. While CsA inhibits both calcineurin and NFATc1, autumnalamide did not produce any effect. From these results we can conclude that, autumnalamide targeted mitochondrion and prevent T-cells from IL-2 production through the modulation of SOC Ca 2+ channels. Copyright © 2016 Elsevier GmbH. All rights reserved.

Potential mosquito repellent compounds of Ocimum species against 3N7H and 3Q8I of Anopheles gambiae.

PubMed

Gaddaguti, Venugopal; Venkateswara Rao, Talluri; Prasada Rao, Allu

2016-06-01

Mosquitoes are exceptionally efficient in detecting their hosts for blood meal using odorant binding proteins, viz. 3N7H and 3Q8I and spread several dreadful diseases. DEET is a synthetic mosquito repellent widely used all over world for protection against mosquito bite. Reports reveal that, synthetic mosquito repellents may pose health problems in considerably large population. In view of the above fact, we made an attempt to discover efficient and novel natural mosquito repellent compounds with least impact on human health. Methanolic leaf extracts of Ocimum basilicum Linn. var. pilosum (willd.)-Benth and Ocimum tenuiflorum var. CIM-AYU were subjected to GC-MS analysis and obtained 35 phytochemical constituents. Repellent potentiality of the Ocimum compounds was assessed against 3Q8I and 3N7H of Anopheles gambiae. PDB structures of mosquito odorant binding proteins were downloaded, processed and docking studies were performed along with reference ligand DEET using Schrodinger MAESTRO 9.2 software. Molecular docking results reveal that phenol, 2-methoxy-3-(2-propenyl)-, licopersin, gamma sitosterol and benzene, 1,2-dimethoxy-4-(2-propenyl)- from O. tenuiflorum var. CIM-AYU are strongly bound with 3N7H. Whereas, 4h-1-benzopyran-4-one, 5-hydroxy-6,7-dimethoxy-2-(4-methoxyphenyl)-, catechol and monoacetin from O. basilicum Linn. var. pilosum (willd.)-Benth. show high binding affinity with odorant binding protein 3Q8I. All natural compounds tested in the present study display better docking scores than DEET. The results further substantiate that the 12 out of 35 compounds of the two Ocimum species found to be ideal candidates for design and development of potential mosquito repellents. ADME properties of the tested compounds further confirm that bioactive compounds of Ocimum species were found to be in acceptable range. Synchronized application of at least two different natural compounds (with best docking scores) which target 3N7H and 3Q8I (Odorant Binding Proteins of mosquito) proteins may provide enhanced protection against mosquitoes bite. Based on the ADME properties, natural compounds of Ocimum species can be considered for design and development of safe mosquito repellents.

Characterization of anti-Toxoplasma activity of SDZ 215-918, a cyclosporin derivative lacking immunosuppressive and peptidyl-prolyl-isomerase-inhibiting activity: possible role of a P glycoprotein in Toxoplasma physiology.

PubMed Central

Silverman, J A; Hayes, M L; Luft, B J; Joiner, K A

1997-01-01

The immunosuppressive agent cyclosporin A (CsA) also possesses broad-spectrum antimicrobial activity. Previous investigators have reported that the obligate intracellular protozoan Toxoplasma gondii is sensitive to CsA. We have measured the sensitivity of Toxoplasma to 26 CsA derivatives that maintain only a subset of the parent compound's activity. We identified one compound, SDZ 215-918, that is a particularly potent inhibitor of parasite invasion and replication, with a 50% inhibitory concentration of 0.45 microg/ml, which is 10-fold lower than that of CsA. Kinetic studies demonstrate that activity has a rapid onset (half-life, < or = 20 min) and is initially reversible, although long-term exposure (> 24 h) to 5 microg/ml is lethal; in contrast, this concentration had no effect on host cell protein synthesis or cell division. SDZ 215-918 acts directly on the parasite, as demonstrated by inhibition of macromolecular synthesis in host-free extracellular parasites. Inhibition of invasion is due to a reduction in parasite motility. SDZ 215-918 does not bind to cyclophilins, the ubiquitous cyclosporin-binding proteins, but is a potent inhibitor of the mammalian P glycoprotein, a member of the ATP binding cassette transporter superfamily and the pump responsible for multidrug resistance in cancer and parasite cell lines. SDZ 215-918 blocks the efflux of rhodamine 123 from extracellular parasites, consistent with inhibition of a P glycoprotein-like pump. We suggest that a P glycoprotein or a related transporter plays a crucial role in the biology of Toxoplasma and may be a novel target for antiparasitic compounds. Preliminary studies with animals indicate that SDZ 215-918 inhibits parasite growth in vivo; its relationship to CsA may make it suitable for clinical development. PMID:9303374

Chloride and salicylate influence prestin-dependent specific membrane capacitance: support for the area motor model.

PubMed

Santos-Sacchi, Joseph; Song, Lei

2014-04-11

The outer hair cell is electromotile, its membrane motor identified as the protein SLC26a5 (prestin). An area motor model, based on two-state Boltzmann statistics, was developed about two decades ago and derives from the observation that outer hair cell surface area is voltage-dependent. Indeed, aside from the nonlinear capacitance imparted by the voltage sensor charge movement of prestin, linear capacitance (Clin) also displays voltage dependence as motors move between expanded and compact states. Naturally, motor surface area changes alter membrane capacitance. Unit linear motor capacitance fluctuation (δCsa) is on the order of 140 zeptofarads. A recent three-state model of prestin provides an alternative view, suggesting that voltage-dependent linear capacitance changes are not real but only apparent because the two component Boltzmann functions shift their midpoint voltages (Vh) in opposite directions during treatment with salicylate, a known competitor of required chloride binding. We show here using manipulations of nonlinear capacitance with both salicylate and chloride that an enhanced area motor model, including augmented δCsa by salicylate, can accurately account for our novel findings. We also show that although the three-state model implicitly avoids measuring voltage-dependent motor capacitance, it registers δCsa effects as a byproduct of its assessment of Clin, which increases during salicylate treatment as motors are locked in the expanded state. The area motor model, in contrast, captures the characteristics of the voltage dependence of δCsa, leading to a better understanding of prestin.

Cyclophilins contribute to Stat3 signaling and survival of multiple myeloma cells.

PubMed

Bauer, K; Kretzschmar, A K; Cvijic, H; Blumert, C; Löffler, D; Brocke-Heidrich, K; Schiene-Fischer, C; Fischer, G; Sinz, A; Clevenger, C V; Horn, F

2009-08-06

Signal transducer and activator of transcription 3 (Stat3) is the major mediator of interleukin-6 (IL-6) family cytokines. In addition, Stat3 is known to be involved in the pathophysiology of many malignancies. Here, we show that the cis-trans peptidyl-prolyl isomerase cyclophilin (Cyp) B specifically interacts with Stat3, whereas the highly related CypA does not. CypB knockdown inhibited the IL-6-induced transactivation potential but not the tyrosine phosphorylation of Stat3. Binding of CypB to Stat3 target promoters and alteration of the intranuclear localization of Stat3 on CypB depletion suggested a nuclear function of Stat3/CypB interaction. By contrast, CypA knockdown inhibited Stat3 IL-6-induced tyrosine phosphorylation and nuclear translocation. The Cyp inhibitor cyclosporine A (CsA) caused similar effects. However, Stat1 activation in response to IL-6 or interferon-gamma was not affected by Cyp silencing or CsA treatment. As a result, Cyp knockdown shifted IL-6 signaling to a Stat1-dominated pathway. Furthermore, Cyp depletion or treatment with CsA induced apoptosis in IL-6-dependent multiple myeloma cells, whereas an IL-6-independent line was not affected. Thus, Cyps support the anti-apoptotic action of Stat3. Taken together, CypA and CypB both play pivotal roles, yet at different signaling levels, for Stat3 activation and function. These data also suggest a novel mechanism of CsA action.

A novel regio‑specific cyclosporin hydroxylase gene revealed through the genome mining of Pseudonocardia autotrophica.

PubMed

Ban, Jun-Gyu; Woo, Min-Woo; Lee, Bo-Ram; Lee, Mi-Jin; Choi, Si-Sun; Kim, Eung-Soo

2014-05-01

The regio-specific hydroxylation at the 4th N-methyl leucine of the immunosuppressive agent cyclosporin A (CsA) was previously proposed to be mediated by a unique cytochrome P450 hydroxylase (CYP), CYP-sb21 from the rare actinomycetes Sebekia benihana. Interestingly, a different rare actinomycetes species, Pseudonocardia autotrophica, was found to possess a different regio-selectivity, the preferential hydroxylation at the 9th N-methyl leucine of CsA. Through an in silico analysis of the whole genome of P. autotrophica, we describe here the classification of 31 total CYPs in P. autotrophica. Three putative CsA CYP genes, showing the highest sequence homologies with CYPsb21, were successfully inactivated using PCR-targeted gene disruption. Only one knock-out mutant, ΔCYP-pa1, failed to convert CsA to its hydroxylated forms. The hydroxylation activity of CsA by CYP-pa1 was confirmed by CYP-pa1 gene complementation as well as heterologous expression in the CsA non-hydroxylating Streptomyces coelicolor. Moreover, the cyclosporine regio-selectivity of CYP-pa1 expressed in the ΔCYP-sb21 S. benihana mutant strain was also confirmed unchanged through cross complementation. These results show that preferential regio-specific hydroxylation at the 9th N-methyl leucine of CsA is carried out by a specific P450 hydroxylase gene in P. autotrophica, CYP-pa1, setting the stage for the biotechnological application of CsA regioselective hydroxylation.

Simulating Memory Impairment for Child Sexual Abuse.

PubMed

Newton, Jeremy W; Hobbs, Sue D

2015-08-01

The current study investigated effects of simulated memory impairment on recall of child sexual abuse (CSA) information. A total of 144 adults were tested for memory of a written CSA scenario in which they role-played as the victim. There were four experimental groups and two testing sessions. During Session 1, participants read a CSA story and recalled it truthfully (Genuine group), omitted CSA information (Omission group), exaggerated CSA information (Commission group), or did not recall the story at all (No Rehearsal group). One week later, at Session 2, all participants were told to recount the scenario truthfully, and their memory was then tested using free recall and cued recall questions. The Session 1 manipulation affected memory accuracy during Session 2. Specifically, compared with the Genuine group's performance, the Omission, Commission, or No Rehearsal groups' performance was characterized by increased omission and commission errors and decreased reporting of correct details. Victim blame ratings (i.e., victim responsibility and provocativeness) and participant gender predicted increased error and decreased accuracy, whereas perpetrator blame ratings predicted decreased error and increased accuracy. Findings are discussed in relation to factors that may affect memory for CSA information. Copyright © 2015 John Wiley & Sons, Ltd.

Mechanisms of Rapid Induction of Interleukin-22 in Activated T Cells and Its Modulation by Cyclosporin A*

PubMed Central

Rudloff, Ina; Bachmann, Malte; Pfeilschifter, Josef; Mühl, Heiko

2012-01-01

IL-22 is an immunoregulatory cytokine displaying pathological functions in models of autoimmunity like experimental psoriasis. Understanding molecular mechanisms driving IL-22, together with knowledge on the capacity of current immunosuppressive drugs to target this process, may open an avenue to novel therapeutic options. Here, we sought to characterize regulation of human IL22 gene expression with focus on the established model of Jurkat T cells. Moreover, effects of the prototypic immunosuppressant cyclosporin A (CsA) were investigated. We report that IL-22 induction by TPA/A23187 (T/A) or αCD3 is inhibited by CsA or related FK506. Similar data were obtained with peripheral blood mononuclear cells or purified CD3+ T cells. IL22 promoter analysis (−1074 to +156 bp) revealed a role of an NF-AT (−95/−91 nt) and a CREB (−194/−190 nt) binding site for gene induction. Indeed, binding of CREB and NF-ATc2, but not c-Rel, under the influence of T/A to those elements could be proven by ChIP. Because CsA has the capability to impair IκB kinase (IKK) complex activation, the IKKα/β inhibitor IKKVII was evaluated. IKKVII likewise reduced IL-22 induction in Jurkat cells and peripheral blood mononuclear cells. Interestingly, transfection of Jurkat cells with siRNA directed against IKKα impaired IL22 gene expression. Data presented suggest that NF-AT, CREB, and IKKα contribute to rapid IL22 gene induction. In particular the crucial role of NF-AT detected herein may form the basis of direct action of CsA on IL-22 expression by T cells, which may contribute to therapeutic efficacy of the drug in autoimmunity. PMID:22170067

Influence of spaceflight on succinate dehydrogenase activity and soma size of rat ventral horn neurons

NASA Technical Reports Server (NTRS)

Ishihara, A.; Ohira, Y.; Roy, R. R.; Nagaoka, S.; Sekiguchi, C.; Hinds, W. E.; Edgerton, V. R.

1996-01-01

Succinate dehydrogenase (SDH) activities and soma cross-sectional areas (CSA) of neurons in the dorsolateral region of the ventral horn at the L5 segmental level of the spinal cord in the rat were determined after 14 days of spaceflight and after 9 days of recovery on earth. The results were compared to those in age-matched ground-based control rats. Spinal cords were quick-frozen, and the SDH activity and CSA of a sample of neurons with a visible nucleus were determined using a digitizer and a computer-assisted image analysis system. An inverse relationship between CSA and SDH activity of neurons was observed in all groups of rats. No change in mean CSA or mean SDH activity or in the size distribution of neurons was observed following spaceflight or recovery. However, there was a selective decrease in the SDH activity of neurons with soma CSA between 500 and 800 microns2 in the flight rats, and this effect persisted for at least 9 days following return to 1 g. It remains to be determined whether the selected population of motoneurons or the specific motor pools affected by spaceflight may be restricted to specific muscles.

Impact of different adhesives on work of adhesion between CAD/CAM polymers and resin composite cements.

PubMed

Keul, Christine; Müller-Hahl, Manuel; Eichberger, Marlis; Liebermann, Anja; Roos, Malgorzata; Edelhoff, Daniel; Stawarczyk, Bogna

2014-09-01

To determine the impact of pre-treatment of adhesive systems on the work of adhesion (WA) between CAD/CAM polymers and resin composite cements and compare with conventional tests of previous studies. Surface parameters were measured by contact angle measurement (2700 measurements) and WA was calculated. Five CAD/CAM polymers were used for fabrication of specimens (n=75/subgroup): artBloc Temp (A), Telio CAD (B), Nano Composite CFI-C (C), exp. CAD/CAM nanohybrid composite (D), and LAVA Ultimate (E). Then, air-abraded specimens were pre-treated (n=15 per group): Ambarino P60 (I), Monobond Plus/Heliobond (II), visio.link (III), VP connect (IV), and no pre-treatment (V). Resin composite cement specimens (n=75) were smoothed out homogeneously on a glass plate (n=15/group): RelyX ARC (RXA), Variolink II (VAR), Panavia F2.0 (PAN), RelyX Unicem (RXU), and Clearfil SA Cement (CSA). Contact angles were determined with 3 drops of distilled water and diiodomethane each. Data were analyzed using Kruskal-Wallis-H test and Spearman-Rho correlation (p<0.05). CAD/CAM materials (B), (A), and (C) showed higher WA compared to (D) and (E). (II) and (IV) resulted in higher WA than (I), (III) and (V). VAR had the significantly lowest WA, followed by RXU, RXA, CSA and PAN. No correlation occurred between WA and TBS/SBS whereas polar component of surface free energy of CAD/CAM resin and spreading coefficient showed significant positive correlation with TBS/SBS. Determination of WA is not a proper method to draw conclusions about the bond between resin materials. Destructive test methods are not dispensable. The successful outcome of fixed dental restorations depends, among others, on the quality of bonding between the tooth and the restoration. Additional pre-treatment of the dental CAD/CAM resin restoration by bonding systems can be recommended for clinical use. Pre-treatment showed a significant impact on the surface properties. Copyright © 2014 Elsevier Ltd. All rights reserved.

Muscle Weakness in the Empty and Full Can Tests Cannot Differentiate Rotator Cuff Tear from Cervical Spondylotic Amyotrophy: Pain Provocation is a Useful Finding.

PubMed

Iwata, Eiichiro; Shigematsu, Hideki; Inoue, Kazuya; Egawa, Takuya; Sakamoto, Yoshihiro; Tanaka, Yasuhito

2017-01-01

Rotator cuff tears and cervical spondylotic amyotrophy (CSA) are often confused as the main symptom in those with difficulty in shoulder elevation. Empty and full can tests are frequently used for the clinical diagnosis of rotator cuff tears. The aim of the present study was to investigate whether the empty and full can test results can help differentiate rotator cuff tears from CSA. Twenty-seven consecutive patients with rotator cuff tears and 25 with CSA were enrolled. We prospectively performed empty and full can tests in patients with rotator cuff tears and CSA. The following signs were considered positive: (a) muscle weakness during the empty can test, (b) muscle weakness during the full can test, (c) pain provocation during the empty can test, and (d) pain provocation during the full can test. We calculated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of rotator cuff tears for each positive finding. The sensitivity and specificity of each index were as follows (sensitivity, specificity, PPV, NPV): (a) 77.8%, 0%, 45.7%, 0%; (b) 66.7%, 4.0%, 42.9%, 10.0%; (c) 88.9%, 96.0%, 96.0%, 88.9%; and (d) 74.1%, 96.0%, 95.2%, 77.4%. There were significant differences for each index. Muscle weakness during the empty and full can tests was not useful in differentiating rotator cuff tears from CSA because of low specificity and PPV. However, pain provocation was useful in differentiating these two conditions because of high specificity and PPV.

Early Stigmatization, PTSD, and Perceived Negative Reactions of Others Predict Subsequent Strategies for Processing Child Sexual Abuse

PubMed Central

Simon, Valerie A.; Feiring, Candice; Cleland, Charles M.

2017-01-01

Objective Trauma processing is central to healthy recovery, but few studies examine how youth process experiences of child sexual abuse (CSA). The current study builds on our prior work identifying individual differences in CSA processing strategies (i.e., Constructive, Absorbed, Avoidant) to examine whether abuse stigmatization, PTSD symptoms, and negative reactions from others experienced during the year after abuse discovery were associated with subsequent CSA processing strategies. Method Participants included 160 ethnically diverse youth (8−15 years, 73% female) with confirmed cases of CSA. Predictors were measured at abuse discovery (T1) and 1 year later (T2). Individual differences in CSA processing strategies were assessed 6 years after discovery (T3) from participants’ abuse narratives. Results The persistence of abuse stigmatization from T1 to T2 significantly increased the odds of using either an Avoidant or Absorbed (vs. Constructive) strategy at T3. Higher levels of PTSD symptoms at T1 as well as their persistence from T1 to T2 each significantly increased the odds of having an Absorbed versus Constructive strategy. The persistence of perceived negative reactions from others from T1 to T2 increased the odds of an Absorbed versus Avoidant strategy. Effect sizes ranged from medium to large (M d = 0.636). Conclusions Results further validate prior work identifying distinct CSA processing strategies and suggest the persistence of abuse-specific disruptions over the year after abuse discovery may be associated with subsequent problems processing CSA experiences. PMID:28936363

Childhood sexual abuse and the development of recurrent major depression in Chinese women.

PubMed

Chen, Jing; Cai, Yiyun; Cong, Enzhao; Liu, Ying; Gao, Jingfang; Li, Youhui; Tao, Ming; Zhang, Kerang; Wang, Xumei; Gao, Chengge; Yang, Lijun; Li, Kan; Shi, Jianguo; Wang, Gang; Liu, Lanfen; Zhang, Jinbei; Du, Bo; Jiang, Guoqing; Shen, Jianhua; Zhang, Zhen; Liang, Wei; Sun, Jing; Hu, Jian; Liu, Tiebang; Wang, Xueyi; Miao, Guodong; Meng, Huaqing; Li, Yi; Hu, Chunmei; Li, Yi; Huang, Guoping; Li, Gongying; Ha, Baowei; Deng, Hong; Mei, Qiyi; Zhong, Hui; Gao, Shugui; Sang, Hong; Zhang, Yutang; Fang, Xiang; Yu, Fengyu; Yang, Donglin; Liu, Tieqiao; Chen, Yunchun; Hong, Xiaohong; Wu, Wenyuan; Chen, Guibing; Cai, Min; Song, Yan; Pan, Jiyang; Dong, Jicheng; Pan, Runde; Zhang, Wei; Shen, Zhenming; Liu, Zhengrong; Gu, Danhua; Wang, Xiaoping; Liu, Xiaojuan; Zhang, Qiwen; Li, Yihan; Chen, Yiping; Kendler, Kenneth S; Shi, Shenxun; Flint, Jonathan

2014-01-01

Our prior study in Han Chinese women has shown that women with a history of childhood sexual abuse (CSA) are at increased risk for developing major depression (MD). Would this relationship be found in our whole data set? Three levels of CSA (non-genital, genital, and intercourse) were assessed by self-report in two groups of Han Chinese women: 6017 clinically ascertained with recurrent MD and 5983 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression. We confirmed earlier results by replicating prior analyses in 3,950 new recurrent MD cases. There were no significant differences between the two data sets. Any form of CSA was significantly associated with recurrent MD (OR 4.06, 95% confidence interval (CI) [3.19-5.24]). This association strengthened with increasing CSA severity: non-genital (OR 2.21, 95% CI 1.58-3.15), genital (OR 5.24, 95% CI 3.52-8.15) and intercourse (OR 10.65, 95% CI 5.56-23.71). Among the depressed women, those with CSA had an earlier age of onset, longer depressive episodes. Recurrent MD patients those with CSA had an increased risk for dysthymia (OR 1.60, 95%CI 1.11-2.27) and phobia (OR 1.41, 95%CI 1.09-1.80). Any form of CSA was significantly associated with suicidal ideation or attempt (OR 1.50, 95% CI 1.20-1.89) and feelings of worthlessness or guilt (OR 1.41, 95% CI 1.02-2.02). Intercourse (OR 3.47, 95%CI 1.66-8.22), use of force and threats (OR 1.95, 95%CI 1.05-3.82) and how strongly the victims were affected at the time (OR 1.39, 95%CI 1.20-1.64) were significantly associated with recurrent MD. In Chinese women CSA is strongly associated with recurrent MD and this association increases with greater severity of CSA. Depressed women with CSA have some specific clinical traits. Some features of CSA were associated with greater likelihood of developing recurrent MD.

Attenuation of cyclosporine A toxicity by sublethal heat shock. Role of catalase.

PubMed

Andrés, David; Bautista, Mirandeli; Cascales, María

2005-02-01

Cyclosporine A (CsA) is the immunosuppressor most frequently used in transplant surgery and in the treatment of autoimmune diseases because of its specific inhibiting effect on signal transduction pathways of cell T receptor. It has been shown that CsA is able to generate reactive oxygen species and lipid peroxidation, which are directly involved in the CsA hepatotoxicity. In the present study, we investigated the effect of a sublethal heat pre-treatment (43 degrees C for 30 min) on the hepatoma cell line HepG2 exposed to cytotoxic concentrations of CsA (10 and 25 microM) for 3 and 24 h. Parameters of cytotoxicity were assayed by measuring LDH (lactate dehydrogenase) leakage into the medium. Peroxide concentration was tested by flow cytometry by measuring the fluorescence intensity of DCF (dichlorofluorescein). Gene expression of catalase was detected by measuring the respective mRNA and proteins, as well as protein level of HSP70. The enzymatic activity of catalase was also determined. Heat pre-treatment significantly reduced CsA cytotoxicity as well as the level of peroxide generation. The protective effect of the previous heat treatment (corroborated by the irreversible catalase inhibitor 3-aminotriazole) against the CsA cytotoxicity was due to an increased expression and activity of catalase that was significantly reduced by the effect of CsA. We conclude that heat pre-treatment strongly protects against CsA injury, and the mechanism of this protection is by means of inducing not only the expression of HSP70 but also the expression and activity of catalase, the main enzyme system involved in H(2)O(2) elimination.

Characterization of Sarcoptes scabiei Tropomyosin and Paramyosin: Immunoreactive Allergens in Scabies.

PubMed

Naz, Shumaila; Desclozeaux, Marion; Mounsey, Kate E; Chaudhry, Farhana Riaz; Walton, Shelley F

2017-09-01

Scabies is a human skin disease due to the burrowing ectoparasite Sarcoptes scabiei var. hominis resulting in intense itching and inflammation and manifesting as a skin allergy. Because of insufficient mite material and lack of in vitro propagation system for antigen preparation, scabies is a challenging disease to develop serological diagnostics. For allergen characterization, full-length S. scabiei tropomyosin (Sar s 10) was cloned, expressed in pET-15b, and assessed for reactivity with IgE antibodies from human sera. IgE binding was observed to Sar s 10 with sera collected from subjects with ordinary scabies, house dust mite (HDM)-positive and naive subjects and a diagnostic sensitivity of < 30% was observed. S. scabiei paramyosin (Sar s 11) was cloned, and expressed in pET-28a in three overlapping fragments designated Sspara1, Sspara2, and Sspara3. IgE and IgG binding was observed to Sspara2 and Sspara3 antigens with sera collected from ordinary scabies, and HDM-positive subjects, but no binding was observed with sera collected from naive subjects. Sspara2 displayed excellent diagnostic potential with 98% sensitivity and 90% specificity observed for IgE binding and 70% sensitivity for IgG. In contrast, the diagnostic sensitivity of Sspara3 was 84% for IgE binding and 40% for IgG binding. In combination, Sspara2 and Sspara3 provided an IgE sensitivity of 94%. This study shows that IgE binding to Sspara2 and Sspara3 is a highly sensitive method for diagnosis of scabies infestation in clinical practice. The developed enzyme-linked immunosorbent assay helps direct future development of a specific diagnostic tool for scabies.

Potential pathways from stigmatization and externalizing behavior to anger and dating aggression in sexually abused youth.

PubMed

Feiring, Candice; Simon, Valerie A; Cleland, Charles M; Barrett, Ellen P

2013-01-01

Although experiencing childhood sexual abuse (CSA) puts youth at risk for involvement in relationship violence, research is limited on the potential pathways from CSA to subsequent dating aggression. The current study examined prospective pathways from externalizing behavior problems and stigmatization (abuse-specific shame and self-blame attributions) to anger and dating aggression. One hundred sixty youth (73% female, 69% ethnic/racial minorities) with confirmed CSA histories were interviewed at the time of abuse discovery (T1, when they were 8-15 years of age), and again 1 and 6 years later (T2 and T3). Externalizing behavior and abuse-specific stigmatization were assessed at T1 and T2. Anger and dating aggression were assessed at T3. The structural equation model findings supported the proposed relations from stigmatization following the abuse to subsequent dating aggression through anger. Only externalizing behavior at T1 was related to later dating aggression, and externalizing was not related to subsequent anger. This longitudinal research suggests that clinical interventions for victims of CSA be sensitive to the different pathways by which youth come to experience destructive conflict behavior in their romantic relationships.

End-Tidal CO2 Tension Is Predictive of Effective Nocturnal Oxygen Therapy in Patients with Chronic Heart Failure and Central Sleep Apnea.

PubMed

Sugimura, Koichiro; Shinozaki, Tsuyoshi; Fukui, Shigefumi; Ogawa, Hiromasa; Shimokawa, Hiroaki

2016-05-01

Central sleep apnea (CSA) is characterized by recurring cycles of crescendo-decrescendo ventilation during sleep, and enhances sympathetic nerve activity. Thus CSA has a prognostic impact in patients with chronic heart failure (CHF). Although nocturnal oxygen (O2) therapy decreases frequency of CSA and improves functional exercise capacity, it is also known that some non-responders to the therapy exist. We thus aimed to identify predictors of responders to nocturnal O2 therapy in CHF patients with CSA. In 12 CHF patients with CSA hospitalized at our department, sleep study was performed at 2 consecutive nights. Patients nasally inhaled O2 at either the first or second night in a randomized manner. To predict the percentage reduction in apnea-hypopnea index (%ΔAHI) in response to the nocturnal O2 therapy, we performed multiple regression analysis with a stepwise method with variables including age, brain-natriuretic peptide, circulation time, baseline AHI, hypercapnic ventilatory response and end-tidal carbon dioxide tension (PETCO2). Nocturnal O2 therapy significantly decreased AHI (from 32 ± 13 /h to 12 ± 10 /h, P < 0.0001). Among the possible predictors, PETCO2 was the only variable that is predictive of % changes in AHI. Receiver operating characteristics analysis determined 4.25% as the optimal cutoff PETCO2 level to identify responder to nocturnal O2 therapy (> 50% reduction of AHI), with 88.9% of sensitivity and 66.7% of specificity. In conclusion, PETCO2 is useful to predict the efficacy of O2 therapy in CHF patients with CSA, providing important information to the current nocturnal O2 therapy.

A high-resolution (13)C 3D CSA-CSA-CSA correlation experiment by means of magic angle turning.

PubMed

Hu, J Z; Ye, C; Pugmire, R J; Grant, D M

2000-08-01

It is shown in this paper that a previously reported 90 degrees sample flipping (13)C 2D CSA-CSA correlation experiment may be carried out alternatively by employing constant slow sample rotation about the magic angle axis and by synchronizing the read pulse to 13 of the rotor cycle. A high-resolution 3D CSA-CSA-CSA correlation experiment based on the magic angle turning technique is reported in which the conventional 90 degrees 2D CSA-CSA powder pattern for each carbon in a system containing a number of inequivalent carbons may be separated according to the isotropic chemical shift value. The technique is demonstrated on 1,2,3-trimethoxybenzene in which all of the overlapping powder patterns that cannot be segregated by the 2D CSA-CSA experiment are resolved successfully by the 3D CSA-CSA-CSA experiment, including even the two methoxy groups (M(1) and M(3)) whose isotropic shifts, confirmed by high-speed MAS, are separated by only 1 ppm. A difference of 4 ppm in the principal value component (delta(33)) between M(1) and M(3) is readily obtained. Copyright 2000 Academic Press.

Genetic diversity of the DBLalpha region in Plasmodium falciparum var genes among Asia-Pacific isolates.

PubMed

Fowler, Elizabeth V; Peters, Jennifer M; Gatton, Michelle L; Chen, Nanhua; Cheng, Qin

2002-03-01

In Plasmodium falciparum a highly polymorphic multi-copy gene family, var, encodes the variant surface antigen P. falciparum erythrocyte membrane protein 1 (PfEMP1), which has an important role in cytoadherence and immune evasion. Using previously described universal PCR primers for the first Duffy binding-like domain (DBLalpha) of var we analysed the DBLalpha repertoires of Dd2 (originally from Thailand) and eight isolates from the Solomon Islands (n=4), Philippines (n=2), Papua New Guinea (n=1) and Africa (n=1). We found 15-32 unique DBLalpha sequence types among these isolates and estimated detectable DBLalpha repertoire sizes ranging from 33-38 to 52-57 copies per genome. Our data suggest that var gene repertoires generally consist of 40-50 copies per genome. Eighteen DBLalpha sequences appeared in more than one Asia-Pacific isolate with the number of sequences shared between any two isolates ranging from 0 to 6 (mean=2.0 +/-1.6). At the amino acid level DBLalpha sequence similarity within isolates ranged from 45.2 +/- 7.1 to 50.2 +/- 6.9%, and was not significantly different from the DBLalpha amino acid sequence similarity among isolates (P>0.1). Comparisons with published sequences also revealed little overlap among DBLalpha sequences from different regions. High DBLalpha sequence diversity and minimal overlap among these isolates suggest that the global var gene repertoire is immense, and may potentially be selected for by the host's protective immune response to the var gene products, PfEMP1.

Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy.

PubMed

Stephen, Joshi; Nampoothiri, Sheela; Banerjee, Aditi; Tolman, Nathanial J; Penninger, Josef Martin; Elling, Ullrich; Agu, Chukwuma A; Burke, John D; Devadathan, Kalpana; Kannan, Rajesh; Huang, Yan; Steinbach, Peter J; Martinis, Susan A; Gahl, William A; Malicdan, May Christine V

2018-04-01

Progressive microcephaly and neurodegeneration are genetically heterogenous conditions, largely associated with genes that are essential for the survival of neurons. In this study, we interrogate the genetic etiology of two siblings from a non-consanguineous family with severe early onset of neurological manifestations. Whole exome sequencing identified novel compound heterozygous mutations in VARS that segregated with the proband: a missense (c.3192G>A; p.Met1064Ile) and a splice site mutation (c.1577-2A>G). The VARS gene encodes cytoplasmic valyl-tRNA synthetase (ValRS), an enzyme that is essential during eukaryotic translation. cDNA analysis on patient derived fibroblasts revealed that the splice site acceptor variant allele led to nonsense mediated decay, thus resulting in a null allele. Three-dimensional modeling of ValRS predicts that the missense mutation lies in a highly conserved region and could alter side chain packing, thus affecting tRNA binding or destabilizing the interface between the catalytic and tRNA binding domains. Further quantitation of the expression of VARS showed remarkably reduced levels of mRNA and protein in skin derived fibroblasts. Aminoacylation experiments on patient derived cells showed markedly reduced enzyme activity of ValRS suggesting the mutations to be loss of function. Bi-allelic mutations in cytoplasmic amino acyl tRNA synthetases are well-known for their role in neurodegenerative disorders, yet human disorders associated with VARS mutations have not yet been clinically well characterized. Our study describes the phenotype associated with recessive VARS mutations and further functional delineation of the pathogenicity of novel variants identified, which widens the clinical and genetic spectrum of patients with progressive microcephaly.

De Novo Design of Skin-Penetrating Peptides for Enhanced Transdermal Delivery of Peptide Drugs.

PubMed

Menegatti, Stefano; Zakrewsky, Michael; Kumar, Sunny; De Oliveira, Joshua Sanchez; Muraski, John A; Mitragotri, Samir

2016-03-09

Skin-penetrating peptides (SPPs) are attracting increasing attention as a non-invasive strategy for transdermal delivery of therapeutics. The identification of SPP sequences, however, currently performed by experimental screening of peptide libraries, is very laborious. Recent studies have shown that, to be effective enhancers, SPPs must possess affinity for both skin keratin and the drug of interest. We therefore developed a computational process for generating and screening virtual libraries of disulfide-cyclic peptides against keratin and cyclosporine A (CsA) to identify SPPs capable of enhancing transdermal CsA delivery. The selected sequences were experimentally tested and found to bind both CsA and keratin, as determined by mass spectrometry and affinity chromatography, and enhance transdermal permeation of CsA. Four heptameric sequences that emerged as leading candidates (ACSATLQHSCG, ACSLTVNWNCG, ACTSTGRNACG, and ACSASTNHNCG) were tested and yielded CsA permeation on par with previously identified SPP SPACE (TM) . An octameric peptide (ACNAHQARSTCG) yielded significantly higher delivery of CsA compared to heptameric SPPs. The safety profile of the selected sequences was also validated by incubation with skin keratinocytes. This method thus represents an effective procedure for the de novo design of skin-penetrating peptides for the delivery of desired therapeutic or cosmetic agents. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cyclophilin B Interacts with Sodium-Potassium ATPase and Is Required for Pump Activity in Proximal Tubule Cells of the Kidney

PubMed Central

Suñé, Guillermo; Sarró, Eduard; Puigmulé, Marta; López-Hellín, Joan; Zufferey, Madeleine; Pertel, Thomas; Luban, Jeremy; Meseguer, Anna

2010-01-01

Cyclophilins (Cyps), the intracellular receptors for Cyclosporine A (CsA), are responsible for peptidyl-prolyl cis-trans isomerisation and for chaperoning several membrane proteins. Those functions are inhibited upon CsA binding. Albeit its great benefits as immunosuppressant, the use of CsA has been limited by undesirable nephrotoxic effects, including sodium retention, hypertension, hyperkalemia, interstial fibrosis and progressive renal failure in transplant recipients. In this report, we focused on the identification of novel CypB-interacting proteins to understand the role of CypB in kidney function and, in turn, to gain further insight into the molecular mechanisms of CsA-induced toxicity. By means of yeast two-hybrid screens with human kidney cDNA, we discovered a novel interaction between CypB and the membrane Na/K-ATPase β1 subunit protein (Na/K-β1) that was confirmed by pull-down, co-immunoprecipitation and confocal microscopy, in proximal tubule-derived HK-2 cells. The Na/K-ATPase pump, a key plasma membrane transporter, is responsible for maintenance of electrical Na+ and K+ gradients across the membrane. We showed that CypB silencing produced similar effects on Na/K-ATPase activity than CsA treatment in HK-2 cells. It was also observed an enrichment of both alpha and beta subunits in the ER, what suggested a possible failure on the maturation and routing of the pump from this compartment towards the plasma membrane. These data indicate that CypB through its interaction with Na/K-β1 might regulate maturation and trafficking of the pump through the secretory pathway, offering new insights into the relationship between cyclophilins and the nephrotoxic effects of CsA. PMID:21085665

Cyclophilin B interacts with sodium-potassium ATPase and is required for pump activity in proximal tubule cells of the kidney.

PubMed

Suñé, Guillermo; Sarró, Eduard; Puigmulé, Marta; López-Hellín, Joan; Zufferey, Madeleine; Pertel, Thomas; Luban, Jeremy; Meseguer, Anna

2010-11-10

Cyclophilins (Cyps), the intracellular receptors for Cyclosporine A (CsA), are responsible for peptidyl-prolyl cis-trans isomerisation and for chaperoning several membrane proteins. Those functions are inhibited upon CsA binding. Albeit its great benefits as immunosuppressant, the use of CsA has been limited by undesirable nephrotoxic effects, including sodium retention, hypertension, hyperkalemia, interstial fibrosis and progressive renal failure in transplant recipients. In this report, we focused on the identification of novel CypB-interacting proteins to understand the role of CypB in kidney function and, in turn, to gain further insight into the molecular mechanisms of CsA-induced toxicity. By means of yeast two-hybrid screens with human kidney cDNA, we discovered a novel interaction between CypB and the membrane Na/K-ATPase β1 subunit protein (Na/K-β1) that was confirmed by pull-down, co-immunoprecipitation and confocal microscopy, in proximal tubule-derived HK-2 cells. The Na/K-ATPase pump, a key plasma membrane transporter, is responsible for maintenance of electrical Na+ and K+ gradients across the membrane. We showed that CypB silencing produced similar effects on Na/K-ATPase activity than CsA treatment in HK-2 cells. It was also observed an enrichment of both alpha and beta subunits in the ER, what suggested a possible failure on the maturation and routing of the pump from this compartment towards the plasma membrane. These data indicate that CypB through its interaction with Na/K-β1 might regulate maturation and trafficking of the pump through the secretory pathway, offering new insights into the relationship between cyclophilins and the nephrotoxic effects of CsA.

Cyclosporin A Inhibits Rotavirus Replication and Restores Interferon-Beta Signaling Pathway In Vitro and In Vivo

PubMed Central

He, Haiyang; Wu, Yuzhang

2013-01-01

Rotavirus (RV) is the most common cause of severe diarrhea among infants and young children. Currently, there is no specific drug available against rotavirus, largely due to the lack of an ideal target molecule which has hampered drug development. Our previous studies have revealed that cyclosporin A (CsA) might be potentially useful as an anti-RV drug. We therefore used both cellular and mouse models to study the immunological safety and effectiveness of CsA as an anti-RV drug. We found that CsA treatment of HT-29 cells before, during, and after viral infection efficiently inhibited Wa strain RV replication and restored IFN-β expression in a HT-29 cell line model. Exploring the underlying mechanisms showed that CsA promoted Interferon Regulatory Factor-5 (IRF-5) expression (a key positive regulator of the type I IFN signaling pathway), but not IRF-1, IRF-3, or IRF-7. Additionally, CsA inhibited SOCS-1 expression (the key negative regulator of IFN-α/β), but not SOCS-2 or SOCS-3. The antiviral effect of CsA was confirmed in an RV-infected neonatal mouse model by evaluation of antigen clearance and assessment of changes in intestinal tissue pathology. Also, no differences in T cell frequency or proliferation between the CsA- and vehicle-treated groups were observed. Thus, both our in vitro and in vivo findings suggest that CsA, through modulating the expression of key regulators in IFN signaling pathway, promote type I IFN-based intracellular innate immunity in RV host cells. These findings suggest that CsA may be a useful candidate to develop a new anti-RV strategy, although further evaluation and characterization of CsA on RV-induced diarrhea are warranted. PMID:23990993

Cyclosporine A normalizes mitochondrial coupling, reactive oxygen species production, and inflammation and partially restores skeletal muscle maximal oxidative capacity in experimental aortic cross-clamping.

PubMed

Pottecher, Julien; Guillot, Max; Belaidi, Elise; Charles, Anne-Laure; Lejay, Anne; Gharib, Abdallah; Diemunsch, Pierre; Geny, Bernard

2013-04-01

By binding to cyclophilin D, cyclosporine A (CsA) inhibits mitochondrial permeability transition pore (mPTP) opening and prevents mitochondrial dysfunction and ultimately cell death after ischemia-reperfusion (IR) injury in cardiac muscle. This study tested whether CsA would decrease skeletal muscle oxidative stress and mitochondrial dysfunctions after aortic cross-clamping related IR. Forty-five Wistar rats were investigated. The sham group (n = 8) had aortic exposure but no ischemia, the IR group (n = 10) had aortic cross-clamping for 3 hours followed by 2 hours of reperfusion, and the IR+CsA group (n = 9) had two intraperitoneal injections of 10 mg of CsA at 90 and 150 minutes of ischemia before reperfusion. Mitochondrial coupling (acceptor control ratio) and mitochondrial respiratory chain complexes' activities were measured. Reactive oxygen species (ROS) production, cyclophilin D expression, and muscle inflammation were determined using dihydroethidium staining, Western blot, and immunohistochemistry, respectively. An additional 18 sham rats were investigated to determine CsA blood levels and the effects of CsA on mitochondrial respiration and calcium retention capacity, a marker of mPTP opening, both in myocardium and gastrocnemius with and without CsA. Compared with sham, IR decreased mitochondrial coupling (1.38 ± 0.06 vs 1.98 ± 0.20; P = .0092), increased ROS production (3992 ± 706 arbitrary units [AU] vs 1812 ± 322 AU; P = .033), was associated with macrophage infiltration, and decreased maximal oxidative capacity (V(max): 4.08 ± 0.38 μmol O(2)/min/g vs 5.98 ± 0.56 μmol O(2)/min/g; P = .015). Despite IR, CsA treatment totally restored mitochondrial coupling (1.93 ± 0.12; P = .023 vs IR), normalized ROS (1569 ± 348 AU; P = .0098 vs IR), and decreased inflammation. The V(max) was slightly enhanced (5.02 ± 0.39 μmol O(2)/min/g; P = .33 vs IR; P = .35 vs sham). Compared with myocardium, gastrocnemius muscle was characterized by a decreased cyclophilin D content (-50%) associated with an earlier opening of mPTP (calcium retention capacity increased from 10.85 ± 1.35 μM/mg dry weight [DW] to 12.11 ± 2.77 μM/mg DW; P = .65; and from 11.07 ± 1.67 to 37.65 ± 11.41 μM/mg DW; P = .0098 in gastrocnemius and heart, respectively). Cyclosporine A normalized ROS production, decreased inflammation, and restored mitochondrial coupling during aortic cross-clamping. Incomplete Vmax protection might be due to low cyclophilin D expression in gastrocnemius, preventing CsA from blocking mPTP opening. Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Changes in cross-sectional area of pulmonary vessels on chest computed tomography after chemotherapy in patients with advanced non-squamous non-small-cell lung cancer.

PubMed

Karayama, Masato; Inui, Naoki; Kusagaya, Hideki; Suzuki, Seiichiro; Inoue, Yusuke; Enomoto, Noriyuki; Fujisawa, Tomoyuki; Nakamura, Yutaro; Suda, Takafumi

2016-05-01

Chemotherapy is associated with a risk of vascular damage. Novel anti-angiogenic agents, which can directly affect tumor angiogenesis, are increasingly being used. However, the effects of these agents on normal vasculature are not well understood. Here, we evaluated the effects of chemotherapy in general, and the anti-angiogenic agent bevacizumab, more specifically, on the pulmonary vasculature in patients with advanced non-squamous non-small-cell lung cancer (NSCLC). For this, we used the cross-sectional area of pulmonary vessels (CSA), which is an easily measurable indicator of small pulmonary vasculature on non-contrast chest computed tomography (CT). We retrospectively reviewed CT scans of the lungs of 75 chemo-naïve patients with advanced non-squamous NSCLC, for measurement of CSA, before and after first-line platinum-based chemotherapy, using a semi-automatic image-processing program. Measured vessels were classified in two groups: small vessels with CSA <5 mm(2) and large vessels with CSA between 5 and 10 mm(2). The CSAs for each group of vessels were calculated and summed separately, and expressed as a percentage of the total lung area (%CSA<5 and %CSA5-10). Chemotherapy was associated with a selective decrease in small-diameter vessels, with a significant decrease in %CSA<5, but not %CSA5-10. When comparing chemotherapy with bevacizumab (n = 38) and without bevacizumab (n = 37), there was no significant difference in the reduction of %CSA<5. Platinum-based chemotherapy might induce small pulmonary vascular damage. Use of bevacizumab does not enhance the reduction in area of pulmonary vessels.

Cyclosporin derivatives inhibit hepatitis B virus entry without interfering with NTCP transporter activity.

PubMed

Shimura, Satomi; Watashi, Koichi; Fukano, Kento; Peel, Michael; Sluder, Ann; Kawai, Fumihiro; Iwamoto, Masashi; Tsukuda, Senko; Takeuchi, Junko S; Miyake, Takeshi; Sugiyama, Masaya; Ogasawara, Yuki; Park, Sam-Yong; Tanaka, Yasuhito; Kusuhara, Hiroyuki; Mizokami, Masashi; Sureau, Camille; Wakita, Takaji

2017-04-01

The sodium taurocholate co-transporting polypeptide (NTCP) is the main target of most hepatitis B virus (HBV) specific entry inhibitors. Unfortunately, these agents also block NTCP transport of bile acids into hepatocytes, and thus have the potential to cause adverse effects. We aimed to identify small molecules that inhibit HBV entry while maintaining NTCP transporter function. We characterized a series of cyclosporine (CsA) derivatives for their anti-HBV activity and NTCP binding specificity using HepG2 cells overexpressing NTCP and primary human hepatocytes. The four most potent derivatives were tested for their capacity to prevent HBV entry, but maintain NTCP transporter function. Their antiviral activity against different HBV genotypes was analysed. We identified several CsA derivatives that inhibited HBV infection with a sub-micromolar IC 50 . Among them, SCY446 and SCY450 showed low activity against calcineurin (CN) and cyclophilins (CyPs), two major CsA cellular targets. This suggested that instead, these compounds interacted directly with NTCP to inhibit viral attachment to host cells, and have no immunosuppressive function. Importantly, we found that SCY450 and SCY995 did not impair the NTCP-dependent uptake of bile acids, and inhibited multiple HBV genotypes including a clinically relevant nucleoside analog-resistant HBV isolate. This is the first example of small molecule selective inhibition of HBV entry with no decrease in NTCP transporter activity. It suggests that the anti-HBV activity can be functionally separated from bile acid transport. These broadly active anti-HBV molecules are potential candidates for developing new drugs with fewer adverse effects. In this study, we identified new compounds that selectively inhibited hepatitis B virus (HBV) entry, and did not impair bile acid uptake. Our evidence offers a new strategy for developing anti-HBV drugs with fewer side effects. Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Childhood Sexual Abuse and the Development of Recurrent Major Depression in Chinese Women

PubMed Central

Chen, Jing; Cai, Yiyun; Cong, Enzhao; Liu, Ying; Gao, Jingfang; Li, Youhui; Tao, Ming; Zhang, Kerang; Wang, Xumei; Gao, Chengge; Yang, Lijun; Li, Kan; Shi, Jianguo; Wang, Gang; Liu, Lanfen; Zhang, Jinbei; Du, Bo; Jiang, Guoqing; Shen, Jianhua; Zhang, Zhen; Liang, Wei; Sun, Jing; Hu, Jian; Liu, Tiebang; Wang, Xueyi; Miao, Guodong; Meng, Huaqing; Li, Yi; Hu, Chunmei; Li, Yi; Huang, Guoping; Li, Gongying; Ha, Baowei; Deng, Hong; Mei, Qiyi; Zhong, Hui; Gao, Shugui; Sang, Hong; Zhang, Yutang; Fang, Xiang; Yu, Fengyu; Yang, Donglin; Liu, Tieqiao; Chen, Yunchun; Hong, Xiaohong; Wu, Wenyuan; Chen, Guibing; Cai, Min; Song, Yan; Pan, Jiyang; Dong, Jicheng; Pan, Runde; Zhang, Wei; Shen, Zhenming; Liu, Zhengrong; Gu, Danhua; Wang, Xiaoping; Liu, Xiaojuan; Zhang, Qiwen; Li, Yihan; Chen, Yiping; Kendler, Kenneth S.; Shi, Shenxun; Flint, Jonathan

2014-01-01

Background Our prior study in Han Chinese women has shown that women with a history of childhood sexual abuse (CSA) are at increased risk for developing major depression (MD). Would this relationship be found in our whole data set? Method Three levels of CSA (non-genital, genital, and intercourse) were assessed by self-report in two groups of Han Chinese women: 6017 clinically ascertained with recurrent MD and 5983 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression. Results We confirmed earlier results by replicating prior analyses in 3,950 new recurrent MD cases. There were no significant differences between the two data sets. Any form of CSA was significantly associated with recurrent MD (OR 4.06, 95% confidence interval (CI) [3.19–5.24]). This association strengthened with increasing CSA severity: non-genital (OR 2.21, 95% CI 1.58–3.15), genital (OR 5.24, 95% CI 3.52–8.15) and intercourse (OR 10.65, 95% CI 5.56–23.71). Among the depressed women, those with CSA had an earlier age of onset, longer depressive episodes. Recurrent MD patients those with CSA had an increased risk for dysthymia (OR 1.60, 95%CI 1.11–2.27) and phobia (OR 1.41, 95%CI 1.09–1.80). Any form of CSA was significantly associated with suicidal ideation or attempt (OR 1.50, 95% CI 1.20–1.89) and feelings of worthlessness or guilt (OR 1.41, 95% CI 1.02–2.02). Intercourse (OR 3.47, 95%CI 1.66–8.22), use of force and threats (OR 1.95, 95%CI 1.05–3.82) and how strongly the victims were affected at the time (OR 1.39, 95%CI 1.20–1.64) were significantly associated with recurrent MD. Conclusions In Chinese women CSA is strongly associated with recurrent MD and this association increases with greater severity of CSA. Depressed women with CSA have some specific clinical traits. Some features of CSA were associated with greater likelihood of developing recurrent MD. PMID:24489940

Detecting UV-lesions in the genome: The modular CRL4 ubiquitin ligase does it best!

PubMed

Scrima, Andrea; Fischer, Eric S; Lingaraju, Gondichatnahalli M; Böhm, Kerstin; Cavadini, Simone; Thomä, Nicolas H

2011-09-16

The DDB1-DDB2-CUL4-RBX1 complex serves as the primary detection device for UV-induced lesions in the genome. It simultaneously functions as a CUL4 type E3 ubiquitin ligase. We review the current understanding of this dual function ubiquitin ligase and damage detection complex. The DDB2 damage binding module is merely one of a large family of possible DDB1-CUL4 associated factors (DCAF), most of which are substrate receptors for other DDB1-CUL4 complexes. DDB2 and the Cockayne-syndrome A protein (CSA) function in nucleotide excision repair, whereas the remaining receptors operate in a wide range of other biological pathways. We will examine the modular architecture of DDB1-CUL4 in complex with DDB2, CSA and CDT2 focusing on shared architectural, targeting and regulatory principles. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Quantitative In Situ Analysis of the Anterior Cruciate Ligament: Length, Midsubstance Cross-sectional Area, and Insertion Site Areas.

PubMed

Fujimaki, Yoshimasa; Thorhauer, Eric; Sasaki, Yusuke; Smolinski, Patrick; Tashman, Scott; Fu, Freddie H

2016-01-01

Quantification of the cross-sectional area (CSA) of the anterior cruciate ligament (ACL) in different loading conditions is important for understanding the native anatomy and thus achieving anatomic reconstruction. The ACL insertion sites are larger than the ACL midsubstance, and the isthmus (region of the smallest CSA) location may vary with the load or flexion angle. To (1) quantify the CSA along the entire ACL, (2) describe the location of the ACL isthmus, (3) explore the relationship between ACL length and CSA, and (4) validate magnetic resonance imaging (MRI) for assessing the CSA of the midsubstance ACL. Descriptive laboratory study. Eight cadaveric knees were dissected to expose the ACL and its attachments. Knees were positioned using a robotic loading system through a range of flexion angles in 3 loading states: (1) unloaded, (2) anterior tibial translation, and (3) combined rotational load of valgus and internal torque. Laser scanning quantified the shape of the ACL and its insertion site boundaries. The CSA of the ACL was measured, and the location of the isthmus was determined; the CSA of the ACL was also estimated from MRI and compared with the laser-scanned data. The CSA of the ACL varied along the ligament, and the isthmus existed at an average (±SD) of 53.8% ± 5.5% of the distance from the tibial insertion center to the femoral insertion center. The average CSA at the isthmus was smallest in extension (39.9 ± 13.7 mm(2)) and increased with flexion (43.9 ± 12.1 mm(2) at 90°). The ACL length was shortest at 90° of flexion and increased by 18.8% ± 10.1% in unloaded extension. Application of an anterior load increased the ACL length by 5.0% ± 3.3% in extension, and application of a combined rotational load increased its length by 4.1% ± 3.0% in extension. The ACL isthmus is located almost half of the distance between the insertion sites. The CSA of the ACL at the isthmus is largest with the knee unloaded and at 90° of flexion, and the area decreases with extension and applied loads. The CSA at the isthmus represents less than half the area of the insertion sites. These results may aid surgical planning, specifically for choosing a graft size and fixation angle that most closely matches the native anatomy and function across the entire range of knee motion. © 2015 The Author(s).

Production and Characterization of a Monoclonal Antibody Raised Against Surface Antigens from Mycelium of Gaeumannomyces graminis var. tritici: Evidence for an Extracellular Polyphenol Oxidase.

PubMed

Thornton, C R; Dewey, F M; Gilligan, C A

1997-01-01

ABSTRACT A murine monoclonal antibody (MAb) of immunoglobulin class M (IgM) was raised against surface antigens from Gaeumannomyces graminis var. tritici and, by enzyme-linked immunosorbent assay, recognized isolates of G. graminis var. tritici, G. graminis var. avenae and G. graminis var. graminis. Characterization of the antigen by heat and protease treatments showed that the epitope recognized by the MAb was a protein. Antigen production was detected only in live mycelia. Immunofluorescence studies showed that the antigen was associated with both the broad melanized macrohyphae and hyaline mycelia of G. graminis var. tritici. Secretion of antigen into an aqueous minimal medium was promoted only by exposure of live mycelia to certain phenolic substrates, including monophenols ortho-, para-, and meta-cresol; 3,4,5-trihydroxybenzoic acid (gallic acid); and phenolic amino acid L-3-(3,4-dihydroxyphenyl) alanine (L-DOPA). Antigen secretion was not promoted by 3-(4-hydroxyphenyl) alanine (L-tyrosine). The MAb reacted strongly with purified enzyme laccase (polyphenol oxidase, EC 1.10.3.2) but did not recognize purified tyrosinase (monophenol oxidase, EC 1.14.18.1). Moreover, chemicals that bind to copper and inhibit copper-containing enzymes such as laccase completely inhibited antigen secretion in response to L-DOPA. The MAb was tested for specificity against a wide range of fungi, common yeast species, and gram positive and negative bacteria. It did not recognize antigens from a broad range of unrelated fungi, including Gliocladium roseum, Fusarium sp., Phoma exigua, Phialophora fastigiata, Penicillium crustosum, Pythium ultimum, Rhizopus stolonifer, Rhizoctonia carotae, R. oryzae, R. tuliparum, and Trichoderma viride, nor did it recognize surface antigens from yeasts or bacteria. The MAb cross-reacted with antigens from Botrytis spp., Chaetomium globosum, R. cerealis, and R. solani. However, secretion of antigen by R. solani and R. cerealis was not promoted by L-DOPA, and secretion by C. globosum in response to the phenolic amino acid was significantly less compared to G. graminis var. tritici.

Complexity of childhood sexual abuse: Predictors of current PTSD, mood disorders, substance use, and sexual risk behavior among adult men who have sex with men

PubMed Central

Boroughs, Michael S.; Valentine, Sarah E.; Ironson, Gail H.; Shipherd, Jillian C.; Safren, Steven A.; Taylor, S. Wade; Dale, Sannisha K.; Baker, Joshua S.; Wilner, Julianne G.; O'Cleirigh, Conall

2016-01-01

Men who have sex with men (MSM) are the group most at risk for HIV and represent the majority of new infections in the United States. Rates of childhood sexual abuse (CSA) among MSM have been estimated as high as 46%. CSA is associated with increased risk of HIV and greater likelihood of HIV sexual risk behavior. The purpose of this study was to identify the relationships between CSA complexity indicators and mental health, substance use, sexually transmitted infections (STIs) and HIV sexual risk among MSM. MSM with CSA histories (n = 162) who were screened for an HIV-prevention efficacy trial completed comprehensive psychosocial assessments. Five indicators of complex CSA experiences were created: CSA by family member, CSA with penetration, CSA with physical injury, CSA with intense fear, and first CSA in adolescence. Adjusted regression models were used to identify relationships between CSA complexity and outcomes. Participants reporting CSA by family member were at 2.6 odds of current alcohol use disorder (OR: 2.64: CI 1.24 – 5.63), 2 times higher odds of substance use disorder (OR 2.1: CI 1.02 – 2.36), and 2.7 times higher odds of reporting an STI in the past year (OR 2.7: CI 1.04 – 7.1). CSA with penetration was associated with increased likelihood of current PTSD (OR 3.17: CI 1.56 – 6.43), recent HIV sexual risk behavior (OR 2.7: CI 1.16 – 6.36) and a greater number of casual sexual partners (p = .02). Both CSA with Physical Injury (OR 4.05: CI 1.9 – 8.7) and CSA with Intense Fear (OR 5.16: CI 2.5 – 10.7) were related to increased odds for current PTSD. First CSA in adolescence was related to increased odds of major depressive disorder. These findings suggest that CSA, with one or more complexities, creates patterns of vulnerabilities for MSM, including PTSD, substance use, and sexual risk taking and suggests the need for detailed assessment of CSA and the development of integrated HIV prevention programs that address mental health and substance use comorbidities. PMID:26159863

DOE Office of Scientific and Technical Information (OSTI.GOV)

El-Gowelli, Hanan M.; Helmy, Maged W.; Ali, Rabab M.

Endothelin (ET) signaling provokes nephrotoxicity induced by the immunosuppressant drug cyclosporine A (CSA). We tested the hypotheses that (i): celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, counterbalances renal derangements caused by CSA in rats and (ii) the COX-2/endothelin ET{sub B} receptor signaling mediates the CSA-celecoxib interaction. Ten-day treatment with CSA (20 mg/kg/day) significantly increased biochemical indices of renal function (serum urea, creatinine), inflammation (interleukin-2, IL-2) and fibrosis (transforming growth factor-β{sub 1}, TGF-β{sub 1}). Histologically, CSA caused renal tubular atrophy along with interstitial fibrosis. These detrimental renal effects of CSA were largely reduced in rats treated concurrently with celecoxib (10 mg/kg/day). Wemore » also report that cortical glomerular and medullary tubular protein expressions of COX-2 and ET{sub B} receptors were reduced by CSA and restored to near-control values in rats treated simultaneously with celecoxib. The importance of ET{sub B} receptors in renal control and in the CSA-celecoxib interaction was further verified by the findings (i) most of the adverse biochemical, inflammatory, and histopathological profiles of CSA were replicated in rats treated with the endothelin ET{sub B} receptor antagonist BQ788 (0.1 mg/kg/day, 10 days), and (ii) the BQ788 effects, like those of CSA, were alleviated in rats treated concurrently with celecoxib. Together, the data suggest that the facilitation of the interplay between the TGF-β1/IL-2/COX-2 pathway and the endothelin ET{sub B} receptors constitutes the cellular mechanism by which celecoxib ameliorates the nephrotoxic manifestations of CSA in rats. - Highlights: • Celecoxib abolishes nephrotoxic manifestations of CSA in rats. • Blockade of ETB receptors by BQ788 mimicked the nephrotoxic effects of CSA. • CSA or BQ788 reduces renal protein expression of COX-2 and endothelin ETB receptors. • Enhanced TGFβ1/IL-2/COX2/ETB signaling mediates celecoxib renoprotection.« less

Left Atrial Size, Chemosensitivity, and Central Sleep Apnea in Heart Failure

PubMed Central

Calvin, Andrew D.; Somers, Virend K.; Johnson, Bruce D.; Scott, Christopher G.

2014-01-01

BACKGROUND: Central sleep apnea (CSA) is common among patients with heart failure (HF) and is promoted by elevated CO2 chemosensitivity. Left atrial size is a marker of the hemodynamic severity of HF. The aim of this study was to determine if left atrial size predicts chemosensitivity to CO2 and CSA in patients with HF. METHODS: Patients with HF with left ventricular ejection fraction ≤ 35% underwent polysomnography for detection of CSA, echocardiography, and measurement of CO2 chemosensitivity. CSA was defined as an apnea-hypopnea index (AHI) ≥ 15/h with ≥ 50% central apneic events. The relation of clinical and echocardiographic parameters to chemosensitivity and CSA were evaluated by linear regression, estimation of ORs, and receiver operator characteristics. RESULTS: Of 46 subjects without OSA who had complete data for analysis, 25 had CSA. The only parameter that significantly correlated with chemosensitivity was left atrial volume index (LAVI) (r = 0.40, P < .01). LAVI was greater in those with CSA than those without CSA (59.2 mL/m2 vs 36.4 mL/m2, P < .001) and significantly correlated with log-transformed AHI (r = 0.46, P = .001). LAVI was the best predictor of CSA (area under the curve = 0.83). A LAVI ≤ 33 mL/m2 was associated with 22% risk for CSA, while LAVI ≥ 53 mL/m2 was associated with 92% risk for CSA. CONCLUSIONS: Increased LAVI is associated with heightened CO2 chemosensitivity and greater frequency of CSA. LAVI may be useful to guide referral for polysomnography for detection of CSA in patients with HF. PMID:24522490

Synthesis of chondroitin sulfate CC and DD tetrasaccharides and interactions with 2H6 and LY111.

PubMed

Matsushita, Kenya; Nakata, Tomomi; Takeda-Okuda, Naoko; Nadanaka, Satomi; Kitagawa, Hiroshi; Tamura, Jun-Ichi

2018-03-01

We synthesized the biotinylated chondroitin sulfate tetrasaccharides CS-CC [-3)βGalNAc6S(1-4)βGlcA(1-] 2 and CS-DD [-3)βGalNAc6S(1-4)βGlcA2S(1-] 2 which possess sulfate groups at O-6 of GalNAc and an additional sulfate group at O-2 of GlcA, respectively. We also analyzed interactions among CS-CC and CS-DD and the antibodies 2H6 and LY111, both of which are known to bind with CS-A, while CS-DD was shown for the first time to bind with both antibodies. Copyright © 2018 Elsevier Ltd. All rights reserved.

Complexity of childhood sexual abuse: predictors of current post-traumatic stress disorder, mood disorders, substance use, and sexual risk behavior among adult men who have sex with men.

PubMed

Boroughs, Michael S; Valentine, Sarah E; Ironson, Gail H; Shipherd, Jillian C; Safren, Steven A; Taylor, S Wade; Dale, Sannisha K; Baker, Joshua S; Wilner, Julianne G; O'Cleirigh, Conall

2015-10-01

Men who have sex with men (MSM) are the group most at risk for HIV and represent the majority of new infections in the United States. Rates of childhood sexual abuse (CSA) among MSM have been estimated as high as 46 %. CSA is associated with increased risk of HIV and greater likelihood of HIV sexual risk behavior. The purpose of this study was to identify the relationships between CSA complexity indicators and mental health, substance use, sexually transmitted infections, and HIV sexual risk among MSM. MSM with CSA histories (n = 162) who were screened for an HIV prevention efficacy trial completed comprehensive psychosocial assessments. Five indicators of complex CSA experiences were created: CSA by family member, CSA with penetration, CSA with physical injury, CSA with intense fear, and first CSA in adolescence. Adjusted regression models were used to identify relationships between CSA complexity and outcomes. Participants reporting CSA by family member were at 2.6 odds of current alcohol use disorder (OR 2.64: CI 1.24-5.63), two times higher odds of substance use disorder (OR 2.1: CI 1.02-2.36), and 2.7 times higher odds of reporting an STI in the past year (OR 2.7: CI 1.04-7.1). CSA with penetration was associated with increased likelihood of current PTSD (OR 3.17: CI 1.56-6.43), recent HIV sexual risk behavior (OR 2.7: CI 1.16-6.36), and a greater number of casual sexual partners (p = 0.02). Both CSA with Physical Injury (OR 4.05: CI 1.9-8.7) and CSA with Intense Fear (OR 5.16: CI 2.5-10.7) were related to increased odds for current PTSD. First CSA in adolescence was related to increased odds of major depressive disorder. These findings suggest that CSA, with one or more complexities, creates patterns of vulnerabilities for MSM, including post-traumatic stress disorder, substance use, and sexual risk taking, and suggests the need for detailed assessment of CSA and the development of integrated HIV prevention programs that address mental health and substance use comorbidities.

Murine Anti-vaccinia Virus D8 Antibodies Target Different Epitopes and Differ in Their Ability to Block D8 Binding to CS-E

PubMed Central

Matho, Michael H.; de Val, Natalia; Miller, Gregory M.; Brown, Joshua; Schlossman, Andrew; Meng, Xiangzhi; Crotty, Shane; Peters, Bjoern; Xiang, Yan; Hsieh-Wilson, Linda C.; Ward, Andrew B.; Zajonc, Dirk M.

2014-01-01

The IMV envelope protein D8 is an adhesion molecule and a major immunodominant antigen of vaccinia virus (VACV). Here we identified the optimal D8 ligand to be chondroitin sulfate E (CS-E). CS-E is characterized by a disaccharide moiety with two sulfated hydroxyl groups at positions 4′ and 6′ of GalNAc. To study the role of antibodies in preventing D8 adhesion to CS-E, we have used a panel of murine monoclonal antibodies, and tested their ability to compete with CS-E for D8 binding. Among four antibody specificity groups, MAbs of one group (group IV) fully abrogated CS-E binding, while MAbs of a second group (group III) displayed widely varying levels of CS-E blocking. Using EM, we identified the binding site for each antibody specificity group on D8. Recombinant D8 forms a hexameric arrangement, mediated by self-association of a small C-terminal domain of D8. We propose a model in which D8 oligomerization on the IMV would allow VACV to adhere to heterogeneous population of CS, including CS-C and potentially CS-A, while overall increasing binding efficiency to CS-E. PMID:25474621

Murine anti-vaccinia virus D8 antibodies target different epitopes and differ in their ability to block D8 binding to CS-E.

PubMed

Matho, Michael H; de Val, Natalia; Miller, Gregory M; Brown, Joshua; Schlossman, Andrew; Meng, Xiangzhi; Crotty, Shane; Peters, Bjoern; Xiang, Yan; Hsieh-Wilson, Linda C; Ward, Andrew B; Zajonc, Dirk M

2014-12-01

The IMV envelope protein D8 is an adhesion molecule and a major immunodominant antigen of vaccinia virus (VACV). Here we identified the optimal D8 ligand to be chondroitin sulfate E (CS-E). CS-E is characterized by a disaccharide moiety with two sulfated hydroxyl groups at positions 4' and 6' of GalNAc. To study the role of antibodies in preventing D8 adhesion to CS-E, we have used a panel of murine monoclonal antibodies, and tested their ability to compete with CS-E for D8 binding. Among four antibody specificity groups, MAbs of one group (group IV) fully abrogated CS-E binding, while MAbs of a second group (group III) displayed widely varying levels of CS-E blocking. Using EM, we identified the binding site for each antibody specificity group on D8. Recombinant D8 forms a hexameric arrangement, mediated by self-association of a small C-terminal domain of D8. We propose a model in which D8 oligomerization on the IMV would allow VACV to adhere to heterogeneous population of CS, including CS-C and potentially CS-A, while overall increasing binding efficiency to CS-E.

Professionals' Attitude Toward Reporting Child Sexual Abuse in Saudi Arabia.

PubMed

Al-Saif, Dalia M; Al-Eissa, Majid; Saleheen, Hassan; Al-Mutlaq, Huda; Everson, Mark D; Almuneef, Maha A

2018-01-01

Child sexual abuse (CSA) requires specialized knowledge and training that includes forensic interview skills. The aim of this study was to determine variations in professionals' attitudes toward CSA by measuring three aspects of forensic attitudes (sensitivity, specificity, and skepticism) and evaluating disagreements concerning the assessment of CSA cases in Saudi Arabia. A cross-sectional, web-based study, in which the Child Forensic Attitude Scale was used to measure professionals' attitudes, was conducted. Professionals who dealt with suspected cases of CSA as part of their jobs or were in professions that necessitated involvement with such cases, were selected as participants. Of 327 participants, 53% were aged ≤40 years, and 54% were men. In addition, 24% were doctors/nurses, 20% were therapists/psychiatrists, 24% were social workers, 17% were educators, 9% were law enforcement professionals, and 5% were medical examiners. Attitude subscale scores differed significantly according to participants' sex, specialty, and training. Women, healthcare professionals, and those who had participated in more than five training courses were more concerned about the underreporting of abuse (high sensitivity) relative to other professionals. In comparison, men, medical examiners, law enforcement officers, and undertrained professionals tended to underreport suspected sexual abuse cases (high specificity). High specificity in attitudes toward suspected cases of CSA could affect professionals' judgment and contribute to low reporting rates. Certain strategies, including increasing self-awareness of personal bias, specific CSA recognition courses, and team approaches to case assessment and management, should be implemented to control the influence of subjective factors.

Hydration of calcium sulfoaluminate cements - Experimental findings and thermodynamic modelling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Winnefeld, Frank, E-mail: Frank.Winnefeld@empa.c; Lothenbach, Barbara

Calcium sulfoaluminate cements (CSA) are a promising low-CO{sub 2} alternative to ordinary Portland cements and are as well of interest concerning their use as binder for waste encapsulation. In this study, the hydration of two CSA cements has been investigated experimentally and by thermodynamic modelling between 1 h and 28 days at w/c ratios of 0.72 and 0.80, respectively. The main hydration product of CSA is ettringite, which precipitates together with amorphous Al(OH){sub 3} until the calcium sulfate is consumed after around 1-2 days of hydration. Afterwards, monosulfate is formed. In the presence of belite, straetlingite occurs as an additionalmore » hydration product. The pore solution analysis reveals that straetlingite can bind a part of the potassium ions, which are released by the clinker minerals. The microstructure of both cements is quite dense even after 16 h of hydration, with not much pore space available at a sample age of 28 days. The pore solution of both cements is dominated during the first hours of hydration by potassium, sodium, calcium, aluminium and sulfate; the pH is around 10-11. When the calcium sulfate is depleted, the sulfate concentration drops by a factor of 10. This increases pH to around 12.5-12.8. Based on the experimental data, a thermodynamic hydration model for CSA cements based on cement composition, hydration kinetics of clinker phases and calculations of thermodynamic equilibria by geochemical speciation has been established. The modelled phase development with ongoing hydration agrees well with the experimental findings.« less

Disrupted Reinforcement Learning and Maladaptive Behavior in Women with a History of Childhood Sexual Abuse: A High-Density Event-Related Potential Study

PubMed Central

Pechtel, Pia; Pizzagalli, Diego A.

2013-01-01

Context Childhood sexual abuse (CSA) has been associated with psychopathology, particularly major depressive disorder (MDD), and high-risk behaviors. Despite grave epidemiological data, the mechanisms underlying these maladaptive outcomes remain poorly understood. Objective We examined whether CSA history, particularly in conjunction with past MDD, is associated with behavioral and neural dysfunction in reinforcement learning, and whether such dysfunction is linked to maladaptive behavior. Design Participants completed a clinical evaluation and a probabilistic reinforcement task while 128-channel event-related potentials were recorded. Setting Academic setting; participants recruited from the community. Participants Fifteen remitted depressed females with CSA history (CSA+rMDD), 16 remitted depressed females without CSA history (rMDD), and 18 healthy females. Main Outcome Measures Participants’ preference for choosing the most rewarded stimulus and avoiding the most punished stimulus was evaluated. The feedback-related negativity (FRN) and error-related negativity (ERN)–hypothesized to reflect activation in the anterior cingulate cortex–were used as electrophysiological indices of reinforcement learning. Results No group differences emerged in the acquisition of reinforcement contingencies. In trials requiring to rely partially or exclusively on previously rewarded information, the CSA+rMDD group showed (1) lower accuracy (relative to both controls and rMDD), (2) blunted electrophysiological differentiation between correct and incorrect responses (relative to controls), and (3) increased activation in the subgenual anterior cingulate cortex (relative to rMDD). CSA history was not associated with impairments in avoiding the most punished stimulus. Self-harm and suicidal behaviors correlated with poorer performance of previously rewarded–but not previously punished–trials. Conclusions Irrespective of past MDD, women with CSA histories showed neural and behavioral deficits in utilizing previous reinforcement to optimize decision-making in the absence of feedback (blunted “Go learning”). While the current study provides initial evidence for reward-specific deficits associated with CSA, future research is warranted to determine if disrupted positive reinforcement learning predicts high-risk behavior following CSA. PMID:23487253

KIAA1530 Protein Is Recruited by Cockayne Syndrome Complementation Group Protein A (CSA) to Participate in Transcription-coupled Repair (TCR)

PubMed Central

Fei, Jia; Chen, Junjie

2012-01-01

Transcription-coupled repair (TCR) is the major pathway involved in the removal of UV-induced photolesions from the transcribed strand of active genes. Two Cockayne syndrome (CS) complementation group proteins, CSA and CSB, are important for TCR repair. The molecular mechanisms by which CS proteins regulate TCR remain elusive. Here, we report the characterization of KIAA1530, an evolutionarily conserved protein that participates in this pathway through its interaction with CSA and the TFIIH complex. We found that UV irradiation led to the recruitment of KIAA1530 onto chromatin in a CSA-dependent manner. Cells lacking KIAA1530 were highly sensitive to UV irradiation and displayed deficiency in TCR. In addition, KIAA1530 depletion abrogated stability of the CSB protein following UV irradiation. More excitingly, we found that a unique CSA mutant (W361C), which was previously identified in a patient with UVsS syndrome, showed defective KIAA1530 binding and resulted in a failure of recruiting KIAA1530 and stabilizing CSB after UV treatment. Together, our data not only reveal that KIAA1530 is an important player in TCR but also lead to a better understanding of the molecular mechanism underlying UVsS syndrome. PMID:22902626

The combined rapid detection and species-level identification of yeasts in simulated blood culture using a colorimetric sensor array

PubMed Central

Lim, Sung H.; Wilson, Deborah A.; SalasVargas, Ana Victoria; Churi, Yair S.; Rhodes, Paul A.; Mazzone, Peter J.; Procop, Gary W.

2017-01-01

Background A colorimetric sensor array (CSA) has been demonstrated to rapidly detect and identify bacteria growing in blood cultures by obtaining a species-specific “fingerprint” of the volatile organic compounds (VOCs) produced during growth. This capability has been demonstrated in prokaryotes, but has not been reported for eukaryotic cells growing in culture. The purpose of this study was to explore if a disposable CSA could differentially identify 7 species of pathogenic yeasts growing in blood culture. Methods Culture trials of whole blood inoculated with a panel of clinically important pathogenic yeasts at four different microorganism loads were performed. Cultures were done in both standard BacT/Alert and CSA-embedded bottles, after adding 10 mL of spiked blood to each bottle. Color changes in the CSA were captured as images by an optical scanner at defined time intervals. The captured images were analyzed to identify the yeast species. Time to detection by the CSA was compared to that in the BacT/Alert system. Results One hundred sixty-two yeast culture trials were performed, including strains of several species of Candida (Ca. albicans, Ca. glabrata, Ca. parapsilosis, and Ca. tropicalis), Clavispora (synonym Candida) lusitaniae, Pichia kudriavzevii (synonym Candida krusei) and Cryptococcus neoformans, at loads of 8.2 × 105, 8.3 × 103, 8.5 × 101, and 1.7 CFU/mL. In addition, 8 negative trials (no yeast) were conducted. All negative trials were correctly identified as negative, and all positive trials were detected. Colorimetric responses were species-specific and did not vary by inoculum load over the 500000-fold range of loads tested, allowing for accurate species-level identification. The mean sensitivity for species-level identification by CSA was 74% at detection, and increased with time, reaching almost 95% at 4 hours after detection. At an inoculum load of 1.7 CFU/mL, mean time to detection with the CSA was 6.8 hours (17%) less than with the BacT/Alert platform. Conclusion The CSA combined rapid detection of pathogenic yeasts in blood culture with accurate species-level identification. PMID:28296967

The combined rapid detection and species-level identification of yeasts in simulated blood culture using a colorimetric sensor array.

PubMed

Shrestha, Nabin K; Lim, Sung H; Wilson, Deborah A; SalasVargas, Ana Victoria; Churi, Yair S; Rhodes, Paul A; Mazzone, Peter J; Procop, Gary W

2017-01-01

A colorimetric sensor array (CSA) has been demonstrated to rapidly detect and identify bacteria growing in blood cultures by obtaining a species-specific "fingerprint" of the volatile organic compounds (VOCs) produced during growth. This capability has been demonstrated in prokaryotes, but has not been reported for eukaryotic cells growing in culture. The purpose of this study was to explore if a disposable CSA could differentially identify 7 species of pathogenic yeasts growing in blood culture. Culture trials of whole blood inoculated with a panel of clinically important pathogenic yeasts at four different microorganism loads were performed. Cultures were done in both standard BacT/Alert and CSA-embedded bottles, after adding 10 mL of spiked blood to each bottle. Color changes in the CSA were captured as images by an optical scanner at defined time intervals. The captured images were analyzed to identify the yeast species. Time to detection by the CSA was compared to that in the BacT/Alert system. One hundred sixty-two yeast culture trials were performed, including strains of several species of Candida (Ca. albicans, Ca. glabrata, Ca. parapsilosis, and Ca. tropicalis), Clavispora (synonym Candida) lusitaniae, Pichia kudriavzevii (synonym Candida krusei) and Cryptococcus neoformans, at loads of 8.2 × 105, 8.3 × 103, 8.5 × 101, and 1.7 CFU/mL. In addition, 8 negative trials (no yeast) were conducted. All negative trials were correctly identified as negative, and all positive trials were detected. Colorimetric responses were species-specific and did not vary by inoculum load over the 500000-fold range of loads tested, allowing for accurate species-level identification. The mean sensitivity for species-level identification by CSA was 74% at detection, and increased with time, reaching almost 95% at 4 hours after detection. At an inoculum load of 1.7 CFU/mL, mean time to detection with the CSA was 6.8 hours (17%) less than with the BacT/Alert platform. The CSA combined rapid detection of pathogenic yeasts in blood culture with accurate species-level identification.

cDNA cloning, molecular modeling and docking calculations of L-type lectins from Swartzia simplex var. grandiflora (Leguminosae, Papilionoideae), a member of the tribe Swartzieae.

PubMed

Maranhão, Paulo A C; Teixeira, Claudener S; Sousa, Bruno L; Barroso-Neto, Ito L; Monteiro-Júnior, José E; Fernandes, Andreia V; Ramos, Marcio V; Vasconcelos, Ilka M; Gonçalves, José F C; Rocha, Bruno A M; Freire, Valder N; Grangeiro, Thalles B

2017-07-01

The genus Swartzia is a member of the tribe Swartzieae, whose genera constitute the living descendants of one of the early branches of the papilionoid legumes. Legume lectins comprise one of the main families of structurally and evolutionarily related carbohydrate-binding proteins of plant origin. However, these proteins have been poorly investigated in Swartzia and to date, only the lectin from S. laevicarpa seeds (SLL) has been purified. Moreover, no sequence information is known from lectins of any member of the tribe Swartzieae. In the present study, partial cDNA sequences encoding L-type lectins were obtained from developing seeds of S. simplex var. grandiflora. The amino acid sequences of the S. simplex grandiflora lectins (SSGLs) were only averagely related to the known primary structures of legume lectins, with sequence identities not greater than 50-52%. The SSGL sequences were more related to amino acid sequences of papilionoid lectins from members of the tribes Sophoreae and Dalbergieae and from the Cladratis and Vataireoid clades, which constitute with other taxa, the first branching lineages of the subfamily Papilionoideae. The three-dimensional structures of 2 representative SSGLs (SSGL-A and SSGL-E) were predicted by homology modeling using templates that exhibit the characteristic β-sandwich fold of the L-type lectins. Molecular docking calculations predicted that SSGL-A is able to interact with D-galactose, N-acetyl-D-galactosamine and α-lactose, whereas SSGL-E is probably a non-functional lectin due to 2 mutations in the carbohydrate-binding site. Using molecular dynamics simulations followed by density functional theory calculations, the binding free energies of the interaction of SSGL-A with GalNAc and α-lactose were estimated as -31.7 and -47.5 kcal/mol, respectively. These findings gave insights about the carbohydrate-binding specificity of SLL, which binds to immobilized lactose but is not retained in a matrix containing D-GalNAc as ligand. Copyright © 2017 Elsevier Ltd. All rights reserved.

Design of inhibitors of thymidylate kinase from Variola virus as new selective drugs against smallpox.

PubMed

Guimarães, Ana P; de Souza, Felipe R; Oliveira, Aline A; Gonçalves, Arlan S; de Alencastro, Ricardo B; Ramalho, Teodorico C; França, Tanos C C

2015-02-16

Recently we constructed a homology model of the enzyme thymidylate kinase from Variola virus (VarTMPK) and proposed it as a new target to the drug design against smallpox. In the present work, we used the antivirals cidofovir and acyclovir as reference compounds to choose eleven compounds as leads to the drug design of inhibitors for VarTMPK. Docking and molecular dynamics (MD) studies of the interactions of these compounds inside VarTMPK and human TMPK (HssTMPK) suggest that they compete for the binding region of the substrate and were used to propose the structures of ten new inhibitors for VarTMPK. Further docking and MD simulations of these compounds, inside VarTMPK and HssTMPK, suggest that nine among ten are potential selective inhibitors of VarTMPK. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Category Specificity in Normal Episodic Learning: Applications to Object Recognition and Category-Specific Agnosia

ERIC Educational Resources Information Center

Bukach, Cindy M.; Bub, Daniel N.; Masson, Michael E. J.; Lindsay, D. Stephen

2004-01-01

Studies of patients with category-specific agnosia (CSA) have given rise to multiple theories of object recognition, most of which assume the existence of a stable, abstract semantic memory system. We applied an episodic view of memory to questions raised by CSA in a series of studies examining normal observers' recall of newly learned attributes…

Celecoxib offsets the negative renal influences of cyclosporine via modulation of the TGF-β1/IL-2/COX-2/endothelin ET(B) receptor cascade.

PubMed

El-Gowelli, Hanan M; Helmy, Maged W; Ali, Rabab M; El-Mas, Mahmoud M

2014-03-01

Endothelin (ET) signaling provokes nephrotoxicity induced by the immunosuppressant drug cyclosporine A (CSA). We tested the hypotheses that (i): celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, counterbalances renal derangements caused by CSA in rats and (ii) the COX-2/endothelin ET(B) receptor signaling mediates the CSA-celecoxib interaction. Ten-day treatment with CSA (20 mg/kg/day) significantly increased biochemical indices of renal function (serum urea, creatinine), inflammation (interleukin-2, IL-2) and fibrosis (transforming growth factor-β₁, TGF-β₁). Histologically, CSA caused renal tubular atrophy along with interstitial fibrosis. These detrimental renal effects of CSA were largely reduced in rats treated concurrently with celecoxib (10 mg/kg/day). We also report that cortical glomerular and medullary tubular protein expressions of COX-2 and ET(B) receptors were reduced by CSA and restored to near-control values in rats treated simultaneously with celecoxib. The importance of ET(B) receptors in renal control and in the CSA-celecoxib interaction was further verified by the findings (i) most of the adverse biochemical, inflammatory, and histopathological profiles of CSA were replicated in rats treated with the endothelin ETB receptor antagonist BQ788 (0.1 mg/kg/day, 10 days), and (ii) the BQ788 effects, like those of CSA, were alleviated in rats treated concurrently with celecoxib. Together, the data suggest that the facilitation of the interplay between the TGF-β1/IL-2/COX-2 pathway and the endothelin ET(B) receptors constitutes the cellular mechanism by which celecoxib ameliorates the nephrotoxic manifestations of CSA in rats. Copyright © 2014 Elsevier Inc. All rights reserved.

Characterization of the pH-Mediated solubility of Bacillus thuringiensis var. san diego native δ-endotoxin crystals

Treesearch

C. N. Koller; L. S. Bauer; R. M. Hollingworth

1992-01-01

Native crystals of Bacillus thuringiensis var. san diego, a coleopteran-specific δ-endotoxin, were metabolically labeled with [35S]methionine. Specific activity was 82,000 CPM/μg (2.44 Ci/mmol). Using a universal buffer formulated with the same ionic strength at every pH, we determined that...

Muscle fiber type characteristics in females with chronic obstructive pulmonary disease. A preliminary study.

PubMed

Green, Howard J; Burnett, M E; D'Arsigny, C; Iqbal, S; Ouyang, J; Webb, K A; O'Donnell, D E

2009-02-01

Chronic obstructive pulmonary disease (COPD) is known to elicit intrinsic abnormalities in male skeletal muscle. However, it is unclear to what extent these changes occur in women and whether they are fiber-type specific. We investigated fiber-type specific differences in selected histochemical properties in muscle obtained from women with moderate to severe COPD compared to healthy control (CON) women. Tissue was obtained from the vastus lateralis in five COPD patients (age 66.9 +/- 2.6 years; FEV1 = 43 +/- 7%) and eight CON (age 68 +/- 4.9 years; FEV1 = 113 +/- 4.2%). Compared to CON, the distribution (30.6 +/- 5.2 vs. 57.9 +/- 4.6%) and cross sectional area of type I (CSA, 5660 +/- 329 vs. 3586 +/- 257 microm2) and type IIA (2770 +/- 302 vs. 2099 +/- 206 microm2) were lower (P < 0.05) and higher (P < 0.05), respectively, in COPD. Disease state did not alter either the distribution or CSA of the IIA, IIAX or type X subtypes. Although differences were found between fiber types in the number of capillary contacts (n) (I > IIAX, IIX; IIA > IIX) and the capillaries per CSA (microm210(-3)) (I < IIA, IIAX, IIX), no differences were found between CON and COPD. Succinic dehydrogenase activity and sarcoplasmic reticulum (SR) Ca2+-ATPase activity, measured photometrically (OD units), were higher (P < 0.05), and lower (P < 0.05), respectively, in type I compared to the type II fiber subtypes. These properties were not altered with COPD. COPD in females is accompanied by a higher percent of type II fibers, a larger CSA of type I and type IIA fibers, both of which occur in the absence of differences in oxidative potential and the potential for SR Ca2+-sequestration.

[Magnetic resonance imaging study of effects of accommodation on human lens morphological characters].

PubMed

Zheng, Sui-lian; Zhang, Ai; Shi, Jian-jing; Zhou, Yun-xin

2013-11-05

To evaluate the effects of accommodation on lens morphological characters. From January 2011 to June 2011, magnetic resonance images of eyes were acquired from 30 subjects aged 20 to 24 years during accommodation and at rest. The optimal images were analyzed by Autocad 2010 to obtain the total lens cross-sectional area (CSA) and CSA of anterior and posterior portions of lens, anterior chamber depth, lens thickness, lens diameter, vitreous chamber depth and axial length during accommodation and at rest. Paired-t test was performed. The anterior curvature radius (mm), posterior curvature radius (mm), CSA of anterior portion (mm(2)), CSA of posterior portion (mm(2)), total lens CSA (mm(2)) was (8.7 ± 0.8), (6.2 ± 0.5), (7.5 ± 2.1), (12.0 ± 2.6), (20 ± 4) during relaxed accommodation; anterior curvature radius (mm), posterior curvature radius (mm), CSA of anterior portion (mm(2)), CSA of posterior portion (mm(2)), total lens CSA (mm(2)) was (7.1 ± 1.3), (5.6 ± 0.5), (14.7 ± 2.9), (12.2 ± 2.1) and (27 ± 4) during accommodation. The total lens CSA (t = -11.556, P < 0.01) and CSA of anterior portion (t = -15.653, P < 0.01) both increased in accommodative states. The CSA of posterior portion of lens (t = -0.437, P > 0.05) under a statistically independent accommodative state. There was significant difference in the anterior chamber depth (t = 4.366, P < 0.01), lens thickness (t = -5.456, P < 0.01) and lens diameter (t = 4.597, P < 0.01) in accommodative states. There were insignificant differences both in vitreous chamber depth (t = 0.428, P > 0.05) and axial length (t = 0.418, P > 0.05) under accommodative states. During accommodation, the anterior chamber depth decreases, lens thickness increases and diameter of lens decreases while anterior portions and total lens CSA increase. There are insignificant changes in posterior portions of lens CSA, vitreous chamber depth and axial length. The accommodative changes in CSA indicate that the anterior portion of lens may be related with the properties of anterior capsule and lens material, the position of zonular attachments and the location of fetal nucleus. Helmholtz theory is supported.

Adsorption and desorption performance of benzene over hierarchically structured carbon-silica aerogel composites.

PubMed

Dou, Baojuan; Li, Jinjun; Wang, Yufei; Wang, Hailin; Ma, Chunyan; Hao, Zhengping

2011-11-30

Hierarchically structured carbon-silica aerogel (CSA) composites were synthesized from cheap water glass precursors and granulated activated carbon via a post-synthesis surface modification with trimethylchlorosilane (TMCS) and a low-cost ambient pressure drying procedure. The resultant CSA composites possess micro/mesoporous structure and hydrophobic surface. The adsorption and desorption performance of benzene on carbon-silica aerogel composite (CSA-2) under static and dynamic conditions were investigated, comparing with pure silica aerogel (CSA-0) and microporous activated carbon (AC). It was found that CSA-2 has high affinity towards aromatic molecules and fast adsorption kinetics. Excellent performance of dynamic adsorption and desorption observed on CSA-2 is related to its higher adsorption capacity than CSA-0 and less mass transfer resistance than AC, arising from the well-developed microporosity and open foam mesostructure in the CSA composites. Copyright © 2011 Elsevier B.V. All rights reserved.

Pulmonary hypertension and computed tomography measurement of small pulmonary vessels in severe emphysema.

PubMed

Matsuoka, Shin; Washko, George R; Yamashiro, Tsuneo; Estepar, Raul San Jose; Diaz, Alejandro; Silverman, Edwin K; Hoffman, Eric; Fessler, Henry E; Criner, Gerard J; Marchetti, Nathaniel; Scharf, Steven M; Martinez, Fernando J; Reilly, John J; Hatabu, Hiroto

2010-02-01

Vascular alteration of small pulmonary vessels is one of the characteristic features of pulmonary hypertension in chronic obstructive pulmonary disease. The in vivo relationship between pulmonary hypertension and morphological alteration of the small pulmonary vessels has not been assessed in patients with severe emphysema. We evaluated the correlation of total cross-sectional area of small pulmonary vessels (CSA) assessed on computed tomography (CT) scans with the degree of pulmonary hypertension estimated by right heart catheterization. In 79 patients with severe emphysema enrolled in the National Emphysema Treatment Trial (NETT), we measured CSA less than 5 mm(2) (CSA(<5)) and 5 to 10 mm(2) (CSA(5-10)), and calculated the percentage of total CSA for the lung area (%CSA(<5) and %CSA(5-10), respectively). The correlations of %CSA(<5) and %CSA(5-10) with pulmonary arterial mean pressure (Ppa) obtained by right heart catheterization were evaluated. Multiple linear regression analysis using Ppa as the dependent outcome was also performed. The %CSA(<5) had a significant negative correlation with Ppa (r = -0.512, P < 0.0001), whereas the correlation between %CSA(5-10) and Ppa did not reach statistical significance (r = -0.196, P = 0.083). Multiple linear regression analysis showed that %CSA(<5) and diffusing capacity of carbon monoxide (DL(CO)) % predicted were independent predictors of Ppa (r(2) = 0.541): %CSA (<5) (P < 0.0001), and DL(CO) % predicted (P = 0.022). The %CSA(<5) measured on CT images is significantly correlated to Ppa in severe emphysema and can estimate the degree of pulmonary hypertension.

The Effects of Arthroscopic Lateral Acromioplasty on the Critical Shoulder Angle and the Anterolateral Deltoid Origin: An Anatomic Cadaveric Study.

PubMed

Katthagen, J Christoph; Marchetti, Daniel Cole; Tahal, Dimitri S; Turnbull, Travis Lee; Millett, Peter J

2016-04-01

To investigate if (1) an anterolateral acromioplasty and (2) a lateral acromion resection alter the critical shoulder angle (CSA) without affecting the deltoid origin. First, the native CSAs of 10 human cadaveric shoulders (6 male and 4 female specimens; mean age, 54.2 years) were determined with the use of fluoroscopy. Setup allowed for consistent repetitive measurements. Next, a standard arthroscopic anterolateral acromioplasty was performed to create a type 1 acromion, and the CSA was reassessed fluoroscopically. Afterward, a lateral acromioplasty was performed with a 5-mm lateral acromion resection using a 5-mm burr, and the CSA was measured again. The native CSA was compared with (1) the CSA after acromioplasty and (2) the CSA after acromioplasty and lateral acromion resection using a paired t test. Finally, the acromial deltoid attachment was evaluated anatomically for damage to the anterolateral origin. The mean native CSA (34.3° ± 2.1°) was reduced significantly by acromioplasty (33.1° ± 2.0°, P < .001) and further reduced by lateral acromion resection (31.5° ± 1.7°, P < .001). Anterolateral acromioplasty reduced the CSA by a mean of 1.4° (95% confidence interval boundaries, 0.8° and 1.9°), and in combination with lateral acromion resection, the CSA was reduced by a mean of 2.8° (95% confidence interval boundaries, 2.1° and 3.5°). In all specimens (5 of 5) with a presurgery CSA of 35° or greater, the CSA was reduced to the range of 30° to 35° by the combination of both techniques. However, in 2 specimens with a CSA of approximately 32°, the CSA was reduced to less than 30°. The acromial deltoid attachment was found to be well preserved in all specimens. Arthroscopic anterolateral acromioplasty and a 5-mm lateral acromion resection each reduced the CSA significantly and did not damage the deltoid origin. The combination of both techniques could potentially be used in clinical practice to reduce a CSA greater than 35° to the desired range of 30° to 35°. Copyright © 2016 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

Disrupted reinforcement learning and maladaptive behavior in women with a history of childhood sexual abuse: a high-density event-related potential study.

PubMed

Pechtel, Pia; Pizzagalli, Diego A

2013-05-01

Childhood sexual abuse (CSA) has been associated with psychopathology, particularly major depressive disorder (MDD), and high-risk behaviors. Despite the epidemiological data available, the mechanisms underlying these maladaptive outcomes remain poorly understood. We examined whether a history of CSA, particularly in conjunction with a past episode of MDD, is associated with behavioral and neural dysfunction in reinforcement learning, and whether such dysfunction is linked to maladaptive behavior. Participants completed a clinical evaluation and a probabilistic reinforcement task while 128-channel event-related potentials were recorded. Academic setting; participants recruited from the community. Fifteen women with a history of CSA and remitted MDD (CSA + rMDD), 16 women with remitted MDD with no history of CSA (rMDD), and 18 healthy women (controls). Three or more episodes of coerced sexual contact (mean [SD] duration, 3.00 [2.20] years) between the ages of 7 and 12 years by at least 1 male perpetrator. Participants' preference for choosing the most rewarded stimulus and avoiding the most punished stimulus was evaluated. The feedback-related negativity and error-related negativity-hypothesized to reflect activation in the anterior cingulate cortex-were used as electrophysiological indices of reinforcement learning. No group differences emerged in the acquisition of reinforcement contingencies. In trials requiring participants to rely partially or exclusively on previously rewarded information, the CSA + rMDD group showed (1) lower accuracy (relative to both controls and the rMDD group), (2) blunted electrophysiological differentiation between correct and incorrect responses (relative to controls), and (3) increased activation in the subgenual anterior cingulate cortex (relative to the rMDD group). A history of CSA was not associated with impairments in avoiding the most punished stimulus. Self-harm and suicidal behaviors correlated with poorer performance of previously rewarded, but not previously punished, trials. Irrespective of past MDD episodes, women with a history of CSA showed neural and behavioral deficits in utilizing previous reinforcement to optimize decision making in the absence of feedback (blunted "Go learning"). Although our study provides initial evidence for reward-specific deficits associated with CSA, future research is warranted to determine if disrupted positive reinforcement learning predicts high-risk behavior following CSA.

Experiences of Mothers Who Are Child Sexual Abuse Survivors: A Qualitative Exploration

PubMed Central

Cavanaugh, Courtenay E.; Harper, Bianca; Classen, Catherine C.; Palesh, Oxana; Koopman, Cheryl; Spiegel, David

2018-01-01

Child sexual abuse (CSA) has been associated with a number of problems affecting women over their lifespan, including difficulties with parenting. However, there is a modest number of qualitative studies examining the impact of CSA on survivors who are mothers. There is a particular need for qualitative investigations that ask survivors who are mothers general questions about the impact of CSA on their lives rather than those that specifically ask about the impact of CSA on parenting. The former approach would allow survivors to describe effects that may impact parenting, but which survivors do not consciously link to affecting their parenting. Such information may inform interventions to assist this population of survivors. This secondary data analysis examined themes revealed in interviews with 44 survivors of CSA who were mothers. Participants were seeking treatment for their CSA and completed an in-person interview where they were asked open-ended questions about the sexual abuse they experienced as a child and how their abuse affects them now as adults. The interviews were recorded, transcribed, and coded using thematic analysis. The following six themes emerged from the narratives: 1) being a parent, 2) family of origin dysfunction, 3) the impact of abuse, 4) the abuse history and response to abuse, 5) coping, and 6) hopes and desires for the future. This study highlights several ways in which CSA impacts survivors who are mothers, areas for further study, and the need for interventions to assist this population in meeting the challenges they face as mothers. PMID:26301437

Forensic child sexual abuse evaluations: assessing subjectivity and bias in professional judgements.

PubMed

Everson, Mark D; Sandoval, Jose Miguel

2011-04-01

Evaluators examining the same evidence often arrive at substantially different conclusions in forensic assessments of child sexual abuse (CSA). This study attempts to identify and quantify subjective factors that contribute to such disagreements so that interventions can be devised to improve the reliability of case decisions. Participants included 1106 professionals in the field of child maltreatment representing a range of professional positions or job titles and years of experience. Each completed the Child Forensic Attitude Scale (CFAS), a 28-item survey assessing 3 forensic attitudes believed to influence professional judgments about CSA allegations: emphasis-on-sensitivity (i.e., a focus on minimizing false negatives or errors of undercalling abuse); emphasis-on-specificity (i.e., a focus on minimizing false positives or errors of overcalling abuse); and skepticism toward child and adolescent reports of CSA. A subset of 605 professionals also participated in 1 of 3 diverse decision exercises to assess the influence of the 3 forensic attitudes on ratings of case credibility. Exploratory factor analysis identified 4 factors or attitude subscales that corresponded closely with the original CFAS scales: 2 subscales for emphasis-on-sensitivity and 1 each for emphasis-on-specificity and skepticism. Attitude subscale scores differed significantly by sample source (in-state trainings vs. national conferences), gender, years of experience, and professional position, with Child Protective Service workers unexpectedly more concerned about overcalling abuse and more skeptical of child disclosures than other professionals-a pattern of scores associated with an increased probability of disbelieving CSA allegations. The 3 decision exercises offered validation of the attitude subscales as predictors of professional ratings of case credibility, with adjusted R(2)s for the three exercises ranging from .06 to .24, suggesting highly variable effect sizes. Evaluator disagreements about CSA allegations can be explained, in part, by individual differences in 3 attitudes related to forensic decision-making: emphasis-on-sensitivity, emphasis-on-specificity, and skepticism toward child reports of abuse. These attitudes operate as predispositions or biases toward viewing CSA allegations as likely true or likely false. Several strategies for curbing the influence of subjective factors are highlighted including self-awareness of personal biases and team approaches to assessment. Copyright © 2011 Elsevier Ltd. All rights reserved.

Ape parasite origins of human malaria virulence genes

PubMed Central

Larremore, Daniel B.; Sundararaman, Sesh A.; Liu, Weimin; Proto, William R.; Clauset, Aaron; Loy, Dorothy E.; Speede, Sheri; Plenderleith, Lindsey J.; Sharp, Paul M.; Hahn, Beatrice H.; Rayner, Julian C.; Buckee, Caroline O.

2015-01-01

Antigens encoded by the var gene family are major virulence factors of the human malaria parasite Plasmodium falciparum, exhibiting enormous intra- and interstrain diversity. Here we use network analysis to show that var architecture and mosaicism are conserved at multiple levels across the Laverania subgenus, based on var-like sequences from eight single-species and three multi-species Plasmodium infections of wild-living or sanctuary African apes. Using select whole-genome amplification, we also find evidence of multi-domain var structure and synteny in Plasmodium gaboni, one of the ape Laverania species most distantly related to P. falciparum, as well as a new class of Duffy-binding-like domains. These findings indicate that the modular genetic architecture and sequence diversity underlying var-mediated host-parasite interactions evolved before the radiation of the Laverania subgenus, long before the emergence of P. falciparum. PMID:26456841

A Second Quorum-Sensing System Regulates Cell Surface Properties but Not Phenazine Antibiotic Production in Pseudomonas aureofaciens

PubMed Central

Zhang, Zhongge; Pierson, Leland S.

2001-01-01

The root-associated biological control bacterium Pseudomonas aureofaciens 30-84 produces a range of exoproducts, including protease and phenazines. Phenazine antibiotic biosynthesis by phzXYFABCD is regulated in part by the PhzR-PhzI quorum-sensing system. Mutants defective in phzR or phzI produce very low levels of phenazines but wild-type levels of exoprotease. In the present study, a second genomic region of strain 30-84 was identified that, when present in trans, increased β-galactosidase activity in a genomic phzB::lacZ reporter and partially restored phenazine production to a phzR mutant. Sequence analysis identified two adjacent genes, csaR and csaI, that encode members of the LuxR-LuxI family of regulatory proteins. No putative promoter region is present upstream of the csaI start codon and no lux box-like element was found in either the csaR promoter or the 30-bp intergenic region between csaR and csaI. Both the PhzR-PhzI and CsaR-CsaI systems are regulated by the GacS-GacA two-component regulatory system. In contrast to the multicopy effects of csaR and csaI in trans, a genomic csaR mutant (30-84R2) and a csaI mutant (30-84I2) did not exhibit altered phenazine production in vitro or in situ, indicating that the CsaR-CsaI system is not involved in phenazine regulation in strain 30-84. Both mutants also produced wild-type levels of protease. However, disruption of both csaI and phzI or both csaR and phzR eliminated both phenazine and protease production completely. Thus, the two quorum-sensing systems do not interact for phenazine regulation but do interact for protease regulation. Additionally, the CsaI N-acylhomoserine lactone (AHL) signal was not recognized by the phenazine AHL reporter 30-84I/Z but was recognized by the AHL reporters Chromobacterium violaceum CV026 and Agrobacterium tumefaciens A136(pCF240). Inactivation of csaR resulted in a smooth mucoid colony phenotype and formation of cell aggregates in broth, suggesting that CsaR is involved in regulating biosynthesis of cell surface components. Strain 30-84I/I2 exhibited mucoid colony and clumping phenotypes similar to those of 30-84R2. Both phenotypes were reversed by complementation with csaR-csaI or by the addition of the CsaI AHL signal. Both quorum-sensing systems play a role in colonization by strain 30-84. Whereas loss of PhzR resulted in a 6.6-fold decrease in colonization by strain 30-84 on wheat roots in natural soil, a phzR csaR double mutant resulted in a 47-fold decrease. These data suggest that gene(s) regulated by the CsaR-CsaI system also plays a role in the rhizosphere competence of P. aureofaciens 30-84. PMID:11526037

[Cyclosporin A causes oxidative stress and mitochondrial dysfunction in renal tubular cells].

PubMed

Pérez de Hornedo, J; de Arriba, G; Calvino, M; Benito, S; Parra, T

2007-01-01

Reactive oxygen species (ROS) have been implicated in cyclosporin A (CsA) nephrotoxicity. As mitochondria are one of the main sources of ROS in cells, we evaluated the role of CsA in mitochondrial structure and function in LLC-PK1 cells. We incubated cells with CsA 1 microM for 24 hours and studies were performed with flow citometry and confocal microscopy. We studied mitochondrial NAD(P)H content, superoxide anion (O2.-) production (MitoSOX Red), oxidation of cardiolipin of inner mitochondrial membrane (NAO) and mitochondrial membrane potential (DIOC2(3)). Also we analyzed the intracellular ROS synthesis (H2DCF-DA) and reduced glutation (GSH) of cells. Our results showed that CsA decreased NAD(P)H and membrane potential, and increased O2.- in mitochondria. CsA also provoked oxidation of cardiolipin. Furthermore, CsA increased intracellular ROS production and decreased GSH content. These results suggest that CsA has crucial effects in mitochondria. CsA modified mitochondrial physiology through the decrease of antioxidant mitochondrial compounds as NAD(P)H and the dissipation of mitochondrial membrane potential and increase of oxidants as O2.-. Also, CsA alters lipidic structure of inner mitochondrial membrane through the oxidation of cardiolipin. These effects trigger a chain of events that favour intracellular synthesis of ROS and depletion of GSH that can compromise cellular viability. Nephrotoxic cellular effects of CsA can be explained, at least in part, through its influence on mitochondrial functionalism.

Does the Critical Shoulder Angle Correlate With Rotator Cuff Tear Progression?

PubMed

Chalmers, Peter N; Salazar, Dane; Steger-May, Karen; Chamberlain, Aaron M; Yamaguchi, Ken; Keener, Jay D

2017-06-01

The critical shoulder angle (CSA) has been reported to be associated with rotator cuff disease and has been suggested as an etiology for cuff tears. However, it is unclear whether acromial morphologic characteristics such as CSA are a cause or effect because all studies to date have been retrospective. (1) How often can the CSA be reliably measured? (2) Is the CSA associated with rotator cuff disease? (3) Is the CSA correlated with baseline tear size or tear enlargement? (4) Does the CSA change with time? In this retrospective comparison of longitudinally collected data, patients with asymptomatic rotator cuff tears underwent ultrasonography and standardized AP radiographs at enrollment and yearly thereafter during a median of 4 years. Three hundred ninety-five patients were included, of whom 14 were excluded as they were not yet eligible for 2-year followup and 68 (18%) were lost to followup, leaving 313 study patients who were evaluated with 1433 radiographs. Patients with adhesive capsulitis with normal rotator cuffs and radiographically normal scapulae were included as control subjects (119 subjects). Two observers (PNC, DS) measured the CSA in a blinded fashion. Radiographs that met Suter-Henninger criteria for CSA measurement reliability were included. For the study group, 179 of the 313 (57%) patients with radiographs that met Suter-Henninger criteria were further analyzed; the remainder were excluded from this study. For the control group, 50 of 119 (42%) subjects met criteria and were further analyzed. Tear enlargement was found in 94 patients, and the CSA was compared in patients with tears and control subjects, and in tears with or without enlargement, and was correlated with tear size. In a subgroup of the study group in which 59 of 179 patients had a minimum of 3 years between initial and followup radiographs, two CSA measurements were performed to measure change. In total, of the 1552 radiographs evaluated, only 326 (21%) were of sufficient quality to measure the CSA. The CSA was higher among patients with cuff tears than control subjects (34° ± 4° versus 32° ± 4°; mean difference, 2.0°; 95% CI, 0.7°-3.2°; p = 0.003). The CSA did not correlate with baseline tear length (ρ = 0.22, p = 0.090) or width (ρ = 0.16, p = 0.229). The CSA was not different between tears that enlarged and those that were stable (34° ± 3° versus 34° ± 4°; mean difference, 0.2°; 95% CI, -0.9° to -1.4°; p = 0.683). The CSA did not change over time (CSA Time 1: mean 33° ± 4° SD; CSA Time 2: mean 33° ± 4° SD; mean difference, -0.2°; 95% CI, -0.6° to 0.1°; p = 0.253). Even with a longitudinal protocol, most radiographs are of insufficient quality for CSA measurement. Although patients with a history of degenerative cuff disease have higher CSA values than control subjects, the difference is small enough that it could be influenced by measurement error in practice; in any case, a difference of the magnitude we observed is likely to be clinically unimportant. The CSA is not correlated with tear size or tear progression, and does not seem to change with time. These results suggest that the CSA is unlikely to be related to rotator cuff disease. Level II, prognostic study.

Discovery of non-peptidic small molecule inhibitors of cyclophilin D as neuroprotective agents in Aβ-induced mitochondrial dysfunction

NASA Astrophysics Data System (ADS)

Park, Insun; Londhe, Ashwini M.; Lim, Ji Woong; Park, Beoung-Geon; Jung, Seo Yun; Lee, Jae Yeol; Lim, Sang Min; No, Kyoung Tai; Lee, Jiyoun; Pae, Ae Nim

2017-10-01

Cyclophilin D (CypD) is a mitochondria-specific cyclophilin that is known to play a pivotal role in the formation of the mitochondrial permeability transition pore (mPTP).The formation and opening of the mPTP disrupt mitochondrial homeostasis, cause mitochondrial dysfunction and eventually lead to cell death. Several recent studies have found that CypD promotes the formation of the mPTP upon binding to β amyloid (Aβ) peptides inside brain mitochondria, suggesting that neuronal CypD has a potential to be a promising therapeutic target for Alzheimer's disease (AD). In this study, we generated an energy-based pharmacophore model by using the crystal structure of CypD—cyclosporine A (CsA) complex and performed virtual screening of ChemDiv database, which yielded forty-five potential hit compounds with novel scaffolds. We further tested those compounds using mitochondrial functional assays in neuronal cells and identified fifteen compounds with excellent protective effects against Aβ-induced mitochondrial dysfunction. To validate whether these effects derived from binding to CypD, we performed surface plasmon resonance (SPR)—based direct binding assays with selected compounds and discovered compound 29 was found to have the equilibrium dissociation constants (KD) value of 88.2 nM. This binding affinity value and biological activity correspond well with our predicted binding mode. We believe that this study offers new insights into the rational design of small molecule CypD inhibitors, and provides a promising lead for future therapeutic development.

Delay in disclosure of non-parental child sexual abuse in the context of emotional and physical maltreatment: A pilot study.

PubMed

Tashjian, Sarah M; Goldfarb, Deborah; Goodman, Gail S; Quas, Jodi A; Edelstein, Robin

2016-08-01

The present pilot study sought to identify predictors of delays in child sexual abuse (CSA) disclosure, specifically whether emotional and physical abuse by a parental figure contributes to predicting delays over and above other important victim factors. Alleged CSA victims (N=79), whose parental figures were not the purported sexual abuse perpetrators, were interviewed and their case files reviewed, across two waves of a longitudinal study. Regression analyses indicated that experiencing both emotional and physical abuse by a parental figure was uniquely predictive of longer delays in disclosure of CSA perpetrated by someone other than a parental figure. Victim-CSA perpetrator relationship type and sexual abuse duration also significantly predicted CSA disclosure delay, whereas victim age at the time of the police report, victim gender, and victims' feelings of complicity were not significant unique predictors. Child abuse victims' expectations of lack of parental support may underlie these findings. Parent-child relationships are likely crucial to timely disclosure of CSA, even when a parent is not the CSA perpetrator. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cyclosporine-induced changes in drug metabolizing enzymes in hyperlipemic rabbit kidneys could explain its toxicity.

PubMed

Elbarbry, Fawzy; Ragheb, Ahmed; Attia, Ahmed; Chibbar, Rajni; Marfleet, Travis; Shoker, Ahmed

2010-11-01

This study investigates the mechanism of cyclosporine A (CsA)-mediated nephrotoxicity by examining the hypothesis that CsA toxicity is mediated through its effect on the kidney drug metabolizing enzymes in a hyperlipemic rabbit model. Twenty-four female New Zealand white rabbits divided into four groups. Group 1 received regular diet. Group 2 received 1% cholesterol diet. Group 3 received CsA (25 mg/kg, orally once daily) and group 4 received 1% cholesterol diet and CsA (25 mg/kg, orally once daily). Cytochrome P450 2E1 (CYP2E1) activity in kidney microsomes was assessed by measuring p-nitrophenol hydroxylase activity. Generation of reactive oxygen species (ROS) was assessed by measuring malondialdehyde (MDA) and the protein carbonyl. Effect of CsA and hyperlipidemia on the antioxidant proteins were also assessed using standard techniques. CsA but not the high-cholesterol diet induced significant elevation in MDA, protein carbonyl and CYP2E1 activities in the kidney. The addition of cholesterol to CsA normalized ROS markers without affecting the CsA-enhanced CYP2E1 activity. Alone, CsA caused characteristic tubular injury, whereas the addition of high-cholesterol diet to CsA nearly abolished the tubular damage. CsA-enhanced rabbit kidney ROS and CYP2E1 activities. Hyperlipidemia attenuates CsA tubular injury, most probably due to normalization of renal ROS, but not CYP2E1 activity.

Analysis of Single-cell Gene Transcription by RNA Fluorescent In Situ Hybridization (FISH)

PubMed Central

Ronander, Elena; Bengtsson, Dominique C.; Joergensen, Louise; Jensen, Anja T. R.; Arnot, David E.

2012-01-01

Adhesion of Plasmodium falciparum infected erythrocytes (IE) to human endothelial receptors during malaria infections is mediated by expression of PfEMP1 protein variants encoded by the var genes. The haploid P. falciparum genome harbors approximately 60 different var genes of which only one has been believed to be transcribed per cell at a time during the blood stage of the infection. How such mutually exclusive regulation of var gene transcription is achieved is unclear, as is the identification of individual var genes or sub-groups of var genes associated with different receptors and the consequence of differential binding on the clinical outcome of P. falciparum infections. Recently, the mutually exclusive transcription paradigm has been called into doubt by transcription assays based on individual P. falciparum transcript identification in single infected erythrocytic cells using RNA fluorescent in situ hybridization (FISH) analysis of var gene transcription by the parasite in individual nuclei of P. falciparum IE1. Here, we present a detailed protocol for carrying out the RNA-FISH methodology for analysis of var gene transcription in single-nuclei of P. falciparum infected human erythrocytes. The method is based on the use of digoxigenin- and biotin- labeled antisense RNA probes using the TSA Plus Fluorescence Palette System2 (Perkin Elmer), microscopic analyses and freshly selected P. falciparum IE. The in situ hybridization method can be used to monitor transcription and regulation of a variety of genes expressed during the different stages of the P. falciparum life cycle and is adaptable to other malaria parasite species and other organisms and cell types. PMID:23070076

The Diagnostic Utility of the Child Sexual Behavior Inventory for Sexual Abuse: A Systematic Review.

PubMed

Vrolijk-Bosschaart, Thekla F; Verlinden, Eva; Langendam, Miranda W; De Smet, Vivienne; Teeuw, Arianne H; Brilleslijper-Kater, Sonja N; Benninga, Marc A; Lindauer, Ramón J L

2018-06-11

Children with alleged child sexual abuse (CSA) need to be assessed systematically. The use of validated instruments during the assessment, like the Child Sexual Behavior Inventory (CSBI), could add diagnostic value. We aim to assess the diagnostic utility of the CSBI to differentiate between sexually abused and non-abused children. We conducted a systematic review. We searched the electronic databases MEDLINE and PsychInfo for studies comparing CSBI scores in sexually abused children and non-abused children (2-12 years old). Two independent reviewers extracted data and assessed the methodological quality. We included 7 (out of 1048) articles. The CSBI total scores were significantly higher in CSA-victims compared with non-abused children (in case-control settings). However, in children with suspected CSA, the results were ambiguous. One study reported significant differences. Another study reported weak diagnostic ability for the CSBI-3 in children with suspected CSA (a sensitivity and specificity of 0.50, with a positive predictive value of 0.28, and a negative predictive value of 0.72). Research on the diagnostic utility of the CSBI for suspected CSA is limited and shows disappointing results. Until more research is done, the CSBI should not be used on its own to differentiate between sexually abused and non-abused children.

F99 is critical for dimerization and activation of South African HIV-1 subtype C protease.

PubMed

Naicker, Previn; Seele, Palesa; Dirr, Heini W; Sayed, Yasien

2013-10-01

HIV-1 protease (PR) is an obligate homodimer which plays a pivotal role in the maturation and hence propagation of HIV. Although successful developments on PR active site inhibitors have been achieved, the major limiting factor has been the emergence of HIV drug-resistant strains. Disruption of the dimer interface serves as an alternative mechanism to inactivate the enzyme. The terminal residue, F99, was mutated to an alanine to investigate its contribution to dimer stability in the South African HIV-1 subtype C (C-SA) PR. The F99A PR and wild-type C-SA PR were overexpressed and purified. The activities of the PRs and their ability to bind an active site inhibitor, acetyl-pepstatin, were determined in vitro. The F99A PR showed no activity and the inability to bind to the inhibitor. Secondary and quaternary structure analysis were performed and revealed that the F99A PR is monomeric with reduced β-sheet content. The mutation of F99 to alanine disrupted the presumed 'lock-and-key' motif at the terminal dimer interface, in turn creating a cavity at the N- and C-terminal antiparallel β-sheet. These findings support the design of inhibitors targeting the C-terminus of the C-SA PR, centered on interactions with the bulky F99.

Combined flurbiprofen and cyclosporin-A does not attenuate bone loss and exaggerates renal impairment.

PubMed

Sass, D A; Rucinski, B; Bryer, H P; Mann, G N; Yuan, Z; Ma, Y; Jee, W S; Epstein, S

1996-10-01

Cyclosporine (CsA) is a potent immunosuppressant that has revolutionized the success of organ transplantation. Flurbiprofen (FB), a propionic acid derivative NSAID, has been demonstrated in vivo to reduce osteoclast numbers in normal rats. The aim of this experiment was to determine whether addition of FB to CsA-treated rats could prevent the bone changes associated with CsA therapy. Forty-eight 10-12-week-old male Sprague-Dawley rats were randomized to receive, daily for 28 days: (1) CsA vehicle p.o. plus FB vehicle sc; (2) CsA (15 mg/kg) p.o. plus FB vehicle sc, (3) CsA vehicle p.o. plus FB (1.5 mg/kg) sc; and (4) CsA (15 mg/kg) p.o. plus FB (1.5 mg/kg) sc. Rats were weighed and venous blood sampled at baseline, 14 days, and 28 days for determination of glucose, Ca+2, BUN, creatinine, PTH, osteocalcin, and 1,25(OH)2 vitamin D. Tibiae were removed following killing, after double labeling for histomorphometry. Body mass was significantly lower than control in all rats receiving CsA on days 14 and 28 while blood glucose was only elevated in the CsA alone group. Day 28 BUN and creatinine were significantly elevated in the CsA group and the combination of CsA and FB revealed an exacerbation of this trend. Vitamin D and osteocalcin were consistently increased in the CsA and CsA/FB groups. Bone histomorphometry showed evidence of trabecular osteopenia in CsA and CsA/FB groups. CsA alone resulted in elevated bone turnover. FB was unable to prevent the trabecular bone loss induced by CsA therapy. This experiment indicates no role for FB as a therapeutic option in CsA-induced bone disease at the given doses and duration of treatment by virtue of its lack of bone sparing ability and adverse renal effects when the two drugs are administered concurrently.

An insight to the molecular interactions of the FDA approved HIV PR drugs against L38L↑N↑L PR mutant

NASA Astrophysics Data System (ADS)

Sanusi, Zainab K.; Govender, Thavendran; Maguire, Glenn E. M.; Maseko, Sibusiso B.; Lin, Johnson; Kruger, Hendrik G.; Honarparvar, Bahareh

2018-03-01

The aspartate protease of the human immune deficiency type-1 virus (HIV-1) has become a crucial antiviral target in which many useful antiretroviral inhibitors have been developed. However, it seems the emergence of new HIV-1 PR mutations enhances drug resistance, hence, the available FDA approved drugs show less activity towards the protease. A mutation and insertion designated L38L↑N↑L PR was recently reported from subtype of C-SA HIV-1. An integrated two-layered ONIOM (QM:MM) method was employed in this study to examine the binding affinities of the nine HIV PR inhibitors against this mutant. The computed binding free energies as well as experimental data revealed a reduced inhibitory activity towards the L38L↑N↑L PR in comparison with subtype C-SA HIV-1 PR. This observation suggests that the insertion and mutations significantly affect the binding affinities or characteristics of the HIV PIs and/or parent PR. The same trend for the computational binding free energies was observed for eight of the nine inhibitors with respect to the experimental binding free energies. The outcome of this study shows that ONIOM method can be used as a reliable computational approach to rationalize lead compounds against specific targets. The nature of the intermolecular interactions in terms of the host-guest hydrogen bond interactions is discussed using the atoms in molecules (AIM) analysis. Natural bond orbital analysis was also used to determine the extent of charge transfer between the QM region of the L38L↑N↑L PR enzyme and FDA approved drugs. AIM analysis showed that the interaction between the QM region of the L38L↑N↑L PR and FDA approved drugs are electrostatic dominant, the bond stability computed from the NBO analysis supports the results from the AIM application. Future studies will focus on the improvement of the computational model by considering explicit water molecules in the active pocket. We believe that this approach has the potential to provide information that will aid in the design of much improved HIV-1 PR antiviral drugs.

Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John's wort in renal transplant patients

PubMed Central

Bauer, Steffen; Störmer, Elke; Johne, Andreas; Krüger, Hagen; Budde, Klemens; Neumayer, Hans-Hellmut; Roots, Ivar; Mai, Ingrid

2003-01-01

Aim This study investigated the effects of St John's wort extract (SJW) on the pharmacokinetics and metabolism of the immunosuppressant cyclosporin A (CSA). Methods In an open-label study, 11 renal transplant patients received 600 mg SJW extract daily for 14 days in addition to their regular regimen of CSA. Blood concentrations of CSA and its metabolites AM1, AM1C, AM9, AM19, and AM4N were measured by HPLC. Results After 2 weeks of SJW coadministration, dose-corrected AUC0–12, Cmax and Ctrough values for CSA decreased significantly by 46%[geometric mean ratio baseline/SJW (95% CI): 1.83 (1.63–2.05)], 42%[1.72 (1.42–2.08)], and 41%[1.70 (1.17–2.47)], respectively. CSA doses were increased from a median of 2.7 mg day−1 kg−1 at baseline to 4.2 mg day−1 kg−1 at day 15, with the first dose adjustment required only 3 days after initiation of SJW treatment. Additionally, the metabolite pattern of CSA was substantially altered during SJW treatment. Whereas dose-corrected AUC values for AM1, AM1c and AM4N significantly decreased by 59%, 61%, and 23% compared with baseline, AUC values for AM9 and AM19 were unchanged. Following the increase in CSA dose, observed AUC and Cmax values for AM9, AM19, and AM4N increased by 20–51% and 43–90%, respectively. Conclusion Administration of SJW extract to patients receiving CSA treatment resulted in a rapid and significant reduction of plasma CSA concentrations. Additionally, the substantial alterations in CSA metabolite kinetics observed may affect the toxicity profile of the drug. PMID:12580993

Increased Advanced Oxidation Protein Products Generation by Cyclosporine-A and Angiotensin II in Human Gingival Fibroblasts – Ex-vivo Study

PubMed Central

Subbarayan, Rajasekaran; Ajitkumar, Supraja; Murugan Girija, Dinesh

2017-01-01

Introduction Cyclosporin-A (CsA), an immunosuppressant, induces renal fibrosis and Renin Angiotensin System (RAS) is known to play a major role. CsA has the potential to increase the oxidative stress; specifically through the Advanced Oxidation Protein Products (AOPP) which could possibly stimulate fibrosis. A similar type of pathology occurs even in the gingiva known as CsA Induced Gingival Overgrowth (CIGO). Aim This study was undertaken to estimate the AOPP generation by Human Gingival Fibroblasts (HGF) under the influence of CsA and Angiotensin II (Ang II). Materials and Methods Six healthy gingival tissue samples were obtained during crown lengthening procedure and primary HGF were cultured using enzymatic digestion method. The ideal non-cytotoxic concentrations of CsA and Ang II were identified using cytotoxicity assay. Later, HGF were incubated with CsA and Ang II for 12 hours and AOPP assay was performed at zero and one hour interval. Results There was a statistically significant increase in AOPP production in both the CsA and Ang II when compared to the control group with a p value<0.05. Conclusion CsA can induce oxidative stress and preventing/controlling it may be necessary to prevent untoward effect of the drug. PMID:28274044

Measurement of anterior tibial muscle size using real-time ultrasound imaging.

PubMed

Martinson, H; Stokes, M J

1991-01-01

Cross-sectional images of the anterior tibial muscle group were obtained using real-time ultrasound scanning in 17 normal women. From photographs taken of the images, the cross-sectional area (CSA) and two linear measurements of muscle cross-section were determined. A measurement of the shortest distance of the muscle depth was termed DS, and a measurement of the longest distance through the muscle group was termed DL. Both linear dimensions showed a positive correlation with CSA and the best correlations were obtained when the dimensions were squared or combined (DS x DL). The correlation values were: CSA vs DS2, r = 0.9; CSA vs DL2, r = 0.75 and CSA vs DS x DL, r = 0.88. An approximate value for CSA could be calculated from DS2 by the equation 2 x DS2 + 1. A shape ratio, obtained by dividing DL by DS, was consistent within the group [mean 2.1 (SD 0.2)] and characterised the muscle geometrically. The CSA of repeated scans was assessed for repeatability between-days and between-scans by analysis of variance and the coefficient of variation (CV) calculated. Areas were repeatable between-days (CV 6.5%) and between-scans (CV 3.6%). Linear dimensions of the anterior tibial muscle group reflected CSA and their potential for assessing changes in muscle size with atrophy and hypertrophy have yet to be established.

Cyclosporine A suppresses immunoglobulin G biosynthesis via inhibition of cyclophilin B in murine hybridomas and B cells.

PubMed

Lee, Jisun; Choi, Tae Gyu; Ha, Joohun; Kim, Sung Soo

2012-01-01

Immunoglubulin G (IgG) is a major isotype of antibody, which is predominantly involved in immune response. The complete tetramer is needed to fold and assemble in endoplasmic reticulum (ER) prior to secretion from cells. Protein quality control guided by ER chaperons is most essential for full biological activity. Cyclophilin B (CypB) was initially identified as a high-affinity binding protein for the immunosuppressive drug Cyclosporine A (CsA). CsA suppresses organ rejection by halting productions of pro-inflammatory molecules in T cell and abolishes the enzymatic property of CypB that accelerates the folding of proteins by catalysing the isomerization of peptidyl-proline bonds in ER. Here, we reported that CsA significantly inhibited IgG biosynthesis at posttranslational level in antibody secreting cells. Moreover, CsA stimulated the extracellular secretion of CypB and induced ROS generation, leading to expressions of ER stress markers. In addition, the absence of intracellular CypB impaired the formation of ER multiprotein complex, which is most important for resisting ER stress. Interestingly, CsA interrupted IgG folding via occupying the PPIase domain of CypB in ER. Eventually, unfolded IgG is degraded via Herp-dependent ERAD pathway. Furthermore, IgG biosynthesis was really abrogated by inhibition of CypB in primary B cells. We established for the first time the immunosuppressive effect of CsA on B cells. Conclusively, the combined results of the current study suggest that CypB is a pivotal molecule for IgG biosynthesis in ER quality control. Copyright © 2011 Elsevier B.V. All rights reserved.

Coping style and memory specificity in adolescents and adults with histories of child sexual abuse.

PubMed

Harris, Latonya S; Block, Stephanie D; Ogle, Christin M; Goodman, Gail S; Augusti, Else-Marie; Larson, Rakel P; Culver, Michelle A; Pineda, Annarheen R; Timmer, Susan G; Urquiza, Anthony

2016-09-01

Individuals with histories of childhood trauma may adopt a nonspecific memory retrieval strategy to avoid unpleasant and intrusive memories. In a sample of 93 adolescents and adults with or without histories of child sexual abuse (CSA), we tested the hypothesis that nonspecific memory retrieval is related to an individual's general tendency to use avoidant (i.e., distancing) coping as a personal problem-solving or coping strategy, especially in victims of CSA. We also examined age differences and other individual differences (e.g., trauma-related psychopathology) as predictors of nonspecific memories. Distancing coping was significantly associated with less specific autobiographical memory. Younger age, lower vocabulary scores, and non-CSA childhood maltreatment (i.e., physical and emotional abuse) also uniquely predicted less autobiographical memory specificity, whereas trauma-related psychopathology was associated with more specific memory. Implications for the development of autobiographical memory retrieval in the context of coping with childhood maltreatment are discussed.

Time-dependent differences in cortical measures and their associations with behavioral measures following mild traumatic brain injury.

PubMed

Bajaj, Sahil; Dailey, Natalie S; Rosso, Isabelle M; Rauch, Scott L; Killgore, William D S

2018-05-01

There is currently a critical need to establish an improved understanding of time-dependent differences in brain structure following mild traumatic brain injury (mTBI). We compared differences in brain structure, specifically cortical thickness (CT), cortical volume (CV), and cortical surface area (CSA) in 54 individuals who sustained a recent mTBI and 33 healthy controls (HCs). Individuals with mTBI were split into three groups, depending on their time since injury. By comparing structural measures between mTBI and HC groups, differences in CT reflected cortical thickening within several areas following 0-3 (time-point, TP1) and 3-6 months (TP2) post-mTBI. Compared with the HC group, the mTBI group at TP2 showed lower CSA within several areas. Compared with the mTBI group at TP2, the mTBI group during the most chronic stage (TP3: 6-18 months post-mTBI) showed significantly higher CSA in several areas. All the above reported differences in CT and CSA were significant at a cluster-forming p < .01 (corrected for multiple comparisons). We also found that in the mTBI group at TP2, CT within two clusters (i.e., the left rostral middle frontal gyrus (L. RMFG) and the right postcentral gyrus (R. PostCG)) was negatively correlated with basic attention abilities (L. RMFG: r = -.41, p = .05 and R. PostCG: r = -.44, p = .03). Our findings suggest that alterations in CT and associated neuropsychological assessments may be more prominent during the early stages of mTBI. However, alterations in CSA may reflect compensatory structural recovery during the chronic stages of mTBI. © 2018 Wiley Periodicals, Inc.

Involvement of endoplasmic reticulum in hepatitis B virus replication.

PubMed

Xia, Weiliang; Shen, Yan; Xie, Haiyang; Zheng, Shusen

2006-11-01

The mitochondrial calcium and downstream proline-rich tyrosine kinase-2 (PyK2) signaling pathway are critical to hepatitis B virus (HBV) replication, and the endoplasmic reticulum (ER) plays an important role in intracellular calcium regulation. To investigate the role of ER in HBV replication, the HBV genome transfected HepG2.2.15 cells were treated by cyclosporine A (CsA), cyclopiazonic acid (CPA), ryanodine and U73122, which are all specific blockers of calcium channels located in either ER or mitochondria. The HBV replication level was evaluated by two methods: slot blot hybridization analysis of intracellular HBV DNA and real-time polymerase chain reaction (PCR) analysis of secreted HBV DNA in supernatant; the activation of PyK2 kinase was detected by Western blot analysis. Results indicated that the HBV replication was inhibited when mitochondrial permeability transition pore, ER Ca2+ -ATPase and ER inositol 1,4,5-trisphosphate receptor (IP3R) were blocked by CsA, CPA and U73122, respectively; but not inhibited when ER ryanodine receptor was blocked by ryanodine. The PyK2 phosphorylation level declined after treatment of 2 microg/ml CsA, 5 microM CPA and 25 microM U73122, but not changed apparently after 50 microM ryanodine treatment. Compared with monotreatment, a more powerful inhibitory effect was achieved when the CsA, CPA and U73122 were combined used in twosome or triple manner, while the HBV replication level did not change apparently when ryanodine combined with CsA, CPA or U73122. In conclusion, besides the mitochondria, the ER also participates in the HBV replication through calcium-PyK2 signaling pathway; the calcium channels of ER Ca2+ -ATPase and ER IP3R are responsible for this role; during this complicated process, an interaction between ER and mitochondria maybe involved.

Characterization of the two intra-individual sequence variants in the 18S rRNA gene in the plant parasitic nematode, Rotylenchulus reniformis.

PubMed

Nyaku, Seloame T; Sripathi, Venkateswara R; Kantety, Ramesh V; Gu, Yong Q; Lawrence, Kathy; Sharma, Govind C

2013-01-01

The 18S rRNA gene is fundamental to cellular and organismal protein synthesis and because of its stable persistence through generations it is also used in phylogenetic analysis among taxa. Sequence variation in this gene within a single species is rare, but it has been observed in few metazoan organisms. More frequently it has mostly been reported in the non-transcribed spacer region. Here, we have identified two sequence variants within the near full coding region of 18S rRNA gene from a single reniform nematode (RN) Rotylenchulus reniformis labeled as reniform nematode variant 1 (RN_VAR1) and variant 2 (RN_VAR2). All sequences from three of the four isolates had both RN variants in their sequences; however, isolate 13B had only RN variant 2 sequence. Specific variable base sites (96 or 5.5%) were found within the 18S rRNA gene that can clearly distinguish the two 18S rDNA variants of RN, in 11 (25.0%) and 33 (75.0%) of the 44 RN clones, for RN_VAR1 and RN_VAR2, respectively. Neighbor-joining trees show that the RN_VAR1 is very similar to the previously existing R. reniformis sequence in GenBank, while the RN_VAR2 sequence is more divergent. This is the first report of the identification of two major variants of the 18S rRNA gene in the same single RN, and documents the specific base variation between the two variants, and hypothesizes on simultaneous co-existence of these two variants for this gene.

Characterization of the Two Intra-Individual Sequence Variants in the 18S rRNA Gene in the Plant Parasitic Nematode, Rotylenchulus reniformis

PubMed Central

Nyaku, Seloame T.; Sripathi, Venkateswara R.; Kantety, Ramesh V.; Gu, Yong Q.; Lawrence, Kathy; Sharma, Govind C.

2013-01-01

The 18S rRNA gene is fundamental to cellular and organismal protein synthesis and because of its stable persistence through generations it is also used in phylogenetic analysis among taxa. Sequence variation in this gene within a single species is rare, but it has been observed in few metazoan organisms. More frequently it has mostly been reported in the non-transcribed spacer region. Here, we have identified two sequence variants within the near full coding region of 18S rRNA gene from a single reniform nematode (RN) Rotylenchulus reniformis labeled as reniform nematode variant 1 (RN_VAR1) and variant 2 (RN_VAR2). All sequences from three of the four isolates had both RN variants in their sequences; however, isolate 13B had only RN variant 2 sequence. Specific variable base sites (96 or 5.5%) were found within the 18S rRNA gene that can clearly distinguish the two 18S rDNA variants of RN, in 11 (25.0%) and 33 (75.0%) of the 44 RN clones, for RN_VAR1 and RN_VAR2, respectively. Neighbor-joining trees show that the RN_VAR1 is very similar to the previously existing R. reniformis sequence in GenBank, while the RN_VAR2 sequence is more divergent. This is the first report of the identification of two major variants of the 18S rRNA gene in the same single RN, and documents the specific base variation between the two variants, and hypothesizes on simultaneous co-existence of these two variants for this gene. PMID:23593343

Substance use, childhood sexual abuse, and sexual risk behavior among women in methadone treatment.

PubMed

Cohen, Lisa R; Tross, Susan; Pavlicova, Martina; Hu, Mei-Chen; Campbell, Aimee N; Nunes, Edward V

2009-01-01

Substance use and a history of childhood sexual abuse (CSA) are risk factors for unprotected sex among women, yet questions remain as to how their combined influence may differentially affect sexual risk. The current study investigated how complex relationships among drug use and CSA may contribute to unprotected sexual occasions (USO). A Generalized Linear Mixed Model was used to examine the interaction between current cocaine/stimulants and opioid use and CSA on number of USOs in a sample of 214 sexually active women in outpatient methadone maintenance treatment. For women with CSA, an increase in days of cocaine/stimulant use was associated with a significant increase in USOs. In contrast, an increase in days of opiate use was associated with a significant decrease in USOs. For the group of women who did not report CSA, there was a significant increase in USOs with increased opiate use. Findings indicate that CSA is related to unprotected sexual occasions depending on drug type and severity of use. Women with CSA using cocaine are at particularly high risk for having unprotected sex and should be specifically targeted for HIV prevention interventions.

The effect of ketoconazole on whole blood and skin ciclosporin concentrations in dogs.

PubMed

Gray, Laura L; Hillier, Andrew; Cole, Lynette K; Rajala-Schultz, Päivi J

2013-02-01

Ciclosporin (CSA) is approved for the treatment of canine atopic dermatitis. Ciclosporin is metabolized by liver cytochrome P450 enzymes, a process inhibited by ketoconazole (KTZ). The aims of this study were to determine skin and blood CSA concentrations when CSA was administered alone at 5.0 (Treatment 1) or 2.5 mg/kg (Treatment 2) and when CSA was administered at 2.5 mg/kg concurrently with KTZ at 5 (Treatment 3) or 2.5 mg/kg (Treatment 4). We hypothesized that skin and blood CSA concentrations in Treatment 1 would not differ from those obtained with T3 or T4. In a randomized cross-over study, six healthy research dogs received each of the treatments (Treatment 1, 2, 3 and 4) once daily for 7 days. After the first, fourth and seventh dose for each treatment, a peak and trough skin punch biopsy sample and whole blood sample were collected and analysed with high-performance liquid chromatography-tandem mass spectrometry. Data were analysed using a repeated measures approach with PROC MIXED in SAS. Pairwise comparisons were performed with least squares means and Tukey-Kramer adjustment for multiple comparisons. Mean blood CSA concentrations in Treatment 1 were not different from those in Treatment 2 or 4, but were less than in Treatment 3. Mean skin CSA concentrations in Treatment 1 were greater than in Treatment 2, not different from those in Treatment 4, and less than those in Treatment 3. Administration of CSA and KTZ concurrently at 2.5 mg/kg each may be as effective as CSA alone at 5.0 mg/kg for treatment of canine atopic dermatitis. © 2013 The Authors. Veterinary Dermatology © 2013 ESVD and ACVD.

Mediators of the Relation between Childhood Sexual Abuse and Women’s Sexual Risk Behavior: A Comparison of Two Theoretical Frameworks

PubMed Central

Senn, Theresa E.; Carey, Michael P.; Coury-Doniger, Patricia

2012-01-01

Childhood sexual abuse (CSA) is associated with sexual risk behavior in adulthood, but little research has investigated processes that might mediate this relation. The purpose of this study was to investigate whether constructs suggested by the traumagenic dynamics (TD) model (a theory of the effects of CSA) or constructs suggested by the Information-Motivation-Behavioral skills (IMB) model (a theory of the antecedents of sexual risk behavior) better mediated the relation between CSA and sexual risk behavior in adulthood. Participants were 481 women attending an STI clinic (66% African American) who completed a computerized survey as well as behavioral simulations assessing condom application and sexual assertiveness skills. Forty-five percent of the sample met criteria for CSA and CSA was associated with sexual risk behavior in adulthood. In multiple mediator models, the TD constructs mediated the relation between CSA and the number of sexual partners whereas the IMB constructs mediated the relation between CSA and unprotected sex. In addition, the TD constructs better mediated the relation between CSA and the number of sexual partners; the TD and IMB constructs did not differ in their ability to mediate the relation between CSA and unprotected sex. Sexual risk reduction interventions for women who were sexually abused should target not only the constructs from health behavior models (e.g., motivation and skills to reduce sexual risk), but also constructs that are specific to sexual abuse (e.g., traumatic sexualization and guilt). PMID:22282323

DOE Office of Scientific and Technical Information (OSTI.GOV)

Garman, S.C.; Sechi, S.; Kinet, J.-P.

We have solved the structure of the human high affinity IgE receptor, Fc{var_epsilon}RI{alpha}, in six different crystal forms, showing the structure in 15 different chemical environments. This database of structures shows no change in the overall shape of the molecule, as the angle between domains 1 and 2 (D1 and D2) varies little across the ensemble. However, the receptor has local conformational variability in the C' strand of D2 and in the BC loop of D1. In every crystal form, a residue inserts between tryptophan residues 87 and 110, mimicking the position of a proline from the IgE ligand. Themore » different crystal forms reveal a distribution of carbohydrates lining the front and back surfaces of the structure. An analysis of crystal contacts in the different forms indicates regions where the molecule interacts with other proteins, and reveals a potential new binding site distal to the IgE binding site. The results of this study point to new directions for the design of molecules to inhibit the interaction of Fc{var_epsilon}RI{alpha} with its natural ligand and thus to prevent a primary step in the allergic response.« less

Magnetic hyaluronate hydrogels: preparation and characterization

NASA Astrophysics Data System (ADS)

Tóth, Ildikó Y.; Veress, Gábor; Szekeres, Márta; Illés, Erzsébet; Tombácz, Etelka

2015-04-01

A novel soft way of hyaluronate (HyA) based magnetic hydrogel preparation was revealed. Magnetite nanoparticles (MNPs) were prepared by co-precipitation. Since the naked MNPs cannot be dispersed homogenously in HyA-gel, their surface was modified with natural and biocompatible chondroitin-sulfate-A (CSA) to obtain CSA-coated MNPs (CSA@MNPs). The aggregation state of MNPs and that loaded with increasing amount of CSA up to 1 mmol/g was measured by dynamic light scattering at pH~6. Only CSA@MNP with ≥0.2 mmol/g CSA content was suitable for magnetic HyA-gel preparation. Rheological studies showed that the presence of CSA@MNP with up to 2 g/L did not affect the hydrogel's rheological behavior significantly. The results suggest that the HyA-based magnetic hydrogels may be promising formulations for future biomedical applications, e.g. as intra-articular injections in the treatment of osteoarthritis.

Symmetry and topology code of the cluster self-assembly of framework MT structures of alumophosphates AlPO4(H2O)2 (metavariscite and variscite) and Al2(PO4)2(H2O)3 (APC)

NASA Astrophysics Data System (ADS)

Ilyushin, G. D.; Blatov, V. A.

2017-03-01

The supramolecular chemistry of alumophosphates, which form framework 3D MT structures from polyhedral AlO4(H2O)2 clusters with octahedral O coordination (of M polyhedra) and PO4 and AlO4 with tetrahedral O coordination (of T polyhedra), is considered. A combinatorial-topological modeling of the formation of possible types of linear (six types) and ring (two types) tetrapolyhedral cluster precursors M2T2 from MT monomers is carried out. Different versions of chain formation from linked (MT)2 rings (six types) are considered. The model, which has a universal character, has been used to simulate the cluster selfassembly of the crystal structure of AlPO4(H2O)2 minerals (metavariscite, m-VAR, and variscite, VAR) and zeolite [Al2(PO4)2(H2O)2] · H2O (APC). A tetrapolyhedral linear precursor is established for m-VAR and a ring precursor (MT)2 is established for VAR and APC. The symmetry and topology code of the processes of crystal structure self-assembly from cluster precursors is completely reconstructed. The functional role of the O-H···O hydrogen bonds is considered for the first time. The cluster self-assembly model explains the specific features of the morphogenesis of single crystals: m-VAR prisms, flattened VAR octahedra, and needleshaped APC square-base prisms.

Sexual abuse in childhood and sexual dysfunction in adulthood: an Australian population-based study.

PubMed

Najman, Jake M; Dunne, Michael P; Purdie, David M; Boyle, Francis M; Coxeter, Peter D

2005-10-01

This study examined self-reported adult sexual functioning in individuals reporting a history of childhood sexual abuse (CSA) in a representative sample of the Australian population. A sample of 1793 persons, aged 18-59 years, were randomly selected from the electoral roll for Australian states and territories in April 2000. Respondents were interviewed about their health status and sexual experiences, including unwanted sexual experiences before the age of 16 years. More than one-third of women and approximately one-sixth of men reported a history of CSA. Women were more likely than men to report both non-penetrative and penetrative experiences of CSA. For both sexes, there was a significant association between CSA and symptoms of sexual dysfunction. In assessing the specific nature of the relationship between sexual abuse and sexual dysfunction, statistically significant associations were, in general, evident for women only. CSA was not associated with the level of physical or emotional satisfaction respondents experienced with their sexual activity. The total number of lifetime sexual partners was significantly and positively associated with CSA for females, but not for males; however, the number of sexual partners in the last year was not related to CSA. CSA in the Australian population is common and contributes to significant impairment in the sexual functioning of adults, especially women. These consequences appear not to extend to the other areas of sexual activity considered in this study.

Maximum toe flexor muscle strength and quantitative analysis of human plantar intrinsic and extrinsic muscles by a magnetic resonance imaging technique.

PubMed

Kurihara, Toshiyuki; Yamauchi, Junichiro; Otsuka, Mitsuo; Tottori, Nobuaki; Hashimoto, Takeshi; Isaka, Tadao

2014-01-01

The aims of this study were to investigate the relationships between the maximum isometric toe flexor muscle strength (TFS) and cross-sectional area (CSA) of the plantar intrinsic and extrinsic muscles and to identify the major determinant of maximum TFS among CSA of the plantar intrinsic and extrinsic muscles. Twenty six young healthy participants (14 men, 12 women; age, 20.4 ± 1.6 years) volunteered for the study. TFS was measured by a specific designed dynamometer, and CSA of plantar intrinsic and extrinsic muscles were measured using magnetic resonance imaging (MRI). To measure TFS, seated participants optimally gripped the bar with their toes and exerted maximum force on the dynamometer. For each participant, the highest force produced among three trials was used for further analysis. To measure CSA, serial T1-weighted images were acquired. TFS was significantly correlated with CSA of the plantar intrinsic and extrinsic muscles. Stepwise multiple linear regression analyses identified that the major determinant of TFS was CSA of medial parts of plantar intrinsic muscles (flexor hallucis brevis, flexor digitorum brevis, quadratus plantae, lumbricals and abductor hallucis). There was no significant difference between men and women in TFS/CSA. CSA of the plantar intrinsic and extrinsic muscles is one of important factors for determining the maximum TFS in humans.

Climate-smart agriculture for food security

NASA Astrophysics Data System (ADS)

Lipper, Leslie; Thornton, Philip; Campbell, Bruce M.; Baedeker, Tobias; Braimoh, Ademola; Bwalya, Martin; Caron, Patrick; Cattaneo, Andrea; Garrity, Dennis; Henry, Kevin; Hottle, Ryan; Jackson, Louise; Jarvis, Andrew; Kossam, Fred; Mann, Wendy; McCarthy, Nancy; Meybeck, Alexandre; Neufeldt, Henry; Remington, Tom; Sen, Pham Thi; Sessa, Reuben; Shula, Reynolds; Tibu, Austin; Torquebiau, Emmanuel F.

2014-12-01

Climate-smart agriculture (CSA) is an approach for transforming and reorienting agricultural systems to support food security under the new realities of climate change. Widespread changes in rainfall and temperature patterns threaten agricultural production and increase the vulnerability of people dependent on agriculture for their livelihoods, which includes most of the world's poor. Climate change disrupts food markets, posing population-wide risks to food supply. Threats can be reduced by increasing the adaptive capacity of farmers as well as increasing resilience and resource use efficiency in agricultural production systems. CSA promotes coordinated actions by farmers, researchers, private sector, civil society and policymakers towards climate-resilient pathways through four main action areas: (1) building evidence; (2) increasing local institutional effectiveness; (3) fostering coherence between climate and agricultural policies; and (4) linking climate and agricultural financing. CSA differs from 'business-as-usual' approaches by emphasizing the capacity to implement flexible, context-specific solutions, supported by innovative policy and financing actions.

Bullying victimization and child sexual abuse among left-behind and non-left-behind children in China.

PubMed

Yan, Li; Zhu, Qianqian; Tu, Xiaowen; Zuo, Xiayun; Yu, Chunyan; Lou, Chaohua; Lian, Qiguo

2018-01-01

Bullying is one of the most important factors associated with child abuse. However, robust tests supporting the assumption that being bullied can contribute to child sexual abuse (CSA) among left-behind children (LBC) remain sparse. This study aims to investigate the association of bullying victimization with CSA among LBC in China. A cross-sectional study was conducted in six middle schools of Sichuan and Anhui province in 2015. The bullying victimization was assessed by seven items from the Revised Olweus Bully/Victim Questionnaire. The experience of CSA was measured by ten items CSA scale with good consistency. A total of 1,030 children met the sampling criteria, including 284 LBC and 746 non-LBC. The prevalence of CSA was 22.89% in LBC and 20.19% in non-LBC ( p  > 0.05). Bullying victimization was related to CSA among both LBC (adjusted Odds Ratio [aOR] = 2.52, 95% CI [1.34-4.73]) and non-LBC (aOR = 2.35, 95% CI [1.58-3.53]). The association between bullying victimization and CSA was much higher among left-behind girls (left-behind girls: aOR = 7.36, 95% CI [2.16-24.99]; non-left-behind girls: aOR = 2.38, 95% CI [1.08-5.27]). Also, LBC of a young age (11-15), children with siblings, living in rural areas and non-traditional family structure who were bullied were more likely to suffer CSA than their non-LBC peers. Bullying victimization is associated with a significant increase in CSA among both LBC and non-LBC. Anti-bullying programs should target vulnerable populations including female LBC and LBC with siblings to reduce the risk of CSA.

Bullying victimization and child sexual abuse among left-behind and non-left-behind children in China

PubMed Central

Yan, Li; Zhu, Qianqian; Tu, Xiaowen; Zuo, Xiayun; Yu, Chunyan; Lou, Chaohua

2018-01-01

Background Bullying is one of the most important factors associated with child abuse. However, robust tests supporting the assumption that being bullied can contribute to child sexual abuse (CSA) among left-behind children (LBC) remain sparse. This study aims to investigate the association of bullying victimization with CSA among LBC in China. Methods A cross-sectional study was conducted in six middle schools of Sichuan and Anhui province in 2015. The bullying victimization was assessed by seven items from the Revised Olweus Bully/Victim Questionnaire. The experience of CSA was measured by ten items CSA scale with good consistency. Results A total of 1,030 children met the sampling criteria, including 284 LBC and 746 non-LBC. The prevalence of CSA was 22.89% in LBC and 20.19% in non-LBC (p > 0.05). Bullying victimization was related to CSA among both LBC (adjusted Odds Ratio [aOR] = 2.52, 95% CI [1.34–4.73]) and non-LBC (aOR = 2.35, 95% CI [1.58–3.53]). The association between bullying victimization and CSA was much higher among left-behind girls (left-behind girls: aOR = 7.36, 95% CI [2.16–24.99]; non-left-behind girls: aOR = 2.38, 95% CI [1.08–5.27]). Also, LBC of a young age (11–15), children with siblings, living in rural areas and non-traditional family structure who were bullied were more likely to suffer CSA than their non-LBC peers. Conclusions Bullying victimization is associated with a significant increase in CSA among both LBC and non-LBC. Anti-bullying programs should target vulnerable populations including female LBC and LBC with siblings to reduce the risk of CSA. PMID:29888125

The impact of active site mutations of South African HIV PR on drug resistance: Insight from molecular dynamics simulations, binding free energy and per-residue footprints.

PubMed

Ahmed, Shaimaa M; Maguire, Glenn E M; Kruger, Hendrik G; Govender, Thirumala

2014-04-01

Molecular dynamics simulations and binding free energy calculations were used to provide an understanding of the impact of active site drug-resistant mutations of the South African HIV protease subtype C (C-SA HIV PR), V82A and V82F/I84V on drug resistance. Unique per-residue interaction energy 'footprints' were developed to map the overall drug-binding profiles for the wild type and mutants. Results confirmed that these mutations altered the overall binding landscape of the amino acid residues not only in the active site region but also in the flaps as well. Four FDA-approved drugs were investigated in this study; these include ritonavir (RTV), saquinavir (SQV), indinavir (IDV), and nelfinavir (NFV). Computational results compared against experimental findings were found to be complementary. Against the V82F/I84V variant, saquinavir, indinavir, and nelfinavir lose remarkable entropic contributions relative to both wild-type and V82A C-SA HIV PRs. The per-residue energy 'footprints' and the analysis of ligand-receptor interactions for the drug complexes with the wild type and mutants have also highlighted the nature of drug interactions. The data presented in this study will prove useful in the design of more potent inhibitors effective against drug-resistant HIV strains. © 2013 John Wiley & Sons A/S.

Draft genome sequence of Camellia sinensis var. sinensis provides insights into the evolution of the tea genome and tea quality.

PubMed

Wei, Chaoling; Yang, Hua; Wang, Songbo; Zhao, Jian; Liu, Chun; Gao, Liping; Xia, Enhua; Lu, Ying; Tai, Yuling; She, Guangbiao; Sun, Jun; Cao, Haisheng; Tong, Wei; Gao, Qiang; Li, Yeyun; Deng, Weiwei; Jiang, Xiaolan; Wang, Wenzhao; Chen, Qi; Zhang, Shihua; Li, Haijing; Wu, Junlan; Wang, Ping; Li, Penghui; Shi, Chengying; Zheng, Fengya; Jian, Jianbo; Huang, Bei; Shan, Dai; Shi, Mingming; Fang, Congbing; Yue, Yi; Li, Fangdong; Li, Daxiang; Wei, Shu; Han, Bin; Jiang, Changjun; Yin, Ye; Xia, Tao; Zhang, Zhengzhu; Bennetzen, Jeffrey L; Zhao, Shancen; Wan, Xiaochun

2018-05-01

Tea, one of the world's most important beverage crops, provides numerous secondary metabolites that account for its rich taste and health benefits. Here we present a high-quality sequence of the genome of tea, Camellia sinensis var. sinensis (CSS), using both Illumina and PacBio sequencing technologies. At least 64% of the 3.1-Gb genome assembly consists of repetitive sequences, and the rest yields 33,932 high-confidence predictions of encoded proteins. Divergence between two major lineages, CSS and Camellia sinensis var. assamica (CSA), is calculated to ∼0.38 to 1.54 million years ago (Mya). Analysis of genic collinearity reveals that the tea genome is the product of two rounds of whole-genome duplications (WGDs) that occurred ∼30 to 40 and ∼90 to 100 Mya. We provide evidence that these WGD events, and subsequent paralogous duplications, had major impacts on the copy numbers of secondary metabolite genes, particularly genes critical to producing three key quality compounds: catechins, theanine, and caffeine. Analyses of transcriptome and phytochemistry data show that amplification and transcriptional divergence of genes encoding a large acyltransferase family and leucoanthocyanidin reductases are associated with the characteristic young leaf accumulation of monomeric galloylated catechins in tea, while functional divergence of a single member of the glutamine synthetase gene family yielded theanine synthetase. This genome sequence will facilitate understanding of tea genome evolution and tea metabolite pathways, and will promote germplasm utilization for breeding improved tea varieties. Copyright © 2018 the Author(s). Published by PNAS.

Draft genome sequence of Camellia sinensis var. sinensis provides insights into the evolution of the tea genome and tea quality

PubMed Central

Wei, Chaoling; Yang, Hua; Wang, Songbo; Zhao, Jian; Liu, Chun; Gao, Liping; Xia, Enhua; Lu, Ying; Tai, Yuling; She, Guangbiao; Sun, Jun; Cao, Haisheng; Tong, Wei; Gao, Qiang; Li, Yeyun; Deng, Weiwei; Jiang, Xiaolan; Wang, Wenzhao; Chen, Qi; Zhang, Shihua; Li, Haijing; Wu, Junlan; Wang, Ping; Li, Penghui; Shi, Chengying; Zheng, Fengya; Jian, Jianbo; Huang, Bei; Shan, Dai; Shi, Mingming; Fang, Congbing; Yue, Yi; Li, Fangdong; Li, Daxiang; Wei, Shu; Han, Bin; Jiang, Changjun; Yin, Ye; Xia, Tao; Zhang, Zhengzhu; Bennetzen, Jeffrey L.; Zhao, Shancen; Wan, Xiaochun

2018-01-01

Tea, one of the world’s most important beverage crops, provides numerous secondary metabolites that account for its rich taste and health benefits. Here we present a high-quality sequence of the genome of tea, Camellia sinensis var. sinensis (CSS), using both Illumina and PacBio sequencing technologies. At least 64% of the 3.1-Gb genome assembly consists of repetitive sequences, and the rest yields 33,932 high-confidence predictions of encoded proteins. Divergence between two major lineages, CSS and Camellia sinensis var. assamica (CSA), is calculated to ∼0.38 to 1.54 million years ago (Mya). Analysis of genic collinearity reveals that the tea genome is the product of two rounds of whole-genome duplications (WGDs) that occurred ∼30 to 40 and ∼90 to 100 Mya. We provide evidence that these WGD events, and subsequent paralogous duplications, had major impacts on the copy numbers of secondary metabolite genes, particularly genes critical to producing three key quality compounds: catechins, theanine, and caffeine. Analyses of transcriptome and phytochemistry data show that amplification and transcriptional divergence of genes encoding a large acyltransferase family and leucoanthocyanidin reductases are associated with the characteristic young leaf accumulation of monomeric galloylated catechins in tea, while functional divergence of a single member of the glutamine synthetase gene family yielded theanine synthetase. This genome sequence will facilitate understanding of tea genome evolution and tea metabolite pathways, and will promote germplasm utilization for breeding improved tea varieties. PMID:29678829

Mediators of the relationship between childhood sexual abuse and suicidal behavior in borderline personality disorder.

PubMed

Soloff, Paul H; Feske, Ulrike; Fabio, Anthony

2008-06-01

A history of childhood sexual abuse (CSA) increases the risk of suicidal behavior and the lifetime number of suicide attempts in adults with BPD. Despite a strong association, specific variables mediating the relationship between CSA and adult suicidal behavior in BPD have not been identified. This study examined risk factors for suicidal behavior as potential mediators of the relationship between CSA and suicide attempts in 151 men and women with BPD. Diagnostic, clinical, and psychosocial risk factors, as well as CSA, and suicidal behaviors, were assessed by standardized interviews or self-rated measures. Psychotic and schizotypal symptoms, and poor social adjustment, were associated with both CSA and suicidal behavior, and partially mediated the relationship between CSA and attempter status. Psychotic and schizotypal symptoms in BPD define a vulnerability to cognitive and perceptual distortions under stress. They increase the likelihood of suicidal behavior in BPD, especially in the absence of mitigating social support. A theoretical model for suicidal behavior in BPD is presented which integrates direct, mediated, and moderated pathways between childhood sexual abuse and temperament, adolescent and adult risk factors, and suicidal behavior.

Childhood Sexual Abuse Moderates the Association between Sexual Functioning and Sexual Distress in Women

PubMed Central

Stephenson, Kyle R.; Hughan, Corey P.; Meston, Cindy M.

2012-01-01

Objective To assess the degree to which a history of CSA moderates the association between sexual functioning and sexual distress in women. Method Women with (n = 105, M age = 33.71, 66.1% Caucasian) and without (n = 71, M age = 32.63, 74.7% Caucasian) a history of CSA taking part in a larger clinical trial completed self-report questionnaires at intake including the Sexual Satisfaction Scale for Women (SSS-W), the Female Sexual Function Index (FSFI), and the Trauma History Questionnaire (THQ). Results Desire, arousal, lubrication, and orgasm interacted with sexual abuse status in predicting sexual distress such that sexual functioning was more weakly associated with distress for women with a history of CSA. This disconnect was more pronounced for women who were abused by a family member. Conclusion CSA status serves as an important moderator of the association between sexual functioning and sexual distress in women. Specifically, women with a history of CSA show higher levels of distress in the context of good sexual functioning as compared to women without a history of CSA. Possible explanations and clinical implications are discussed. PMID:22391416

Cyclophilin B stimulates RNA synthesis by the HCV RNA dependent RNA polymerase

PubMed Central

Heck, Julie A.; Meng, Xiao; Frick, David N.

2009-01-01

Cyclophilins are cellular peptidyl isomerases that have been implicated in regulating hepatitis C virus (HCV) replication. Cyclophilin B (CypB) is a target of cyclosporin A (CsA), an immunosuppressive drug recently shown to suppress HCV replication in cell culture. Watashi et al. recently demonstrated that CypB is important for efficient HCV replication, and proposed that it mediates the anti-HCV effects of CsA through an interaction with NS5B (Mol. Cell 19:111). We examined the effects of purified CypB proteins on the enzymatic activity of NS5B. Recombinant CypB purified from insect cells directly stimulated NS5B-catalyzed RNA synthesis. CypB increased RNA synthesis by NS5B derived from genotype 1a, 1b, and 2a HCV strains. Stimulation appears to arise from an increase in productive RNA binding. NS5B residue Pro540, a previously proposed target of CypB peptidyl-prolyl isomerase activity, is not required for stimulation of RNA synthesis. PMID:19174155

CSA/AZA, in the absence of prednisone, improves linear growth in renal transplanted children.

PubMed

David-Neto, E; Nahas, W; Sampaio, E C; Ianhez, L E; Sabbaga, E; Arap, S

1992-01-01

We compared the results of 44 renal transplants in children, of whom 24 were treated with CSA/AZA and 20 with prednisone in combination with AZA and/or CSA. There were no differences in age distribution or mean ages at transplant between the two treatment groups. The CSA/AZA group had a longer follow-up (29 +/- 33 vs 17 +/- 18 months). At the last follow-up, five children in the CSA/AZA and none in the prednisone group had lost their grafts. Serum creatinine increased in both groups from 0.7 +/- 0.1 mg/dl and 0.9 +/- 0.1 mg/dl at the end of the first month to 1.1 +/- 0.2 mg/dl in the 36th month (CSA/AZA group) (P < 0.0001) and to 1.5 +/- 0.6 mg/dl in the 18th month (prednisone group) (P < 0.05), respectively. Total cholesterol level was 189 +/- 52 mg/dl and 178 +/- 60 mg/dl and LDL level was 117 +/- 48 mg/dl and 115 +/- 51 mg/dl for the prednisone and CSA/AZA groups, respectively. HDL was greater in the CSA/AZA group (50 +/- 10 vs 41 +/- 10 mg/dl) (P < 0.03), and VLDL was greater in the prednisone group (31 +/- 13 vs 22 +/- 8 mg/dl) (P < 0.05). Serum triglyceride was greater in the prednisone group (174 +/- 93 vs 112 +/- 50 mg/dl) (P < 0.03). The standard deviation score for height of the children in the prednisone group did not change (-2.4 +/- 1.4 vs -2.1 +/- 1.4 SDS), whereas the SDS height score for the CSA/AZA children increased from -3.1 +/- 1.7 to -2.6 +/- 1.5, -1.9 +/- 1.4 and -1.7 +/- 1.4, at 12, 24 and 36 months, respectively (P < 0.001). CSA/AZA is a good immunosuppressive regime for the first renal transplant in children, but only 75% tolerated AZA/CSA without same damage to their grafts.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wurzburg, Beth A.; Tarchevskaya, Svetlana S.; Jardetzky, Theodore S.

CD23, the low-affinity receptor for IgE (Fc{var_epsilon}RII), regulates IgE synthesis and also mediates IgE-dependent antigen transport and processing. CD23 is a unique Fc receptor belonging to the C-type lectin-like domain superfamily and binds IgE in an unusual, non-lectin-like manner, requiring calcium but not carbohydrate. We have solved the high-resolution crystal structures of the human CD23 lectin domain in the presence and absence of Ca{sup 2+}. The crystal structures differ significantly from a previously determined NMR structure and show that calcium binding occurs at the principal binding site, but not at an auxiliary site that appears to be absent in humanmore » CD23. Conformational differences between the apo and Ca{sup 2+} bound structures suggest how IgE-Fc binding can be both calcium-dependent and carbohydrate-independent.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hang, Bo; Guliaev, Anton B.; Chenna, Ahmed

1,N{sup 6}-Ethanoadenine (EA) is an exocyclic adduct formed from DNA reaction with the antitumor agent, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). To understand the role of this adduct in the mechanism of mutagenicity or carcinogenicity by BCNU, an oligonucleotide with a site-specific EA was synthesized using phosphoramidite chemistry. We now report the in vitro miscoding properties of EA in translesion DNA synthesis catalyzed by mammalian DNA polymerases (pols) {alpha}, {beta}, {eta} and {iota}. These data were also compared with those obtained for the structurally related exocyclic adduct, 1,N{sup 6}-ethenoadenine ({var_epsilon}A). Using a primer extension assay, both pols {alpha} and {beta} were primarily blocked bymore » EA or {var_epsilon}A with very minor extension. Pol {eta} a member of the Y family of polymerases, was capable of catalyzing a significant amount of bypass across both adducts. Pol {eta} incorporated all four nucleotides opposite EA and {var_epsilon}A, but with differential preferences and mainly in an error-prone manner. Human pol {iota}, a paralog of human pol {eta}, was blocked by both adducts with a very small amount of synthesis past {var_epsilon}A. It incorporated C and, to a much lesser extent, T, opposite either adduct. In addition, the presence of an A adduct, e.g. {var_epsilon}A, could affect the specificity of pol {iota} toward the template T immediately 3 feet to the adduct. In conclusion, the four polymerases assayed on templates containing an EA or {var_epsilon}A showed differential bypass capacity and nucleotide incorporation specificity, with the two adducts not completely identical in influencing these properties. Although there was a measurable extent of error-free nucleotide incorporation, all these polymerases primarily misincorporated opposite EA, indicating that the adduct, similar to {var_epsilon}A, is a miscoding lesion.« less

Overgeneral autobiographical memory and age of onset of childhood sexual abuse in patients with recurrent suicidal behaviour.

PubMed

Crane, Catherine; Duggan, Danielle S

2009-03-01

To explore the association between age of onset of childhood sexual abuse (CSA) and overgeneral memory (OGM) in a clinical sample. Presence and age of onset of CSA and levels of OGM were assessed in 49 patients attending hospital following a recurrence of suicidal behaviour. Twenty six participants reported CSA. Earlier age of onset of CSA was associated with greater OGM, indexed by fewer specific and more categoric memories. The association was not accounted for either by elevated levels of depression in those reporting earlier abuse, nor by levels of general verbal fluency. The findings are consistent with previous work and support the hypothesis that abuse occurring earlier in development results in more pronounced OGM.

Preclinical characterization of naturally occurring polyketide cyclophilin inhibitors from the sanglifehrin family.

PubMed

Gregory, Matthew A; Bobardt, Michael; Obeid, Susan; Chatterji, Udayan; Coates, Nigel J; Foster, Teresa; Gallay, Philippe; Leyssen, Pieter; Moss, Steven J; Neyts, Johan; Nur-e-Alam, Mohammad; Paeshuyse, Jan; Piraee, Mahmood; Suthar, Dipen; Warneck, Tony; Zhang, Ming-Qiang; Wilkinson, Barrie

2011-05-01

Cyclophilin inhibitors currently in clinical trials for hepatitis C virus (HCV) are all analogues of cyclosporine (CsA). Sanglifehrins are a group of naturally occurring cyclophilin binding polyketides that are structurally distinct from the cyclosporines and are produced by a microorganism amenable to biosynthetic engineering for lead optimization and large-scale production by fermentation. Preclinical characterization of the potential utility of this class of compounds for the treatment of HCV revealed that the natural sanglifehrins A to D are all more potent than CsA at disrupting formation of the NS5A-CypA, -CypB, and -CypD complexes and at inhibition of CypA, CypB, and CypD isomerase activity. In particular, sanglifehrin B (SfB) was 30- to 50-fold more potent at inhibiting the isomerase activity of all Cyps tested than CsA and was also shown to be a more potent inhibitor of the 1b subgenomic replicon (50% effective concentrations [EC50s] of 0.070 μM and 0.16 μM in Huh 5-2 and Huh 9-13 cells, respectively). Physicochemical and mouse pharmacokinetic analyses revealed low oral bioavailability (F<4%) and low solubility (<25 μM), although the half-lives (t1/2) of SfA and SfB in mouse blood after intravenous (i.v.) dosing were long (t1/2>5 h). These data demonstrate that naturally occurring sanglifehrins are suitable lead compounds for the development of novel analogues that are less immunosuppressive and that have improved metabolism and pharmacokinetic properties.

Preclinical Characterization of Naturally Occurring Polyketide Cyclophilin Inhibitors from the Sanglifehrin Family▿†

PubMed Central

Gregory, Matthew A.; Bobardt, Michael; Obeid, Susan; Chatterji, Udayan; Coates, Nigel J.; Foster, Teresa; Gallay, Philippe; Leyssen, Pieter; Moss, Steven J.; Neyts, Johan; Nur-e-Alam, Mohammad; Paeshuyse, Jan; Piraee, Mahmood; Suthar, Dipen; Warneck, Tony; Zhang, Ming-Qiang; Wilkinson, Barrie

2011-01-01

Cyclophilin inhibitors currently in clinical trials for hepatitis C virus (HCV) are all analogues of cyclosporine (CsA). Sanglifehrins are a group of naturally occurring cyclophilin binding polyketides that are structurally distinct from the cyclosporines and are produced by a microorganism amenable to biosynthetic engineering for lead optimization and large-scale production by fermentation. Preclinical characterization of the potential utility of this class of compounds for the treatment of HCV revealed that the natural sanglifehrins A to D are all more potent than CsA at disrupting formation of the NS5A-CypA, -CypB, and -CypD complexes and at inhibition of CypA, CypB, and CypD isomerase activity. In particular, sanglifehrin B (SfB) was 30- to 50-fold more potent at inhibiting the isomerase activity of all Cyps tested than CsA and was also shown to be a more potent inhibitor of the 1b subgenomic replicon (50% effective concentrations [EC50s] of 0.070 μM and 0.16 μM in Huh 5-2 and Huh 9-13 cells, respectively). Physicochemical and mouse pharmacokinetic analyses revealed low oral bioavailability (F < 4%) and low solubility (<25 μM), although the half-lives (t1/2) of SfA and SfB in mouse blood after intravenous (i.v.) dosing were long (t1/2 > 5 h). These data demonstrate that naturally occurring sanglifehrins are suitable lead compounds for the development of novel analogues that are less immunosuppressive and that have improved metabolism and pharmacokinetic properties. PMID:21383094

Effect of an intravitreal cyclosporine implant on experimental uveitis in horses.

PubMed

Gilger, B C; Malok, E; Stewart, T; Horohov, D; Ashton, P; Smith, T; Jaffe, G J; Allen, J B

2000-10-31

The purpose of this study was to determine the effects of an intravitreal device releasing cyclosporine A (CsA) on recurrent inflammatory episodes in experimental uveitis. Nine normal horses were immunized peripherally with H37RA-mTB antigen twice, and then received 25 microg of H37RA-mTB antigen intravitreally in the right eye and an equal volume of balanced salt solution intravitreally in the left eye. Two weeks later, the animals randomly received either a CsA or a polymer implant (without CsA) in both eyes 1 week following implantation of the devices, 25 microg of H37RA-mTB antigen was reinjected into the right eye of each animal. Clinical signs of ophthalmic inflammation were graded following injections and implantation. The animals from each group were euthanized at 3, 14, and 28 days following the second injection. Aqueous and vitreous humor protein concentrations were measured. The presence, number, and type (CD4, 5 and 8) of infiltrating inflammatory cells and amount of tissue destruction were determined. Total RNA was isolated and quantitative reverse transcriptase-polymerase chain reaction was performed for equine specific interleukin (IL) 2 and 4, interferon-gamma (IFN gamma) and beta-actin. In addition, aqueous and vitreous humor and peripheral blood were collected at the termination of the experiments and analyzed for CsA concentration by HPLC. Within 4h of the first intravitreal H37RA-mTB antigen injection, each animal developed epiphora, blepharospasm, mild corneal edema, aqueous flare, myosis, and vitreous opacity. The severity of signs peaked 48 to 72 h after injection and subsequently decreased back to normal within 14 days. Following the second injection, clinical signs in the eyes with the CsA device were less severe and significantly shorter in duration than signs with the polymer only implant eyes. Aqueous and vitreous humor protein levels, infiltrating cell numbers, total number of T-lymphocytes, and levels of IL-2 and IFN gamma-mRNA were significantly less in eyes with the CsA implant compared to eyes with the polymer only. CsA implants did not completely eliminate the development of a second ('recurrent') experimental inflammatory episode in these horses. However, the duration and severity of inflammation, cellular infiltration, tissue destruction, and pro-inflammatory cytokines RNA transcript levels were significantly less in those eyes implanted with the CsA device.

Critical Shoulder Angle and Acromial Index Do Not Influence 24-Month Functional Outcome After Arthroscopic Rotator Cuff Repair.

PubMed

Lee, Merrill; Chen, Jerry Yongqian; Liow, Ming Han Lincoln; Chong, Hwei Chi; Chang, Paul; Lie, Denny

2017-11-01

Recent studies have shown a correlation between scapular geometry and the development of atraumatic rotator cuff tears. However, a paucity of literature is available on the effects of critical shoulder angle (CSA) and acromial index (AI) on functional outcomes after arthroscopic rotator cuff repair. Hypothesis/Purpose: The purpose was to investigate the influence of CSA and AI on 24-month functional outcomes after arthroscopic rotator cuff repair. The hypothesis was that a larger CSA or AI would result in poorer postoperative outcomes. Cohort study; Level of evidence, 3. The study included 147 patients who underwent arthroscopic double-row rotator cuff repair for radiologically documented full-thickness supraspinatus tears. An independent reviewer measured the CSA and AI on preoperative radiographs. These patients were prospectively enrolled and were evaluated preoperatively as well as at 3, 6, 12, and 24 months postoperatively. Functional outcome was assessed with the Constant Shoulder Score (CSS), Oxford Shoulder Score (OSS), and University of California at Los Angeles (UCLA) Shoulder Rating Scale. The patients were first divided based on CSA: (1) ≤35° (control CSA) and (2) >35° (increased CSA); and then based on AI: (1) ≤0.7 and (2) >0.7. The Student unpaired t test, Pearson chi-square test, and Pearson correlation were performed to examine the influence of CSA and AI on postoperative functional outcome scores. At 6 months of follow-up, the CSS, OSS, and UCLA Shoulder Rating Scale were 10 ± 1, 4 ± 2, and 3 ± 1 points poorer in the increased CSA group compared with the control CSA group ( P = .005, P = .030, and P = .035, respectively). These scores were not significantly different between both AI groups. By 24 months of follow-up, all outcome scores were comparable between both CSA groups as well as between both AI groups. No significant correlation was found between either CSA or AI when compared with CSS, OSS, or UCLA Shoulder Rating Scale at 24 months of follow-up. CSA and AI do not appear to influence 24-month functional outcomes postoperatively and hence are not contraindications to arthroscopic rotator cuff repair.

High-resolution nerve ultrasound and magnetic resonance neurography as complementary neuroimaging tools for chronic inflammatory demyelinating polyneuropathy

PubMed Central

Pitarokoili, Kalliopi; Kronlage, Moritz; Bäumer, Philip; Schwarz, Daniel; Gold, Ralf; Bendszus, Martin; Yoon, Min-Suk

2018-01-01

Background: We present a clinical, electrophysiological, sonographical and magnetic resonance neurography (MRN) study examining the complementary role of two neuroimaging methods of the peripheral nervous system for patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Furthermore, we explore the significance of cross-sectional area (CSA) increase through correlations with MRN markers of nerve integrity. Methods: A total of 108 nerve segments on the median, ulnar, radial, tibial and fibular nerve, as well as the lumbar and cervical plexus of 18 CIDP patients were examined with high-resonance nerve ultrasound (HRUS) and MRN additionally to the nerve conduction studies. Results: We observed a fair degree of correlation of the CSA values for all nerves/nerve segments between the two methods, with a low random error in Bland–Altman analysis (bias = HRUS-CSA − MRN-CSA, −0.61 to −3.26 mm). CSA in HRUS correlated with the nerve T2-weighted (nT2) signal increase as well as with diffusion tensor imaging parameters such as fractional anisotropy, a marker of microstructural integrity. HRUS-CSA of the interscalene brachial plexus correlated significantly with the MRN-CSA and nT2 signal of the L5 and S1 roots of the lumbar plexus. Conclusions: HRUS allows for reliable CSA imaging of all peripheral nerves and the cervical plexus, and CSA correlates with markers of nerve integrity. Imaging of proximal segments as well as the estimation of nerve integrity require MRN as a complementary method. PMID:29552093

Effects of High-Intensity Interval Exercise Training on Skeletal Myopathy of Chronic Heart Failure.

PubMed

Tzanis, Georgios; Philippou, Anastassios; Karatzanos, Eleftherios; Dimopoulos, Stavros; Kaldara, Elisavet; Nana, Emmeleia; Pitsolis, Theodoros; Rontogianni, Dimitra; Koutsilieris, Michael; Nanas, Serafim

2017-01-01

It remains controversial which type of exercise elicits optimum adaptations on skeletal myopathy of heart failure (HF). Our aim was to evaluate the effect of high-intensity interval training (HIIT), with or without the addition of strength training, on skeletal muscle of HF patients. Thirteen male HF patients (age 51 ± 13 years, body mass index 27 ± 4 kg/m 2 ) participated in either an HIIT (AER) or an HIIT combined with strength training (COM) 3-month program. Biopsy samples were obtained from the vastus lateralis. Analyses were performed on muscle fiber type, cross-section area (CSA), capillary density, and mRNA expression of insulin-like growth factor (IGF) 1 isoforms (ie, IGF-1Ea, IGF-1Eb, IGF-1Ec), type-1 receptor (IGF-1R), and binding protein 3 (IGFBP-3). Increased expression of IGF-1Ea, IGF-1Eb, IGF-1Ec, and IGFBP-3 transcripts was found (1.7 ± 0.8, 1.5 ± 0.8, 2.0 ± 1.32.4 ± 1.4 fold changes, respectively; P < .05). Type I fibers increased by 21% (42 ± 10% to 51 ± 7%; P < .001) and capillary/fiber ratio increased by 24% (1.27 ± 0.22 to 1.57 ± 0.41; P = .005) in both groups as a whole. Fibers' mean CSA increased by 10% in total, but the increase in type I fibers' CSA was greater after AER than COM (15% vs 6%; P < .05). The increased CSA correlated with the increased expression of IGF-1Ea and IGF-1Εb. HIIT reverses skeletal myopathy of HF patients, with the adaptive responses of the IGF-1 bioregulation system possibly contributing to these effects. AER program seemed to be superior to COM to induce muscle hypertrophy. Copyright © 2016 Elsevier Inc. All rights reserved.

The prevalence and impact of childhood sexual abuse on HIV-risk behaviors among men who have sex with men (MSM) in India.

PubMed

Tomori, Cecilia; McFall, Allison M; Srikrishnan, Aylur K; Mehta, Shruti H; Nimmagadda, Nymisha; Anand, Santhanam; Vasudevan, Canjeevaram K; Solomon, Suniti; Solomon, Sunil S; Celentano, David D

2016-08-12

Childhood sexual abuse (CSA) is a significant global public health problem, which is associated with negative psychosocial outcomes and high-risk sexual behaviors in adults. Men who have sex with men (MSM) often report higher prevalence of CSA history than the general population, and CSA may play a key role in MSM's greater vulnerability to HIV. This study examined the prevalence of CSA history and its impact on the number of recent HIV-related risk behaviors (unprotected anal intercourse, high number of male and female sexual partners, alcohol use, drug use, and sex work in prior 6 months) and lifetime risk behaviors and experiences (high number of lifetime male and female sexual partners, early sexual debut, injection drug use, sex work, and intimate partner violence) among 11,788 adult MSM recruited via respondent driven sampling across 12 sites in India, with additional insights from thematic analysis of qualitative research with 363 MSM from 15 sites. Nearly a quarter (22.4 %) of participants experienced CSA, with substantially higher prevalence of CSA in the South and among kothis (feminine sexual identity). Qualitative findings revealed that older, trusted men may target young and, especially, gender nonconforming boys, and perpetrators' social position facilitates nondisclosure. CSA may also initiate further same-sex encounters, including sex work. In multivariable analysis, MSM who experienced CSA had 21 % higher rate of recent (adjusted rate ratio [aRR = 1.21], 95 % confidence interval [CI]: 1.14-1.28), and 2.0 times higher lifetime (aRR = 2.04, 95 % CI: 1.75-2.38) HIV-related behaviors/experiences compared with those who did not. This large, mixed-methods study found high overall prevalence of CSA among MSM (22.4 %), with substantially higher prevalence among MSM residing in the South and among more feminine sexual identities. Qualitative findings highlighted boys' vulnerabilities to CSA, especially gender nonconformity, and CSA's role in further sexual encounters, including sex work. Additionally, CSA was associated with an elevated rate of recent, and an even higher rate of lifetime HIV-related risk factors. Our results suggest an acute need for the development of CSA prevention interventions and the integration of mental health services for MSM with histories of CSA as part of HIV-prevention efforts.

Conformational Space Annealing explained: A general optimization algorithm, with diverse applications

NASA Astrophysics Data System (ADS)

Joung, InSuk; Kim, Jong Yun; Gross, Steven P.; Joo, Keehyoung; Lee, Jooyoung

2018-02-01

Many problems in science and engineering can be formulated as optimization problems. One way to solve these problems is to develop tailored problem-specific approaches. As such development is challenging, an alternative is to develop good generally-applicable algorithms. Such algorithms are easy to apply, typically function robustly, and reduce development time. Here we provide a description for one such algorithm called Conformational Space Annealing (CSA) along with its python version, PyCSA. We previously applied it to many optimization problems including protein structure prediction and graph community detection. To demonstrate its utility, we have applied PyCSA to two continuous test functions, namely Ackley and Eggholder functions. In addition, in order to provide complete generality of PyCSA to any types of an objective function, we demonstrate the way PyCSA can be applied to a discrete objective function, namely a parameter optimization problem. Based on the benchmarking results of the three problems, the performance of CSA is shown to be better than or similar to the most popular optimization method, simulated annealing. For continuous objective functions, we found that, L-BFGS-B was the best performing local optimization method, while for a discrete objective function Nelder-Mead was the best. The current version of PyCSA can be run in parallel at the coarse grained level by calculating multiple independent local optimizations separately. The source code of PyCSA is available from http://lee.kias.re.kr.

Symptomatology and health care utilization of women primary care patients who experienced childhood sexual abuse.

PubMed

Hulme, P A

2000-11-01

The purpose of this study was to (1) determine the symptomatology of women primary care patients who experienced childhood sexual abuse (CSA), using both a self-report survey and a chart review, and (2) determine their health care utilization patterns, using chart and information system reviews. An ex post facto research design was used. Women primary care patients who experienced CSA were compared with those who reported no CSA. Participants were recruited from a random sample of women patients from a large primary care clinic. They were mailed the survey; chart and information system reviews were conducted on those who returned surveys. Of the 395 participants, 23% reported past CSA on the survey. Women who experienced CSA reported 44 out of 51 physical and psychosocial symptoms more frequently than their counterparts who reported no past CSA. Further, they experienced these symptoms more intensely and in greater number. In their charts, however, far fewer differences in symptoms between groups were found. Nonetheless, women who experienced CSA visited the primary care clinic an average of 1.33 more times than women with no CSA, and they incurred an average of $150 more in primary care charges over a 2-year period. The findings indicate that many women primary care patients who experienced CSA suffer multiple symptoms that are not reflected in their charts. In addition, the findings demonstrate that not only is CSA associated with increased primary care visits, but also increased primary care costs, as measured by charges.

The childhood sexual abuse among youth in three Asian cities: Taipei, Shanghai, and Hanoi.

PubMed

Li, Nan; Zabin, Laurie S; Ahmed, Saifuddin

2015-03-01

The article describes the prevalence and risk factors of childhood sexual abuse (CSA) among youth in Hanoi, Shanghai, and Taipei. Data used in this study are from the Three-City Asian Study of Adolescents and Youth, 2006-2007. Descriptive analysis and logistic regression models were used. The self-reported lifetime prevalence of CSA was 5.2% in Taipei, 1.3% in Shanghai, and 0.5% in Hanoi. The overall prevalence was 2.2% for females and 1.7% for males. The average age of first CSA was 10.5 years. Household instability, migration before age 14, and low maternal warmth were found to be positively associated with CSA, whereas discussing problems with father and being close to mother were negatively associated with CSA, after adjusting for sociodemographic characteristics. Our findings suggested the importance of prevention programs for preteen aged children, public education to raise awareness, and further prospective studies to identify various risk markers for CSA in Asia. © 2013 APJPH.

Hydrophobic binding peptide-conjugated hybrid lipid-mesoporous silica nanoparticles for effective chemo-photothermal therapy of pancreatic cancer.

PubMed

Thapa, Raj Kumar; Nguyen, Hanh Thuy; Gautam, Milan; Shrestha, Aarajana; Lee, Eung Seok; Ku, Sae Kwang; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh

2017-11-01

Nanoparticle-based drug delivery systems are designed to reach tumor sites based on their enhanced permeation and retention effects. However, a lack of interaction of these nanoparticles with cancer cells might lead to reduced uptake in the tumors, which might compromise the therapeutic efficacy of the system. Therefore, we developed bortezomib and IR-820-loaded hybrid-lipid mesoporous silica nanoparticles conjugated with the hydrophobic-binding peptide, cyclosporine A (CsA), and referred to them as CLMSN/BIR. Upon reaching the tumor site, CsA interacts hydrophobically with the cancer cell membranes to allow effective uptake of the nanoparticles. Nanoparticles ∼160 nm in size were prepared and the stability of IR-820 significantly improved. High cellular uptake of the nanoparticles was evident with pronounced apoptotic effects in PANC-1 and MIA PaCa-2 cells that were mediated by the chemotherapeutic effect of bortezomib and the photothermal and reactive oxygen species generation effects of IR-820. An in vivo biodistribution study indicated there was high accumulation in the tumor with an enhanced photothermal effect in PANC-1 xenograft mouse tumors. Furthermore, enhanced antitumor effects in PANC-1 xenograft tumors were observed with minimal toxicity induction in the organs of mice. Cumulatively, these results indicated the promising effects of CLMSN/BIR for effective chemo-phototherapy of pancreatic cancers.

Childhood sexual abuse severity and disclosure as predictors of depression among adult African American and Latina women

PubMed Central

Sciolla, Andres; Glover, Dorie A.; Loeb, Tamra B.; Zhang, Muyu; Myers, Hector F.; Wyatt, Gail E.

2011-01-01

A history of childhood sexual abuse (CSA) has been associated with adult depression, but data on abuse severity and disclosure are scant, particularly among low income ethnic minorities. CSA often co-occurs with other adversities, which also increase the risk of depression. This study examined the peri-trauma variable of abuse severity and the post-trauma variables of disclosure and self-blame as predictors of current depression symptoms in 94 low-income African American and Latina women with histories of CSA. After controlling for non-sexual childhood adversity and adult burden (i.e., chronic stress), severe CSA overall was associated with higher depression scores, especially among Latinas who disclosed their abuse. Depression symptoms among African American women were highest in those who disclosed and reported high levels of self-blame at the time of the incident. The link between depression and specific peri- and post-CSA factors in minority women may help guide future interventions. PMID:21716061

[Effect of glutamate on membrane potential and volume of the skeletal muscle fibers in rats following NO-synthase inhibition in vivo].

PubMed

Khairova, P A; Malomuzh, A I; Naumenko, N V; Urazaev, A Kh

2002-11-01

Cross-sectional area (CSA) of muscle fibers incubated in culture medium 199 for 3 hours dramatically increases, whereas resting membrane potential (RMP) decreases compared to "freshly-isolated" muscles. Both glutamate and sodium nitroprusside prevent these changes. MK-801, a specific inhibitor of NMDA-receptors, eliminates protective effects of glutamate on both CSA and RMP. NO-synthase inhibition in vivo promotes an increase of initial CSA and decrease of mean RMP. Under these conditions, effects of glutamate and sodium nitroprusside on CSA and RMP of denervated muscles are less obvious. It has been concluded that synaptic glutamate is able to participate in regulation of RMP and cell volume in muscle fibers through the activation of postsynaptic NMDA-receptors and muscle NO-synthase.

Incremental change in cross sectional area in small endotracheal tubes: A call for more size options.

PubMed

Mortelliti, Caroline L; Mortelliti, Anthony J

2016-08-01

To elucidate the relatively large incremental percent change (IPC) in cross sectional area (CSA) in currently available small endotracheal tubes (ETTs), and to make recommendation for lesser incremental change in CSA in these smaller ETTs, in order to minimize iatrogenic airway injury. The CSAs of a commercially available line of ETTs were calculated, and the IPC of the CSA between consecutive size ETTs was calculated and graphed. The average IPC in CSA with large ETTs was applied to calculate identical IPC in the CSA for a theoretical, smaller ETT series, and the dimensions of a new theoretical series of proposed small ETTs were defined. The IPC of CSA in the larger (5.0-8.0 mm inner diameter (ID)) ETTs was 17.07%, and the IPC of CSA in the smaller ETTs (2.0-4.0 mm ID) is remarkably larger (38.08%). Applying the relatively smaller IPC of CSA from larger ETTs to a theoretical sequence of small ETTs, starting with the 2.5 mm ID ETT, suggests that intermediate sizes of small ETTs (ID 2.745 mm, 3.254 mm, and 3.859 mm) should exist. We recommend manufacturers produce additional small ETT size options at the intuitive intermediate sizes of 2.75 mm, 3.25 mm, and 3.75 mm ID in order to improve airway management for infants and small children. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Potential Pathways from Stigmatization and Externalizing Behavior to Anger and Dating Aggression in Sexually Abused Youth

ERIC Educational Resources Information Center

Feiring, Candice; Simon, Valerie A.; Cleland, Charles M.; Barrett, Ellen P.

2013-01-01

Although experiencing childhood sexual abuse (CSA) puts youth at risk for involvement in relationship violence, research is limited on the potential pathways from CSA to subsequent dating aggression. The current study examined prospective pathways from externalizing behavior problems and stigmatization (abuse-specific shame and self-blame…

VarMod: modelling the functional effects of non-synonymous variants

PubMed Central

Pappalardo, Morena; Wass, Mark N.

2014-01-01

Unravelling the genotype–phenotype relationship in humans remains a challenging task in genomics studies. Recent advances in sequencing technologies mean there are now thousands of sequenced human genomes, revealing millions of single nucleotide variants (SNVs). For non-synonymous SNVs present in proteins the difficulties of the problem lie in first identifying those nsSNVs that result in a functional change in the protein among the many non-functional variants and in turn linking this functional change to phenotype. Here we present VarMod (Variant Modeller) a method that utilises both protein sequence and structural features to predict nsSNVs that alter protein function. VarMod develops recent observations that functional nsSNVs are enriched at protein–protein interfaces and protein–ligand binding sites and uses these characteristics to make predictions. In benchmarking on a set of nearly 3000 nsSNVs VarMod performance is comparable to an existing state of the art method. The VarMod web server provides extensive resources to investigate the sequence and structural features associated with the predictions including visualisation of protein models and complexes via an interactive JSmol molecular viewer. VarMod is available for use at http://www.wasslab.org/varmod. PMID:24906884

Protein Supplementation Does Not Further Increase Latissimus Dorsi Muscle Fiber Hypertrophy after Eight Weeks of Resistance Training in Novice Subjects, but Partially Counteracts the Fast-to-Slow Muscle Fiber Transition.

PubMed

Paoli, Antonio; Pacelli, Quirico F; Cancellara, Pasqua; Toniolo, Luana; Moro, Tatiana; Canato, Marta; Miotti, Danilo; Neri, Marco; Morra, Aldo; Quadrelli, Marco; Reggiani, Carlo

2016-06-01

The response to resistance training and protein supplementation in the latissimus dorsi muscle (LDM) has never been investigated. We investigated the effects of resistance training (RT) and protein supplementation on muscle mass, strength, and fiber characteristics of the LDM. Eighteen healthy young subjects were randomly assigned to a progressive eight-week RT program with a normal protein diet (NP) or high protein diet (HP) (NP 0.85 vs. HP 1.8 g of protein·kg(-1)·day(-1)). One repetition maximum tests, magnetic resonance imaging for cross-sectional muscle area (CSA), body composition, and single muscle fibers mechanical and phenotype characteristics were measured. RT induced a significant gain in strength (+17%, p < 0.0001), whole muscle CSA (p = 0.024), and single muscle fibers CSA (p < 0.05) of LDM in all subjects. Fiber isometric force increased in proportion to CSA (+22%, p < 0.005) and thus no change in specific tension occurred. A significant transition from 2X to 2A myosin expression was induced by training. The protein supplementation showed no significant effects on all measured outcomes except for a smaller reduction of 2X myosin expression. Our results suggest that in LDM protein supplementation does not further enhance RT-induced muscle fiber hypertrophy nor influence mechanic muscle fiber characteristics but partially counteracts the fast-to-slow fiber shift.

The Cycle of Abuse: When Victims Become Offenders.

PubMed

Plummer, Malory; Cossins, Annie

2016-07-19

Various psychological theories exist in the literature to explain the behavior of men who commit child sex offences, including the belief that child sexual abuse (CSA) is a predisposing factor for the transition from victim to offender. These theories are, however, unable to explain the fact that while most victims of CSA are female, most perpetrators of CSA are male. The sex specificity of CSA in terms of victims and offenders suggests that the experience of CSA and its psychosocial effects may be different for boys, compared to girls. We hypothesize that CSA experiences may involve risk factors that affect the development of sexually abusive behavior for boys, rather than girls. Our aim was to determine whether the literature provides evidence of a cycle of abuse from victim to offender, and, if so, to document its characteristics. We undertook a comprehensive literature review of studies on both victims and offenders, including studies which revealed the following: age of onset of CSA, duration of abuse, gender of the abuser, the relationship between victim and abuser, grooming behaviors, the types and severity of abuse, and disclosure of abuse. While we found no evidence for the existence of a cycle of abuse for female CSA victims, we discovered evidence to support the existence of a cycle of abuse for male CSA victims who had experienced particular abuse characteristics. As an original contribution to the literature, we identified four factors that may be associated with a boy's transition from victim to offender as well as the methodological issues to be addressed in future research. Based on criminological theories, we argue that these four factors share a common theme, that is, that they represent experiences of power (for the abuser) and powerlessness (for the victim). © The Author(s) 2016.

The economic burden of child sexual abuse in the United States.

PubMed

Letourneau, Elizabeth J; Brown, Derek S; Fang, Xiangming; Hassan, Ahmed; Mercy, James A

2018-05-01

The present study provides an estimate of the U.S. economic impact of child sexual abuse (CSA). Costs of CSA were measured from the societal perspective and include health care costs, productivity losses, child welfare costs, violence/crime costs, special education costs, and suicide death costs. We separately estimated quality-adjusted life year (QALY) losses. For each category, we used the best available secondary data to develop cost per case estimates. All costs were estimated in U.S. dollars and adjusted to the reference year 2015. Estimating 20 new cases of fatal and 40,387 new substantiated cases of nonfatal CSA that occurred in 2015, the lifetime economic burden of CSA is approximately $9.3 billion, the lifetime cost for victims of fatal CSA per female and male victim is on average $1,128,334 and $1,482,933, respectively, and the average lifetime cost for victims of nonfatal CSA is of $282,734 per female victim. For male victims of nonfatal CSA, there was insufficient information on productivity losses, contributing to a lower average estimated lifetime cost of $74,691 per male victim. If we included QALYs, these costs would increase by approximately $40,000 per victim. With the exception of male productivity losses, all estimates were based on robust, replicable incidence-based costing methods. The availability of accurate, up-to-date estimates should contribute to policy analysis, facilitate comparisons with other public health problems, and support future economic evaluations of CSA-specific policy and practice. In particular, we hope the availability of credible and contemporary estimates will support increased attention to primary prevention of CSA. Copyright © 2018. Published by Elsevier Ltd.

Stable bioavailability of cyclosporin A, regardless of food intake, from soft gelatin capsules containing a new self-nanoemulsifying formulation.

PubMed

Yang, S G; Kim, D D; Chung, S J; Shim, C K

2006-05-01

We recently succeeded in preparing soft gelatin capsules containing a new self-nanoemulsifying formulation consisting of cyclosporin A (CsA), triacetin, polyoxyl 40 hydrogenated castor oil, polysorbate 20, medium chain triglycerides and medium chain mono- and diglycerides. The soft capsules containing the new formulation exhibited a significantly improved physical stability in terms of the appearance of the gelatin capsule shells and the composition of the fill mass during long-term storage, compared to commercially available soft capsules containing CsA, in which ethanol was employed as a cosolvent of CsA. In the present study, the influence of a fat-rich meal on the bioavailability of CsA from the soft capsule containing the new formulation (test drug) was evaluated and the results compared to those obtained with a representative soft capsule of CsA. A randomized, open-label, 3-way crossover study was performed in the test capsules and reference soft capsules, in a fasted state or after a fat-rich breakfast. 18 healthy male volunteers received a single dose of the reference formulation (Neoral, Novartis AG, Basel, Switzerland) or test formulation (2 capsules each, 200 mg as CsA) with 240 ml of water with a 1-week washout period between the treatments, after a fat-rich (670 kcal, 45 g fat) breakfast (for the test drug, Treatment A; for the reference drug, Treatment B) or a 12-h fasting (for the test drug, Treatment C). Serial blood samples, collected over a 24-h period after the administration, were assayed for blood CsA concentrations using a specific monoclonal radioimmunoassay. The differences in bioavailability parameters (i.e., AUC(0-24h), AUC(0-infinity) and C(max)) between the treatments were within the range of 80-125% of the reference treatment. An analysis of variance (ANOVA) revealed no significant differences (p > 0.05) between subjects, formulations or periods. The 90% confidence intervals (CI) indicated that the differences between the treatments (Treatments A and B, Treatments A and C) were also within the criteria. These results indicate that the bioavailability of CsA from the test drug is equivalent to reference in the fed state, and is likely to be less influenced by a fat-rich meal. Therefore, the new formulation of CsA using triacetin appears to have an advantage over the commercial soft capsules of CsA using a volatile cosolvent such as ethanol.

Use of commercial soil amendments in initial soils (II) - Impact on soil respiratory and carbon isotopic characteristics

NASA Astrophysics Data System (ADS)

Nii-Annang, S.; Rodionov, A.; Dilly, O.; Bens, O.; Raab, T.; Hüttl, R. F.

2009-04-01

The search for viable re-cultivation techniques for the reclamation of large scale soil disturbances induced by mining of mineral resources has increasingly received attention in recent times. These techniques should favour plant growth under dry conditions and under nutrient-poor substrates; a problem in the lignite mining district in Lusatia, Germany. Substrates with basal respiration around 0.04 µg CO2 g-1 h-1, which is relatively low compared to mature soils, were amended with two nutrient rich commercial soil additives (CSA 1 and CSA 2). The CSA 1 is a synthetic-mineral mixture and CSA 2 an organo-mineral mixture. The amendment stimulated basal respiration based on both carbon dioxide evolution and oxygen uptake by 150 and 125 % for SCA 1 and CSA 2, respectively when 1 % of each additive was thoroughly mixed with substrate in a laboratory study. The stimulating effect was evident after glucose addition to CSA 2. The CSA 1 application in the field at lower rates still showed apparent stimulation of soil respiratory activities after one year. Similarly, the organo-mineral-mixture has prominent effects on basal respiration and substrate-induced respiration when glucose was added. We concluded that the commercial additives used as long-term amelioration techniques increased both nutrient preservation and, to some extent, soil microbial activity.

Biomaterials Approaches for Utilizing the Regenerative Potential of the Peripheral Nerve Injury Microenvironment

NASA Astrophysics Data System (ADS)

Wrobel, Melissa Renee

Clinically available treatments are insufficient to achieve full functional recovery in large (> 3cm) peripheral nerve injuries (PNI). The objectives in this thesis were 1) to study often overlooked elements of intrinsic PNI repair including release of inhibitory CSPGs and post-injury responses of inflammatory macrophages and dedifferentiated Schwann cells; 2) to create biomaterial scaf-folds featuring topographical and adhesive cues to enhance neurite outgrowth; and 3) to test the ability of those cues to direct macrophages and Schwann cells towards a pro-regenerative phe-notype. It is hypothesized that recapitulating the positive and negative cues of the PNI microenvi-ronment can better improve regeneration. The effect of a characteristic CSPG, Chondroitin Sul-fate A (CSA), was tested on neurite dynamics of dissociated chick embryo dorsal root ganglion (DRG) neurons using time lapse video microscopy. DRG growth was recorded on different ad-hesive substrates, including a novel, porcine-derived spinal cord matrix (SCM). The SCM signifi-cantly increased neurite extension, reduced neurite stalling, and mitigated CSA inhibition. Flow cytometry was used to measure changes in cell-substrate binding receptor expression in the neurons. Results showed a significant increase in Syndecan-3 receptor expression in neurons treated with CSA, suggesting a possible priming of the cells for regrowth. The CSA was success-fully immobilized within electrospun hyaluronic acid (HA) nanofibers using a methacrylation re-action. Blended electrospinning was used to create scaffolds featuring the CSA and SCM cues. Results showed significantly increased neurite outgrowth on scaffolds with the SCM and low levels of CSA. Higher incorporation of CSA maintained its inhibitory properties. Next the CSA, SCM, and HA fiber cues were tested for their effects on macrophage and Schwann cell pheno-type. It was hypothesized that one or more of the cues would accelerate the macrophages return to rest following classical activation (M1/pro-inflammatory) with lipopolysaccharide (LPS; 1microg/mL) and would accelerate the transformation of Schwann cells from an immature state fol-lowing injury to a mature/pro-myelinating one. Cell phenotypes were functionally assessed using quantified reverse transcription polymerase chain reaction (qRT-PCR), immunofluorescence, and sandwich-ELISA based antibody arrays to measure changes in mRNA expression, mor-phology, and cytokine release, respectively. Macrophages cultured with the SCM and HA fibers had significantly reduced M1 gene expression, released lower levels of M1 cytokines (IL-1a, RANTES and TFN-a) and assumed an elongated morphology indicative of M2. These cues also induced changes in the Schwann cells including significantly reduced area, increased elongation, decreased expression of immature genes (GFAP) and increased expression of mature genes (Krox20 and Oct6). These results suggest that the SCM and HA nanofibers could trigger non-neuronal cells towards regenerative programs more quickly than traditional PNI interventions. Changes induced by biomaterials have distinct benefits over the use of immunomodulatory cy-tokines and would be a novel approach to direct repair. Our collective studies offer improved in-sight into the endogenous potential of the injured peripheral nerve and offer ways to incorporate intrinsic repair cues into a biomaterial system for treating large gaps.

Cyclosporine A regulate oxidative stress-induced apoptosis in cardiomyocytes: mechanisms via ROS generation, iNOS and Hsp70

PubMed Central

Chen, Huei-Wen; Chien, Chiang-Ting; Yu, Sung-Liang; Lee, Yuan-Teh; Chen, Wen-Jone

2002-01-01

Previous study suggested that cyclosporine A (CsA) could partially reduce ischaemia/reperfusion-induced injury in isolated heart, but the mechanism was still unclear. In this study, the possible mechanisms of cyclosporine A in regulating oxidative stress-induced cardiomyocyte apoptosis were examined. Morphological (cell shrinkage, apoptotic body formation, and DNA fragmentation) and biochemical (annexin-V staining for exposed phosphatidylserine residues) evidences showed that both hydrogen peroxide (H2O2) and hypoxia/reoxygenation could induce apoptotic change in the embryonal rat heart myoblast-derived cells (H9c2). These effects were inhibited by pre-treatment with CsA at concentration of 0.01–1.0 μM for 24 h, but were increased with 10.0 μM CsA. While examining the mechanisms of CsA in protecting cardiomyocyte apoptosis, we found that the collapse of mitochondria membrane potential (ΔΨm) induced by oxidative stress was partially reversed by CsA (0.01–1.0 μM). Compared to the control, CSA at the concentration of 0.1 and 10.0 μM significantly increased the level of intracellular reactive oxygen species (ROS) to 117.2±12.4% and 234.4±9.3%, respectively. Co-incubating with the antioxidant, ascorbic acid (10.0 μM), could partially reduce the protective effect of CsA (0.01–1.0 μM) and the toxic effect of 10.0 μM CsA. Pre-treatment with CsA at concentration of 0.01–1.0 μM for 24 h produced up-regulation of heat shock protein 70 (Hsp 70), inducible nitric oxide synthase (iNOS) and also induced NO production, indicating that these factors might be associated with the cell protective effects of CsA. These results suggest that CsA could protect the oxidative stress-induced cardiomyocyte apoptosis not only by preventing the loss of ΔΨm in mitochondria, but also through ROS generation, Hsp70, and iNOS up-regulation. PMID:12411407

Prevalence and predictors of Axis I disorders in a large sample of treatment-seeking victims of sexual abuse and incest.

PubMed

McElroy, Eoin; Shevlin, Mark; Elklit, Ask; Hyland, Philip; Murphy, Siobhan; Murphy, Jamie

2016-01-01

Childhood sexual abuse (CSA) is a common occurrence and a robust, yet non-specific, predictor of adult psychopathology. While many demographic and abuse factors have been shown to impact this relationship, their common and specific effects remain poorly understood. This study sought to assess the prevalence of Axis I disorders in a large sample of help-seeking victims of sexual trauma, and to examine the common and specific effects of demographic and abuse characteristics across these different diagnoses. The participants were attendees at four treatment centres in Denmark that provide psychological therapy for victims of CSA (N=434). Axis I disorders were assessed using the Millon Clinical Multiaxial Inventory-III (MCMI-III). Multivariate logistic regression analysis was used to examine the associations between CSA characteristics (age of onset, duration, number of abusers, number of abusive acts) and 10 adult clinical syndromes. There was significant variation in the prevalence of disorders and the abuse characteristics were differentially associated with the outcome variables. Having experienced sexual abuse from more than one perpetrator was the strongest predictor of psychopathology. The relationship between CSA and adult psychopathology is complex. Abuse characteristics have both unique and shared effects across different diagnoses.

Effects of seasonal variations on antioxidant activity of pink guava fruits

NASA Astrophysics Data System (ADS)

Ahmad, Haniza; Abdullah, Aminah

2014-09-01

This study aimed to evaluate the effects of seasonal variations during rainy and hot season on antioxidant activity of pink guava fruits in approximately one year duration specifically on November 2012, December 2012, January 2013, March 2013, April 2013, May 2013, July 2013, August 2013 and November 2013. Fruit samples (Sungkai and Semenyih variants) were collected from Sime Darby Beverages plantation located in Sitiawan. The fruits were samples for 9 times from Nov 2012 to Nov 2013 except Feb 2013, Jun 2013, Sept 2013 and Oct 2013. Fruits were peeled, seeded and blended into uniform puree. Samples were then extracted for its antioxidant activity determination using 50% acetone. Antioxidant activity was evaluated using total phenolic compounds (TPC) assay, ferric-reducing antioxidant power assay (FRAP) and 1,1-diphenyl1-2-picrylhydrazyl free radical-scavenging capacity (DPPH). Analysis was conducted using 96-well microplate spectrophotometer UV. The highest TPC result was Semenyih var recorded 2192.80 mg GAE/100g FW whilst Sungkai var 1595.98 mg GAE/100g FW both on July 2013 with rainfall was at the least (45mm) and the lowest for Sungkai var was 792.75 mg GAE/100g FW and 1032.41 mg GAE/100g FW for Semenyih var, both on Nov 2012 with 185mm rainfall. There were significant negative correlation between TPC and rainfall (mm) for both Semenyih var (r = - 0.699, p<0.005, r2 = 0.489) and Sungkai var (r = -0.72, p<0.05, r2 = 0.531). The highest FRAP result (mg TE/100g FW) was 1677.74 for Semenyih var (Aug 2013, rainfall = 160.5mm) and the highest FRAP for Sungkai var was 1104.60 (Jul 2013, rainfall = 45.0mm) whereas the lowest for Semenyih and Sungkai var was 1090.22 (Mar 2013, rainfall = 97.5mm) and 767.88 (Nov 2012, rainfall = 185.50) respectively. There was weak negative correlation between FRAP and rainfall(mm) for both Sungkai var (r = - 0.324, p<0.05, r2 = 0.105) and Semenyih var (r = - 0.362, p<0.05, r2 = 0.132). The highest DPPH for Semenyih var was 88.40% (Aug 2013, rainfall = 160.50mm) whilst Sungkai var was 79.71% (July 2013, rainfall = 45.0mm). There was no significant difference in correlation coefficient of DPPH and rainfall (mm). Meanwhile, there was significant correlation between TPC and FRAP (r = 0.794, p<0.05, r2 = 0.629), TPC and DPPH (r = 0.901,p<0.05, r2= 0.812) and FRAP and DPPH (r = 0.889, p<0.05, r2 = 0.792).

[Child sexual abuse: a study among 892 female students of a medical school].

PubMed

Chen, Jing-qi; Han, Ping; Dunne, Michael P

2004-01-01

This study was designed to ascertain the prevalence of child sexual abuse (CSA) among female students of a medical school and to explore the impact of CSA on the mental health and health related risk behaviors of the victims being sexually abused and to provide useful reference for CSA prevention. A cross-sectional survey was carried out among 892 female students from a medical school by anonymous self-administered questionnaire during Oct. 2002. The questionnaire used for this study mainly included (1) general demographic information; (2) sexual experiences; (3) 12 forms of CSA. In this study, cases of CSA were defined as those who answered positively to one or more of the 12 questions relating to childhood sexual experiences (including non-physical contact CSA and physical contact CSA) occurring before age 16 with a person when a child did not want to. (4) Center for Epidemiologic Studies (CES)-Depression Scale; (5) Self Esteem Scale; (6) Risk Behaviors; (7) Health status' self-evaluation. Survey procedures were designed to protect students' privacy by allowing anonymous and voluntary participation. Students were seated separately, completed the self-administered questionnaire in their classrooms during a regular class period. Respondents were encouraged to participate in this survey, but given the sensitive nature of the subject, they could skip portion of the questionnaire if they were not comfortable with the questions. The completed questionnaires were sealed in envelopes by students themselves (the envelope was distributed with questionnaire at the same time), and then collected together. Data were analysed by using the Statistical Package for the Social Sciences software. Frequency, percentage, Chi-square test and t-test of statistics were used to analyze the CSA prevalence and explore the influence of CSA on mental health of students. Among 892 female students, 25.6% reported having experienced CSA (any one of 12 forms non-physical contact and physical contact CSA) before the age of 16 years. The median age at first episode was 12 years. Comparing the rates of CSA of female students in different parents' education level, between one-child in a family and more than one-child in a family, among rural area, county and city, there were no significant differences. Compared to the students who had not experienced CSA, the students who had experienced CSA reported higher levels of depression (CES-D score 18.78 vs. 16.68, t = 2.81, P = 0.005), lower levels of health status self-evaluation (score 3.53 vs. 3.78, t = 2.94, P = 0.003); higher proportion of subjects who reported drinking alcohol and having ever smoked during the past 30 days (drinking 32.7% vs. 22.9%, chi(2) = 8.51, P = 0.004; smoking 8.8% vs. 4.4%, chi(2) = 6.17, P = 0.013); a higher percentage engaged in sexual intercourse (19.3% vs. 5.9%, chi(2) = 33.48, P = 0.000); ever seriously considered attempting suicide (23.7% vs. 15.4%, chi(2) = 8.09, P = 0.004), making a plan about how would attempt suicide (17.9% vs. 9.7%, chi(2) = 10.62, P = 0.001), being threatened or injured by someone with a weapon such as a knife, or club on school property (3.5% vs. 1.1%, chi(2) = 6.17, P = 0.013), being involved in physical fight (16.7% vs. 5.6%, chi(2) = 27.05, P = 0.000) during the 12 months preceding the survey. The results further showed that the CSA of girls in our country is not uncommon, as reported before in our country and in the other countries and is associated with poor mental health and risky behaviors. The findings highlight the urgent need for the further research into CSA epidemiological characteristics, health services for the victims abused sexually, sexual abuse prevention programs in schools and the general community in China.

Multisite analytical evaluation of the Abbott ARCHITECT cyclosporine assay.

PubMed

Wallemacq, Pierre; Maine, Gregory T; Berg, Keith; Rosiere, Thomas; Marquet, Pierre; Aimo, Giuseppe; Mengozzi, Giulio; Young, Julianna; Wonigeit, Kurt; Kretschmer, Robert; Wermuth, Bendicht; Schmid, Rainer W

2010-04-01

The objective of this study was to evaluate the analytical performance of the Abbott ARCHITECT Cyclosporine (CsA) immunoassay in 7 clinical laboratories in comparison to liquid chromatography/tandem mass spectrometry (LC/MS/MS), Abbott TDx, Cobas Integra 800, and the Dade Dimension Xpand immunoassay. The ARCHITECT assay uses a whole blood specimen, a pretreatment step with organic reagents to precipitate proteins and extract the drug, followed by a 2-step automated immunoassay with magnetic microparticles coated with anti-CsA antibody and an acridinium-CsA tracer. Imprecision testing at the 7 evaluation sites gave a range of total % coefficient of variations of 7.5%-12.2% at 87.5 ng/mL, 6.6%-14.3% at 411 ng/mL, and 5.2%-10.7% at 916 ng/mL. The lower limit of quantification ranged from 12 to 20 ng/mL. Purified CsA metabolites AM1, AM1c, AM4N, AM9, and AM19 were tested in whole blood by the ARCHITECT assay and showed minimal cross-reactivity at all 7 sites. In particular, AM1 and AM9 cross-reactivity in the ARCHITECT assay, ranged from -2.5% to 0.2% and -0.8% to 2.2%, respectively, and was significantly lower than for the TDx assay, in which the values were 3.2% and 16.1%, respectively. Comparable testing of metabolites in the Dade Dimension Xpand assay at 2 evaluation sites showed cross-reactivity to AM4N (6.4% and 6.8%) and AM9 (2.6% and 3.6%) and testing on the Roche Integra 800 showed cross-reactivity to AM1c (2.4%), AM9 (10.7%), and AM19 (2.8%). Cyclosporine International Proficiency Testing Scheme samples, consisting of both pooled specimens from patients receiving CsA therapy as well as whole-blood specimens supplemented with CsA, were tested by the ARCHITECT assay at 6 sites and showed an average bias of -24 to -58 ng/mL versus LC/MSMS CsA and -2 to -37 ng/mL versus AxSYM CsA. Studies were performed with the ARCHITECT CsA assay on patient specimens with the following results: ARCHITECT CsA assay versus LC/MSMS, average bias of 31 ng/mL; ARCHITECT versus the Dade Dimension assay (4 sites), average biases of -7 to -228 ng/mL; ARCHITECT versus AxSYM and TDx, average biases of -4 and -53 ng/mL, respectively. Spearman correlation coefficients were >or=0.89. The ARCHITECT CsA assay has significantly reduced CsA metabolite interference relative to other immunoassays and is a convenient and sensitive semiautomated method to measure CsA in whole blood.

Gendered pathways from child sexual abuse to sexual aggression victimization and perpetration in adolescence and young adulthood.

PubMed

Krahé, Barbara; Berger, Anja

2017-01-01

This study aimed to examine the pathways from child sexual abuse to sexual assault victimization and perpetration in adolescence and early adulthood, considering risky sexual behavior and lowered sexual self-esteem as mediator variables. In a two-wave longitudinal study with 2251 college students in Germany, male and female participants provided reports of sexual aggression victimization and perpetration since age 14 (T1) and again a year later (T2), covering the last 12 months. In addition, child sexual abuse (CSA; before the age of 14), risky sexual behavior, and sexual self-esteem were assessed at T1, and risky sexual behavior and sexual-self-esteem were assessed again at T2. Experience of CSA was significantly associated with greater likelihood of sexual aggression victimization and perpetration, lower sexual self-esteem, and more risky sexual behavior in both gender groups at T1 and was directly related to victimization at T2 among male participants. In both gender groups, CSA indirectly contributed to a higher probability of sexual victimization at T2 via its impact on victimization T1. In males, the indirect path from CSA to T2 perpetration via T1 perpetration was also significant. Through its negative impact on sexual self-esteem, CSA indirectly increased the probability of sexual victimization among women and the probability of sexual aggression perpetration among men. Risky sexual behavior mediated the pathway from CSA to sexual victimization at T2 for men and women and the pathway from CSA to sexual aggression perpetration for women. The findings contribute to the understanding of gendered effects of CSA on revictimization and the victim-to-perpetrator cycle. Copyright © 2016 Elsevier Ltd. All rights reserved.

Endothelin ETA receptor/lipid peroxides/COX-2/TGF-β1 signalling underlies aggravated nephrotoxicity caused by cyclosporine plus indomethacin in rats.

PubMed

Helmy, Maged W; El-Gowelli, Hanan M; Ali, Rabab M; El-Mas, Mahmoud M

2015-09-01

Cyclosporine (CSA) and non-steroidal anti-inflammatory drugs (NSAIDs) are co-prescribed for some arthritic conditions. We tested the hypothesis that this combined regimen elicits exaggerated nephrotoxicity in rats via the up-regulation of endothelin (ET) receptor signalling. The effects of a 10 day treatment with CSA (20 mg · kg(-1) · day(-1)), indomethacin (5 mg · kg(-1) · day(-1)) or their combination on renal biochemical, inflammatory, oxidative and structural profiles were assessed. The roles of ETA receptor and COX-2 pathways in the interaction were evaluated. Oral treatment with CSA or indomethacin elevated serum urea and creatinine, caused renal tubular atrophy and interstitial fibrosis, increased renal TGF-β1, and reduced immunohistochemical expressions of ETA receptors and COX-2. CSA, but not indomethacin, increased renal ET-1, the lipid peroxidation product malondialdehyde (MDA) and GSH activity. Compared with individual treatments, simultaneous CSA/indomethacin exposure caused: (i) greater elevations in serum creatinine and renal MDA; (ii) loss of the compensatory increase in GSH; (iii) renal infiltration of inflammatory cells and worsening of fibrotic and necrotic profiles; and (iv) increased renal ET-1 and decreased ETA receptor and COX-2 expressions. Blockade of ETA receptors by atrasentan ameliorated the biochemical, structural, inflammatory and oxidative abnormalities caused by the CSA/indomethacin regimen. Furthermore, atrasentan partly reversed the CSA/indomethacin-evoked reductions in the expression of ETA receptor and COX-2 protein. The exaggerated oxidative insult and associated dysregulation of the ETA receptor/COX-2/TGF-β1 signalling might account for the aggravated nephrotoxicity caused by the CSA/indomethacin regimen. The potential renoprotective effect of ETA receptor antagonism might be exploited therapeutically. © 2015 The British Pharmacological Society.

A Comparison of Ultrasound and MRI Measurements of the Cross-Sectional Area of the Median Nerve at the Wrist.

PubMed

Hersh, Beverly; D'Auria, Jennifer; Scott, Michael; Fowler, John R

2018-05-01

Ultrasound (US) measurement of cross-sectional area (CSA) of the median nerve has emerged as a viable alternative to electromyography/nerve conduction studies (EMG/NCS) for diagnosis of carpal tunnel syndrome (CTS). The purpose of this study is to compare CSA of the median nerve between US and MRI using current MRI and US technology. The null hypothesis is there is no difference between US and MRI CSA measurements. The study design was an observational cohort, enrolling patients presenting to clinic with MRI of the wrist. Participants with clinical signs and symptoms of CTS were excluded. The CSA measurements of the median nerve on MRI T1-weighted axial images were performed by a hand fellow blinded to results of US measurements, and US measurement of median nerve CSA was performed by a hand fellowship trained surgeon blinded to results of the MRI measurements. Results were analyzed via percent error, Pearson correlation, and t tests. Twenty participants were enrolled with mean age of 29.4 years. Four left wrists and 16 right wrists were measured. The US mean CSA of the median nerve was 6.8 mm 2 (±2.330 mm 2 ). The MRI mean CSA of the median nerve was 6.8 mm 2 (±2.153 mm 2 ), P = .442. Pearson correlation between modalities was 0.93, suggesting near-perfect correlation. Mean percent error was 8.8%. Results of this study suggest that US is an accurate method to measure CSA of the median nerve at the carpal tunnel inlet. The mean difference between US and MRI was unlikely to be clinically significant.

Relation of Natriuretic Peptide Concentrations to Central Sleep Apnea in Patients With Heart Failure

PubMed Central

Calvin, Andrew D.; Somers, Virend K.; van der Walt, Christelle; Scott, Christopher G.

2011-01-01

Background: Central sleep apnea (CSA) is frequent among patients with heart failure (HF) and associated with increased morbidity and mortality. Elevated cardiac filling pressures promote CSA and atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) secretion. We hypothesized that circulating natriuretic peptide concentrations predict CSA. Methods: Consecutive patients with HF (n = 44) with left ventricular ejection fraction (LVEF) ≤ 35% underwent polysomnography for detection of CSA. CSA was defined as an apnea-hypopnea index ≥ 15 with ≥ 50% central apneic events. The relation of natriuretic peptide concentrations to CSA was evaluated by estimation of ORs and receiver operator characteristics (ROCs). Results: Twenty-seven subjects (61%) had CSA, with men more frequently affected than women (73% vs 27%; OR, 7.1; P = .01); given that only three women had CSA, further analysis was restricted to men. Subjects with CSA had higher mean ANP (4,336 pg/mL vs 2,510 pg/mL, P = .03) and BNP concentrations (746 pg/mL vs 379 pg/mL, P = .05). ANP and BNP concentrations were significantly related to CSA (OR, 3.7 per 3,000 pg/mL, P = .03 and OR, 1.5 per 200 pg/mL, P = .04, respectively), whereas age, LVEF, and New York Heart Association functional class were not. Concentrations of ANP and BNP were predictive of CSA as ROC demonstrated areas under the curve of 0.75 and 0.73, respectively. Conclusions: Risk of CSA is related to severity of HF. ANP and BNP concentrations performed similarly for detection of CSA; low concentrations appear associated with low risk for CSA in men. PMID:21636668

Ultrasonography has a diagnostic value in the assessment of cervical radiculopathy: A prospective pilot study.

PubMed

Takeuchi, Mikinobu; Wakao, Norimitsu; Hirasawa, Atsuhiko; Murotani, Kenta; Kamiya, Mitsuhiro; Osuka, Koji; Takayasu, Masakazu

2017-08-01

This study investigated the diagnostic accuracy of the difference in the cross-sectional areas (CSAs) of affected cervical nerve roots (NRs) for diagnosing cervical radiculopathy (CR). In total, 102 CR patients and 219 healthy volunteers were examined with ultrasound. The CSA of the cervical NR at each level was measured on the affected side and the contralateral side in CR patients by blinded ultrasonographic technicians. The difference between the CSAs of CR patients and normal volunteers and the difference in the laterality of CSA at the same affected level (ΔCSA) were calculated for each cervical level. The CSAs of the affected NRs in CR patients were significantly larger than those of the unaffected NRs in CR patients and those of the control group at the C5, C6 and C7 levels (P<0.005). ΔCSA was also significantly larger in the CR group at all levels (P<0.001). A receiver operating characteristic analysis demonstrated that the threshold values were 9.6 mm 2 (CSA) for C5NR and 15 mm 2 for both C6NR and C7NR. This study revealed that the CSAs of affected NRs were enlarged and that the laterality of the CSA (ΔCSA) was greater in CR patients than in control patients. • Cervical radiculopathy is diagnosed through ultrasonographic measurement of the CSAs. • The CSAs of affected nerve roots were significantly enlarged. • The ΔCSA in the CR group was significantly higher than in the control group. • Diagnostic CSA and ΔCSA thresholds were identified.

False Memory for Trauma-Related DRM Lists in Adolescents and Adults with Histories of Child Sexual Abuse

PubMed Central

Goodman, Gail S.; Ogle, Christin M.; Block, Stephanie D.; Harris, LaTonya S.; Larson, Rakel P.; Augusti, Else-Marie; Cho, Young Il; Beber, Jonathan; Timmer, Susan; Urquiza, Anthony

2014-01-01

The purpose of the present research was to examine Deese-Roediger-McDermott (DRM) false memory for trauma-related and nontrauma-related lists in adolescents and adults with and without documented histories of child sexual abuse (CSA). Individual differences in psychopathology and adult attachment were also explored. Participants were administered free recall and recognition tests after hearing CSA, negative, neutral, and positive DRM lists. In free recall, CSA and negative lists produced the most false memory. In sharp contrast, for recognition, CSA lists enjoyed the highest d’ scores. CSA-group adolescents who evinced greater PTSD symptoms had higher rates of false memory compared to: 1) nonCSA-group adolescents with higher PTSD symptom scores (free recall), and 2) CSA-group adolescents with lower PTSD symptom scores (recognition). Regression analyses revealed that individuals with higher PTSD scores and greater fearful-avoidant attachment tendencies showed less proficient memory monitoring for CSA lists. Implications for trauma and memory development and for translational research are discussed. PMID:23786687

Prevalence of Child Sexual Abuse Reported by a Cross-Sectional Sample of New Zealand Women

ERIC Educational Resources Information Center

Fanslow, Janet L.; Robinson, Elizabeth M.; Crengle, Sue; Perese, Lana

2007-01-01

Objective: The objective is to describe the prevalence of child sexual abuse (CSA) among women in New Zealand, document ethnic specific rates, and outline the frequency of abuse experienced and the most commonly identified perpetrators. Associations between CSA and later adverse consequences were also explored. Methods: Retrospective report from a…

Abuse-Specific Self-Schemas and Self-Functioning: A Prospective Study of Sexually Abused Youth

ERIC Educational Resources Information Center

Feiring, Candice; Cleland, Charles M.; Simon, Valerie A.

2010-01-01

Potential pathways from childhood sexual abuse (CSA) to negative self-schemas to subsequent dissociative symptoms and low global self-esteem were examined in a prospective longitudinal study of 160 ethnically diverse youth with confirmed CSA histories. Participants were interviewed at the time of abuse discovery, when they were 8 to 15 years of…

Kuipers sets up the CSA-CP in the U.S. Laboratory

NASA Image and Video Library

2012-01-26

ISS030-E-156455 (26 Jan. 2012) --- European Space Agency astronaut Andre Kuipers, Expedition 30 flight engineer, sets up the Compound Specific Analyzer - Combustion Products (CSA-CP) in the Destiny laboratory of the International Space Station. The purpose of the analyzer is to measure the concentrations of carbon monoxide, hydrogen cyanide, hydrogen chloride and oxygen.

Outcomes of Child Sexual Abuse as Predictors of Later Sexual Victimization

ERIC Educational Resources Information Center

Reese-Weber, Marla; Smith, Dana M.

2011-01-01

The association between a history of child sexual abuse (CSA) and specific negative outcomes (attachment, feelings of power, and self-esteem) was explored as was the relationship between those negative outcomes and sexual victimization during the first semester of college. Two groups of freshman college women (67 who had experienced CSA and 55 who…

Tensor sufficient dimension reduction

PubMed Central

Zhong, Wenxuan; Xing, Xin; Suslick, Kenneth

2015-01-01

Tensor is a multiway array. With the rapid development of science and technology in the past decades, large amount of tensor observations are routinely collected, processed, and stored in many scientific researches and commercial activities nowadays. The colorimetric sensor array (CSA) data is such an example. Driven by the need to address data analysis challenges that arise in CSA data, we propose a tensor dimension reduction model, a model assuming the nonlinear dependence between a response and a projection of all the tensor predictors. The tensor dimension reduction models are estimated in a sequential iterative fashion. The proposed method is applied to a CSA data collected for 150 pathogenic bacteria coming from 10 bacterial species and 14 bacteria from one control species. Empirical performance demonstrates that our proposed method can greatly improve the sensitivity and specificity of the CSA technique. PMID:26594304

Large Critical Shoulder Angle Has Higher Risk of Tendon Retear After Arthroscopic Rotator Cuff Repair.

PubMed

Li, Hong; Chen, Yuzhou; Chen, Jiwu; Hua, Yinghui; Chen, Shiyi

2018-05-01

The critical shoulder angle (CSA) is the angle created between the superior and inferior bone margins of the glenoid and the most lateral border of the acromion. A few studies recently investigated the relation between CSA and functional outcomes after rotator cuff repair. However, there is a lack of research investigating the effect of CSA on postoperative tendon integrity after rotator cuff repair. To assess the effects of the CSA on postoperative tendon integrity after rotator cuff repair. Cohort study; Level of evidence, 3. All patients who underwent rotator cuff repair for full-thickness supraspinatus tears by 1 senior surgeon between January 2010 and January 2014 were included in this study. All patients had standardized anteroposterior shoulder radiographs the day before surgery. CSA and acromial index (AI) were measured. AI was derived by measuring the distance from the glenoid plane to the lateral border of the acromion and dividing it by the distance from the glenoid plane to the lateral aspect of the humeral head. Functional scores-including American Shoulder and Elbow Surgeons shoulder evaluation form, modified University of California at Los Angeles score, Constant-Murley score, and visual analog scale for pain-were used to evaluate shoulder function at a minimum follow-up of 2 years. Meanwhile, magnetic resonance imaging examinations were performed to evaluate rotator cuff integrity according to the Sugaya method and the signal/noise quotient (SNQ) of the rotator cuff tendon. A total of 90 patients were included in this study: 42 patients with a single-row repair and 48 with a double-row repair. There was a significant positive correlation between CSA or AI and tendon SNQ. On the basis of CSA, the patients were divided into 2 groups: large CSA (>38°) and control (CSA ≤38°). At final follow-up, the large CSA group and the control CSA group demonstrated no significant differences in American Shoulder and Elbow Surgeons, University of California at Los Angeles, Constant, and visual analog scale scores. Postoperative magnetic resonance imaging revealed that the large CSA group had 9 cases of retear, with a significantly higher retear rate than the control group (15% vs 0%, P = .03). Furthermore, the tendon SNQ of the large CSA group was significantly greater than that of the control group. CSA did not appear to influence postoperative functional outcomes, while those in the large CSA group had poor tendon integrity after rotator cuff repair. These findings indicate that a large CSA is associated with an increased risk of rotator cuff tendon retear after repair.

Evaluation of hepatitis B virus replication and proteomic analysis of HepG2.2.15 cell line after cyclosporine A treatment.

PubMed

Xie, Hai-Yang; Xia, Wei-Liang; Zhang, Chun-Chao; Wu, Li-Ming; Ji, Hao-Feng; Cheng, Yu; Zheng, Shu-Sen

2007-07-01

The effect of cyclosporine A (CsA) on hepatitis B virus (HBV) replication was investigated, and proteomics expression differentiation after CsA treatment was studied in order to provide clues to explore the effect of CsA on HBV replication. Methyl thiazolyl tetrazolium (MTT) assay was used to evaluate the cytotoxicity of CsA. The HBV replication level in the HBV genomic DNA transfected HepG2.2.15 cell line was determined by an ELISA analysis of hepatitis B surface antigens (HBsAg) and Hepatitis B e antigens (HBeAg) in culture supernatant, while the intracellular HBV DNA replication level was analyzed by slot blot hybridization. Two-dimensional electrophoresis was used to investigate the alteration of protein expression in HepG2.2.15 after CsA treatment in vitro. The differentially-expressed proteins were identified by Matrix-assisted laser desorption/ionization-time of flight mass spectrometry combined with an online database search. CsA was able to inhibit the expression of HBsAg, HBeAg, and HBV DNA replication in vitro in a dose-dependent manner. A proteomics analysis indicated that the expression of 17 proteins changed significantly in the CsA treatment group compared to the control group. Eleven of the 17 proteins were identified, including the overexpression of eukaryotic translation initiation factors (eIF) 3k, otubain 1, 14.3.3 protein, eIF2-1 alpha, eIF5A, and the tyrosine 3/tryptophan 5-mono-oxygenase activation protein in CsA-treated HepG2.2.15 cells. The downregulation of the ferritin light subunit, erythrocyte cytosolic protein of 51 kDa (ECP-51), stathmin 1/oncoprotein, adenine phosphoribosyl-transferase, and the position of a tumor protein, translationally controlled 1, was shifted, suggesting it had undergone posttranslational modifications. Our study identified the inhibitory effect of CsA on HBV replication, and found that a group of proteins may be responsible for this inhibitory effect.

Short-term systemic insulin-like growth factor-1 is unable to prevent cyclosporin A-induced osteopenia in the rat.

PubMed

Mann, G N; Sass, D A; Chen, H K; Buchinsky, F J; Bryer, H P; Ma, Y F; Jee, W S; Rucinski, B; Epstein, S

1996-07-01

Immunosuppression with cyclosporin A (CsA) is effective in a number of immune-mediated diseases and in preventing rejection following organ transplantation. We have repeatedly demonstrated that CsA in the rat model produces accelerated bone remodelling with net bone loss, best characterized in trabecular bone. IGF-I holds promise as a treatment for various osteopenic conditions. Although currently a subject of much controversy, various studies have suggested that in vivo it is anabolic to cortical as well as trabecular bone. The purpose of this study was, in part, to further characterize the effects of CsA and IGF-I on trabecular and cortical bone, and to see whether systemic IGF-I is able to modulate CsA's deleterious skeletal effects. Sixty 10 week-old, male, Sprague-Dawley rats were randomized to receive the following daily for 3 weeks: (1) CsA vehicle (veh) per os (po) + recombinant human (rh) IGF-1 veh subcutaneously (sc); (2) CsA 15 mg/kg po + rhIGF-I-veh; (3) CsA-veh + rhIGF-I 200 microg/kg sc; (4) CsA-veh + rhIGF-I 600 microg/kg sc; (5) CsA 15 mg/kg + rhIGF-I 200 microg/kg, and (6) CsA 15 mg/kg + rhIGF-I 600 microg/kg. Rats were weighed and venous blood was sampled serially for determination of glucose, ionized calcium (Ca2+), PTH, vitamin D, and osteocalcin. Following sacrifice on day 20, histomorphometry was performed on double calcein-labeled tibial metaphysis and diaphysis. All rats receiving CsA had elevated levels of blood glucose and osteocalcin by day 9 and vitamin D at day 20. PTH was similar in all groups, and Ca2+ was only raised in the CsA and CsA + IGF-I 200 microg/kg groups. Rats receiving IGF-I 200 microg/kg and IGF-I 600 microg/kg gained more weight than either vehicle- or CsA-treated animals, attesting to IGF-1's anabolic properties. CsA caused severe trabecular bone loss, not prevented by IGF-I; it even further increased the eroded surface. CsA and IGF-I had little effect on cortical bone volume or marrow area. IGF-I increased endocortical matrix synthesis, as evidenced by the increases in the percent endocortical osteoid perimeter, an effect negated by the addition of CsA. This experiment demonstrates that trabecular bone is more susceptible than cortical bone to the deleterious effects of CsA and indicates little role for IGF-1 in the pathophysiology or treatment of CsA-induced bone disease at the given doses and duration of treatment.

Aluminum exacerbates cyclosporin induced nephrotoxicity in rats.

PubMed

Tariq, M; Morais, C; Sujata, B; Sobki, S; al Sulaiman, M; al Khader, A

1999-01-01

Cyclosporin (CSA) has been universally used as an immunosuppressant for the management of allotransplantation and autoimmune diseases. However, nephrotoxicity of CSA limits its use to optimum level. Aluminum (Al) is an extensively distributed element in the environment and human exposure to this metal is unavoidable. Recent studies suggest that even a slight impairment of renal function may increase the Al body burden significantly, which may lead to neurotoxicity, nephrotoxicity, osteodystrophy or hypochromic anemia. In the present study, an attempt was made to study the effect of concomitant use of Al and CSA on structure and function of kidney in rats. This study was undertaken in two steps. In the first set of experiments, the effect of single dose of Al (1% Al2(SO4)3 18H2O) on the nephrotoxicity of multiple doses of CSA (12.5 mg/kg, 25 mg/kg and 50 mg/kg) was studied, where as in the second set of experiments the effect of multiple doses of Al (0.25%, 0.5% and 1%) on single dose of CSA (50 mg/kg) was undertaken. Male Sprague-Dawley rats (weighing 230 +/- 20 g) were used in this study. CSA was given once a day by gavage for seven days, where as Al was given in drinking water for the same period. Twenty four hours after the last dose of CSA, animals were sacrificed and blood and kidney were collected for biochemical and histopathological studies. The bio-chemical parameters included blood urea nitrogen (BUN), serum creatinine (SCr), CSA and Al levels. The kidney homogenates were assayed for malondialdehyde (MDA) and lipid hydroperoxides (LPH). Treatment of rats with CSA alone produced dose-dependent structural and functional changes in kidney. Although Al alone failed to produce any deleterious effect on renal function, it significantly increased the bioavailability and nephrotoxicity of CSA. Al also exacerbated CSA induced increase in oxidative stress (as evident by increased MDA and LPH). Thus, the exacerbation of CSA nephrotoxicity by Al may be attributed to increased bioavailability of CSA and excessive generation of free radicals following concomitant use of these drugs.

Childhood Sexual Abuse Is Highly Associated With HIV Risk–Taking Behavior and Infection Among MSM in the EXPLORE Study

PubMed Central

Mimiaga, Matthew J.; Noonan, Elizabeth; Donnell, Deborah; Safren, Steven A.; Koenen, Karestan C.; Gortmaker, Steven; O’Cleirigh, Conall; Chesney, Margaret A.; Coates, Thomas J.; Koblin, Beryl A.; Mayer, Kenneth H.

2012-01-01

Background Previous studies have found high rates of childhood sexual abuse (CSA) among US men who have sex with men (MSM). CSA history has been associated with a variety of negative effects later in life including behaviors that place MSM at greater risk for HIV acquisition and transmission. The present analysis is the first to examine the longitudinal association between CSA and HIV infection, unprotected anal sex, and serodiscordant unprotected anal sex, as well as mediators of these relationships among a large sample of HIV-uninfected MSM. Methods The EXPLORE Study was a behavioral intervention trial conducted in 6 US cities over 48 months with HIV infection as the primary efficacy outcome. Behavioral assessments were done every 6 months via confidential computerized assessments. Longitudinal regression models were constructed, adjusting for randomization arm, geographical location of study site, age at enrollment, education, and race/ethnicity. Results Of the 4295 participants enrolled, 39.7% had a history of CSA. Participants with a history of CSA [adjusted hazards ratio = 1.30, 95% confidence interval (CI): 1.02 to 1.69] were at increased risk for HIV infection over study follow-up. A significant association was seen between history of CSA and unprotected anal sex (adjusted odds ratio = 1.24, 95% CI: 1.12 to 1.36) and serodiscordant unprotected anal sex (adjusted odds ratio = 1.30, 95% CI: 1.18 to 1.43). Among participants reporting CSA, the EXPLORE intervention had no effect in reducing HIV infection rates. Participants reporting CSA were significantly more likely to have symptoms of depression and use nonprescription drugs. Conclusions A predictive relationship between a history of CSA and subsequent HIV infection was observed among this large sample of HIV-uninfected MSM. Findings indicate that HIV-uninfected MSM with CSA histories are at greater risk for HIV infection, report higher rates of HIV sexual risk behavior, and may derive less benefit from prevention programs. Future HIV prevention interventions should address the specific mental health concerns of MSM with a history of CSA. PMID:19367173

Selective assay for CyPA and CyPB in human blood using highly specific anti-peptide antibodies.

PubMed

Allain, F; Boutillon, C; Mariller, C; Spik, G

1995-01-13

Cyclophilins A and B (CyPA and CyPB) are known to be the main binding proteins for cyclosporin A (CsA), a potent immunosuppressive drug. Due to the high homology between the two proteins, antibodies to CyPB were found to cross-react with CyPA. In order to avoid this phenomenon, we raised specific antibodies against peptides copying the most divergent parts of the two sequences. These antibodies allowed us to develop an ELISA capture assay selective for either isotype. Thus, we showed that leukocyte CyPB concentration was almost ten times lower than that of CyPA, and that in contrast to the results described in the literature, only CyPB was released in plasma. Moreover, CyPB levels in leukocytes and plasma were found to correlate for the same donor, but no relationship was found with CyPA level.

Childhood Sexual Abuse Patterns, Psychosocial Correlates, and Treatment Outcomes among Adults in Drug Abuse Treatment

ERIC Educational Resources Information Center

Boles, Sharon M.; Joshi, Vandana; Grella, Christine; Wellisch, Jean

2005-01-01

This study reports on the effects of having a history of childhood sexual abuse (CSA) on treatment outcomes among substance abusing men and women (N = 2,434) in a national, multisite study of drug treatment outcomes. A history of CSA was reported by 27.2% of the women and 9.2% of the men. Controlling for gender, compared to patients without CSA,…

Using pre-operative MRI to predict intraoperative hamstring graft size for anterior cruciate ligament reconstruction.

PubMed

Leiter, Jeff; Elkurbo, Mohamed; McRae, Sheila; Chiu, James; Froese, Warren; MacDonald, Peter

2017-01-01

Large variation in tendon size between individuals makes hamstring graft diameter for anterior cruciate ligament (ACL) reconstruction unpredictable. Inadequate graft diameter may necessitate an alternative source of tissue requiring pre-operative planning. The purpose of this study was to determine whether magnetic resonance image (MRI) measurements and clinical anthropometric data are predictive of hamstring tendon graft diameter. Data from 109 patients having ACL reconstruction with semitendinosus-gracilis (STGT) autograft were retrospectively evaluated. Cross-sectional area (CSA) of the gracilis tendon (GT) and semitendinosus tendon (ST) were determined from pre-operative MRI scans. Variables included pre-operative height, weight, body mass index (BMI), age and gender; and intra-operative graft diameter. Correlations between anthropometric variables, hamstring tendons CSA and intra-operative graft diameter were calculated. Multiple stepwise regression was performed to assess the predictive value of these variables to graft diameter. Sensitivity and specificity were calculated to evaluate the utility of MRI CSA measurements in accurately identifying inadequate graft diameter (<8 mm). All anthropometric variables were positively correlated with intraoperative graft diameter (p < 0.01). Semitendinosus-gracilis tendon CSA (p < 0.001) and STGT CSA and weight (p < 0.001) were significantly predictive models of graft diameter. Sensitivity and specificity were 79 and 74 %, respectively. The strongest indicators of a four-stranded STGT graft for primary ACL reconstruction were STGT CSA on MRI plus weight. Measurement of graft diameter can be performed pre-operatively via MRI to identify tendons that may be of inadequate size for ACL reconstruction. This can assist with surgical planning to determine the most appropriate graft choice. III.

"Chitin-specific" peroxidases in plants.

PubMed

Maksimov, I V; Cherepanova, E A; Khairullin, R M

2003-01-01

The activity of various plant peroxidases and the ability of their individual isoforms to bind chitin was studied. Some increase in peroxidase activity was observed in crude extracts in the presence of chitin. Activated peroxidases of some species fell in the fraction not sorbed on chitin and those of other species can bind chitin. Only anionic isoperoxidases from oat (Avena sativa), rice (Oryza sativa), horseradish (Armoracia rusticana), garden radish (Raphanus sativus var. radicula), peanut (Arachis hypogaea), and tobacco (Nicotiana tabacum Link et Otto) were sorbed on chitin. Both anionic and cationic isoforms from pea (Pisum sativum), galega(Galega orientalis), cucumber (Cucumis sativus), and zucchini (Cucurbita pepo L.) were sorbed on chitin. Peroxidase activation under the influence of chitin was correlated to the processes that occur during hypersensitive reaction and lignification of sites, in which pathogenic fungus penetrates into a plant. The role of chitin-specific isoperoxidases in inhibition of fungal growth and connection of this phenomenon with structural characteristics of isoperoxidases are also discussed.

Investigating the protective effects of aged garlic extract on cyclosporin-induced nephrotoxicity in rats.

PubMed

Wongmekiat, Orawan; Thamprasert, Kamthorn

2005-10-01

Cyclosporin A (CsA) nephrotoxicity has been described in solid organ recipients and in the patients who were treated for autoimmune diseases. Reactive oxygen species-induced oxidative stress and lipid peroxidations are implicated in the pathophysiology of CsA-induced renal injury. Aged garlic extract (AGE) has been reported to exhibit potent antioxidative and free radical scavenging abilities in various disease conditions. The present study was designed to investigate whether AGE could possibly have a protective effect against nephrotoxicity induced by CsA. Male Wistar rats were treated orally with CsA (50 mg/kg/day), CsA + AGE (0.25, 0.5, 1, and 2 g/kg/day started 3 days before the first dose of CsA), or the vehicle of CsA for a period of 10 days. Blood urea nitrogen, serum creatinine, creatinine clearance, and renal histopathological changes were evaluated after 24 h of the last treatment. CsA caused an increase in blood urea nitrogen and serum creatinine by 117 and 100%, respectively, whereas it decreased creatinine clearance by 78% compared with the vehicle-treated rats (all P < 0.001). AGE treatment (0.5, 1 and 2 g/kg) significantly protected animals against CsA-induced biochemical changes, albeit blood urea nitrogen and creatinine clearance in the 0.5 g/kg AGE treated-animals were only partially restored. Kidney sections taken from CsA-treated rats showed severe vacuolations and tubular necrosis. These histopathological changes were markedly improved by pretreatment of rats with AGE at the dose of 0.5--2 g/kg. The results indicate that AGE ameliorates renal dysfunction and morphological changes induced by CsA, and imply that it could be a beneficial remedy for attenuating the CsA nephrotoxicity.

Initial Assessment of CSA Group Niobium Boron Based Coatings on 4340 Steel

DTIC Science & Technology

2017-07-01

Technical Report ARWSB-TR-17026 Initial Assessment of CSA Group Niobium- Boron Based Coatings on 4340 Steel C.P. Mulligan...REPORT TYPE Technical 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Initial Assessment of CSA Group Niobium- Boron Based Coatings on 4340...metallographic mounts reported as (1) thin and (2) thick Niobium- Boron (Nb-B) type coatings on steel. CSA Group is interested in providing coatings for potential

Comparison of pedometer and accelerometer measures of free-living physical activity.

PubMed

Tudor-Locke, Catrine; Ainsworth, Barbara E; Thompson, Raymond W; Matthews, Charles E

2002-12-01

The purpose of this investigation was 1) to evaluate agreement between dual-mode CSA accelerometer outputs and Yamax pedometer outputs assessed concurrently under free-living conditions; 2) to determine the relationship between pedometer-steps per day and CSA-time spent in inactivity and in light-, moderate-, and vigorous-intensity activities; and 3) to identify a value of pedometer-steps per day that corresponds with a minimum of 30 CSA-min x d(-1) of moderate ambulatory activity. Data were analyzed from 52 participants (27 men, 25 women; mean age = 38.2 +/- 12.0 yr; mean BMI = 26.4 +/- 4.5 kg x m(-2)) who were enrolled in the International Physical Activity Questionnaire study and wore both motion sensors during waking hours for 7 consecutive days. Participants averaged 415.0+/-159.5 CSA-counts x min(-1) x d(-1), 357,601 +/- 138,425 CSA-counts x d(-1), 11,483 +/- 3,856 CSA-steps x d(-1), and 9,638 +/- 4,030 pedometer-steps x d(-1). There was a strong relationship between all CSA outputs and pedometer outputs (r = 0.74-0.86). The mean difference in steps detected between instruments was 1845+/-2116 steps x d(-1) (CSA > pedometer; t = 6.29, P < 0.0001). There were distinct differences (effect sizes >0.80) in mean CSA-time (min x d(-1)) in moderate and vigorous activity with increasing pedometer-determined activity quartiles; no differences were noted for inactivity or light activity. Approximately 33 CSA-min x d(-1) of moderate activity corresponded with 8000 pedometer-steps x d(-1). Differences in mean steps per day detected may be due to differences in set instrument sensitivity thresholds and/or attachment. Additional studies with different populations are needed to confirm a recommended number of steps per day associated with the duration and intensity of public health recommendations for ambulatory activity.

Predicting distant failure in early stage NSCLC treated with SBRT using clinical parameters.

PubMed

Zhou, Zhiguo; Folkert, Michael; Cannon, Nathan; Iyengar, Puneeth; Westover, Kenneth; Zhang, Yuanyuan; Choy, Hak; Timmerman, Robert; Yan, Jingsheng; Xie, Xian-J; Jiang, Steve; Wang, Jing

2016-06-01

The aim of this study is to predict early distant failure in early stage non-small cell lung cancer (NSCLC) treated with stereotactic body radiation therapy (SBRT) using clinical parameters by machine learning algorithms. The dataset used in this work includes 81 early stage NSCLC patients with at least 6months of follow-up who underwent SBRT between 2006 and 2012 at a single institution. The clinical parameters (n=18) for each patient include demographic parameters, tumor characteristics, treatment fraction schemes, and pretreatment medications. Three predictive models were constructed based on different machine learning algorithms: (1) artificial neural network (ANN), (2) logistic regression (LR) and (3) support vector machine (SVM). Furthermore, to select an optimal clinical parameter set for the model construction, three strategies were adopted: (1) clonal selection algorithm (CSA) based selection strategy; (2) sequential forward selection (SFS) method; and (3) statistical analysis (SA) based strategy. 5-cross-validation is used to validate the performance of each predictive model. The accuracy was assessed by area under the receiver operating characteristic (ROC) curve (AUC), sensitivity and specificity of the system was also evaluated. The AUCs for ANN, LR and SVM were 0.75, 0.73, and 0.80, respectively. The sensitivity values for ANN, LR and SVM were 71.2%, 72.9% and 83.1%, while the specificity values for ANN, LR and SVM were 59.1%, 63.6% and 63.6%, respectively. Meanwhile, the CSA based strategy outperformed SFS and SA in terms of AUC, sensitivity and specificity. Based on clinical parameters, the SVM with the CSA optimal parameter set selection strategy achieves better performance than other strategies for predicting distant failure in lung SBRT patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Considerations for Using Hybrid Ensemble-Variational Data Assimilation in NASA-GMAO's Next Reanalysis System

NASA Technical Reports Server (NTRS)

El Akkraoui, Amal; Todling, Ricardo

2017-01-01

The Modern-Era Retrospective Analysis for Research and Applications, version 2 (MERRA-2) is the latest reanalysis produced by GMAO, and provides global data spanning the period 1980-present. The atmospheric data assimilation component of MERRA-2 used a 3D-Var scheme, which was operational at the time of its design. Since then, a Hybrid 3D-Var, then a Hybrid 4D-EnVar were implemented, adding an ensemble component to the data assimilation scheme. In this work, we will be examining the benefits of using hybrid ensemble flow-dependent covariances to represent errors and uncertainties in historic periods. Specifically, periods of pre- and post-satellites, as well as periods of active tropical cyclone seasons. Finally, we will also be exploring the use of adaptive localization scales.

Down-regulation of transforming growth factor beta-2 expression is associated with the reduction of cyclosporin induced gingival overgrowth in rats treated with roxithromycin: an experimental study

PubMed Central

2009-01-01

Background Gingival overgrowth (GO) is a common side effect of the chronic use of cyclosporine (CsA), an immunosuppressant widely used to prevent rejection in transplant patients. Recent studies have reported elevated levels of specific cytokines in gingival overgrowth tissue, particularly TGF-beta, suggesting that this growth factor plays a role in the accumulation of extracellular matrix materials. The effectiveness of azithromycin, a macrolide antibiotic, in the regression of this undesirable side effect has also been demonstrated. Methods In this study, we created an experimental model for assessing the therapeutic effect of roxithromycin in GO and the expression of transforming growth factor beta (TGF-beta2) through immunohistochemistry. We used four groups of rats totaling 32 individuals. GO was induced during five weeks and drug treatment was given on the 6th week as follows: group 1 received saline; group 2 received CsA and was treated with saline on the 6th week; group 3 received CsA and, on the 6th week, ampicilin; and group 4 received CsA during 5 weeks and, on the 6th week, was treated with roxithromycin. Results The results demonstrated that roxithromycin treatment was effective in reducing cyclosporine-induced GO in rats. Both epithelial and connective tissue showed a decrease in thickness and a significant reduction in TGF-beta2 expression, with a lower number of fibroblasts, reduction in fibrotic areas and decrease in inflammatory infiltrate. Conclusion The present data suggest that the down-regulation of TGF-beta2 expression may be an important mechanism of action by which roxithromycin inhibits GO. PMID:19995419

Enhanced colonic delivery of ciclosporin A self-emulsifying drug delivery system encapsulated in coated minispheres.

PubMed

Keohane, Kieran; Rosa, Mónica; Coulter, Ivan S; Griffin, Brendan T

2016-01-01

Investigate the potential of coated minispheres (SmPill®) to enhance localized Ciclosporin A (CsA) delivery to the colon. CsA self-emulsifying drug delivery systems (SEDDS) were encapsulated into SmPill® minispheres. Varying degrees of coating thickness (low, medium and high) were applied using ethylcellulose and pectin (E:P) polymers. In vitro CsA release was evaluated in simulated gastric and intestinal media. Bioavailability of CsA in vivo following oral administration to pigs of SmPill® minispheres was compared to Neoral® po and Sandimmun® iv in a pig model. CsA concentrations in blood and intestinal tissue were determined by HPLC-UV. In vitro CsA release from coated minispheres decreased with increasing coating thickness. A linear relationship was observed between in vitro CsA release and in vivo bioavailability (r(2) = 0.98). CsA concentrations in the proximal, transverse and distal colon were significantly higher following administration of SmPill®, compared to Neoral® po and Sandimmun® iv (p < 0.05). Analysis of transverse colon tissue subsections also revealed significantly higher CsA concentrations in the mucosa and submucosa using SmPill® minispheres (p < 0.05). Modulating E:P coating thickness controls release of CsA from SmPill® minispheres. Coated minispheres limited CsA release in the small intestine and enhanced delivery and uptake in the colon. These findings demonstrate clinical advantages of an oral coated minisphere-enabled CsA formulation in the treatment of inflammatory conditions of the large intestine.

Childhood Sexual Abuse and Fear of Abandonment Moderate the Relation of Intimate Partner Violence to Severity of Dissociation.

PubMed

Zerubavel, Noga; Messman-Moore, Terri L; DiLillo, David; Gratz, Kim L

2018-01-01

Betrayal trauma theory proposes a relation between intimate partner violence (IPV) and dissociation, suggesting that dissociation among victims of IPV may function to restrict awareness of abuse in order to preserve attachments perceived as vital. We investigated two factors that may moderate the relation between IPV and dissociation-childhood sexual abuse (CSA) severity and fear of abandonment-among 348 women currently in a relationship. The relation between frequency of IPV (sexual and physical) and dissociation (amnesia and depersonalization) was moderated by CSA severity and fear of abandonment. Specifically, among women with clinically relevant fear of abandonment, the strength of the relation between IPV and dissociation became stronger as CSA severity increased. This study is the first to demonstrate the moderating roles of fear of abandonment and CSA history in the relation between IPV and dissociation among women. Findings suggest that it may be important to target fear of abandonment in interventions with IPV victims who have a CSA history. Results suggest that fear of abandonment warrants greater attention in research on IPV revictimization.

Correlates and Consequences Central Sleep Apnea in a National Sample of U.S. Veterans.

PubMed

Ratz, David; Wiitala, Wyndy; Badr, M S; Burns, Jennifer; Chowdhuri, Susmita

2018-03-28

The prevalence and consequences of central sleep apnea (CSA) in adults are not well- described. By utilizing the large Veterans Health Administration (VHA) national administrative databases, we sought to determine the incidence, clinical correlates and impact of CSA on healthcare utilization in Veterans. Analysis of a retrospective cohort of patients with sleep disorders was performed from outpatient visits and inpatient admissions from fiscal years 2006 through 2012. The CSA group, defined by International Classification of Diseases-9, was compared to a non-CSA group. The number of newly diagnosed CSA cases increased 5-fold during this timeframe; however, the prevalence was highly variable depending on the VHA site. The important predictors of CSA were male gender (Odds Ratio(OR)=2.31, 95% C.I.:1.94-2.76, p<0.0001), heart failure(HF) (OR=1.78, 95% C.I.:1.64-1.92, p<0.0001), atrial fibrillation (OR=1.83, 95% C.I.: 1.69-2.00, p<0.0001), pulmonary hypertension (OR=1.38, 95% C.I.:1.19-1.59, p<0.0001), stroke (OR=1.65, 95% C.I.:1.50-1.82, p<0.0001), and chronic prescription opioid use (OR=1.99, 95% C.I.:1.87-2.13, p<0.0001). Veterans with CSA were at an increased risk for hospital admissions related to cardiovascular disorders compared to the control group (Incidence Rate Ratio(IRR)=1.50, 95% C.I.:1.16-1.95, p=0.002). Additionally, the effect of prior HF on future admissions was greater in the CSA group (IRR: 4.78,95% C.I.: 3.87-5.91, p<0.0001) compared to the comparison group (IRR=3.32, 95% C.I.: 3.18-3.47, P<0.0001). Thus, CSA in Veterans is associated with cardiovascular disorders, chronic prescription opioid use and increased admissions related to the comorbid cardiovascular disorders. Furthermore, there is a need for standardization of diagnostics methods across the VHA to accurately diagnose CSA in high-risk populations.

Assessment of physical activity with the Computer Science and Applications, Inc., accelerometer: laboratory versus field validation.

PubMed

Nichols, J F; Morgan, C G; Chabot, L E; Sallis, J F; Calfas, K J

2000-03-01

Our purpose was to compare the validity of the Computer Science and Applications, (CSA) Inc., accelerometer in laboratory and field settings and establish CSA count ranges for light, moderate, and vigorous physical activity. Validity was determined in 60 adults during treadmill exercise, using oxygen consumption (VO2) as the criterion measure, while 30 adults walked and jogged outdoors on a 400-m track. The relationship between CSA counts and VO2 was linear (R2 = .89 SEE = 3.72 ml.kg-1.min-1), as was the relationship between velocity and counts in the field (R2 = .89, SEE = 0.89 mi.hr-1). However, significant differences were found (p < .05) between laboratory and field measures of CSA counts for light and vigorous intensity. We conclude that the CSA can be used to quantify walking and jogging outdoors on level ground; however, laboratory equations may not be appropriate for use in field settings, particularly for light and vigorous activity.

VarMod: modelling the functional effects of non-synonymous variants.

PubMed

Pappalardo, Morena; Wass, Mark N

2014-07-01

Unravelling the genotype-phenotype relationship in humans remains a challenging task in genomics studies. Recent advances in sequencing technologies mean there are now thousands of sequenced human genomes, revealing millions of single nucleotide variants (SNVs). For non-synonymous SNVs present in proteins the difficulties of the problem lie in first identifying those nsSNVs that result in a functional change in the protein among the many non-functional variants and in turn linking this functional change to phenotype. Here we present VarMod (Variant Modeller) a method that utilises both protein sequence and structural features to predict nsSNVs that alter protein function. VarMod develops recent observations that functional nsSNVs are enriched at protein-protein interfaces and protein-ligand binding sites and uses these characteristics to make predictions. In benchmarking on a set of nearly 3000 nsSNVs VarMod performance is comparable to an existing state of the art method. The VarMod web server provides extensive resources to investigate the sequence and structural features associated with the predictions including visualisation of protein models and complexes via an interactive JSmol molecular viewer. VarMod is available for use at http://www.wasslab.org/varmod. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Familial support as perceived by adult victims of childhood sexual abuse.

PubMed

Stroud, D D

1999-04-01

With the increasing popularity of family therapies in cases of childhood sexual abuse (CSA), many studies have discussed the importance of familial support in the successful recovery of victims. Therefore, a systematic study exploring family support of victims was undertaken to shed light on the level of family support perceived by adult victims of CSA. It was anticipated that victims of intrafamilial CSA would report more family dissatisfaction and perceive less family support than extrafamilial victims. As hypothesized, intrafamilial victims reported significantly more general family dissatisfaction and specifically, perceived significantly less father, parent, and brother support. Additionally, the gender of the victim played a significant role: Male victims reported less father, parent and sister support and less family protectiveness after disclosure when compared to female victims. Based on the results, clinicians should be aware that issues of gender and relatedness may play a significant part in the effectiveness of their CSA clients' family support systems.

Endotoxin-associated protein: a potent stimulus for human granulocytopoietic activity which may be accessory cell independent.

PubMed Central

Bjornson, B H; Agura, E; Harvey, J M; Johns, M; Andrews, R G; McCabe, W R

1988-01-01

Proteins coextracted with endotoxin, termed endotoxin-associated protein (EAP), have been shown to exert interleukin 1-like activities. The present studies demonstrate that EAP also exerts potent granulopoietic colony-stimulating activity (CSA) on human peripheral blood and bone marrow progenitor cells, comparable to that seen with various types of conditioned media. The CSA observed with EAP appeared to be heat (100 degrees C, 30 min) and trypsin resistant and partially pronase resistant. Similar resistance was observed with the porin proteins of the outer membrane of gram-negative bacteria, and similar CSA activity was observed with a purified porin preparation of Neisseria gonorrhoeae. The CSA of EAP could be demonstrated in human peripheral blood and bone marrow leukocytes rigorously depleted of monocytes, T lymphocytes, and B lymphocytes by treatment with specific monoclonal antibodies and complement. PMID:2836311

Context matters: the benefits and costs of expressing positive emotion among survivors of childhood sexual abuse.

PubMed

Bonanno, George A; Colak, Deniz M; Keltner, Dacher; Shiota, Michelle N; Papa, Anthony; Noll, Jennie G; Putnam, Frank W; Trickett, Penelope K

2007-11-01

Positive emotions promote adjustment to aversive life events. However, evolutionary theory and empirical research on trauma disclosure suggest that in the context of stigmatized events, expressing positive emotions might incur social costs. To test this thesis, the authors coded genuine (Duchenne) smiling and laughter and also non-Duchenne smiling from videotapes of late-adolescent and young adult women, approximately half with documented histories of childhood sexual abuse (CSA), as they described the most distressing event of their lives. Consistent with previous studies, genuine positive emotional expression was generally associated with better social adjustment two years later. However, as anticipated, CSA survivors who expressed positive emotion in the context of describing a past CSA experience had poorer long-term social adjustment, whereas CSA survivors who expressed positive emotion while describing a nonabuse experience had improved social adjustment. These findings suggest that the benefits of positive emotional expression may often be context specific.

In vitro evaluation of the potential for resistance development to ceragenin CSA-13

PubMed Central

Pollard, Jake E.; Snarr, Jason; Chaudhary, Vinod; Jennings, Jacob D.; Shaw, Hannah; Christiansen, Bobbie; Wright, Jonathan; Jia, Wenyi; Bishop, Russell E.; Savage, Paul B.

2012-01-01

Objectives Though most bacteria remain susceptible to endogenous antimicrobial peptides, specific resistance mechanisms are known. As mimics of antimicrobial peptides, ceragenins were expected to retain antibacterial activity against Gram-positive and -negative bacteria, even after prolonged exposure. Serial passaging of bacteria to a lead ceragenin, CSA-13, was performed with representative pathogenic bacteria. Ciprofloxacin, vancomycin and colistin were used as comparators. The mechanisms of resistance in Gram-negative bacteria were elucidated. Methods Susceptible strains of Staphylococcus aureus, Pseudomonas aeruginosa and Acinetobacter baumannii were serially exposed to CSA-13 and comparators for 30 passages. MIC values were monitored. Alterations in the Gram-negative bacterial membrane composition were characterized via mass spectrometry and the susceptibility of antimicrobial-peptide-resistant mutants to CSA-13 was evaluated. Results S. aureus became highly resistant to ciprofloxacin after <20 passages. After 30 passages, the MIC values of vancomycin and CSA-13 for S. aureus increased 9- and 3-fold, respectively. The Gram-negative organisms became highly resistant to ciprofloxacin after <20 passages. MIC values of colistin for P. aeruginosa and A. baumannii increased to ≥100 mg/L after 20 passages. MIC values of CSA-13 increased to ∼20–30 mg/L and plateaued over the course of the experiment. Bacteria resistant to CSA-13 displayed lipid A modifications that are found in organisms resistant to antimicrobial peptides. Conclusions CSA-13 retained potent antibacterial activity against S. aureus over the course of 30 serial passages. Resistance generated in Gram-negative bacteria correlates with modifications to the outer membranes of these organisms and was not stable outside of the presence of the antimicrobial. PMID:22899801

Adaptive servo-ventilation as treatment of persistent central sleep apnea in post-acute ischemic stroke patients.

PubMed

Brill, Anne-Kathrin; Rösti, Regula; Hefti, Jacqueline Pichler; Bassetti, Claudio; Gugger, Matthias; Ott, Sebastian R

2014-11-01

Adaptive servo-ventilation (ASV) is a well-established treatment of central sleep apnea (CSA) related to congestive heart failure (CHF). Few studies have evaluated the effectiveness and adherence in patients with CSA of other etiologies, and even less is known about treatment of CSA in patients of post ischemic stroke. A single-centre retrospective analysis of ASV treatment for CSA in post-acute ischemic stroke patients without concomitant CHF was performed. Demographics, clinical data, sleep studies, ventilator settings, and adherence data were evaluated. Out of 154 patients on ASV, 15 patients had CSA related to ischemic stroke and were started on ASV a median of 11 months after the acute cerebrovascular event. Thirteen out of the 15 patients were initially treated with continuous positive airway pressure (11/15) and bilevel positive airway pressure (2/15) therapy with unsatisfactory control of CSA. ASV significantly improved AHI (46.7 ± 24.3 vs 8.5 ± 12/h, P = 0.001) and reduced ESS (8.7 ± 5.7 vs 5.6 ± 2.5, P = 0.08) with a mean nightly use of ASV of 5.4 ± 2.4 h at 3 months after the initiation of treatment. Results were maintained at 6 months. ASV was well tolerated and clinically effective in this group of patients with persistent CSA after ischemic stroke. Copyright © 2014 Elsevier B.V. All rights reserved.

Electrical Stimulation During Gait Promotes Increase of Muscle Cross-sectional Area in Quadriplegics: A Preliminary Study

PubMed Central

Cliquet, Alberto; Rondina, Jane Maryan; Cendes, Fernando

2008-01-01

Increases in muscular cross-sectional area (CSA) occur in quadriplegics after training, but the effects of neuromuscular electrical stimulation (NMES) along with training are unknown. Thus, we addressed two questions: (1) Does NMES during treadmill gait training increase the quadriceps CSA in complete quadriplegics?; and (2) Is treadmill gait training alone enough to observe an increase in CSA? Fifteen quadriplegics were divided into gait (n = 8) and control (n = 7) groups. The gait group performed training with NMES for 6 months twice a week for 20 minutes each time. After 6 months of traditional therapy, the control group received the same gait training protocol but without NMES for an additional 6 months. Axial images of the thigh were acquired at the beginning of the study, at 6 months (for both groups), and at 12 months for the control group to determine the average quadriceps CSA. After 6 months, there was an increase of CSA in the gait group (from 49.8 ± 9.4 cm2 to 57.3 ± 10.3 cm2), but not in the control group (from 43.6 ± 7.6 cm2 to 41.8 ± 8.4 cm2). After another 6 months of gait without NMES in the control group, the CSA did not change (from 41.8 ± 8.4 cm2 to 41.7 ± 7.9 cm2). The increase in quadriceps CSA after gait training in patients with chronic complete quadriplegia appears associated with NMES. PMID:18791775

Comparison of the BBL CHROMagar Staph aureus Agar Medium to Conventional Media for Detection of Staphylococcus aureus in Respiratory Samples

PubMed Central

Flayhart, Diane; Lema, Clara; Borek, Anita; Carroll, Karen C.

2004-01-01

Screening for Staphylococcus aureus has become routine in certain patient populations. This study is the first clinical evaluation of the BBL CHROMagar Staph aureus agar (CSA) medium (BD Diagnostics, Sparks, Md.) for detection of S. aureus in nasal surveillance cultures and in respiratory samples from cystic fibrosis (CF) patients. S. aureus colonies appear mauve on CSA. Other organisms are inhibited or produce a distinctly different colony color. S. aureus was identified from all media by slide coagulase, exogenous DNase, and mannitol fermentation assays. Susceptibility testing was performed using the agar dilution method. A total of 679 samples were evaluated. All samples were inoculated onto CSA. Nasal surveillance cultures were inoculated onto sheep blood agar (SBA) (BD Diagnostics), and samples from CF patients were inoculated onto mannitol salt agar (MSA) (BD Diagnostics). Of the 679 samples cultured, 200 organisms produced a mauve color on CSA (suspicious for S. aureus) and 180 were positive for S. aureus on SBA or MSA. Of 200 CSA-positive samples 191 were identified as S. aureus. Nine mauve colonies were slide coagulase negative and were subsequently identified as Staphylococcus lugdunensis (one), Staphylococcus epidermidis (three), Staphylococcus haemolyticus (one), and Corynebacterium species (four). CSA improved the ability to detect S. aureus by recovering 12 S. aureus isolates missed by conventional media. Of the 192 S. aureus isolates recovered, 122 were methicillin susceptible and 70 were methicillin resistant. Overall, the sensitivity and specificity of CSA in this study were 99.5 and 98%, respectively. There was no difference in the performance of the slide coagulase test or in susceptibility testing performed on S. aureus recovered from CSA compared to SBA or MSA. Our data support the use of CSA in place of standard culture media for detection of S. aureus in heavily contaminated respiratory samples. PMID:15297498

A Multicenter Randomized Controlled Trial of Rituximab versus Cyclosporine in the Treatment of Idiopathic Membranous Nephropathy (MENTOR).

PubMed

Fervenza, Fernando C; Canetta, Pietro A; Barbour, Sean J; Lafayette, Richard A; Rovin, Brad H; Aslam, Nabeel; Hladunewich, Michelle A; Irazabal, Maria V; Sethi, Sanjeev; Gipson, Debbie S; Reich, Heather N; Brenchley, Paul; Kretzler, Matthias; Radhakrishnan, Jai; Hebert, Lee A; Gipson, Patrick E; Thomas, Leslie F; McCarthy, Ellen T; Appel, Gerald B; Jefferson, J Ashley; Eirin, Alfonso; Lieske, John C; Hogan, Marie C; Greene, Eddie L; Dillon, John J; Leung, Nelson; Sedor, John R; Rizk, Dana V; Blumenthal, Samuel S; Lasic, Lada B; Juncos, Luis A; Green, Dollie F; Simon, James; Sussman, Amy N; Philibert, David; Cattran, Daniel C

2015-01-01

Idiopathic membranous nephropathy remains the leading cause of nephrotic syndrome in Caucasian adults. Immunosuppressive therapy with cyclosporine (CSA) is often successful in reducing proteinuria, but its use is associated with a high relapse rate. Rituximab, a monoclonal antibody that specifically targets CD20 on the surface of B-cells, is effective in achieving a complete remission of proteinuria in patients with idiopathic membranous nephropathy. However, whether rituximab is as effective as CSA in inducing and maintaining complete or partial remission of proteinuria in these patients is unknown. The membranous nephropathy trial of rituximab (MENTOR) hypothesizes that B-cell targeting with rituximab is non-inferior to CSA in inducing long-term remission of proteinuria. Patients with idiopathic membranous nephropathy, proteinuria ≥5 g/24 h, and a minimum of 3 months of Angiotensin-II blockade will be randomized into a 12-month treatment period with i.v. rituximab, 1,000 mg (2 infusions, 14 days apart; repeated at 6 months if a substantial reduction in proteinuria (equal to or >25%) is seen at 6 months) or oral CSA 3.5-5 mg/kg/day for 6 months (continued for another 6 months if a substantial reduction in proteinuria (equal to or >25%) is seen at 6 months). The efficacy of treatment will be assessed by the remission status (based on changes in proteinuria) at 24 months from randomization. Patient safety will be assessed via collection of adverse event data and evaluation of pre- and posttreatment laboratory data. At the 6-month post-randomization visit, patients who have been randomized to either CSA or rituximab but who do not have a reduction in proteinuria ≥25% (confirmed on repeat measurements within 2 weeks) will be considered treatment failures and exit the study. This study will test for the first time whether treatment with rituximab is non-inferior to CSA in inducing long-term remission (complete or partial) of proteinuria in patients with idiopathic membranous nephropathy. 2015 S. Karger AG, Basel.

Microfluidic assay of circulating endothelial cells in coronary artery disease patients with angina pectoris

PubMed Central

Chen, Shuiyu; Sun, Yukun; Neoh, Kuang Hong; Chen, Anqi; Li, Weiju; Yang, Xiaorui

2017-01-01

Background Circulating endothelial cells (CECs) are widely reported as a promising biomarker of endothelial damage/dysfunction in coronary artery disease (CAD). The two popular methods of CEC quantification include the use of immunomagnetic beads separation (IB) and flow cytometry analysis (FC); however, they suffer from two main shortcomings that affect their diagnostic and prognostic responses: non-specific bindings of magnetic beads to non-target cells and a high degree of variability in rare cell identification, respectively. We designed a microfluidic chip with spatially staggered micropillars for the efficient harvesting of CECs with intact cellular morphology in an attempt to revisit the diagnostic goal of CEC counts in CAD patients with angina pectoris. Methods A label-free microfluidic assay that involved an in-situ enumeration and immunofluorescent identification (DAPI+/CD146+/VEGFR1+/CD45-) of CECs was carried out to assess the CEC count in human peripheral blood samples. A total of 55 CAD patients with angina pectoris [16 with chronic stable angina (CSA) and 39 with unstable angina (UA)], together with 15 heathy controls (HCs) were enrolled in the study. Results CEC counts are significantly higher in both CSA and UA groups compared to the HC group [respective medians of 6.9, 10.0 and 1.5 cells/ml (p < 0.01)]. Further, a significant elevation of CEC count was observed in the three UA subgroups [low risk (5.3) vs. intermediate risk (10.8) vs. high risk (18.0) cells/ml, p < 0.001) classified in accordance to the TIMI NSTEMI/UA risk score system. From the receiver-operating characteristic curve analysis, the AUCs for distinguishing CSA and UA from HC were 0.867 and 0.938, respectively. The corresponding sensitivities were 87.5% and 84.6% and the specificities were 66.7% and 86.7%, respectively. Conclusions Our microfluidic assay system is efficient and stable for CEC capture and enumeration. The results showed that the CEC count has the potential to be a promising clinical biomarker for the assessment of endothelial damage/dysfunction in CAD patients with angina pectoris. PMID:28704506

Microfluidic assay of circulating endothelial cells in coronary artery disease patients with angina pectoris.

PubMed

Chen, Shuiyu; Sun, Yukun; Neoh, Kuang Hong; Chen, Anqi; Li, Weiju; Yang, Xiaorui; Han, Ray P S

2017-01-01

Circulating endothelial cells (CECs) are widely reported as a promising biomarker of endothelial damage/dysfunction in coronary artery disease (CAD). The two popular methods of CEC quantification include the use of immunomagnetic beads separation (IB) and flow cytometry analysis (FC); however, they suffer from two main shortcomings that affect their diagnostic and prognostic responses: non-specific bindings of magnetic beads to non-target cells and a high degree of variability in rare cell identification, respectively. We designed a microfluidic chip with spatially staggered micropillars for the efficient harvesting of CECs with intact cellular morphology in an attempt to revisit the diagnostic goal of CEC counts in CAD patients with angina pectoris. A label-free microfluidic assay that involved an in-situ enumeration and immunofluorescent identification (DAPI+/CD146+/VEGFR1+/CD45-) of CECs was carried out to assess the CEC count in human peripheral blood samples. A total of 55 CAD patients with angina pectoris [16 with chronic stable angina (CSA) and 39 with unstable angina (UA)], together with 15 heathy controls (HCs) were enrolled in the study. CEC counts are significantly higher in both CSA and UA groups compared to the HC group [respective medians of 6.9, 10.0 and 1.5 cells/ml (p < 0.01)]. Further, a significant elevation of CEC count was observed in the three UA subgroups [low risk (5.3) vs. intermediate risk (10.8) vs. high risk (18.0) cells/ml, p < 0.001) classified in accordance to the TIMI NSTEMI/UA risk score system. From the receiver-operating characteristic curve analysis, the AUCs for distinguishing CSA and UA from HC were 0.867 and 0.938, respectively. The corresponding sensitivities were 87.5% and 84.6% and the specificities were 66.7% and 86.7%, respectively. Our microfluidic assay system is efficient and stable for CEC capture and enumeration. The results showed that the CEC count has the potential to be a promising clinical biomarker for the assessment of endothelial damage/dysfunction in CAD patients with angina pectoris.

Integrating multi-omics analyses of Nonomuraea dietziae to reveal the role of soybean oil in [(4'-OH)MeLeu]4-CsA overproduction.

PubMed

Liu, Huanhuan; Huang, Di; Jin, Lina; Wang, Cheng; Liang, Shaoxiong; Wen, Jianping

2017-07-14

Nonomuraea dietziae is a promising microorganism to mediate the region-specific monooxygenation reaction of cyclosporine A (CsA). The main product [(4'-OH)MeLeu] 4 -CsA possesses high anti-HIV/HCV and hair growth-stimulating activities while avoiding the immunosuppressive effect of CsA. However, the low conversion efficiency restricts the clinical application. In this study, the production of [(4'-OH)MeLeu] 4 -CsA was greatly improved by 55.6% from 182.8 to 284.4 mg/L when supplementing soybean oil into the production medium, which represented the highest production of [(4'-OH)MeLeu] 4 -CsA so far. To investigate the effect of soybean oil on CsA conversion, some other plant oils (corn oil and peanut oil) and the major hydrolysates of soybean oil were fed into the production medium, respectively. The results demonstrated that the plant oils, rather than the hydrolysates, could significantly improve the [(4'-OH)MeLeu] 4 -CsA production, suggesting that soybean oil might not play its role in the lipid metabolic pathway. To further unveil the mechanism of [(4'-OH)MeLeu] 4 -CsA overproduction under the soybean oil condition, a proteomic analysis based on the two-dimensional gel electrophoresis coupled with MALDI TOF/TOF mass spectrometry was implemented. The results showed that central carbon metabolism, genetic information processing and energy metabolism were significantly up-regulated under the soybean oil condition. Moreover, the gas chromatography-mass spectrometry-based metabolomic analysis indicated that soybean oil had a great effect on amino acid metabolism and tricarboxylic acid cycle. In addition, the transcription levels of cytochrome P450 hydroxylase (CYP) genes for CsA conversion were determined by RT-qPCR and the results showed that most of the CYP genes were up-regulated under the soybean oil condition. These findings indicate that soybean oil could strengthen the primary metabolism and the CYP system to enhance the mycelium growth and the monooxygenation reaction, respectively, and it will be a guidance for the further metabolic engineering of this strain.

Clinical characteristic and risk factors of recurrent sexual abuse and delayed reported sexual abuse in childhood.

PubMed

Hu, Mei-Hua; Huang, Go-Shine; Huang, Jing-Long; Wu, Chang-Teng; Chao, An-Shine; Lo, Fu-Sung; Wu, Han-Ping

2018-04-01

Child sexual abuse (CSA) is a global problem that affects children of all ages, and the evaluation of these victims by psychologic and gynecologic experts in pediatric emergency departments is an important issue. Few data are available on the characteristics of children admitted to pediatric emergency department with recurrent CSA and delayed reported CSA. The aim of the present study was to describe the clinical features of, and risk factors for, recurrent CSA and delayed reported CSA. The study retrospectively analyzed victims of CSA who were admitted to a pediatric emergency department. Chi-square tests and univariate analyses were performed to assess the risk factors of recurrent or delayed reported CSA. Of the 91 CSA cases, 32 (35.2%) were recurrent assaults. Of the 70 cases recorded the duration of the event, 22 (31.4%) were delayed report cases. Comparisons of the non-recurrent and recurrent CSA assault groups revealed a significant increase in comorbidities (odds ratio [OR]: 4.46, 95% confidence interval [CI]: 1.54-12.93), acute psychiatric problems (OR: 3.18, CI: 1.26-8.06), attempted suicide (OR: 4.23, CI: 1.28-13.99), and the need for treatment with antipsychotic medications (OR: 5.57, CI: 1.37-22.65). Compared with non-delayed reported cases, the delay reported cases of CSA were significantly more likely to have anxiety (P < .05). The CSA victims in the present study exhibited acute medical and/or psychosocial problems, which indicate that pediatric emergency professionals have a responsibility to look for and recognize particular characteristics in these victims.

Early-age hydration and volume change of calcium sulfoaluminate cement-based binders

NASA Astrophysics Data System (ADS)

Chaunsali, Piyush

Shrinkage cracking is a predominant deterioration mechanism in structures with high surface-to-volume ratio. One way to allay shrinkage-induced stresses is to use calcium sulfoaluminate (CSA) cement whose early-age expansion in restrained condition induces compressive stress that can be utilized to counter the tensile stresses due to shrinkage. In addition to enhancing the resistance against shrinkage cracking, CSA cement also has lower carbon footprint than that of Portland cement. This dissertation aims at improving the understanding of early-age volume change of CSA cement-based binders. For the first time, interaction between mineral admixtures (Class F fly ash, Class C fly ash, and silica fume) and OPC-CSA binder was studied. Various physico-chemical factors such as the hydration of ye'elimite (main component in CSA cement), amount of ettringite (the main phase responsible for expansion in CSA cement), supersaturation with respect to ettringite in cement pore solution, total pore volume, and material stiffness were monitored to examine early-age expansion characteristics. This research validated the crystallization stress theory by showing the presence of higher supersaturation level of ettringite, and therefore, higher crystallization stress in CSA cement-based binders. Supersaturation with respect to ettringite was found to increase with CSA dosage and external supply of gypsum. Mineral admixtures (MA) altered the expansion characteristics in OPC-CSA-MA binders with fixed CSA cement. This study reports that fly ash (FA) behaves differently depending on its phase composition. The Class C FA-based binder (OPC-CSA-CFA) ceased expanding beyond two days unlike other OPC-CSA-MA binders. Three factors were found to govern expansion of CSA cement-based binders: 1) volume fraction of ettringite in given pore volume, 2) saturation level of ettringite, and 3) dynamic modulus. Various models were utilized to estimate the macroscopic tensile stress in CSA cement-based binders without taking into account the viscoelastic effects. For the first time, model based on poromechanics was used to calculate the macroscopic tensile stress that develops in CSA cement-based binders due to crystallization of ettringite. The models enabled a reasonable prediction of tensile stress due to crystallization of ettringite including the failure of an OPC-CSA binder which had high CSA cement content. Elastic strain based on crystallization stress was calculated and compared with the observed strain. A mismatch between observed and calculated elastic strain indicated the presence of early-age creep. Lastly, the application of CSA cement in concretes is discussed to link the paste and concrete behavior.

Childhood sexual abuse and its association with adult physical and mental health: results from a national cohort of young Australian women.

PubMed

Coles, Jan; Lee, Adeline; Taft, Angela; Mazza, Danielle; Loxton, Deborah

2015-07-01

Childhood sexual abuse (CSA) occurs across the world, with a prevalence of 20% internationally. Our aim was to investigate the associations between CSA, CSA plus adult violence experiences, and selected self-reported physical and mental health in a community sample of women. Data from 7,700 women aged 28-33 years from the 1973-1978 cohort who completed Survey 4 of the Australian Longitudinal Study on Women's Health (ALSWH) were analyzed. Questions about prior abuse experience such as child sexual abuse, IPV, adult physical and sexual assaults, andphysical and mental health. Women who experienced CSA were 1.4 times more likely to experience bodily pain (adjusted odds ratio [AOR] = 1.37, confidence interval [CI] = [1.19, 1.58]), 1.3 times more likely to have poorer general health (AOR = 1.33, CI = [1.15, 1.54]), and 1.4 times more likely to be depressed in the past 3 years (AOR = 1.44, CI = [1.22, 1.71]) compared with those without abuse.. Women who experienced both CSA and adult violence were 2.4 to 3.1 times more likely to experience poor general (AOR = 2.35, CI = [1.76, 3.14]) and mental health (AOR = 2.69, CI = [1.98, 3.64]), and suffer from depression (AOR = 2.84, CI = [2.13, 3.78]) and anxiety (AOR = 3.10, CI = [2.12, 4.53]) compared with women with no abuse. This study demonstrates the importance of CSA in pain and poorer long-term mental and physical health.. It emphasizes how prior CSA may amplify pain and poorer long-term mental and physical health among women who are again exposed to violence in adulthood. © The Author(s) 2014.

Parental reflective functioning as a moderator of child internalizing difficulties in the context of child sexual abuse.

PubMed

Ensink, Karin; Bégin, Michaël; Normandin, Lina; Fonagy, Peter

2017-11-01

The objective was to examine pathways from child sexual abuse (CSA) and maternal mentalizing to child internalizing and externalizing difficulties and to test a model of MRF as a moderator of the relationships between CSA and child difficulties. The sample was comprised of 154 mothers and children aged 2-12 where 64 children had experienced CSA. To assess parental mentalizing the Parental Development Interview was rated with the Parental Reflective Functioning Scale. Child internalizing and externalizing difficulties were assessed with the Child Behavior Checklist (CBCL). Results indicate that there were significant inverse relationships between maternal mentalizing and child internalizing and externalizing difficulties. When maternal mentalizing was considered together with CSA, only maternal mentalizing was a significant predictor of child difficulties. Furthermore, maternal mentalizing moderated the relationship between CSA and child internalizing difficulties. These findings provide evidence of the importance of the parents' mentalizing stance for psychiatric symptoms of children aged 2-12, as well as children's recovery from CSA. The clinical implications of the findings are discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

Contractile properties are disrupted in Becker muscular dystrophy, but not in limb girdle type 2I.

PubMed

Løkken, Nicoline; Hedermann, Gitte; Thomsen, Carsten; Vissing, John

2016-09-01

We investigated whether a linear relationship between muscle strength and cross-sectional area (CSA) is preserved in calf muscles of patients with Becker muscular dystrophy (BMD, n = 14) and limb-girdle type 2I muscular dystrophy (LGMD2I, n = 11), before and after correcting for muscle fat infiltration. The Dixon magnetic resonance imaging technique was used to quantify fat and calculate a fat-free contractile CSA. Strength was assessed by dynamometry. Muscle strength/CSA relationships were significantly lower in patients versus controls. The strength/contractile-CSA relationship was still severely lowered in BMD, but was almost normalized in LGMD2I. Our findings suggest close to intact contractile properties in LGMD2I, which are severely disrupted in BMD. Ann Neurol 2016;80:466-471. © 2016 American Neurological Association.

csa2sac—A program for computing discharge from continuous slope-area stage data

USGS Publications Warehouse

Wiele, Stephen M.

2015-12-17

In addition to csa2sac, the SAC7 program is required. It is the same as the original SAC program, except that it is compiled for 64-bit Windows operating systems and has a slightly different command line input. It is available online (http://water.usgs.gov/software/SAC/) as part of the SACGUI installation program. The program name, “SAC7.exe,” is coded into csa2sac, and must not be changed.

The effect of cyclosporin A, FK506 and rapamycin on the murine contact sensitivity reaction

PubMed Central

Salerno, A; Bonanno, C T; Caccamo, N; Cigna, D; Dominici, R; Ferro, C; Sireci, G; Dieli, F

1998-01-01

We have evaluated the effects of three potent immunosuppressive agents, cyclosporin A (CsA), FK506 and rapamycin, on the murine contact sensitivity (CS) reaction to the hapten trinitrochlorobenzene. Development of CS reaction requires participation of three distinct T cell subsets: αβ+, CD4+ T lymphocytes, which are the classical effector cell of the CS reaction, γδ+ T lymphocytes, and αβ+, double-negative (CD4− CD8−) T lymphocytes that express the B220 molecule and produce IL-4. We found that all three drugs inhibit the development of the CS reaction, but they affect different target cells. In fact, rapamycin and FK-506 block both αβ+, CD4+ and γδ+ T lymphocytes, while CsA inhibits only the αβ+, CD4+ T lymphocyte. None of the three drugs exerted any inhibitory activity on the αβ+, double-negative (CD4− CD8−) T lymphocytes. Hapten-immune lymph node cells from mice treated in vivo with CsA or FK506 failed to proliferate and to produce IL-2 when re-exposed to the specific antigen in vitro. In contrast, immune lymph node cells from mice that had been treated in vivo with rapamycin gave optimal antigen-specific proliferation and IL-2 production in vitro. The implications of these observations are discussed in relation to the use of these immunosuppressive agents for prevention of allograft rejection. PMID:9566798

Cyclosporine A and palmitic acid treatment synergistically induce cytotoxicity in HepG2 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Luo, Yi, E-mail: yi.luo@pfizer.com; Rana, Payal; Will, Yvonne

Immunosuppressant cyclosporine A (CsA) treatment can cause severe side effects. Patients taking immunosuppressant after organ transplantation often display hyperlipidemia and obesity. Elevated levels of free fatty acids have been linked to the etiology of metabolic syndromes, nonalcoholic fatty liver and steatohepatitis. The contribution of free fatty acids to CsA-induced toxicity is not known. In this study we explored the effect of palmitic acid on CsA-induced toxicity in HepG2 cells. CsA by itself at therapeutic exposure levels did not induce detectible cytotoxicity in HepG2 cells. Co-treatment of palmitic acid and CsA resulted in a dose dependent increase in cytotoxicity, suggesting thatmore » fatty acid could sensitize cells to CsA-induced cytotoxicity at the therapeutic doses of CsA. A synergized induction of caspase-3/7 activity was also observed, indicating that apoptosis may contribute to the cytotoxicity. We demonstrated that CsA reduced cellular oxygen consumption which was further exacerbated by palmitic acid, implicating that impaired mitochondrial respiration might be an underlying mechanism for the enhanced toxicity. Inhibition of c-Jun N-terminal kinase (JNK) attenuated palmitic acid and CsA induced toxicity, suggesting that JNK activation plays an important role in mediating the enhanced palmitic acid/CsA-induced toxicity. Our data suggest that elevated FFA levels, especially saturated FFA such as palmitic acid, may be predisposing factors for CsA toxicity, and patients with underlying diseases that would elevate free fatty acids may be susceptible to CsA-induced toxicity. Furthermore, hyperlipidemia/obesity resulting from immunosuppressive therapy may aggravate CsA-induced toxicity and worsen the outcome in transplant patients. -- Highlights: ► Palmitic acid and cyclosporine (CsA) synergistically increased cytotoxicity. ► The impairment of mitochondrial functions may contribute to the enhanced toxicity. ► Inhibition of JNK activity attenuated palmitate/ CsA induced toxicity. ► Palmitate sensitizes cells to the toxicity induced by CsA at therapeutic exposure. ► Elevated free fatty acids may predispose the patients to CsA-induced toxicity.« less

Neuroglobin overexpression inhibits oxygen-glucose deprivation-induced mitochondrial permeability transition pore opening in primary cultured mouse cortical neurons.

PubMed

Yu, Zhanyang; Liu, Ning; Li, Yadan; Xu, Jianfeng; Wang, Xiaoying

2013-08-01

Neuroglobin (Ngb) is an endogenous neuroprotective molecule against hypoxic/ischemic brain injury, but the underlying mechanisms remain largely undefined. Our recent study revealed that Ngb can bind to voltage-dependent anion channel (VDAC), a regulator of mitochondria permeability transition (MPT). In this study we examined the role of Ngb in MPT pore (mPTP) opening following oxygen-glucose deprivation (OGD) in primary cultured mouse cortical neurons. Co-immunoprecipitation (Co-IP) and immunocytochemistry showed that the binding between Ngb and VDAC was increased after OGD compared to normoxia, indicating the OGD-enhanced Ngb-VDAC interaction. Ngb overexpression protected primary mouse cortical neurons from OGD-induced neuronal death, to an extent comparable to mPTP opening inhibitor, cyclosporine A (CsA) pretreatment. We further measured the role of Ngb in OGD-induced mPTP opening using Ngb overexpression and knockdown approaches in primary cultured neurons, and recombinant Ngb exposure to isolated mitochondria. Same as CsA pretreatment, Ngb overexpression significantly reduced OGD-induced mPTP opening markers including mitochondria swelling, mitochondrial NAD(+) release, and cytochrome c (Cyt c) release in primary cultured neurons. Recombinant Ngb incubation significantly reduced OGD-induced NAD(+) release and Cyt c release from isolated mitochondria. In contrast, Ngb knockdown significantly increased OGD-induced neuron death, and increased OGD-induced mitochondrial NAD(+) release and Cyt c release as well, and these outcomes could be rescued by CsA pretreatment. In summary, our results demonstrated that Ngb overexpression can inhibit OGD-induced mPTP opening in primary cultured mouse cortical neurons, which may be one of the molecular mechanisms of Ngb's neuroprotection. Copyright © 2013 Elsevier Inc. All rights reserved.

Sexual self-schemas of female child sexual abuse survivors: relationships with risky sexual behavior and sexual assault in adolescence.

PubMed

Niehaus, Ashley F; Jackson, Joan; Davies, Stephanie

2010-12-01

Childhood sexual trauma has been demonstrated to increase survivors' risk for engaging in unrestricted sexual behaviors and experiencing adolescent sexual assault. The current study used the sexual self-schema construct to examine cognitive representations of sexuality that might drive these behavioral patterns. In Study 1 (N = 774), we attempted to improve the content validity of the Sexual Self Schema Scale for child sexual abuse (CSA) survivors, introducing a fourth sexual self-schema factor titled the "immoral/irresponsible" factor. In Study 2 (N = 1150), the potential differences in sexual self-views, as assessed by the four sexual self-schema factors, between CSA survivors and non-victims were explored. In addition, Study 2 evaluated how these sexual self-schema differences may contribute to participation in unrestricted sexual behaviors and risk for sexual assault in adolescence. Results indicated that a history of CSA impacted the way women viewed themselves as a sexual person on each of the four factors. CSA survivors were found to view themselves as more open and possessing more immoral/irresponsible cognitions about sexuality as compared to women who did not have a CSA history. In addition, the CSA survivors endorsed less embarrassment and passionate/romantic views of their sexual selves. The interaction of CSA severity and the sexual self-schemas explained variance in adolescent sexual assault experiences above and beyond the severity of CSA history and participation in risky sexual behaviors. The findings suggest that sexual self-views may serve to moderate the relationship between CSA and adolescent sexual assault. Implications of these findings and directions for future research are discussed.

Incidence and Progression of Cardiac Surgery-associated Acute Kidney Injury and its Relationship with Bypass and Cross Clamp Time

PubMed Central

Karim, Habib Md Reazaul; Yunus, Mohd; Saikia, Manuj Kumar; Kalita, Jyoti Prasad; Mandal, Mrinal

2017-01-01

Introduction: Cardiac surgery-associated kidney injury (CSA-AKI) is common but relatively less is known about its progression. The present study is aimed at evaluating the incidence and course of CSA-AKI and its relationship with the different durations of cardiopulmonary bypass (CPB) and cross clamp times. Materials and Methods: Occurrences of CSA-AKI are evaluated as per the Akin Kidney Injury Network (AKIN) criteria over the course of 5 postoperative day (POD) in 100 patients. The relationship of different durations of CPB and aortic cross clamp time with CSA-AKI is analyzed by Chi-squared test for trend and other appropriate tests using INSTAT software. Results: One hundred (43 male, 57 female; mean age of 37.01 ± 12.28 years, and baseline mean serum creatinine 0.99 ± 0.20 mg %) patients undergone mostly valve replacement, and congenital heart disease correction was evaluated. Nearly 49% suffered CSA-AKI (81.63% AKIN Class I) with maximum numbers on 2nd POD. Serum creatinine followed a falling trend 3rd POD onward except in 8.16% cases of CSA-AKI. Oliguria was absent even in AKIN Class II. The CPB time >70 min and cross clamp time >60 min increase CSA-AKI risk by an OR of 4.76 and 2.84, respectively (P < 0.05). Conclusion: CSA-AKI is very prevalent; mostly of AKIN Class I and increases with increasing CPB and cross clamp time. Urine output is not a reliable indicator of CSA-AKI. The AKIN Class II on the very 1st POD or increasing trend of serum creatinine beyond 3rd POD should alert for early intervention. PMID:28074790

Birth experiences in adult women with a history of childhood sexual abuse.

PubMed

Leeners, Brigitte; Görres, Gisela; Block, Emina; Hengartner, Michael Pascal

2016-04-01

Although childhood sexual abuse (CSA) may seriously impair childbirth experiences, few systematic evaluations on associations, mediating influences, risk and protective factors are available. As such information is mandatory to improve obstetric care, the present study aimed to provide such data. The study compared childbirth experiences from 85 women after CSA and at least one pregnancy resulting in a life birth with those from 170 control women matched for nationality, personal age and children's age. Trained specialists from support centers investigated CSA. Obstetrical data were collected from the official personal clinical record of each pregnancy (Mutterpass) and data on CSA as well as childbirth experiences were examined by questionnaires. Childbirth was more often highly frightening (24.7 vs. 5.3%; p<0.01) and a negative experience (40.7 vs. 19.6%, p<0.01) in women with a history of CSA than in controls. Multivariate regression models support the hypothesis that at least part of this association was mediated by covariates (specifically, birth preparation classes, presence of a trusted person, participation in medical decision-making, pain relief, emergency during labor and extreme duration of labor), which represent important resources in improving obstetric care. In 41% of women with CSA, memories of traumatic experiences intruded during childbirth, whereas about 58% experienced dissociation. While dissociation may result in loss of contact with obstetric staff, it was also used to reduce labor pain. Childbirth following a history of CSA is associated with particular challenges. Creating a trusting environment by evaluating and integrating individual needs could ameliorate birth experiences. Copyright © 2016 Elsevier Inc. All rights reserved.

Molecular Basis for Strain Variation in the Saccharomyces cerevisiae Adhesin Flo11p

PubMed Central

Li, Li; Lipke, Peter N.; Dranginis, Anne M.

2016-01-01

ABSTRACT FLO11 encodes a yeast cell wall flocculin that mediates a variety of adhesive phenotypes in Saccharomyces cerevisiae. Flo11p is implicated in many developmental processes, including flocculation, formation of pseudohyphae, agar invasion, and formation of microbial mats and biofilms. However, Flo11p mediates different processes in different yeast strains. To investigate the mechanisms by which FLO11 determines these differences in colony morphology, flocculation, and invasion, we studied gene structure, function, and expression levels. Nonflocculent Saccharomyces cerevisiae Σ1278b cells exhibited significantly higher FLO11 mRNA expression, especially in the stationary phase, than highly flocculent S. cerevisiae var. diastaticus. The two strains varied in cell surface hydrophobicity, and Flo11p contributed significantly to surface hydrophobicity in S. cerevisiae var. diastaticus but not in strain Σ1278b. Sequencing of the FLO11 gene in S. cerevisiae var. diastaticus revealed strain-specific differences, including a 15-amino-acid insertion in the adhesion domain. Flo11p adhesion domains from strain Σ1278b and S. cerevisiae var. diastaticus were expressed and used to coat magnetic beads. The adhesion domain from each strain bound preferentially to homologous cells, and the preferences were independent of the cells in which the adhesion domains were produced. These results are consistent with the idea that strain-specific variations in the amino acid sequences in the adhesion domains cause different Flo11p flocculation activities. The results also imply that strain-specific differences in expression levels, posttranslational modifications, and allelic differences outside the adhesion domains have little effect on flocculation. IMPORTANCE As a nonmotile organism, Saccharomyces cerevisiae employs the cell surface flocculin Flo11/Muc1 as an important means of adapting to environmental change. However, there is a great deal of strain variation in the expression of Flo11-dependent phenotypes, including flocculation. In this study, we investigated the molecular basis of this strain-specific phenotypic variability. Our data indicate that strain-specific differences in the level of flocculation result from significant sequence differences in the FLO11 alleles and do not depend on quantitative differences in FLO11 expression or on surface hydrophobicity. We further have shown that beads coated with amino-terminal domain peptide bind preferentially to homologous cells. These data show that variability in the structure of the Flo11 adhesion domain may thus be an important determinant of membership in microbial communities and hence may drive selection and evolution. PMID:27547826

Childhood Sexual Abuse Moderates the Relationship Between Obesity and Mental Health in Low-Income Women.

PubMed

Ramirez, Jennifer C; Milan, Stephanie

2016-02-01

We examined whether a history of self-reported childhood sexual abuse (CSA) moderates the relationship between obesity and mental health symptoms (depression, anxiety, and posttraumatic stress disorder) in an ethnically diverse sample of low-income women. A community sample of 186 women completed self-report measures and had their weight and height measured. Body mass index and CSA had an interactive effect on all mental health measures, such that obese women with a CSA history reported substantially higher levels of all symptoms. These results give greater specificity to the obesity-mental health link reported in previous studies and provide possible directions for targeted intervention. © The Author(s) 2015.

Pain relief for women undergoing oocyte retrieval for assisted reproduction.

PubMed

Kwan, Irene; Wang, Rui; Pearce, Emily; Bhattacharya, Siladitya

2018-05-15

Various methods of conscious sedation and analgesia (CSA) have been used during oocyte retrieval for assisted reproduction. The choice of agent has been influenced by the quality of sedation and analgesia and by concerns about possible detrimental effects on reproductive outcomes. To assess the effectiveness and safety of different methods of conscious sedation and analgesia for pain relief and pregnancy outcomes in women undergoing transvaginal oocyte retrieval. We searched; the Cochrane Gynaecology and Fertility specialised register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL, and trials registers in November 2017. We also checked references, and contacted study authors for additional studies. We included randomised controlled trials (RCTs) comparing different methods and administrative protocols for conscious sedation and analgesia during oocyte retrieval. We used standard methodological procedures expected by Cochrane. Our primary outcomes were intraoperative and postoperative pain. Secondary outcomes included clinical pregnancy, patient satisfaction, analgesic side effects, and postoperative complications. We included 24 RCTs (3160 women) in five comparisons. We report the main comparisons below. Evidence quality was generally low or very low, mainly owing to poor reporting and imprecision.1. CSA versus other active interventions.All evidence for this comparison was of very low quality.CSA versus CSA plus acupuncture or electroacupunctureData show more effective intraoperative pain relief on a 0 to 10 visual analogue scale (VAS) with CSA plus acupuncture (mean difference (MD) 1.00, 95% confidence interval (CI) 0.18 to 1.82, 62 women) or electroacupuncture (MD 3.00, 95% CI 2.23 to 3.77, 62 women).Data also show more effective postoperative pain relief (0 to 10 VAS) with CSA plus acupuncture (MD 0.60, 95% CI -0.10 to 1.30, 61 women) or electroacupuncture (MD 2.10, 95% CI 1.40 to 2.80, 61 women).Evidence was insufficient to show whether clinical pregnancy rates were different between CSA and CSA plus acupuncture (odds ratio (OR) 0.61, 95% CI 0.20 to 1.86, 61 women). CSA alone may be associated with fewer pregnancies than CSA plus electroacupuncture (OR 0.22, 95% CI 0.07 to 0.66, 61 women).Evidence was insufficient to show whether rates of vomiting were different between CSA and CSA plus acupuncture (OR 1.64, 95% CI 0.46 to 5.88, 62 women) or electroacupuncture (OR 1.09, 95% CI 0.33 to 3.58, 62 women).Trialists provided no usable data for other outcomes of interest.CSA versus general anaesthesia Postoperative pain relief was greater in the CSA group (0 to 3 Likert: mean difference (MD) 1.9, 95% CI 2.24 to 1.56, one RCT, 50 women).Evidence was insufficient to show whether groups differed in clinical pregnancy rates (OR 1.00, 95% CI 0.43 to 2.35, two RCTs, 108 women, I 2 = 0%).Evidence was insufficient to show whether groups differed in rates of vomiting (OR 0.46, 95% CI 0.08 to 2.75, one RCT, 50 women) or airway obstruction (OR 0.14, 95% CI 0.02 to 1.22, one RCT, 58 women). Fewer women needed mask ventilation in the CSA group (OR 0.05, 95% CI 0.01 to 0.20, one RCT, 58 women).Evidence was also insufficient to show whether groups differed in satisfaction rates (OR 0.66, 95% CI 0.11 to 4.04, two RCTs, 108 women, I 2 = 34%; very low-quality evidence).Trialists provided no usable data for outcomes of interest.2. CSA + paracervical block (PCB) versus other interventions.CSA + PCB versus electroacupuncture + PCB Intraoperative pain scores were lower in the CSA + PCB group (0 to 10 VAS: MD -0.66, 95% CI -0.93 to -0.39, 781 women, I 2 = 76%; low-quality evidence).Evidence was insufficient to show whether groups differed in clinical pregnancy rates (OR 0.96, 95% CI 0.72 to 1.29, 783 women, I 2 = 9%; low-quality evidence).Trialists provided no usable data for other outcomes of interest.CSA + PCB versus general anaesthesiaEvidence was insufficient to show whether groups differed in postoperative pain scores (0 to 10 VAS: MD 0.49, 95% CI -0.13 to 1.11, 50 women; very low-quality evidence).Evidence was insufficient to show whether groups differed in clinical pregnancy rates (OR 0.70, 95% CI 0.22 to 2.26, 51 women; very low-quality evidence).Trialists provided no usable data for other outcomes of interest.CSA + PCB versus spinal anaesthesiaPostoperative pain scores were higher in the CSA + PCB group (0 to 10 VAS: MD 1.02, 95% CI 0.48 to 1.56, 36 women; very low-quality evidence).Evidence was insufficient to show whether groups differed in clinical pregnancy rates (OR 0.93, 95% CI 0.24 to 3.65, 38 women; very low-quality evidence).Trialists provided no usable data for other outcomes of interest.CSA + PCB versus PCBEvidence was insufficient to show whether groups differed in clinical pregnancy rates (OR 0.93, 95% CI 0.44 to 1.96, 150 women; low-quality evidence) or satisfaction (OR 1.63, 95% CI 0.68 to 3.89, 150 women, low-quality evidence).Trialists provided no usable data for other outcomes of interest.CSA + PCB versus CSA only Evidence was insufficient to show whether groups differed in clinical pregnancy rates (OR 0.62, 95% CI 0.28 to 1.36, one RCT, 100 women; very low-quality evidence). Rates of postoperative nausea and vomiting were lower in the CS + PCB group (OR 0.42, 95% CI 0.18 to 0.97, two RCTs, 140 women, I 2 = 40%; very low-quality evidence).Trialists provided no usable data for other outcomes of interest. The evidence does not support one particular method or technique over another in providing effective conscious sedation and analgesia for pain relief during and after oocyte retrieval. Simultaneous use of sedation combined with analgesia such as the opiates, further enhanced by paracervical block or acupuncture techniques, resulted in better pain relief than occurred with one modality alone. Evidence was insufficient to show conclusively whether any of the interventions influenced pregnancy rates. All techniques reviewed were associated with a high degree of patient satisfaction. Women's preferences and resource availability for choice of pain relief merit consideration in practice.

Association between childhood sexual abuse and adverse psychological outcomes among youth in Taipei.

PubMed

Li, Nan; Ahmed, Saifuddin; Zabin, Laurie S

2012-03-01

The objective of this study was to examine the relationship between a history of childhood sexual abuse (CSA) and negative psychological consequences in adulthood, controlling for family environments and Confucian values. The data used in this study were collected from Taipei. The final analysis sample comprised 4,084 participants aged 15-24 years. Three sets of logistic regression models were fitted to verify the association between CSA and negative psychological outcomes. Sociodemographic variables, household instability, and parenting variables, as well as Confucian value variables were controlled in models step by step. The overall prevalence of CSA in our analysis sample was 5.2%. The overall prevalence of depression, anxiety, and suicidal ideation among Taipei respondents was 11.8%, 16.4%, and 16.7%, respectively, but young people who experienced CSA had significantly higher rates of all three than young adults who had not experienced CSA. After controlling for other covariates, the odds ratios of depression, anxiety, and suicidal ideation associated with a history of CSA were 1.78 (95% confidence intervals [CI]: 1.25-2.54), 1.77 (95% CI: 1.28-2.44), and 2.56 (95% CI: 1.56-4.29), respectively. Our findings suggested that CSA was an independent predictor of negative psychological consequences in adulthood. In our analysis, we controlled for household, parenting, and Confucian culture factors, which provides a better understanding of how they work together to affect adult psychological status. Copyright © 2012 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

Childhood sexual abuse and two stages of cigarette smoking in African-American and European-American young women.

PubMed

Sartor, Carolyn E; Grant, Julia D; Duncan, Alexis E; McCutcheon, Vivia V; Nelson, Elliot C; Calvert, Wilma J; Madden, Pamela A F; Heath, Andrew C; Bucholz, Kathleen K

2016-09-01

The aim of the current study was to determine whether the higher rates of childhood sexual abuse (CSA) but lower rates of cigarette smoking in African-American vs. European-American women can be explained in part by a lower magnitude of association between CSA and smoking in African-American women. Data were drawn from a same-sex female twin study of substance use (n=3521; 14.3% African-American). Cox proportional hazards regression analyses using CSA to predict smoking initiation and progression to regular smoking were conducted separately by race/ethnicity. Co-twin status on the smoking outcome was used to adjust for familial influences on smoking (which may overlap with family-level influences on CSA exposure). After adjusting for co-twin status, CSA was associated with smoking initiation in European Americans (hazard ratio (HR)=1.43, 95% confidence intervals (CI): 1.26-1.62) and with smoking initiation ≤16 in African Americans (HR=1.70, CI: 1.26-2.29). CSA was associated with regular smoking onset ≤15 in European Americans (HR=1.63, CI: 1.21-2.18), with no change in HR after adjusting for co-twin status. In the African-American subsample, the HR for CSA was reduced to non-significance after adjusting for co-twin status (from HR=3.30, CI: 1.23-8.89 to HR=1.16, CI: 0.71-1.92 for regular smoking ≤15). CSA is associated with moderate elevation in risk for initiating smoking among African-American and European-American women. By contrast, CSA is associated with elevated risk for (adolescent onset) regular smoking only in European-American women. Furthermore, there is significant overlap between risk conferred by CSA and familial influences on regular smoking in African-American but not European-American women. Copyright © 2016 Elsevier Ltd. All rights reserved.

Relationship between central sleep apnea and Cheyne-Stokes Respiration.

PubMed

Flinta, Irena; Ponikowski, Piotr

2016-03-01

Central sleep apnea (CSA) in patients with heart failure (HF) occurs frequently and shows a serious influence on prognosis in this population. The key elements in the pathophysiology of CSA are respiratory instability with chronic hyperventilation, changes of arterial carbon dioxide pressure (pCO2) and elongated circulation time. The main manifestation of CSA in patients with HF is Cheyne-Stokes Respiration (CSR). The initial treatment is the optimization of HF therapy. However, many other options of the therapeutic management have been studied, particularly those based on positive airway pressure methods. In patients with heart failure we often can observe the overlap of CSA and CSR; we will discuss the differences between these forms of breathing disorders during sleep. We will also discuss when CSA and CSR occur independently of each other and the importance of CSR occurring during the daytime in context of CSA during the nighttime. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Pulmonary Hypertension and Computed Tomography Measurement of Small Pulmonary Vessels in Severe Emphysema

PubMed Central

Matsuoka, Shin; Washko, George R.; Yamashiro, Tsuneo; Estepar, Raul San Jose; Diaz, Alejandro; Silverman, Edwin K.; Hoffman, Eric; Fessler, Henry E.; Criner, Gerard J.; Marchetti, Nathaniel; Scharf, Steven M.; Martinez, Fernando J.; Reilly, John J.; Hatabu, Hiroto

2010-01-01

Rationale: Vascular alteration of small pulmonary vessels is one of the characteristic features of pulmonary hypertension in chronic obstructive pulmonary disease. The in vivo relationship between pulmonary hypertension and morphological alteration of the small pulmonary vessels has not been assessed in patients with severe emphysema. Objectives: We evaluated the correlation of total cross-sectional area of small pulmonary vessels (CSA) assessed on computed tomography (CT) scans with the degree of pulmonary hypertension estimated by right heart catheterization. Methods: In 79 patients with severe emphysema enrolled in the National Emphysema Treatment Trial (NETT), we measured CSA less than 5 mm2 (CSA<5) and 5 to 10 mm2 (CSA5−10), and calculated the percentage of total CSA for the lung area (%CSA<5 and %CSA5–10, respectively). The correlations of %CSA<5 and %CSA5–10 with pulmonary arterial mean pressure (\\documentclass[10pt]{article} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{pmc} \\usepackage[Euler]{upgreek} \\pagestyle{empty} \\oddsidemargin -1.0in \\begin{document} \\begin{equation*}\\overline{Ppa}\\end{equation*}\\end{document}) obtained by right heart catheterization were evaluated. Multiple linear regression analysis using \\documentclass[10pt]{article} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{pmc} \\usepackage[Euler]{upgreek} \\pagestyle{empty} \\oddsidemargin -1.0in \\begin{document} \\begin{equation*}\\overline{Ppa}\\end{equation*}\\end{document} as the dependent outcome was also performed. Measurements and Main Results: The %CSA<5 had a significant negative correlation with \\documentclass[10pt]{article} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{pmc} \\usepackage[Euler]{upgreek} \\pagestyle{empty} \\oddsidemargin -1.0in \\begin{document} \\begin{equation*}\\overline{Ppa}\\end{equation*}\\end{document} (r = −0.512, P < 0.0001), whereas the correlation between %CSA5–10 and \\documentclass[10pt]{article} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{pmc} \\usepackage[Euler]{upgreek} \\pagestyle{empty} \\oddsidemargin -1.0in \\begin{document} \\begin{equation*}\\overline{Ppa}\\end{equation*}\\end{document} did not reach statistical significance (r = −0.196, P = 0.083). Multiple linear regression analysis showed that %CSA<5 and diffusing capacity of carbon monoxide (DlCO) % predicted were independent predictors of \\documentclass[10pt]{article} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{pmc} \\usepackage[Euler]{upgreek} \\pagestyle{empty} \\oddsidemargin -1.0in \\begin{document} \\begin{equation*}\\overline{Ppa}\\end{equation*}\\end{document} (r2 = 0.541): %CSA <5 (P < 0.0001), and DlCO % predicted (P = 0.022). Conclusions: The %CSA<5 measured on CT images is significantly correlated to \\documentclass[10pt]{article} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{pmc} \\usepackage[Euler]{upgreek} \\pagestyle{empty} \\oddsidemargin -1.0in \\begin{document} \\begin{equation*}\\overline{Ppa}\\end{equation*}\\end{document} in severe emphysema and can estimate the degree of pulmonary hypertension. PMID:19875683

Arginine Interactions with Anatase TiO2 (100) Surface and the Perturbation of 49Ti NMR Chemical Shifts - A DFT Investigation: Relevance to Renu-Seeram Bio Solar Cell

DOE Office of Scientific and Technical Information (OSTI.GOV)

Koch, Rainer; Lipton, Andrew S.; Filipek, S.

2011-06-01

Density functional theoretical calculations have been utilized to investigate the interaction of the amino acid arginine with the (100) surface of anatase and the reproduction of experimentally measured 49Ti NMR chemical shifts of anatase. Significant binding of arginine through electrostatic interaction and hydrogen bonds of the arginine guanidinium protons to the TiO2 surface oxygen atoms is observed, allowing attachment of proteins to titania surfaces in the construction of bio-sensitized solar cells. GIAO-B3LYP/6-31G(d) NMR calculation of a three-layer model based on the experimental structure of this TiO2 modification gives an excellent reproduction of the experimental value (-927 ppm) within +/- 7more » ppm, however, the change in relative chemical shifts, EFGs and CSA suggest that the effect of the electrostatic arginine binding might be too small for experimental detection.« less

Interleukin-13-induced MUC5AC expression is regulated by a PI3K–NFAT3 pathway in mouse tracheal epithelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yan, Fugui; Li, Wen; Zhou, Hongbin

Highlights: • IL-13 specifically induced NFAT3 activation in mouse tracheal epithelial cells. • CsA and LY294002 significantly blocked IL-13-induced MUC5AC production. • The PI3K–NFAT3 pathway is positively involved in IL-13-induced MUC5AC production. - Abstract: Interleukin-13 (IL-13) plays a critical role in asthma mucus overproduction, while the mechanisms underlying this process are not fully elucidated. Previous studies showed that nuclear factor of activated T cells (NFAT) is involved in the pathogenesis of asthma, but whether it can directly regulate IL-13-induced mucus (particularly MUC5AC) production is still not clear. Here we showed that IL-13 specifically induced NFAT3 activation through promoting its dephosphorylationmore » in air–liquid interface (ALI) cultures of mouse tracheal epithelial cells (mTECs). Furthermore, both Cyclosporin A (CsA, a specific NFAT inhibitor) and LY294002 (a Phosphoinositide 3-kinase (PI3K) inhibitor) significantly blocked IL-13-induced MUC5AC mRNA and protein production through the inhibition of NFAT3 activity. We also confirmed that CsA could not influence the forkhead Box A2 (Foxa2) and mouse calcium dependent chloride channel 3 (mClca3) expression in IL-13-induced MUC5AC production, which both are known to be important in IL-13-stimulated mucus expression. Our study is the first to demonstrate that the PI3K–NFAT3 pathway is positively involved in IL-13-induced mucus production, and provided novel insights into the molecular mechanism of asthma mucus hypersecretion.« less

An Evaluation of Voluntary Varicella Vaccination Coverage in Zhejiang Province, East China.

PubMed

Hu, Yu; Chen, Yaping; Zhang, Bing; Li, Qian

2016-06-03

In 2014 a 2-doses varicella vaccine (VarV) schedule was recommended by the Zhejiang Provincial Center for Disease Control and Prevention. We aimed to assess the coverage of the 1st dose of VarV (VarV₁) and the 2nd dose of VarV (VarV₂) among children aged 2-6 years through the Zhejiang Provincial Immunization Information System (ZJIIS) and to explore the determinants associated with the VarV coverage. Children aged 2-6 years (born from 1 January 2009 to 31 December 2013) registered in ZJIIS were enrolled. Anonymized individual records of target children were extracted from the ZJIIS database on 1 January 2016, including their VarV and (measles-containing vaccine) MCV vaccination information. The VarV₁ and VarV₂ coverage rates were evaluated for each birth cohorts. The coverage of VarV also was estimated among strata defined by cities, gender and immigration status. We also evaluated the difference in coverage between VarV and MCV. A total of 3,028,222 children aged 2-6 years were enrolled. The coverage of VarV₁ ranged from 84.8% to 87.9% in the 2009-2013 birth cohorts, while the coverage of VarV₂ increased from 31.8% for the 2009 birth cohort to 48.7% for the 2011 birth cohort. Higher coverage rates for both VarV₁ and VarV₂ were observed among resident children in relevant birth cohorts. The coverage rates of VarV₁ and VarV₂ were lower than those for the 1st and 2nd dose of MCV, which were above 95%. The proportion of children who were vaccinated with VarV₁ at the recommended age increased from 34.6% for the 2009 birth cohort to 75.2% for the 2013 birth cohort, while the proportion of children who were vaccinated with VarV₂ at the recommended age increased from 19.7% for the 2009 birth cohort to 48.7% for the 2011 birth cohort. Our study showed a rapid increasing VarV₂ coverage of children, indicating a growing acceptance of the 2-doses VarV schedule among children's caregivers and physicians after the new recommendation released. We highlighted the necessity for a 2-doses VarV vaccination school-entry requirement to achieve the high coverage of >90% and to eliminate disparities in coverage among sub-populations. We also recommended continuous monitoring of the VarV coverage via ZJIIS over time.

Clinical characteristic and risk factors of recurrent sexual abuse and delayed reported sexual abuse in childhood

PubMed Central

Hu, Mei-Hua; Huang, Go-Shine; Huang, Jing-Long; Wu, Chang-Teng; Chao, An-Shine; Lo, Fu-Sung; Wu, Han-Ping

2018-01-01

Abstract Child sexual abuse (CSA) is a global problem that affects children of all ages, and the evaluation of these victims by psychologic and gynecologic experts in pediatric emergency departments is an important issue. Few data are available on the characteristics of children admitted to pediatric emergency department with recurrent CSA and delayed reported CSA. The aim of the present study was to describe the clinical features of, and risk factors for, recurrent CSA and delayed reported CSA. The study retrospectively analyzed victims of CSA who were admitted to a pediatric emergency department. Chi-square tests and univariate analyses were performed to assess the risk factors of recurrent or delayed reported CSA. Of the 91 CSA cases, 32 (35.2%) were recurrent assaults. Of the 70 cases recorded the duration of the event, 22 (31.4%) were delayed report cases. Comparisons of the non-recurrent and recurrent CSA assault groups revealed a significant increase in comorbidities (odds ratio [OR]: 4.46, 95% confidence interval [CI]: 1.54–12.93), acute psychiatric problems (OR: 3.18, CI: 1.26–8.06), attempted suicide (OR: 4.23, CI: 1.28–13.99), and the need for treatment with antipsychotic medications (OR: 5.57, CI: 1.37–22.65). Compared with non-delayed reported cases, the delay reported cases of CSA were significantly more likely to have anxiety (P < .05). The CSA victims in the present study exhibited acute medical and/or psychosocial problems, which indicate that pediatric emergency professionals have a responsibility to look for and recognize particular characteristics in these victims. PMID:29620636

The calcineurin–NFAT pathway allows for urokinase receptor-mediated beta3 integrin signaling to cause podocyte injury

PubMed Central

Shi, Wei; Ma, Juan; Sloan, Alexis; Faul, Christian; Wei, Changli; Reiser, Jochen; Yang, Yun; Liu, Shuangxin; Wang, Wenjian

2014-01-01

Circulating and podocyte-bound urokinase receptor (uPAR) is a mediator of podocyte injury, proteinuria, and focal segmental glomerulosclerosis (FSGS) allowing pathological activation of the uPAR-β3 integrin signaling axis. Clinically, calcineurin inhibitors (e.g., cyclosporine A, CsA) are known to suppress T cells, yet are also being used to reduce proteinuria in FSGS, suggesting the possibility of signal cross talk between uPAR and calcineurin. Calcineurin is known to facilitate the nuclear translocation of the nuclear factor of activated T cells (NFAT). Accordingly, in vivo conditional NFATc1 activation in podocytes leads to proteinuria in mice, yet the downstream targets of NFAT remain unclear. Here, we show that inducible podocyte-specific expression of constitutively active NFATc1 increased podocyte uPAR expression by binding to the Plaur gene promoter (encoding uPAR) in chromatin immunoprecipitation assays. Pathological uPAR signals in podocytes are independent of T cells and affect cell motility via activation, but not expression, changes of the β3 integrin and can be blocked by CsA, NFAT-siRNA, or the cell-permeable NFAT inhibitor (11R-VIVIT) using rodent models of glomerular disease (LPS; 5/6 nephrectomized rats). Taken together, these findings identify podocyte uPAR as a downstream target of NFAT and provide further insights into the pathogenesis of FSGS. PMID:23015147

Somatic Embryogenesis in Olive (Olea europaea L. subsp. europaea var. sativa and var. sylvestris).

PubMed

Rugini, Eddo; Silvestri, Cristian

2016-01-01

Protocols for olive somatic embryogenesis from zygotic embryos and mature tissues have been described for both Olea europaea sub. europaea var. sativa and var. sylvestris. Immature zygotic embryos (no more than 75 days old), used after fruit collection or stored at 12-14 °C for 2-3 months, are the best responsive explants and very slightly genotype dependent, and one single protocol can be effective for a wide range of genotypes. On the contrary, protocols for mature zygotic embryos and for mature tissue of cultivars are often genotype specific, so that they may require many adjustments according to genotypes. The use of thidiazuron and cefotaxime seems to be an important trigger for induction phase particularly for tissues derived from cultivars. Up to now, however, the application of this technique for large-scale propagation is hampered also by the low rate of embryo germination; it proves nonetheless very useful for genetic improvement.

CSA-90 Promotes Bone Formation and Mitigates Methicillin-resistant Staphylococcus aureus Infection in a Rat Open Fracture Model.

PubMed

Mills, Rebecca; Cheng, Tegan L; Mikulec, Kathy; Peacock, Lauren; Isaacs, David; Genberg, Carl; Savage, Paul B; Little, David G; Schindeler, Aaron

2018-06-01

Infection of open fractures remains a significant cause of morbidity and mortality to patients worldwide. Early administration of prophylactic antibiotics is known to improve outcomes; however, increasing concern regarding antimicrobial resistance makes finding new compounds for use in such cases a pressing area for further research. CSA-90, a synthetic peptidomimetic compound, has previously demonstrated promising antimicrobial action against Staphylococcus aureus in rat open fractures. However, its efficacy against antibiotic-resistant microorganisms, its potential as a therapeutic agent in addition to its prophylactic effects, and its proosteogenic properties all require further investigation. (1) Does prophylactic treatment with CSA-90 reduce infection rates in a rat open fracture model inoculated with S aureus, methicillin-resistant S aureus (MRSA), and methicillin-resistant Staphylococcus epidermidis (MRSE) as measured by survival, radiographic union, and deep tissue swab cultures? (2) Does CSA-90 reduce infection rates when administered later in the management of an open fracture as measured by survival, radiographic union, and deep tissue swab cultures? (3) Does CSA-90 demonstrate a synergistic proosteogenic effect with bone morphogenetic protein 2 (BMP-2) in a noninfected rat ectopic bone formation assay as assessed by micro-CT bone volume measurement? (4) Can CSA-90 elute and retain its antimicrobial efficacy in vitro when delivered using clinically relevant agents measured using a Kirby-Bauer disc diffusion assay? All in vivo studies were approved by the local animal ethics committee. In the open fracture studies, 12-week-old male Wistar rats underwent open midshaft femoral fractures stabilized with a 1.1-mm Kirschner wire and 10 µg BMP-2 ± 500 µg CSA-90 was applied to the fracture site using a collagen sponge along with 1 x 10 colony-forming units of bacteria (S aureus/MRSA/MRSE; n = 10 per group). In the delayed treatment study, débridement and treatment with 500 µg CSA-90 were performed at Day 1 and Day 5 after injury and bacterial insult (S aureus). All animals were reviewed daily for signs of local infection and/or sepsis. An independent, blinded veterinarian reviewed twice-weekly radiographs, and rats showing osteolysis and/or declining overall health were culled at his instruction. The primary outcome of both fracture studies was fracture infection, incorporating survival, radiographic union, and deep tissue swab cultures. For the ectopic bone formation assay, 0 to 10 µg BMP-2 and 0 to 500 µg CSA-90 were delivered on a collagen sponge into bilateral quadriceps muscle pouches of 8-week-old rats (n = 10 per group). Micro-CT quantification of bone volume and descriptive histologic analysis were performed for all in vivo studies. Modified Kirby-Bauer disc diffusion assays were used to quantify antimicrobial activity in vitro using four different delivery methods, including bone cement. Infection was observed in none of the MRSA inoculated open fractures treated with CSA-90 with 10 of 10 deep tissue swab cultures negative at the time of cull. Median survival was 43 days (range, 11-43 days) in the treated group versus 11 days (range, 8-11 days) in the untreated MRSA inoculated group (p < 0.001). However, delayed débridement and treatment of open fractures with CSA-90 at either Day 1 or Day 5 did not prevent infection, resulting in early culls by Day 21 with positive swab cultures (10 of 10 for each time point). Maximal ectopic bone formation was achieved with 500 μg CSA-90 and 10 μg BMP-2 (mean volume, 9.58 mm; SD, 7.83), creating larger bone nodules than formed with 250 μg CSA-90 and 10 μg BMP-2 (mean volume, 1.7 mm; SD, 1.07; p < 0.001). Disc diffusion assays showed that CSA-90 could successfully elute from four potential delivery agents including calcium sulphate (mean zone of inhibition, 11.35 mm; SD, 0.957) and bone cement (mean, 4.67 mm; SD, 0.516). CSA-90 shows antimicrobial action against antibiotic-resistant Staphylococcal strains in vitro and in an in vivo model of open fracture infection. The antimicrobial properties of CSA-90 combined with further evidence of its proosteogenic potential make it a promising compound to develop further for orthopaedic applications.

Brainstem Involvement as a Cause of Central Sleep Apnea: Pattern of Microstructural Cerebral Damage in Patients with Cerebral Microangiopathy

PubMed Central

Duning, Thomas; Deppe, Michael; Brand, Eva; Stypmann, Jörg; Becht, Charlotte; Heidbreder, Anna; Young, Peter

2013-01-01

Background The exact underlying pathomechanism of central sleep apnea with Cheyne-Stokes respiration (CSA-CSR) is still unclear. Recent studies have demonstrated an association between cerebral white matter changes and CSA. A dysfunction of central respiratory control centers in the brainstem was suggested by some authors. Novel MR-imaging analysis tools now allow far more subtle assessment of microstructural cerebral changes. The aim of this study was to investigate whether and what severity of subtle structural cerebral changes could lead to CSA-CSR, and whether there is a specific pattern of neurodegenerative changes that cause CSR. Therefore, we examined patients with Fabry disease (FD), an inherited, lysosomal storage disease. White matter lesions are early and frequent findings in FD. Thus, FD can serve as a "model disease" of cerebral microangiopathy to study in more detail the impact of cerebral lesions on central sleep apnea. Patients and Methods Genetically proven FD patients (n = 23) and age-matched healthy controls (n = 44) underwent a cardio-respiratory polysomnography and brain MRI at 3.0 Tesla. We applied different MR-imaging techniques, ranging from semiquantitative measurement of white matter lesion (WML) volumes and automated calculation of brain tissue volumes to VBM of gray matter and voxel-based diffusion tensor imaging (DTI) analysis. Results In 5 of 23 Fabry patients (22%) CSA-CSR was detected. Voxel-based DTI analysis revealed widespread structural changes in FD patients when compared to the healthy controls. When calculated as a separate group, DTI changes of CSA-CSR patients were most prominent in the brainstem. Voxel-based regression analysis revealed a significant association between CSR severity and microstructural DTI changes within the brainstem. Conclusion Subtle microstructural changes in the brainstem might be a neuroanatomical correlate of CSA-CSR in patients at risk of WML. DTI is more sensitive and specific than conventional structural MRI and other advanced MR analyses tools in demonstrating these abnormalities. PMID:23637744

Leptin Deficiency Promotes Central Sleep Apnea in Patients With Heart Failure

PubMed Central

Cundrle, Ivan; Somers, Virend K.; Singh, Prachi; Johnson, Bruce D.; Scott, Christopher G.; van der Walt, Christelle

2014-01-01

Background: Leptin-deficient animals hyperventilate. Leptin expression by adipocytes is attenuated by atrial natriuretic peptide (ANP). Increased circulating natriuretic peptides (NPs) are associated with an increased risk of central sleep apnea (CSA). This study tested whether serum leptin concentration is inversely correlated to NP concentration and decreased in patients with heart failure (HF) and CSA. Methods: Subjects with HF (N = 29) were studied by measuring leptin, NPs, CO2 chemosensitivity (Δminute ventilation [V.e]/Δpartial pressure of end-tidal CO2 [Petco2]), and ventilatory efficiency (V.e/CO2 output [V.co2]) and were classified as CSA or no sleep-disordered breathing by polysomnography. CSA was defined as a central apnea-hypopnea index ≥ 15. The Student t test, Mann-Whitney U test, and logistic regression were used for analysis, and data were summarized as mean ± SD; P < .05 was considered significant. Results: Subjects with CSA had higher ANP and brain natriuretic peptide (BNP) concentrations (P < .05), ΔV.e/ΔPetco2 (2.39 ± 1.03 L/min/mm Hg vs 1.54 ± 0.35 L/min/mm Hg, P = .01), and V.e/V.co2 (43 ± 9 vs 34 ± 7, P < .01) and lower leptin concentrations (8 ± 10.7 ng/mL vs 17.1 ± 8.8 ng/mL, P < .01). Logistic regression analysis (adjusted for age, sex, and BMI) demonstrated leptin (OR = 0.07; 95% CI, 0.01-0.71; P = .04) and BNP (OR = 4.45; 95% CI, 1.1-17.9; P = .05) to be independently associated with CSA. Conclusions: In patients with HF and CSA, leptin concentration is low and is inversely related to NP concentration. Counterregulatory interactions of leptin and NP may be important in ventilatory control in HF. PMID:24030529

Arabidopsis VARIEGATED 3 encodes a chloroplast-targeted, zinc-finger protein required for chloroplast and palisade cell development.

PubMed

Naested, Henrik; Holm, Agnethe; Jenkins, Tom; Nielsen, H Bjørn; Harris, Cassandra A; Beale, Michael H; Andersen, Mathias; Mant, Alexandra; Scheller, Henrik; Camara, Bilal; Mattsson, Ole; Mundy, John

2004-09-15

The stable, recessive Arabidopsis variegated 3 (var3) mutant exhibits a variegated phenotype due to somatic areas lacking or containing developmentally retarded chloroplasts and greatly reduced numbers of palisade cells. The VAR3 gene, isolated by transposon tagging, encodes the 85.9 kDa VAR3 protein containing novel repeats and zinc fingers described as protein interaction domains. VAR3 interacts specifically in yeast and in vitro with NCED4, a putative polyene chain or carotenoid dioxygenase, and both VAR3 and NCED4 accumulate in the chloroplast stroma. Metabolic profiling demonstrates that pigment profiles are qualitatively similar in wild type and var3, although var3 accumulates lower levels of chlorophylls and carotenoids. These results indicate that VAR3 is a part of a protein complex required for normal chloroplast and palisade cell development.

Pedophilic sexual interests and psychopathy in child sexual abusers working with children.

PubMed

Turner, Daniel; Rettenberger, Martin; Lohmann, Lena; Eher, Reinhard; Briken, Peer

2014-02-01

Research has identified stable and dynamic characteristics in child sexual abusers working with children (CSA-W) that may distinguish them from other child sexual abusers (CSA). However, in previous research CSA-W have usually been included in the group of extra-familial CSA (CSA-E). Two hundred and forty-eight forensic-sexological reports about CSA conducted by the Federal Evaluation Centre for Violent and Sexual Offenders in the Austrian Prison System were evaluated retrospectively. One hundred and nineteen intra-familial CSA (CSA-I), 66 CSA-E, and 38 CSA-W were compared with regard to static risk factors, indicators of psychopathy, and pedophilic sexual interests. CSA-E had the highest risk of recidivism as measured by the Static-99 total score, followed by CSA-W. Furthermore, CSA-E had more previous convictions than CSA-W. Both CSA-E and CSA-I had higher total scores on the Psychopathy Checklist-Revised than CSA-W. CSA-W had the highest prevalence of pedophilia diagnoses according to DSM-IV-TR criteria, as well as the highest rate of pedophilia with an orientation toward male children, and the highest frequency of male victims. CSA-W also had the highest total scores in the Screening Scale for Pedophilic Interests. CSA-W seem to constitute a group with particular risk factors and criminogenic needs, that is, they show more indicators of pedophilic sexual interests but less general antisociality and psychopathy, and would thus seem to be distinguishable from other CSA. Future research should focus in particular on evaluating differences in the grooming strategies used by CSA-W to commit and disclose child sexual abuse, as well as on the resources of this particular offender group. Copyright © 2013 Elsevier Ltd. All rights reserved.

A Quantitative Study on Gender Differences in Disclosing Child Sexual Abuse and Reasons for Nondisclosure.

PubMed

Okur, Pinar; van der Knaap, Leontien M; Bogaerts, Stefan

2017-07-01

Despite the available literature on disclosure of child sexual abuse (CSA), little is known about how gender affects disclosure. This article aims to quantitatively examine whether gender differences exist in formal (to legal or child protection authorities) and informal (to a family member or friend) disclosure of CSA and, if so, to assess whether this relation is associated with abuse characteristics and attitudes toward gender roles. The study also aimed to examine whether gender differences exist in reasons not to disclose CSA. Data of a sample of 586 participants, who reported to have experienced CSA committed by a single person, have been used for the analyses. There were no gender differences for formal disclosure, but the informal disclosure rate of CSA was 2.4 times higher for women than men, and this effect remained significant after controlling for abuse characteristics and attitudes, even though the gender difference decreased slightly. Furthermore, women and men reported different reasons for not disclosing CSA in their personal network. Women were more worried than men that family and friends would discover the abuse and reported more insecurity of what to do in this situation. Professionals in the field of CSA should consider a gender perspective when developing guidelines. Men have rarely been the subject of studies of disclosure after CSA. Professionals should focus more on general mental health outcomes of men that are not related with CSA directly, but where the effects of CSA may exert more indirectly through associations with other problems in life.

Allostatic Perspectives in Women Veterans With a History of Childhood Sexual Assault.

PubMed

Groër, Maureen Wimberly; Kostas-Polston, Elizabeth A; Dillahunt-Aspillaga, Christina; Beckie, Theresa M; Johnson-Mallard, Versie; Duffy, Allyson; Evans, Mary E

2016-07-01

Women veterans have increased reports of sexual victimization compared to women in general, including childhood sexual assault (CSA) before military service, increasing the risk of military sexual trauma. Findings from recent studies reveal negative health effects following a history of CSA. There is a strong relationship between CSA and revictimization in civilian and military life, which may contribute to allostatic load. (1) To determine the relationship between women veterans' CSA history and later sexual assault history and (2) to determine the relationships between women veterans' CSA and primary mediators and secondary and tertiary outcomes of allostasis. Cross-sectional. Women (N = 81), 18-70 years old, veterans of the U.S. Armed Services. Participants completed questionnaires and blood and hair samples were collected. Several scales were utilized: Posttraumatic Checklist-Military, Center for Epidemiological Studies-Depression Scale, Pain Outcomes Questionnaire-Short Form, Cohen's Perceived Stress Scale (PSS), Profile of Mood States, and an investigator-developed sexual harassment/assault instrument. Thirty-three percent of participants reported CSA; of these, 38.5% reported military sexual assault and 70.3% sexual assault during civilian life. Those with CSA had higher cholesterol, triglycerides, perceived stress scores, and greater pain and fatigue than those without CSA. Hair cortisol was marginally lower in women with CSA when PSS was controlled, suggesting a dampened hypothalamic-pituitary-adrenal axis. These data suggest that some women veterans with a history of CSA may have increased allostatic load and be at increased risk for a variety of later life illnesses. © The Author(s) 2016.

Resistance exercise-induced fluid shifts: change in active muscle size and plasma volume

NASA Technical Reports Server (NTRS)

Ploutz-Snyder, L. L.; Convertino, V. A.; Dudley, G. A.

1995-01-01

The purpose of this study was to test the hypothesis that the reduction in plasma volume (PV) induced by resistance exercise reflects fluid loss to the extravascular space and subsequently selective increase in cross-sectional area (CSA) of active but not inactive skeletal muscle. We compared changes in active and inactive muscle CSA and PV after barbell squat exercise. Magnetic resonance imaging (MRI) was used to quantify muscle involvement in exercise and to determine CSA of muscle groups or individual muscles [vasti (VS), adductor (Add), hamstring (Ham), and rectus femoris (RF)]. Muscle involvement in exercise was determined using exercise-induced contrast shift in spin-spin relaxation time (T2)-weighted MR images immediately postexercise. Alterations in muscle size were based on the mean CSA of individual slices. Hematocrit, hemoglobin, and Evans blue dye were used to estimate changes in PV. Muscle CSA and PV data were obtained preexercise and immediately postexercise and 15 and 45 min thereafter. A hierarchy of muscle involvement in exercise was found such that VS > Add > Ham > RF, with the Ham and RF showing essentially no involvement. CSA of the VS and Add muscle groups were increased 10 and 5%, respectively, immediately after exercise in each thigh with no changes in Ham and RF CSA. PV was decreased 22% immediately following exercise. The absolute loss of PV was correlated (r2 = 0.75) with absolute increase in muscle CSA immediately postexercise, supporting the notion that increased muscle size after resistance exercise reflects primarily fluid movement from the vascular space into active but not inactive muscle.

Superior outcome using cyclosporin A alone versus cyclosporin A plus methotrexate for post-transplant immunosuppression in children with acute leukemia undergoing sibling hematopoietic stem cell transplantation.

PubMed

Weiss, Melissa; Steinbach, Daniel; Zintl, Felix; Beck, James; Gruhn, Bernd

2015-06-01

The outcome of cyclosporin A (CSA) alone (n = 19) as graft-versus-host disease (GVHD) prophylaxis was compared to that of CSA combined with methotrexate (MTX) (n = 43) in children with acute leukemia who underwent hematopoietic stem cell transplantation. All respective donors were HLA-identical siblings. All patients received CSA at a dose of 3 mg/kg/day starting on day -1. A CSA level of 80-130 ng/ml was aimed for. The 43 patients in the historical control were given an additional 10 mg/m(2) dosage of MTX on days 1, 3, 6, and 11. Patients who received CSA alone had a significantly reduced cumulative incidence of relapse (5 vs. 40 %; p = 0.002), a significantly increased 5-year event-free survival (84 vs. 35 %; p = 0.001), and a significantly increased 5-year overall survival (84 vs. 42 %; p = 0.004). The incidence of acute GVHD grade II-IV and chronic GVHD in patients in the CSA group was equivalent to the CSA+MTX group (26 vs. 19 %; p = 0.440, and 32 vs. 23 %; p = 0.428). In conclusion, post-transplant immunosuppression consisting of CSA alone is well tolerated and may contribute to a superior outcome.

Protein Supplementation Augments Muscle Fiber Hypertrophy but Does Not Modulate Satellite Cell Content During Prolonged Resistance-Type Exercise Training in Frail Elderly.

PubMed

Dirks, Marlou L; Tieland, Michael; Verdijk, Lex B; Losen, Mario; Nilwik, Rachel; Mensink, Marco; de Groot, Lisette C P G M; van Loon, Luc J C

2017-07-01

Protein supplementation increases gains in lean body mass following prolonged resistance-type exercise training in frail older adults. We assessed whether the greater increase in lean body mass can be attributed to muscle fiber type specific hypertrophy with concomitant changes in satellite cell (SC) content. A total of 34 frail elderly individuals (77 ± 1 years, n = 12 male adults) participated in this randomized, double-blind, placebo-controlled trial with 2 arms in parallel. Participants performed 24 weeks of progressive resistance-type exercise training (2 sessions per week) during which they were supplemented twice-daily with milk protein (2 × 15 g) or a placebo. Muscle biopsies were taken at baseline, and after 12 and 24 weeks of intervention, to determine type I and type II muscle fiber specific cross-sectional area (CSA), SC content, and myocellular characteristics. In the placebo group, a trend for a 20% ± 11% increase in muscle fiber CSA was observed in type II fibers only (P = .051), with no increase in type I muscle fiber CSA. In the protein group, type I and II muscle fiber CSA increased by 23% ± 7% and 34% ± 10% following 6 months of training, respectively (P < .01). Myonuclear domain size increased over time in both groups and fiber types (P < .001), with no significant differences between groups (P > .05). No changes in myonuclear content and SC contents were observed over time in either group (both P > .05). Regression analysis showed that changes in myonuclear content and domain size are predictive of muscle fiber hypertrophy. Protein supplementation augments muscle fiber hypertrophy following prolonged resistance-type exercise training in frail older people, without changes in myonuclear and SC content. Copyright © 2017 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.

Medicinal activities of the leaves of Musa sapientum var. sylvesteris in vitro

PubMed Central

Sahaa, Repon Kumer; Acharyaa, Srijan; Shovon, Syed Sohidul Haque; Royb, Priyanka

2013-01-01

Objective This study is to investigate the medicinal value of methanolic extract of the leaves of Musa sapientum var. sylvesteris in Bangladesh. Methods Several biochemical assays, thin layer chormatogarphy and ultra-violet spectroscopy were used to detect the presence of various types of compounds in this extract. Antioxidant effects were measured by DPPH scavenging assay, total reducing assay and hydrogen peroxide scavenging assay. Receptor binding activities and hydrogen peroxide induced hemolysis assay were performed by hemagglutination assay and hemolysis assay using erythrocytes. Disk diffusion assay was performed to show the antibacterial effect of the extract. Results Methanolic extract of the leaves showed antioxidant and antibacterial activity in vitro. The extract showed hemaglutination inhibition activities and hydrogen peroxide induced hemolysis inhibition activity of human red blood cells. Conclusion Musa sapientum var. sylvesteris can be an useful medicinal plant. PMID:23730561

Cell cycle arrest and induction of apoptosis by cajanin stilbene acid from Cajanus cajan in breast cancer cells.

PubMed

Fu, Yujie; Kadioglu, Onat; Wiench, Benjamin; Wei, Zuofu; Gao, Chang; Luo, Meng; Gu, Chengbo; Zu, Yuangang; Efferth, Thomas

2015-04-15

The low abundant cajanin stilbene acid (CSA) from Pigeon Pea (Cajanus cajan) has been shown to kill estrogen receptor α positive cancer cells in vitro and in vivo. Downstream effects such as cell cycle and apoptosis-related mechanisms have not been analyzed yet. We analyzed the activity of CSA by means of flow cytometry (cell cycle distribution, mitochondrial membrane potential, MMP), confocal laser scanning microscopy (MMP), DNA fragmentation assay (apoptosis), Western blotting (Bax and Bcl-2 expression, caspase-3 activation) as well as mRNA microarray hybridization and Ingenuity pathway analysis. CSA induced G2/M arrest and apoptosis in a concentration-dependent manner from 8.88 to 14.79 µM. The MMP broke down, Bax was upregulated, Bcl-2 downregulated and caspase-3 activated. Microarray profiling revealed that CSA affected BRCA-related DNA damage response and cell cycle-regulated chromosomal replication pathways. CSA inhibited breast cancer cells by DNA damage and cell cycle-related signaling pathways leading to cell cycle arrest and apoptosis. Copyright © 2015 Elsevier GmbH. All rights reserved.

Brain natriuretic peptide in patients with congestive heart failure and central sleep apnea.

PubMed

Carmona-Bernal, Carmen; Quintana-Gallego, Esther; Villa-Gil, Manuel; Sánchez-Armengol, Angeles; Martínez-Martínez, Angel; Capote, Francisco

2005-05-01

To assess the possible relationship between Cheyne-Stokes respiration (CSR) associated with central sleep apnea (CSA) syndrome and brain natriuretic peptide (BNP) in an outpatient population presenting with stable congestive heart failure (CHF). Ninety patients with CHF due to systolic dysfunction (left ventricular ejection fraction

Alcohol Myopia and Sexual Abdication among Women: Examining the Moderating Effect of Child Sexual Abuse

PubMed Central

Staples, Jennifer M.; George, William H.; Stappenbeck, Cynthia A.; Davis, Kelly Cue; Norris, Jeanette; Heiman, Julia

2014-01-01

HIV and other STIs are major public health concerns for women, and risky sexual behaviors increase the risk of transmission. Risky sexual behaviors include sexual abdication, that is, willingness to let a partner decide how far to go sexually. Alcohol intoxication is a risk factor for risky sexual behavior, and the Inhibition Conflict Model of Alcohol Myopia may help explain this relationship (Steele et al., 1985). This model suggests that in order for intoxication to influence behavior there must be high conflict, meaning the strength of the instigatory cues and inhibitory cues are both high. Recent research indicates that the degree to which cues are experienced as high in instigation or inhibition is subject to individual difference factors. One individual difference factor associated with alcohol-related sexual risk taking is child sexual abuse (CSA) history. The current study examined the influence of acute alcohol intoxication, CSA, and inhibition conflict on sexual abdication with 131 women (mean age 25) randomized into a 2 (alcohol, control) x 2 (high conflict, low conflict) experimental design. Regression analyses yielded a significant 3-way interaction, F (1,122) = 8.15, R2 = .14, p <.01. When there was high conflict, intoxicated CSA women were more likely to abdicate than sober CSA women, however, sober CSA women were less likely to abdicate than sober NSA women. When there was low conflict, CSA history and alcohol intoxication had no influence on abdication. These results may help explain the association between alcohol and risky sexual decision making among women with CSA. PMID:25310825

Alcohol myopia and sexual abdication among women: examining the moderating effect of child sexual abuse.

PubMed

Staples, Jennifer M; George, William H; Stappenbeck, Cynthia A; Davis, Kelly Cue; Norris, Jeanette; Heiman, Julia R

2015-02-01

HIV and other STIs are major public health concerns for women, and risky sexual behaviors increase the risk of transmission. Risky sexual behaviors include sexual abdication, that is, willingness to let a partner decide how far to go sexually. Alcohol intoxication is a risk factor for risky sexual behavior, and the Inhibition Conflict Model of Alcohol Myopia may help explain this relationship. This model suggests that in order for intoxication to influence behavior there must be high conflict, meaning the strength of the instigatory cues and inhibitory cues are both high. Recent research indicates that the degree to which cues are experienced as high in instigation or inhibition is subject to individual difference factors. One individual difference factor associated with alcohol-related sexual risk taking is child sexual abuse (CSA) history. The current study examined the influence of acute alcohol intoxication, CSA, and inhibition conflict on sexual abdication with 131 women (mean age 25) randomized into a 2 (alcohol, control)×2 (high conflict, low conflict) experimental design. Regression analyses yielded a significant 3-way interaction, F (1,122)=8.15, R(2)=.14, p<.01. When there was high conflict, intoxicated CSA women were more likely to abdicate than sober CSA women, however, sober CSA women were less likely to abdicate than sober NSA women, when there was low conflict, CSA history and alcohol intoxication had no influence on abdication. These results may help explain the association between alcohol and risky sexual decision making among women with CSA. Copyright © 2014 Elsevier Ltd. All rights reserved.

Mouse forepaw lumbrical muscles are resistant to age-related declines in force production.

PubMed

Russell, Katelyn A; Ng, Rainer; Faulkner, John A; Claflin, Dennis R; Mendias, Christopher L

2015-05-01

A progressive loss of skeletal muscle mass and force generating capacity occurs with aging. Mice are commonly used in the study of aging-associated changes in muscle size and strength, with most models of aging demonstrating 15-35% reductions in muscle mass, cross-sectional area (CSA), maximum isometric force production (Po) and specific force (sPo), which is Po/CSA. The lumbrical muscle of the mouse forepaw is exceptionally small, with corresponding short diffusion distances that make it ideal for in vitro pharmacological studies and measurements of contractile properties. However, the aging-associated changes in lumbrical function have not previously been reported. To address this, we tested the hypothesis that compared to adult (12month old) mice, the forepaw lumbrical muscles of old (30month old) mice exhibit aging-related declines in size and force production similar to those observed in larger limb muscles. We found that the forepaw lumbricals were composed exclusively of fibers with type II myosin heavy chain isoforms, and that the muscles accumulated connective tissue with aging. There were no differences in the number of fibers per whole-muscle cross-section or in muscle fiber CSA. The whole muscle CSA in old mice was increased by 17%, but the total CSA of all muscle fibers in a whole-muscle cross-section was not different. No difference in Po was observed, and while sPo normalized to total muscle CSA was decreased in old mice by 22%, normalizing Po by the total muscle fiber CSA resulted in no difference in sPo. Combined, these results indicate that forepaw lumbrical muscles from 30month old mice are largely protected from the aging-associated declines in size and force production that are typically observed in larger limb muscles. Copyright © 2015 Elsevier Inc. All rights reserved.

Delineation of the calcineurin-interacting region of cyclophilin B.

PubMed

Carpentier, M; Allain, F; Haendler, B; Slomianny, M C; Spik, G

2000-12-01

The immunosuppressant drug cyclosporin A (CsA) inhibits T-cell function by blocking the phosphatase activity of calcineurin. This effect is mediated by formation of a complex between the drug and cyclophilin (CyP), which creates a composite surface able to make high-affinity contacts with calcineurin. In vitro, the CyPB/CsA complex is more effective in inhibiting calcineurin than the CyPA/CsA and CyPC/CsA complexes, pointing to fine structural differences in the calcineurin-binding region. To delineate the calcineurin-binding region of CyPB, we mutated several amino acids, located in two loops corresponding to CyPA regions known to be involved, as follows: R76A, G77H, D155R, and D158R. Compared to wild-type CyPB, the G77H, D155R, and D158R mutants had intact isomerase and CsA-binding activities, indicating that no major conformational changes had taken place. When complexed to CsA, they all displayed only reduced affinity for calcineurin and much decreased inhibition of calcineurin phosphatase activity. These results strongly suggest that the three amino acids G77, D155, and D158 are directly involved in the interaction of CyPB/CsA with calcineurin, in agreement with their exposed position. The G77, D155, and D158 residues are not maintained in CyPA and might therefore account for the higher affinity of the CyPB/CsA complex for calcineurin.

Family Violence and Child Sexual Abuse Among South Asians in the US.

PubMed

Robertson, Hillary A; Chaudhary Nagaraj, Nitasha; Vyas, Amita N

2016-08-01

Family violence, including child sexual abuse (CSA), is a significant public health problem in the United States. It is particularly difficult to assess family violence and CSA among South Asians because it is often hidden due to cultural and familial stigma. A web-based survey was administered to a convenience sample (n = 368) of South Asian adults in the US. One-fourth (25.2 %) of the sample reported CSA; 13.8 % reported abuse involving exposure; 21.5 % reported abuse involving touching; 4.5 % reported attempted sexual intercourse; and 3.5 % reported forced sexual intercourse. Adjusted odds ratios found that participants who reported any relationship violence were significantly more likely to have experienced CSA (OR 2.28; 95 % CI 1.26-4.13); and suicide attempt was significantly associated with CSA (OR 3.96; 95 % CI 1.27-12.3). The findings presented in this formative study will assist in guiding future studies and interventions for South Asians in the United States.

WaterSense Specification for Showerheads Supporting Statement

EPA Pesticide Factsheets

WaterSense collaborated with the American Society of Mechanical Engineers (ASME)/Canadian Standards Association (CSA) Joint Harmonization Task Force to develop the specification criteria for high-efficiency showerheads.

Molecular and antigenic traits on hemagglutinin gene of avian influenza H9N2 viruses: Evidence of a new escape mutant in Egypt adapted in quails.

PubMed

Adel, Amany; Arafa, Abdelsatar; Hussein, Hussein A; El-Sanousi, Ahmed A

2017-06-01

The LPAI viruses of H9N2 subtype became widely distributed in Middle Eastern countries, causing great economic losses in poultry industry especially when complicated with other pathogens. The H9N2 viruses in Egypt have a wide spread nature since its first occurrence in 2011. In this study, we collected cloacal and tracheal samples from 19 flocks for detection and propagation of H9N2 virus using real-time RT-PCR and egg inoculation. We studied the molecular evolution of the Hemagglutinin gene of H9N2 viruses by full HA gene sequencing, then the antigenic characterization was implemented using the cross HI assay and analyzed using 3D Bioinformatics cartography software. The phylogenetic analysis of the HA gene of Egyptian H9N2 viruses clearly points out the presence of only one group (Egy/G1) of originally introduced viruses in 2011 related to the G1 lineage within group B, with the presence of multiple minor clusters includes viruses from 2011 to 2015. However, a new variant (Egy/G1var) cluster was detected in quails since 2012. Genetically, Egy/G1var viruses characterized by presence of 20 amino acid substitutions within and adjacent to the antigenic sites in comparison to other Egyptian viruses. In addition, two glycosylation sites at amino acid residues 127 and 189 were determined in close to the receptor binding and antigenic sites. The antigenic analysis based on 3D antigenic mapping showed that the Egy/G1var cluster was clearly distinct from the original Egy/G1 viruses. In conclusion, Egy/G1var is shown to be a new escape mutant variant cluster with an adaptive evolution in quails. Copyright © 2017 Elsevier Ltd. All rights reserved.

Ketoconazole and the modulation of multidrug resistance-mediated transport in Caco-2 and MDCKII-MDR1 drug transport models.

PubMed

Fan, Y; Rodriguez-Proteau, R

2008-02-01

The hypothesis tested was that ketoconazole can modulate P-glycoprotein, thereby altering cellular uptake and apparent permeability (P(app)) of multidrug-resistant substrates, such as cyclosporin A (CSA) and digoxin, across Caco-2, MDCKII-MDR1, and MDCKII wild-type cell transport models. (3)H-CSA/(3)H-digoxin transport experiments were performed with and without co-exposure to ketoconazole, and (3)H-ketoconzole transport experiments were performed with and without co-exposure to dietary flavonoids, epigallocatechin-3-gallate, and xanthohumol. Ketoconazole (3 microM) reduced the P(app) efflux of CSA and digoxin from 5.07 x 10(-6) to 2.91 x 10(-6) cm s(-1) and from 2.60 x 10(-6) to 1.41 x 10(-6) cm s(-1), respectively, in Caco-2 cells. In the MDCKII-MDR1 cells, ketoconazole reduced the P(app) efflux of CSA and increased the P(app) absorption of digoxin. Cellular uptake of ketoconazole in the Caco-2 cells was significantly inhibited by CSA and digoxin, whereas epigallocatechin-3-gallate and xanthohumol exhibited biphasic responses. In conclusion, ketoconazole modulates the P(app) of P-glycoprotein substrates by interacting with MDR1 protein. Epigallocatechin-3-gallate and xanthohumol modulate the transport and uptake of ketoconazole.

First experience of using new adaptive servo-ventilation device for Cheyne-Stokes respiration with central sleep apnea among Japanese patients with congestive heart failure: report of 4 clinical cases.

PubMed

Kasai, Takatoshi; Narui, Koji; Dohi, Tomotaka; Takaya, Hisashi; Yanagisawa, Naotake; Dungan, George; Ishiwata, Sugao; Ohno, Minoru; Ymaguchi, Tetsu; Momomura, Shin-ichi

2006-09-01

Cheyne-Stokes respiration with central sleep apnea (CSR-CSA) in congestive heart failure (CHF) is generally considered a poor prognostic indicator, but treatment of CSR-CSA using an adaptive servo-ventilation (ASV) device has been developed. This is the first evaluation of its use in the management of CSR-CSA in Japanese CHF patients. Four CHF patients with CSR-CSA that was unresponsive to conventional positive airway pressure (CPAP) underwent 3 nights of polysomnography: baseline, CPAP or bi-level PAP, and on the ASV. The apnea - hypopnea index (AHI) and central-AHI (CAHI) were markedly improved on ASV (AHI 62.7+/-10.1 to 5.9+/-2.2 /h, p=0.0006, CAHI 54.5+/-6.7 to 5.6+/-2.3 /h, p=0.007). In addition, the sleep quality improved significantly on ASV, including arousal index (62.0+/-10.5 to 18.7 +/-6.2 /h, p=0.012), percentage of slow-wave sleep (2.6+/-2.6 to 19.4+/-4.8 %, p=0.042). ASV markedly improved CSR-CSA in patients with CHF. It is a promising treatment for Japanese patients with CHF.

Contrasting effects of lower body positive pressure on upper airways resistance and partial pressure of carbon dioxide in men with heart failure and obstructive or central sleep apnea.

PubMed

Kasai, Takatoshi; Motwani, Shveta S; Yumino, Dai; Gabriel, Joseph M; Montemurro, Luigi Taranto; Amirthalingam, Vinoban; Floras, John S; Bradley, T Douglas

2013-03-19

This study sought to test the effects of rostral fluid displacement from the legs on transpharyngeal resistance (Rph), minute volume of ventilation (Vmin), and partial pressure of carbon dioxide (PCO2) in men with heart failure (HF) and either obstructive (OSA) or central sleep apnea (CSA). Overnight rostral fluid shift relates to severity of OSA and CSA in men with HF. Rostral fluid displacement may facilitate OSA if it shifts into the neck and increases Rph, because pharyngeal obstruction causes OSA. Rostral fluid displacement may also facilitate CSA if it shifts into the lungs and induces reflex augmentation of ventilation and reduces PCO2, because a decrease in PCO2 below the apnea threshold causes CSA. Men with HF were divided into those with mainly OSA (obstructive-dominant, n = 18) and those with mainly CSA (central-dominant, n = 10). While patients were supine, antishock trousers were deflated (control) or inflated for 15 min (lower body positive pressure [LBPP]) in random order. LBPP reduced leg fluid volume and increased neck circumference in both obstructive- and central-dominant groups. However, in contrast to the obstructive-dominant group in whom LBPP induced an increase in Rph, a decrease in Vmin, and an increase in PCO2, in the central-dominant group, LBPP induced a reduction in Rph, an increase in Vmin, and a reduction in PCO2. These findings suggest mechanisms by which rostral fluid shift contributes to the pathogenesis of OSA and CSA in men with HF. Rostral fluid shift could facilitate OSA if it induces pharyngeal obstruction, but could also facilitate CSA if it augments ventilation and lowers PCO2. Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Continuous In Situ Measurements of Near Bottom Chemistry and Sediment-Water Fluxes with the Chimney Sampler Array (CSA)

NASA Astrophysics Data System (ADS)

Martens, C. S.; Mendlovitz, H. P.; White, B. L.; Hoer, D.; Sleeper, K.; Chanton, J.; Wilson, R.; Lapham, L.

2011-12-01

The Chimney Sampler Array (CSA) was designed to measure in situ chemical and physical parameters within the benthic boundary layer plus methane and oxygen sediment-water chemical fluxes at upper slope sites in the northern Gulf of Mexico. The CSA can monitor temporal changes plus help to evaluate oceanographic and sub-seafloor processes that can influence the formation and stability of gas hydrates in underlying sediments. The CSA consists of vertical cylinders (chimneys) equipped with internal chemical sensors and with laboratory flume-calibrated washout rates. Chimney washout rates multiplied by chimney mean versus ambient concentrations allow calculation of net O2 and methane sediment-water fluxes. The CSA is emplaced on the seafloor by a ROVARD lander using a ROV for chimney deployments. The CSA presently includes two 30 cm diameter by 90 cm length cylinders that seal against the sediment with lead pellet beanbags; within each chimney cylinder are optode, conductivity and methane sensors. The CSA's data logger platform also includes pressure and turbidity sensors external to the chimneys along with an acoustic Doppler current meter to measure temporal variation in ambient current velocity and direction. The CSA was deployed aboard a ROVARD lander on 9/13/2010 in the northern Gulf of Mexico (Lat. 28 51.28440, Long. 088 29.39421) on biogeochemically active sediments within Block MC-118. A ROV was utilized for chimney deployment away from the ROVARD lander. The CSA monitored temporal changes in water column physical parameters, obtained near-bottom chemical data to compare with pore fluid and sediment core measurements and measured temporal variability in oxygen and methane sediment-water fluxes at two closely spaced stations at MC-118. A continuous, three-week data set was obtained that revealed daily cycles in chemical parameters and episodic flux events. Lower than ambient chimney dissolved O2 concentrations controlled by temporal variability in washout rates were used to calculate sediment O2 demand. Episodic events yielding turbidity spikes produced episodic spikes in chimney methane concentrations and sediment-water fluxes. The robust data set reveals new capabilities for long-term monitoring of near-bottom processes in biogeochemically active, continental margin environments.

Profiles of musculoskeletal development in limbs of college Olympic weightlifters and wrestlers.

PubMed

Kanehisa, H; Fukunaga, T

1999-04-01

To investigate the event-related profiles of musculoskeletal development in weight-categorized athletes, we measured the cross-sectional areas (CSA) of bone and muscle in the forearm, upper arm, lower leg and thigh, using a B-mode ultrasound apparatus, in college Olympic weightlifters (OWL, n = 19) and wrestlers (WR, n = 17) and untrained men (UM, n = 24), whose body masses were within the range from 55 kg to 78 kg. Both bone and muscle CSA at all sites were significantly correlated to the two-thirds power of fat-free mass (FFM(2/3)) with correlation coefficients of 0.430-40.741 (P < 0.05) and 0.608-0.718 (P < 0.05), respectively. Moreover, there were significant correlations between bone and muscle CSA at all sites (r = 0.664-0.829, P < 0.05). Even when bone and muscle CSA were expressed relative value to FFM(2/3), both OWL and WR showed significantly greater values than UM at all sites except for the lower leg. Furthermore, the comparison of the lean (bone + muscle) CSA ratio from site to site indicated a higher distribution of lean tissues in the upper extremities in OWL and WR compared to UM. While there was no significant difference between the two athlete groups in FFM(2/3), OWL showed significantly larger values than WR in the bone CSA of the upper arm and thigh and in the muscle CSA of the lower leg and thigh. However, lean CSA ratios of the upper extremities to the lower ones were significantly higher in WR than in OWL. Thus, the present results indicated that, compared to UM, OWL and WR had a greater lean tissue CSA in limbs, especially in the upper extremities, even when the difference in FFM was normalized. Moreover, the relative distribution of lean tissues in limbs differed between the two weight-categorized athletes in spite of there being no difference in FFM, which may be attributable to their own training regimens and/or competition style.

Allometric scaling of biceps strength before and after resistance training in men.

PubMed

Zoeller, Robert F; Ryan, Eric D; Gordish-Dressman, Heather; Price, Thomas B; Seip, Richard L; Angelopoulos, Theodore J; Moyna, Niall M; Gordon, Paul M; Thompson, Paul D; Hoffman, Eric P

2007-06-01

The purposes of this study were 1) derive allometric scaling models of isometric biceps muscle strength using pretraining body mass (BM) and muscle cross-sectional area (CSA) as scaling variables in adult males, 2) test model appropriateness using regression diagnostics, and 3) cross-validate the models before and after 12 wk of resistance training. A subset of FAMuSS (Functional SNP Associated with Muscle Size and Strength) study data (N=136) were randomly split into two groups (A and B). Allometric scaling models using pretraining BM and CSA were derived and tested for group A. The scaling exponents determined from these models were then applied to and tested on group B pretraining data. Finally, these scaling exponents were applied to and tested on group A and B posttraining data. BM and CSA models produced scaling exponents of 0.64 and 0.71, respectively. Regression diagnostics determined both models to be appropriate. Cross-validation of the models to group B showed that the BM model, but not the CSA model, was appropriate. Removal of the largest six subjects (CSA>30 cm) from group B resulted in an appropriate fit for the CSA model. Application of the models to group A posttraining data showed that both models were appropriate, but only the body mass model was successful for group B. These data suggest that the application of scaling exponents of 0.64 and 0.71, using BM and CSA, respectively, are appropriate for scaling isometric biceps strength in adult males. However, the scaling exponent using CSA may not be appropriate for individuals with biceps CSA>30 cm. Finally, 12 wk of resistance training does not alter the relationship between BM, CSA, and muscular strength as assessed by allometric scaling.

Effects of protein-pheromone complexation on correlated chemical shift modulations.

PubMed

Perazzolo, Chiara; Wist, Julien; Loth, Karine; Poggi, Luisa; Homans, Steve; Bodenhausen, Geoffrey

2005-12-01

Major urinary protein (MUP) is a pheromone-carrying protein of the lipocalin family. Previous studies by isothermal titration calorimetry (ITC) show that the affinity of MUP for the pheromone 2-methoxy-3-isobutylpyrazine (IBMP) is mainly driven by enthalpy, with a small unfavourable entropic contribution. Entropic terms can be attributed in part to changes in internal motions of the protein upon binding. Slow internal motions can lead to correlated or anti-correlated modulations of the isotropic chemical shifts of carbonyl C' and amide N nuclei. Correlated chemical shift modulations (CSM/CSM) in MUP have been determined by measuring differences of the transverse relaxation rates of zero- and double-quantum coherences ZQC{C'N} and DQC{C'N}, and by accounting for the effects of correlated fluctuations of dipole-dipole couplings (DD/DD) and chemical shift anisotropies (CSA/CSA). The latter can be predicted from tensor parameters of C' and N nuclei that have been determined in earlier work. The effects of complexation on slow time-scale protein dynamics can be determined by comparing the temperature dependence of the relaxation rates of APO-MUP (i.e., without ligand) and HOLO-MUP (i.e., with IBMP as a ligand).

Cyclophilin B stimulates RNA synthesis by the HCV RNA dependent RNA polymerase.

PubMed

Heck, Julie A; Meng, Xiao; Frick, David N

2009-04-01

Cyclophilins are cellular peptidyl isomerases that have been implicated in regulating hepatitis C virus (HCV) replication. Cyclophilin B (CypB) is a target of cyclosporin A (CsA), an immunosuppressive drug recently shown to suppress HCV replication in cell culture. Watashi et al. recently demonstrated that CypB is important for efficient HCV replication, and proposed that it mediates the anti-HCV effects of CsA through an interaction with NS5B [Watashi K, Ishii N, Hijikata M, Inoue D, Murata T, Miyanari Y, et al. Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase. Mol Cell 2005;19:111-22]. We examined the effects of purified CypB proteins on the enzymatic activity of NS5B. Recombinant CypB purified from insect cells directly stimulated NS5B-catalyzed RNA synthesis. CypB increased RNA synthesis by NS5B derived from genotype 1a, 1b, and 2a HCV strains. Stimulation appears to arise from an increase in productive RNA binding. NS5B residue Pro540, a previously proposed target of CypB peptidyl-prolyl isomerase activity, is not required for stimulation of RNA synthesis.

Topical administration of Esculetin as a potential therapy for experimental dry eye syndrome.

PubMed

Jiang, D; Liu, X; Hu, J

2017-12-01

PurposeIn this study, we investigated the therapeutic effects of topical Esculetin for dry eye rabbits through the ocular tests, inflammatory factor levels and specific phosphorylated protein expressions of ERK1/2 singnal pathway.Patients and methodsThirty-two healthy adult male New Zealand white rabbits were chosen for the study. DES models were established after removing of the main lacrimal gland, Harderian gland and nictitating membrane in the left eyes and randomly divided into group DES control, group CsA, group Esculetin and group Esculetin combined with CsA (C&E), meanwhile the right eyes served as group Normal control. Schirmer's I tests, fluorescein scores, goblet cell densities, inflammatory cytokines IL-1α,IL-1β,TNF-αlevels were observed by slit-lamp microscope, conjunctival impression cytology and ELISA essay at week 0, 1, 2, 4, 8. Phosphorylated-ERK1/2 expressions were detected in Western blot analysis at week 8.ResultsAfter induction of DES, aqueous tear production and goblet cell density were decreased, FL score was much higher in group DES control throughout the study (P<0.05). Both topical Esculetin and Esculetin combing CsA increased the SIT values (10±1 mm, 14±3 mm, P<0.05) and goblet cell densities (77±12/HP, 92±12/HP, P<0.05), decreased FL scores (7.48±0.33, 5.09±0.24, P<0.05) at week 8. Alternations of IL-1α,IL-1β,TNF-αlevels had similar trend. In Western blot analysis, downregulations of p-ERK1/2 were observed in therapy groups when compared with group DES control and the most decreasing was found in group C&E (P<0.05).ConclusionTopical Esculetin improved DES symptoms, downregulated the inflammatory cytokine expressions, suppressed the ERK1/2 pathway and enhanced the therapeutic effect of CsA.

Child Sexual Abuse and Negative Affect as Shared Risk Factors for Sexual Aggression and Sexual HIV Risk Behavior in Heterosexual Men.

PubMed

Peterson, Zoё D; Janssen, Erick; Goodrich, David; Fortenberry, J Dennis; Hensel, Devon J; Heiman, Julia R

2018-02-01

Previous research has suggested that sexually aggressive behavior and sexual HIV risk behavior are associated. Childhood sexual abuse (CSA) is a well-established risk factor for both types of problematic sexual behavior. Negative affect (i.e., anxiety, depression, and anger) is a less well-studied risk factor, but it has been theorized to relate to both sexual aggression and HIV risk behavior. Thus, this study sought to (1) confirm the relationship between sexual aggression and HIV risk behavior, (2) establish CSA and negative affect as shared risk factors for sexual aggression and HIV risk behavior, and (3) evaluate whether negative affect mediates the relationship between CSA and sexual aggression and between CSA and HIV sexual risk in a sample of heterosexual men. We recruited 18- to 30-year-old heterosexual men (N = 377) from urban sexually transmitted infection clinics. Men completed measures of sexual HIV risk history (number of partners and condom use), sexual aggression history, CSA history, and trait negative affect (anger, anxiety, and depression). Structural equation modeling was used to examine hypothesized direct and indirect relationships. In the final SEM model, sexual aggression history and sexual HIV risk behavior were correlated. CSA was associated with both types of problematic sexual behavior. Anxiety significantly mediated the relationship between CSA and sexual aggression and between CSA and sexual HIV risk behavior (χ 2 [1300] = 2121.79, p < .001; CFI = 0.905; RMSEA [90% CI] = .044 [.041-.047]). Sexual aggression appears to be part of a constellation of sexual risk behaviors; thus, it may be possible to develop prevention programs that target both sexual HIV risk and sexual aggression. CSA is a shared risk factor for sexual aggression and HIV risk behavior through the pathway of anxiety. Thus, anxiety might be one promising target for intervention.

Reported child sexual abuse in Bahrain: 2000-2009.

PubMed

Al-Mahroos, Fadheela; Al-Amer, Eshraq

2011-01-01

Child sexual abuse (CSA) is a common problem with severe short and long-term consequences to the abused child, the family and to society. The aim of this study was to evaluate the extent of CSA, and demographic and other characteristics of the abused and their families. Retrospective and descriptive study based on a review of medical records of CSA cases from 2000-2009 at Sulmaniya Medical Complex, the main secondary and tertiary medical care facility in Bahrain. The review included demographic data, child and family characteristics, manifestations and interventions. The 440 children diagnosed with CSA had a mean age of 8 years (range, 9 months to 17 years); 222 were males (50.5%) and 218 were females (49.5%). There was a steady increase in cases from 31 per year in 2000 to 77 cases in 2009. Children disclosed abuse in 26% of cases, while health sector professionals recognized 53% of the cases. Genital touching and fondling (62.5%) were the most common form of CSA, followed by sodomy in 39%. Gonorrhea was documented in 2% of the cases and pregnancy in 4% of the females. The illiteracy rate among the fathers and mothers was 9% and 12%, respectively, which is higher than the rate among the adult general population. Children came from all socio-economic classes. There was referral to police in 56%, public prosecution in 31% of the cases, but only 8% reached the court. During ten years there has been a 2.5% increase in reported cases of CSA. Improving the skill of professionals in identifying CSA indicators and a mandatory reporting law might be needed to improve the rate of recognition and referral of CSA cases. Further general population-based surveys are needed to determine more accurately the scope of CSA and the risk and protective factors in the family and community.

Reported child sexual abuse in Bahrain: 2000-2009

PubMed Central

Al-Mahroos, Fadheela; Al-Amer, Eshraq

2011-01-01

BACKGROUND AND OBJECTIVE: Child sexual abuse (CSA) is a common problem with severe short and long-term consequences to the abused child, the family and to society. The aim of this study was to evaluate the extent of CSA, and demographic and other characteristics of the abused and their families. DESIGN AND SETTING: Retrospective and descriptive study based on a review of medical records of CSA cases from 2000-2009 at Sulmaniya Medical Complex, the main secondary and tertiary medical care facility in Bahrain. PATIENTS AND METHODS: The review included demographic data, child and family characteristics, manifestations and interventions. RESULTS: The 440 children diagnosed with CSA had a mean age of 8 years (range, 9 months to 17 years); 222 were males (50.5%) and 218 were females (49.5%). There was a steady increase in cases from 31 per year in 2000 to 77 cases in 2009. Children disclosed abuse in 26% of cases, while health sector professionals recognized 53% of the cases. Genital touching and fondling (62.5%) were the most common form of CSA, followed by sodomy in 39%. Gonorrhea was documented in 2% of the cases and pregnancy in 4% of the females. The illiteracy rate among the fathers and mothers was 9% and 12%, respectively, which is higher than the rate among the adult general population. Children came from all socio-economic classes. There was referral to police in 56%, public prosecution in 31% of the cases, but only 8% reached the court. CONCLUSION: During ten years there has been a 2.5% increase in reported cases of CSA. Improving the skill of professionals in identifying CSA indicators and a mandatory reporting law might be needed to improve the rate of recognition and referral of CSA cases. Further general population-based surveys are needed to determine more accurately the scope of CSA and the risk and protective factors in the family and community. PMID:21808114

Phenotyping of Sleep-Disordered Breathing in Patients With Chronic Heart Failure With Reduced Ejection Fraction-the SchlaHF Registry.

PubMed

Arzt, Michael; Oldenburg, Olaf; Graml, Andrea; Erdmann, Erland; Teschler, Helmut; Wegscheider, Karl; Suling, Anna; Woehrle, Holger

2017-11-29

Different sleep-disordered breathing (SDB) phenotypes, including coexisting obstructive and central sleep apnea (OSA-CSA), have not yet been characterized in a large sample of patients with heart failure and reduced ejection fraction (HFrEF) receiving guideline-based therapies. Therefore, the aim of the present study was to determine the proportion of OSA, CSA, and OSA-CSA, as well as periodic breathing, in HFrEF patients with SDB. The German SchlaHF registry enrolled patients with HFrEF receiving guideline-based therapies, who underwent portable SDB monitoring. Polysomnography (n=2365) was performed in patients with suspected SDB. Type of SDB (OSA, CSA, or OSA-CSA), the occurrence of periodic breathing (proportion of Cheyne-Stokes respiration ≥20%), and blood gases were determined in 1557 HFrEF patients with confirmed SDB. OSA, OSA-CSA, and CSA were found in 29%, 40%, and 31% of patients, respectively; 41% showed periodic breathing. Characteristics differed significantly among SDB groups and in those with versus without periodic breathing. There was a relationship between greater proportions of CSA and the presence of periodic breathing. Risk factors for having CSA rather than OSA were male sex, older age, presence of atrial fibrillation, lower ejection fraction, and lower awake carbon dioxide pressure (pco 2 ). Periodic breathing was more likely in men, patients with atrial fibrillation, older patients, and as left ventricular ejection fraction and awake pco 2 decreased, and less likely as body mass index increased and minimum oxygen saturation decreased. SchlaHF data show that there is wide interindividual variability in the SDB phenotype of HFrEF patients, suggesting that individualized management is appropriate. URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01500759. © 2017 The Authors and ResMed Germany Inc. Published on behalf of the American Heart Association, Inc., by Wiley.

C-reactive protein is elevated in heart failure patients with central sleep apnea and Cheyne-Stokes respiration.

PubMed

Schmalgemeier, Heidi; Bitter, Thomas; Fischbach, Thomas; Horstkotte, Dieter; Oldenburg, Olaf

2014-01-01

Manifestation of central sleep apnea (CSA) with Cheyne-Stokes respiration is of major prognostic impact in chronic heart failure (CHF). Inflammatory processes have been linked to a progression of cardiovascular diseases, including heart failure. While an association of C-reactive protein (CRP) levels to obstructive sleep apnea has been documented before, there is a lack of information regarding variation of CRP levels in patients with CSA. The objective of this study was to investigate a potential association of CRP levels to CSA severity in CHF patients. High sensitivity CRP levels were analyzed in 966 patients with CHF (BMI 26.3 ± 4.6, New York Heart Association class 2.6 ± 0.5, left ventricular ejection fraction 29.4 ± 7.9%, N-terminal pro-brain natriuretic peptide, NT-proBNP, level 2,209 ± 3,315 pg/ml) without sleep-disordered breathing (SDB; Apnea-Hypopnea Index, AHI, <5/h) or various degrees of CSA, documented by in-hospital cardiorespiratory polygraphy or polysomnography. The CRP concentration in CHF patients was 0.550 ± 0.794 mg/dl in patients without SDB (AHI 0-4/h, n = 403) versus 0.488 ± 0.708 mg/dl in patients with mild CSA (AHI 5-14/h, n = 123, p = n.s.) and 0.660 ± 0.963 mg/dl in patients with moderate CSA (AHI 15-29/h, n = 160, p = n.s.). In patients with severe CSA (AHI ≥ 30/h, n = 280), significantly higher CRP concentrations were documented (0.893 ± 1.384 mg/dl, p < 0.05). Stepwise regression analysis revealed AHI, NT-proBNP and heart rate to be independently associated with elevated CRP levels. Severe CSA in CHF patients is associated with elevated levels of CRP, a systemic marker of inflammation and cardiovascular risk. This might explain in part the negative prognostic impact of CSA in these patients. Copyright © 2013 S. Karger AG, Basel.

Clinical Utility of Ultrasound Measurements of Plantar Fascia Width and Cross-Sectional AreaA Novel Technique.

PubMed

Bisi-Balogun, Adebisi; Rector, Michael

2017-09-01

We sought to develop a standardized protocol for ultrasound (US) measurements of plantar fascia (PF) width and cross-sectional area (CSA), which may serve as additional outcome variables during US examinations of both healthy asymptomatic PF and in plantar fasciopathy and determine its interrater and intrarater reliability. Ten healthy individuals (20 feet) were enrolled. Participants were assessed twice by two raters each to determine intrarater and interrater reliability. For each foot, three transverse scans of the central bundle of the PF were taken at its insertion at the medial calcaneal tubercle, identified in real time on the plantar surface of the foot, using a fine wire technique. Reliability was determined using intraclass correlation coefficients (ICC), standard errors of measurement (SEM), and limits of agreement (LOA) expressed as percentages of the mean. Reliability of PF width and CSA measurements was determined using PF width and CSA measurements from one sonogram measured once and the mean of three measurements from three sonograms each measured once. Ultrasound measurements of PF width and CSA showed a mean of 18.6 ± 2.0 mm and 69.20 ± 13.6 mm 2 respectively. Intra-reliability within both raters showed an ICC > 0.84 for width and ICC > 0.92 for CSA as well as a SEM% and LOA% < 10% for both width and CSA. Inter-rater reliability showed an ICC of 0.82 for width and 0.87 for CSA as well as a SEM% and LOA% < 10% for width and a SEM% < 10% and LOA% < 20% for CSA. Relative and absolute reliability within and between raters were higher when using the mean of three sonographs compared to one sonograph. Using this novel technique, PF CSA and width may be determined reliably using measurements from one sonogram or the mean of three sonograms. Measurement of PF CSA and width in addition to already established thickness and echogenicity measurements provides additional information on structural properties of the PF for clinicians and researchers in healthy and pathologic PF.

Limited value of cyclosporine A for the treatment of patients with uveitis associated with juvenile idiopathic arthritis.

PubMed

Tappeiner, C; Roesel, M; Heinz, C; Michels, H; Ganser, G; Heiligenhaus, A

2009-05-01

Juvenile idiopathic arthritis (JIA) is often associated with severe chronic anterior uveitis (CAU), and immunosuppressive therapy may be required. In this study, the value of cyclosporine A (CsA) as monotherapy or as combination therapy for treating uveitis was studied in a large cohort of JIA children. Multicentre retrospective study including 82 JIA children (girls n=60) suffering from unilateral or bilateral (n=55) CAU. The indication for CsA was active uveitis, although patients were on topical or systemic corticosteroids, MTX, or other immunosuppressive drugs. Inactivity of uveitis during the entire treatment period (mean 3.9 years) was obtained with CsA monotherapy in 6 of 25 (24%) patients, but more often when CsA was combined with the immunosuppressives (35/72 patients; 48.6%, P=0.037), or MTX (18/37 patients, 48.6%, P=0.065), which had already been given. With CsA (mean dosage 2.9 mg/kg), systemic immunosuppressive drugs and steroids could be reduced by >or=50% (n=19) or topical steroids reduced to

Effects of Gallic Acid and Cyclosporine A on Antioxidant Capacity and Cardiac Markers of Rat Isolated Heart After Ischemia/Reperfusion

PubMed Central

Badavi, Mohammad; Sadeghi, Najmeh; Dianat, Mahin; Samarbafzadeh, Alireza

2014-01-01

Background: Myocardial infarction is one of the important causes of death during old ages. Gallic acid as an antioxidant or cyclosporine A (CsA) as inhibitor of mitochondrial permeability transition pore (mPTP) alone could prevent these complications to some extent, but their combination effect has not been investigated. Objectives: The aim of this study was to determine the combined effect of gallic acid and CsA on antioxidant capacity of isolated heart tissues during ischemia reperfusion. Materials and Methods: Eighty male Wistar rats were randomly assigned to different groups: sham, control (Ca, received saline, 1 mL/kg); 3 groups were pretreated with gallic acid (G1a: 7.5, G2a: 15, G3a: 30 mg/kg) for 10 days, and the other 3 groups were pretreated with gallic acid and received CsA (0.2 µM) for 10 minutes before induction of ischemia and during the first 10 minutes of reperfusion (G1b, G2b and G3b) and the last group received CsA alone (Cb). After 10 days of pretreatment, the heart was isolated and transferred to the Langendorff apparatus and exposed to 30 minutes ischemia followed by 60 minutes of reperfusion. After that cardiac markers and antioxidant enzymes were assessed in cardiac tissues. Results: Lactate dehydrogenase (LDH), Superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) activity increased and malondialdehyde (MDA) decreased in animals pretreated with gallic acid significantly. However, pretreatment with gallic acid followed by CsA during reperfusion improved the antioxidant capacity and cardiac marker enzymes and restored the lipid peroxidation more effective than gallic acid or CsA alone. Nevertheless, CsA did not change the cardiac marker enzymes significantly. Conclusions: Gallic acid and CsA combination improved antioxidant capacity and cell membrane integrity more than each one alone. Therefore, it can be a therapeutic approach to reduce the I/R injury. PMID:25068044

Making Meaning of Traumatic Events: Youths’ Strategies for Processing Childhood Sexual Abuse are Associated With Psychosocial Adjustment

PubMed Central

Simon, Valerie A.; Feiring, Candice; McElroy, Sarah Kobielski

2014-01-01

The need to make meaning of childhood sexual abuse (CSA) is common and often persists long after the abuse ends. Although believed to be essential for healthy recovery, there is a paucity of research on how youth process their CSA experiences. The current study identified individual differences in the ways youth process their CSA and examined associations with psychosocial adjustment. A sample of 108 youth with confirmed abuse histories enrolled in the study within 8 weeks of abuse discovery, when they were between 8 and 15 years old. Six years later, they participated in interviews about their CSA experiences, reactions, and perceived effects. Using a coding system developed for this study, youths’ CSA narratives were reliably classified with one of three processing strategies: Constructive (13.9%), Absorbed (50%), or Avoidant (36.1%). Absorbed youth reported the highest levels of psychopathological symptoms, sexual problems, and abuse-specific stigmatization, whereas Constructive youth tended to report the fewest problems. Avoidant youth showed significantly more problems than Constructive youth in some but not all areas. Interventions that build healthy processing skills may promote positive recovery by providing tools for constructing adaptive meanings of the abuse, both in its immediate aftermath and over time. PMID:20498128

Making meaning of traumatic events: youths' strategies for processing childhood sexual abuse are associated with psychosocial adjustment.

PubMed

Simon, Valerie A; Feiring, Candice; Kobielski McElroy, Sarah

2010-08-01

The need to make meaning of childhood sexual abuse (CSA) is common and often persists long after the abuse ends. Although believed to be essential for healthy recovery, there is a paucity of research on how youth process their CSA experiences. The current study identified individual differences in the ways youth process their CSA and examined associations with psychosocial adjustment. A sample of 108 youth with confirmed abuse histories enrolled in the study within 8 weeks of abuse discovery, when they were between 8 and 15 years old. Six years later, they participated in interviews about their CSA experiences, reactions, and perceived effects. Using a coding system developed for this study, youths' CSA narratives were reliably classified with one of three processing strategies: Constructive (13.9%), Absorbed (50%), or Avoidant (36.1%). Absorbed youth reported the highest levels of psychopathological symptoms, sexual problems, and abuse-specific stigmatization, whereas Constructive youth tended to report the fewest problems. Avoidant youth showed significantly more problems than Constructive youth in some but not all areas. Interventions that build healthy processing skills may promote positive recovery by providing tools for constructing adaptive meanings of the abuse, both in its immediate aftermath and over time.

Influence of the rate of infusion on cyclosporine nephrotoxicity in the rat.

PubMed

Finn, W F; McCormack, A J; Sullivan, B A; Hak, L J; Clark, R L

1989-01-01

The effect of the rate of infusion of single and multiple doses of cyclosporine (CsA) on renal function was evaluated in Sprague-Dawley rats. CsA was dissolved in cremophore (Crem) or Tween 80 (Tween) and infused over consecutive 10-min periods at doses of 10, 20, 30 and 40 mg/kg. CsA-Crem and CsA-Tween produced similar and progressive changes in MAP, RBF, and RVR. By the end of the infusion, the mean values (% of control) of MAP (122 +/- 16% and 131 +/- 22%), RBF (56 +/- 11% and 66 +/- 20%), and RVR (222 +/- 38% and 232 +/- 134%) were significantly different from their respective preinfusion values. Infusion of Crem alone resulted in renal vasodilation at low doses and renal vasoconstriction at high doses. Vasoconstriction was not produced by infusion of Tween alone. In addition, animals were treated with vehicle alone (Gp 1), CsA 10 mg/kg/day by injection (Gp 2), or CsA 20 mg/kg/day by i.v. infusion over 4 hr (Gp 3), and were studied at 1 week. Systemic toxicity was greater with the 4-hr infusion as judged by an increase in MAP. The mean values of MAP were 107 +/- 8 (Gp 1), 101 +/- 13 (Gp 2), and 135 +/- 5 mm Hg (Gp 3; p less than 0.05). However, renal function was less severely affected with the 4-hr infusion. The mean values of CIn were 434 +/- 99 (Gp 1), 298 +/- 101 (Gp 2; p less than 0.05), and 425 +/- 114 microL/min/100 g BW (Gp 3); and the mean values for RBF were 2.72 +/- 0.74 (Gp 1), 2.08 +/- 0.17 (Gp 2; p less than 0.05), and 3.35 +/- 0.61 mL/min/100 g BW (Gp 3), respectively. Microangiograms showed marked abnormalities in the intrarenal perfusion pattern in the rats injected with CsA, 10 mg/kg BW. In rats infused over 4 hr with CsA, 20 mg/kg BW, the microangiographic pattern was normal. These studies demonstrate that the acute hemodynamic effects of CsA are directly related to the rate of infusion. Furthermore, the renal toxicity which follows repetitive injection of CsA can be minimized or avoided by administering CsA as a slow infusion. In addition to the total dose administered, the rate of infusion is an important determinant of nephrotoxicity.

Sirolimus and tacrolimus rather than cyclosporine A cause bone loss in healthy adult male rats.

PubMed

Rubert, Mercedes; Montero, Mercedes; Guede, David; Caeiro, Jose-Ramón; Martín-Fernández, Marta; Díaz-Curiel, Manuel; de la Piedra, Concepción

2015-06-01

The aim of this work was to study the effects of cyclosporine (CsA), tacrolimus (FK-506), and rapamycin (RAPA) on bone mass, femoral microstructure, femoral biomechanical properties, and bone remodeling in healthy adult male rats. Forty-eight 5-month-old male Wistar rats were used. CsA (2 mg/kg/day), FK-506 (3 mg/kg/day), RAPA (1.25 mg/kg/day), or water (0.5 ml/rat/day, control group) were administered orally for 3 months. After sacrifice, mean values of immunosuppressants in blood were: CsA (670.4 ng/ml), FK-506 (19.2 ng/ml), and RAPA (4.8 ng/ml). Levels of biochemical parameters were normal in all groups. Femoral BMD was decreased in FK-506 and RAPA groups and lumbar BMD in FK-506 group. Trabecular volume fraction (BV/TV) decreased only in FK-506 group. RAPA and CsA affected femoral cortical structure, but FK-506 did not. FK-506 produced an increase in bone remodeling, and CsA a decrease. FK-506 group showed a decrease in biomechanical parameters relative to all groups. RAPA group showed a decrease in ultimate stress vs control group, and CsA group presented an increase in biomechanical parameters versus control group. We found that administration of both RAPA and FK-506 as monotherapy for healthy rats produced osteopenia. CsA treatment only produces slight damages in the cortical zone of the femur.

Psychological counseling and accuracy of memory for child sexual abuse.

PubMed

Goodman, Gail S; Goldfarb, Deborah; Quas, Jodi A; Lyon, Alexandra

2017-12-01

Tens of thousands of child sexual abuse (CSA) cases are reported to authorities annually. Although some of the child victims obtain psychological counseling or therapy, controversy exists about the potential consequences for the accuracy of victims' memory of CSA, both in childhood and adulthood. Yet, delaying needed therapeutic intervention may have detrimental effects on the victims' well-being and recovery. To address this controversy, this study examined whether psychological counseling during a CSA prosecution predicts accuracy or inaccuracy of long-term memory for CSA. Participants (N = 71) were CSA victims who took part in a longitudinal study of memory and legal involvement. Data regarding participants' counseling attendance during the prosecution and details of their CSA cases were gathered throughout legal involvement and shortly thereafter (Time 1). Ten to 16 years later (Time 2), participants were questioned about a range of topics, including the alleged abuse. Time 1 counseling attendance significantly predicted more correct answers to abuse-related questions and (for corroborated cases) fewer overreporting responses at Time 2. Counseling was unrelated to underreporting responses. These results held even with other potential influences, such as abuse severity, victim-defendant relationship, posttraumatic stress disorder criteria met, testifying in the case, and delay, were statistically controlled. Although further research is needed, this study provides evidence that psychological counseling received by CSA victims during or shortly after prosecutions may improve later memory for abuse-related information. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Targeted cutaneous delivery of ciclosporin A using micellar nanocarriers and the possible role of inter-cluster regions as molecular transport pathways.

PubMed

Lapteva, Maria; Santer, Verena; Mondon, Karine; Patmanidis, Ilias; Chiriano, Gianpaolo; Scapozza, Leonardo; Gurny, Robert; Möller, Michael; Kalia, Yogeshvar N

2014-12-28

Oral administration of ciclosporin A (CsA) is indicated in the treatment of severe recalcitrant plaque psoriasis. However, CsA is both nephro- and hepatotoxic and its systemic administration also exposes the patient to other severe side effects. Although topical delivery of CsA, targeted directly to psoriatic skin, would offer significant advantages, there are no topical formulations approved for dermatological use. The aim of this work was to formulate CsA loaded polymeric micelles using the biodegradable and biocompatible MPEG-dihexPLA diblock copolymer and to evaluate their potential for delivering the drug selectively into the skin without concomitant transdermal permeation. Micelle formulations were characterised with respect to drug content, size and morphology. Micelle and drug penetration pathways were subsequently visualised with confocal laser scanning microscopy (CLSM) using fluorescein labelled CsA (Fluo-CsA) and Nile-Red (NR) labelled copolymer. Visualisation studies typically use fluorescent dyes as "model drugs"; however, these may have different physicochemical properties to the drug molecule under investigation. Therefore, in this study it was decided to chemically modify CsA and to use this structurally similar fluorescent analogue to visualise molecular distribution and transport pathways. Molecular modelling techniques and experimental determination of log D served as molecular scale and macroscopic methods to compare the lipophilicity of CsA and Fluo-CsA. The spherical, homogeneous and nanometre-scale micelles (with Zav from 25 to 52 nm) increased the aqueous solubility of CsA by 518-fold. Supra-therapeutic amounts of CsA were delivered to human skin (1.4±0.6 μg/cm2, cf. a statistically equivalent 1.1±0.5 μg/cm2 for porcine skin) after application of the formulation with the lowest CsA and copolymer content (1.67±0.03 mg/ml of CsA and 5mg/ml of copolymer) for only 1h without concomitant transdermal permeation. Fluo-CsA was successfully synthesised, characterised and incorporated into fluorescent NR-MPEG-dihexPLA micelles; its conformation was not modified by the addition of fluorescein and its log D, measured from pH4 to 8, was equivalent to that of CsA. Fluo-CsA and NR-MPEG-dihexPLA copolymer were subsequently visualised in skin by CLSM. The images indicated that micelles were preferentially deposited between corneocytes and in the inter-cluster regions (i.e. between the clusters of corneocytes). Fluo-CsA skin penetration was deeper in these structures, suggesting that inter-cluster penetration is probably the preferred transport pathway responsible for the increased cutaneous delivery of CsA. Copyright © 2014 Elsevier B.V. All rights reserved.

Sexual abuse in childhood and physical and mental health in adulthood: an Australian population study.

PubMed

Najman, Jake M; Nguyen, My Linh T; Boyle, Frances M

2007-10-01

Although childhood sexual abuse (CSA) is associated with a wide range of health problems later in life, there is also evidence of substantial individual differences. This study describes the mental and physical health of a population sample of Australians, randomly selected from the Commonwealth electoral roll, who have reported their CSA histories. Some 58% of those located from the electoral roll agreed to a telephone interview (n=1,784). Health status was measured using the Short Form 36 questionnaire. Men who had experienced non-penetrative and penetrative sexual abuse in childhood had 2.25 (95% CI=1.32-3.82) and 5.93 (95% CI=2.72-12.95) times respectively the rate of impaired mental health, but no higher rates of impaired physical health. Women who had experienced non-penetrative and penetrative sexual abuse in childhood had 1.87 (95% CI=1.19-2.95) and 3.15 (95% CI=1.87-5.33) times respectively the rate of impaired mental health and 1.87 (95% CI=1.19-2.92) and 2.31 (95% CI=1.34-3.97) times respectively the rate of impaired physical health. However, participants who had experienced CSA were no less likely than those who had not experienced CSA to be in optimum physical and mental health. None of the possible confounding or moderating variables tested appeared to mitigate the impact of CSA on health outcomes. Those with the highest levels of mental and physical health appear to be unaffected by the experience of CSA.

Histomorphometric comparative study of blood vessels and their pattern in follicular cyst, odontogenic keratocyst, and ameloblastoma.

PubMed

Seifi, Safora; Feizi, Farideh; Khafri, Thoraya; Aram, Mehrdad

2013-03-01

The present study aimed at assessment and histomorphometric analysis of intratumoral and peritumoral (cystic) blood vessels in odontogenic lesions and their pattern on their clinical behavior by immunohistochemistry and morphometry. In a descriptive and analytical cross-sectional study, 45 paraffin blocks of ameloblastoma, odontogenic keratocyst, and follicular cyst were selected and stained immunohistochemically for CD34. In each slide, images of 3 microscopic fields with the highest microvessel density in intratumoral and peritumoral (cystic) areas were captured at 40× magnification with attached camera system. Inner vascular diameter (IVD) and outer vascular diameter (OVD), cross-sectional area (CSA), and the wall thickness (WT) of the vessels were measured with Motic Plus 2 software. The vascular pattern in odontogenic lesions was analyzed. Outer vascular diameter, IVD, and CSA of the vessels in peritumoral (cystic) areas were greater in ameloblastoma than keratocyst (P = 0.001) and follicular cyst (P < 0.001). However, WT of the blood vessels did not show any significant statistical difference among the 3 odontogenic lesions (P = 0.05). The differences in OVD, IVD (P = 0.8), CSA (P = 0.6), and WT (P = 0.4) of the blood vessels in intratumoral (cystic) areas were not statistically significant. The blood vessel pattern was circumferential in ameloblastoma, and it was directional in keratocyst and follicular cyst. Morphometric specifications of blood vessels (IVD, OVD, CSA) and their pattern in peritumoral (cystic) areas may influence the aggressive clinical behavior of ameloblastoma in comparison with keratocyst and follicular cyst.

Significant expression of thyroid transcription factor-1 in pulmonary squamous cell carcinoma detected by SPT24 monoclonal antibody and CSA-II system.

PubMed

Kashima, Kenji; Hashimoto, Hisashi; Nishida, Haruto; Arakane, Motoki; Yada, Naomi; Daa, Tsutomu; Yokoyama, Shigeo

2014-01-01

In contrast to the usefulness of thyroid transcription factor-1 (TTF-1) in distinguishing primary adenocarcinoma of the lung from metastatic lesions, TTF-1 expression in pulmonary squamous cell carcinoma is reported to be at low level and not a suitable immunohistochemical marker. We hypothesized that the highly sensitive detection system, CSA-II, can visualize even faint expression of TTF-1 in pulmonary squamous cell carcinoma. In this study, 2 commercially available clones of TTF-1 monoclonal antibody, 8G7G3/1 and SPT24, were used for staining 38 cases of pulmonary squamous cell carcinoma, in combination with the CSA-II and the conventional detection system, EnVision. The combined use of the 8G7G3/1 clone with EnVision and CSA-II showed a positive reaction in only 1 and 4 cases, respectively. The use of SPT24 clone showed positive staining in 5 cases with EnVision and in 20 of 38 cases (52.6%) with the CSA-II. Interestingly, positive staining by the SPT24-CSA-II technique of samples from tissue blocks preserved for <2 years was 73.6% compared with only 31.5% in those preserved for >2 years. In addition, a 6-month preservation of the cut sections resulted in stain fading and decreased positivity (50%), compared with freshly cut sections. We conclude that the use of the SPT24 monoclonal antibody with the CSA-II system can detect even weak expression of TTF-1 in pulmonary squamous cell carcinoma. This staining technique can potentially allow the discrimination of primary squamous cell carcinoma of the lung from metastatic lesions, especially in freshly prepared paraffin sections.

Confirmatory field study for the evaluation of ciclosporin at a target dose of 7.0 mg/kg (3.2 mg/lb) in the control of feline hypersensitivity dermatitis.

PubMed

Roberts, Elizabeth S; Speranza, Cindy; Friberg, Cecilia; Griffin, Craig; Steffan, Jean; Roycroft, Linda; King, Stephen

2016-11-01

Objectives This study was designed to confirm the efficacy and tolerability of a daily dose of 7.0 mg/kg (3.2 mg/lb) ciclosporin (CsA) in the treatment of feline hypersensitivity dermatitis (HD), as this includes some of the most frequently suspected skin diseases in cats and recent publications have reported the successful use of CsA in the treatment of feline HD. Methods In total, 217 cats with feline HD were treated daily for 42 days with a target dose of 7 mg/kg CsA (n = 144) or a placebo control (n = 73) administered either in the food or directly in the mouth following feeding. Clinical and dermatological evaluations were conducted on days 0, 21 and 42, or study exit. Safety was evaluated through physical examinations, clinical pathology and the monitoring of adverse events (AEs). Results Administration of CsA at 7.0 mg/kg produced a significant improvement in the total lesion score ( P <0.0001). The average reduction from visit 1 to visit 3 was 65.1% in the CsA group (9.2% for the placebo). In addition, owners assessed 78.3% of the cases in the CsA group as a success. Statistically significant recoveries were also seen in extent of lesions, investigator assessment of overall improvement, and mean improvement in both the investigators' and owners' assessment of pruritus. Mild gastrointestinal disorders were the most common AEs but did not require cessation of therapy. Conclusions and relevance Results confirm that 7.0 mg/kg CsA dosed daily in food or orally for up to 6 weeks is effective and well tolerated by cats with feline HD.

Repeatability of diagnostic ultrasonography in the assessment of the equine superficial digital flexor tendon.

PubMed

Pickersgill, C H; Marr, C M; Reid, S W

2001-01-01

A quantitative investigation of the variation that can occur during the course of ultrasonography of the equine superficial digital flexor tendons (SDFT) was undertaken. The aim of this investigation was to use an objective measure, namely the measurement of CSA, to quantify the variability occurring during the course of the ultrasonographic assessment of the equine SDFT. The effects of 3 variables on the CSA measurements were determined. 1) Image acquisition operator (IAc): two different operators undertaking the ultrasonographic examination; 2) image analysis operator (IAn): two different operators undertaking the calculation of CSA values from previously stored images; and 3) analytical equipment (used during CSA measurement) (IEq): the use of 2 different sets of equipment during calculation of CSA values. Tendon cross-sectional area (CSA) measurements were used as the comparative variable of 3 potential sources: interoperator, during image acquisition; interoperator, during CSA measurement; and intraoperator, when using different analytical equipment. Two operators obtained transverse ultrasonographic images from the forelimb SDFTs of 16 National Hunt (NH) Thoroughbred (TB) racehorses, each undertaking analysis of their own and the other operator's images. One operator undertook analysis of their images using 2 sets of equipment. There was no statistically significant difference in the results obtained when different operators undertook image acquisition (P>0.05). At all but the most distal level, there was no significant difference when different equipment was used during analysis (P>0.05). A significant difference (P<0.01) was reported when different operators undertook image analysis, one operator consistently returning larger measurements. Different operators undertaking different stages of an examination can result in significant variability. To reduce confounding during ultrasonographic investigations involving multiple persons, one operator should undertake image analysis, although different operators may undertake image acquisition.

A pharmacologically-based array to identify targets of cyclosporine A-induced toxicity in cultured renal proximal tubule cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sarró, Eduard, E-mail: eduard.sarro@vhir.org; Renal Physiopathology, CIBBIM-Nanomedicine, Vall d'Hebron Research Institute; Jacobs-Cachá, Conxita, E-mail: conxita.jacobs@vhir.org

2012-01-15

Mechanisms of cyclosporine A (CsA)-induced nephrotoxicity were generally thought to be hemodynamic in origin; however, there is now accumulating evidence of a direct tubular effect. Although genomic and proteomic experiments by our group and others provided overall information on genes and proteins up- or down-regulated by CsA in proximal tubule cells (PTC), a comprehensive view of events occurring after CsA exposure remains to be described. For this purpose, we applied a pharmacologic approach based on the use of known activities of a large panel of potentially protective compounds and evaluated their efficacy in preventing CsA toxicity in cultured mouse PTC.more » Our results show that compounds that blocked protein synthesis and apoptosis, together with the CK2 inhibitor DMAT and the PI3K inhibitor apigenin, were the most efficient in preventing CsA toxicity. We also identified GSK3, MMPs and PKC pathways as potential targets to prevent CsA damage. Additionally, heparinase-I and MAPK inhibitors afforded partial but significant protection. Interestingly, antioxidants and calcium metabolism-related compounds were unable to ameliorate CsA-induced cytotoxicity. Subsequent experiments allowed us to clarify the hierarchical relationship of targeted pathways after CsA treatment, with ER stress identified as an early effector of CsA toxicity, which leads to ROS generation, phenotypical changes and cell death. In summary, this work presents a novel experimental approach to characterizing cellular responses to cytotoxics while pointing to new targets to prevent CsA-induced toxicity in proximal tubule cells. Highlights: ► We used a novel pharmacological approach to elucidate cyclosporine (CsA) toxicity. ► The ability of a broad range of compounds to prevent CsA toxicity was evaluated. ► CsA toxicity was monitored using LDH release assay and PARP cleavage. ► Protein synthesis, PI3K, GSK3, MMP, PKC and caspase inhibitors prevented CsA toxicity. ► We also identified ER stress as an early effector of CsA toxicity.« less

Relationship between diminution of small pulmonary vessels and emphysema in chronic obstructive pulmonary disease.

PubMed

Mashimo, Shuko; Chubachi, Shotaro; Tsutsumi, Akihiro; Kameyama, Naofumi; Sasaki, Mamoru; Jinzaki, Masahiro; Nakamura, Hidetoshi; Asano, Koichiro; Reilly, John J; Betsuyaku, Tomoko

To investigate the relationship between small pulmonary vessels and extent of emphysema on CT in individual lungs with chronic obstructive pulmonary disease (COPD). Forty-nine patients were included. The percentage of cross-sectional area of vessels <5mm 2 (%CSA <5) and extent of emphysema were assessed. Less than half of the COPD patients demonstrated an inverse correlation between %CSA <5 and percentage of low attenuation area (LAA%). In the remaining patients, %CSA <5 was homogeneously distributed. Not all patients with COPD demonstrated an inverse correlation of the distributions between %CSA <5 and LAA% in individual lungs. Copyright © 2017 Elsevier Inc. All rights reserved.

Prevalence, Defining Characteristics, and Related Factors of the Nursing Diagnosis of Anxiety in Hospitalized Medical-Surgical Patients.

PubMed

Sanson, Gianfranco; Perrone, Annalisa; Fascì, Adriana; D'Agostino, Fabio

2018-03-01

To document the prevalence of the nursing diagnosis of anxiety in hospital patients, based on its level of severity, defining characteristics (DCs), and other related factors, and to identify the key DCs that serve as predictors of clinically significant anxiety (CSA). Cross-sectional study. We enrolled 116 consecutive adult patients hospitalized from October 10 to 16, 2016, in medical-surgical wards within the first 48 hr of admission. The potential DCs and related factors of anxiety were collected based on the NANDA International terminology. Anxiety was considered clinically significant when presenting at moderate, severe, or panic level. The differences in DC prevalence among patients having or not having CSA were analyzed by unpaired student's t-test. Multivariate analysis was used to examine the independent association between the DCs and CSA. The prevalence of CSA was 36.2% and was significantly higher in patients who were older, female, and taking anxiolytic drugs, and among those who had cancer. The most frequent related factor for CSA was major change in health status. In the logistic regression, the presence of the DCs helplessness, altered attention or concentration, and anguish independently increased the odds of having CSA, whereas subjects presenting with Diminished ability to problem-solve had about a 96% reduction in the likelihood to suffer from such a condition. A high prevalence of CSA among medical-surgical patients was shown. Furthermore, a critical cluster of DCs useful to identify CSA was found. The ability to accurately diagnose CSA should help prescribe and deliver the appropriate nursing interventions. © 2018 Sigma Theta Tau International.

Impact of germline and somatic missense variations on drug binding sites.

PubMed

Yan, C; Pattabiraman, N; Goecks, J; Lam, P; Nayak, A; Pan, Y; Torcivia-Rodriguez, J; Voskanian, A; Wan, Q; Mazumder, R

2017-03-01

Advancements in next-generation sequencing (NGS) technologies are generating a vast amount of data. This exacerbates the current challenge of translating NGS data into actionable clinical interpretations. We have comprehensively combined germline and somatic nonsynonymous single-nucleotide variations (nsSNVs) that affect drug binding sites in order to investigate their prevalence. The integrated data thus generated in conjunction with exome or whole-genome sequencing can be used to identify patients who may not respond to a specific drug because of alterations in drug binding efficacy due to nsSNVs in the target protein's gene. To identify the nsSNVs that may affect drug binding, protein-drug complex structures were retrieved from Protein Data Bank (PDB) followed by identification of amino acids in the protein-drug binding sites using an occluded surface method. Then, the germline and somatic mutations were mapped to these amino acids to identify which of these alter protein-drug binding sites. Using this method we identified 12 993 amino acid-drug binding sites across 253 unique proteins bound to 235 unique drugs. The integration of amino acid-drug binding sites data with both germline and somatic nsSNVs data sets revealed 3133 nsSNVs affecting amino acid-drug binding sites. In addition, a comprehensive drug target discovery was conducted based on protein structure similarity and conservation of amino acid-drug binding sites. Using this method, 81 paralogs were identified that could serve as alternative drug targets. In addition, non-human mammalian proteins bound to drugs were used to identify 142 homologs in humans that can potentially bind to drugs. In the current protein-drug pairs that contain somatic mutations within their binding site, we identified 85 proteins with significant differential gene expression changes associated with specific cancer types. Information on protein-drug binding predicted drug target proteins and prevalence of both somatic and germline nsSNVs that disrupt these binding sites can provide valuable knowledge for personalized medicine treatment. A web portal is available where nsSNVs from individual patient can be checked by scanning against DrugVar to determine whether any of the SNVs affect the binding of any drug in the database.

Colour-scent associations in a tropical orchid: three colours but two odours.

PubMed

Delle-Vedove, Roxane; Juillet, Nicolas; Bessière, Jean-Marie; Grison, Claude; Barthes, Nicolas; Pailler, Thierry; Dormont, Laurent; Schatz, Bertrand

2011-06-01

Colour and scent are the major pollinator attractants to flowers, and their production may be linked by shared biosynthetic pathways. Species with polymorphic floral traits are particularly relevant to study the joint evolution of floral traits. We used in this study the tropical orchid Calanthe sylvatica from Réunion Island. Three distinct colour varieties are observed, presenting lilac, white or purple flowers, and named respectively C. sylvaticavar.lilacina (hereafter referred as var. lilacina), C. sylvaticavar. alba (var. alba) and C. sylvatica var. purpurea (var. purpurea). We investigated the composition of the floral scent produced by these colour varieties using the non-invasive SPME technique in the wild. Scent emissions are dominated by aromatic compounds. Nevertheless, the presence of the terpenoid (E)-4,8-dimethylnona-1,3,7-triène (DMNT) is diagnostic of var. purpurea, with the volatile organic compounds (VOC) produced by some individuals containing up to 60% of DMNT. We evidence specific colour-scent associations in C. sylvatica, with two distinct scent profiles in the three colour varieties: the lilacina-like profile containing no or very little DMNT (<2%) and the purpurea-like profile containing DMNT (>2%). Calanthe sylvatica var. alba individuals group with one or the other scent profile independently of their population of origin. We suggest that white-flowered individuals have evolved at least twice, once from var. lilacina and at least once from var. purpurea after the colonisation of la Réunion. White-flowered individuals may have been favoured by the particular pollinator fauna characterising the island. These flowering varieties of C. sylvatica, which display three colours but two scents profiles prove that colour is not always a good indicator of odour and that colour-scent associations may be complex, depending on pollination ecology of the populations concerned. Copyright © 2011 Elsevier Ltd. All rights reserved.

Carpal tunnel syndrome assessment with ultrasonography: value of inlet-to-outlet median nerve area ratio in patients versus healthy volunteers.

PubMed

Fu, Tengfei; Cao, Manlin; Liu, Fang; Zhu, Jiaan; Ye, Dongmei; Feng, Xianxuan; Xu, Yiming; Wang, Gang; Bai, Yuehong

2015-01-01

To evaluate the diagnostic value of the Inlet-to-outlet median nerve area ratio (IOR) in patients with clinically and electrophysiologically confirmed carpal tunnel syndrome (CTS). Forty-six wrists in 46 consecutive patients with clinical and electrodiagnostic evidence of CTS and forty-four wrists in 44 healthy volunteers were examined with ultrasonography. The cross-sectional area (CSA) of the median nerve was measured at the carpal tunnel inlet (the level of scaphoid-pisiform) and outlet (the level of the hook of the hamate), and the IOR was calculated for each wrist. Ultrasonography and electrodiagnostic tests were performed under blinded conditions. Electrodiagnostic testing combined with clinical symptoms were considered to be the gold standard test. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic value between the inlet CSA and IOR. The study population included 16 men and 30 women (mean age, 45.3 years; range, 18-83 years). The control population included 18 men and 26 women (mean age, 50.4 years; range, 18-79 years). The mean inlet CSA was 8.7 mm2 in healthy controls and 14.6mm2 in CTS group (P<0.001). The mean IOR in healthy volunteers (1.0) was smaller than that in patients (1.6, P<0.001). Receiver operating characteristic analysis revealed a diagnostic advantage to using the IOR rather than the inlet CSA (P<0.01). An IOR cutoff value of ≥ 1.3 would yield 93% specificity and 91% sensitivity in the diagnosis of CTS. The IOR of median nerve area promises to be an effective means in the diagnosis of CTS. A large-scale, randomized controlled trial is required to determine how and when this parameter will be used.

Opioid receptors regulate blocking and overexpectation of fear learning in conditioned suppression.

PubMed

Arico, Carolyn; McNally, Gavan P

2014-04-01

Endogenous opioids play an important role in prediction error during fear learning. However, the evidence for this role has been obtained almost exclusively using the species-specific defense response of freezing as the measure of learned fear. It is unknown whether opioid receptors regulate predictive fear learning when other measures of learned fear are used. Here, we used conditioned suppression as the measure of learned fear to assess the role of opioid receptors in fear learning. Experiment 1a studied associative blocking of fear learning. Rats in an experimental group received conditioned stimulus A (CSA) + training in Stage I and conditioned stimulus A and B (CSAB) + training in Stage II, whereas rats in a control group received only CSAB + training in Stage II. The prior fear conditioning of CSA blocked fear learning to conditioned stimulus B (CSB) in the experimental group. In Experiment 1b, naloxone (4 mg/kg) administered before Stage II prevented this blocking, thereby enabling normal fear learning to CSB. Experiment 2a studied overexpectation of fear. Rats received CSA + training and CSB + training in Stage I, and then rats in the experimental group received CSAB + training in Stage II whereas control rats did not. The Stage II compound training of CSAB reduced fear to CSA and CSB on test. In Experiment 2b, naloxone (4 mg/kg) administered before Stage II prevented this overexpectation. These results show that opioid receptors regulate Pavlovian fear learning, augmenting learning in response to positive prediction error and impairing learning in response to negative prediction error, when fear is assessed via conditioned suppression. These effects are identical to those observed when freezing is used as the measure of learned fear. These findings show that the role for opioid receptors in regulating fear learning extends across multiple measures of learned fear.

Differences in muscle cross-sectional area and strength between elite senior and college Olympic weight lifters.

PubMed

Funato, K; Kanehisa, H; Fukunaga, T

2000-12-01

The purpose of this study was to investigate the profiles of muscle cross-sectional area (CSA) and strength capability in relation to lifting ability in Olympic weight lifters. The subjects were 8 elite senior lifters (ESL, age=25.2+/-1.3 years, height=1.64+/-0.03 m, mass=68.6+/-4.2 kg, mean+/-SEM) and 9 college lifters (CL, 20.8+/-0.3 years, 1.67+/-0.03 m, 70.53.4 kg) whose predetermined weight classes were within the same range. The CSAs of elbow or knee extensor and elbow or knee flexor muscles were measured using a B-mode ultrasound apparatus. Concentric and eccentric maximal voluntary forces were determined with an isokinetic dynamometer at a constant velocity of 1.05 rad/sec. The best score of the total mass lifted in the snatch and the clean and jerk lifts was significantly higher in ESL than in CL even in terms of per unit of fat-free mass. There were no significant differences between the two groups in fat-free mass, muscle CSA and force values with the exception that ESL compared to CL showed significantly greater force in concentric knee flexion. However, the ratios of force to muscle CSA (F/CSAs) in concentric and eccentric elbow extensions, eccentric knee extension and concentric knee flexion were significantly higher in ESL than in CL. The present results indicated that the magnitude of muscular development in limbs was similar in elite senior and college lifters whose predetermined weight classes were within the same range. As compared to college lifters, however, elite senior lifters had a higher F/CSA in specific muscle action modes, which might relate to the optimal execution of the Olympic lifts.

Validation of the EULAR definition of arthralgia suspicious for progression to rheumatoid arthritis.

PubMed

Burgers, Leonie E; Siljehult, Filip; Ten Brinck, Robin M; van Steenbergen, Hanna W; Landewé, Robert B M; Rantapää-Dahlqvist, Solbritt; van der Helm-van Mil, Annette H M

2017-12-01

Recently a EULAR-taskforce defined arthralgia suspicious for progression to RA, in order to allow inclusion of homogeneous sets of arthralgia patients in clinical studies. This longitudinal study aimed (i) to validate this definition in arthralgia patients in whom rheumatologists felt that imminent RA was more likely than other arthralgias [clinically suspect arthralgia (CSA)], that is, the target population fulfilling the entry criterion, and (ii) to explore the performance in arthralgia patients who were referred to secondary care prior to rheumatological evaluation, hence ignoring the entry criterion. The definition was assessed in 241 Dutch patients identified with CSA by rheumatologists and 113 patients referred to the Umeå university hospital with recent-onset arthralgia in small joints. The external reference was arthritis development <2 years' follow-up. CSA patients with a positive definition (⩾3/7 parameters present) had an increased risk for developing arthritis compared with definition-negative CSA patients (hazard ratio = 2.1, 95% CI: 0.9, 4.7). The sensitivity was 84% and the positive predictive value 30%. In arthralgia patients in whom the definition was applied before rheumatological evaluation, a positive definition was neither sensitive (10%) nor predictive (positive predictive value 3%). The EULAR definition of arthralgia suspicious for progression to RA is sensitive when used to support the rheumatologist's opinion on imminent RA. This validation study shows that the definition, when used as designed, further homogenizes patients that rheumatologists consider at risk for RA. To arrive at a high specificity, the clinical definition needs to be combined with biomarkers. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

The n-butanolic extract of Opuntia ficus-indica var. saboten enhances long-term memory in the passive avoidance task in mice.

PubMed

Kim, Jong Min; Kim, Dong Hyun; Park, Se Jin; Park, Dong Hyun; Jung, Seo Yun; Kim, Hyoung Ja; Lee, Yong Sup; Jin, Changbae; Ryu, Jong Hoon

2010-08-16

Opuntia ficus-indica var. saboten Makino (Cactaceae) is used to treat burns, edema, dyspepsia, and asthma in traditional medicine. The present study investigated the beneficial effects of the n-butanolic extract of O. ficus-indica var. saboten (BOF) on memory performance in mice and attempts to uncover the mechanisms underlying its action. Memory performance was assessed with the passive avoidance task, and western blotting and immunohistochemistry were used to measure changes in protein expression and cell survival. After the oral administration of BOF for 7 days, the latency time in the passive avoidance task was significantly increased relative to vehicle-treated controls (P<0.05). Western blotting revealed that the expression levels of brain-derived neurotrophic factor (BDNF), phosphorylated cAMP response element binding-protein (pCREB), and phosphorylated extracellular signal-regulated kinase (pERK) 1/2 were significantly increased in hippocampal tissue after 7 days of BOF administration (P<0.05). Doublecortin and 5-bromo-2-deoxyuridine immunostaining also revealed that BOF significantly enhanced the survival of immature neurons, but did not affect neuronal cell proliferation in the subgranular zone of the hippocampal dentate gyrus. These results suggest that the subchronic administration of BOF enhances long-term memory, and that this effect is partially mediated by ERK-CREB-BDNF signaling and the survival of immature neurons. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Chromosome numbers of populations of three varieties of Bidens pilosa in Taiwan.

PubMed

Huang, Ya-Lun; Kao, Wen-Yuan

2015-12-01

Hairy beggar-ticks (Bidens pilosa L.) is a common invasive plant in tropical and subtropical regions. The Flora of Taiwan listed three varieties of B. pilosa in Taiwan, var. minor, var. pilosa and var. radiata. Among the three varieties, var. radiata was the most recently, in 1970s, introduced into Taiwan. However, after its introduction into Taiwan, var. radiata has become dominant over the other two varieties and is considered a serious invasive plant in lowland of Taiwan. Our previous study showed that var. radiata is self-incompatible and the other two varieties are self-fertile. Could it be possible that different chromosome numbers contribute to the different breeding systems of these three varieties? In addition, the heterogeneities of traits of var. radiata were found higher than those of var. minor and var. pilosa. Is the phenomenon resulting from the hybridization between var. radiata with other varieties? We counted chromosome numbers of populations of these three varieties distributed in Taiwan and conducted hand pollination treatment between var. radiata (as pollen receiver) and var. minor or var. pilosa (as pollen donor) to provide answer for the aforementioned questions. No difference was found in chromosome numbers among populations of the same variety. Forty-eight chromosomes (2n = 48) were counted for var. radiata while 72 (2n = 72) chromosomes for var. minor and var. pilosa. Therefore, var. radiata is tetraploid and var. minor and var. pilosa are hexaploid. No successful hybridization was found between var. radiata and var. minor or between var. radiata and var. pilosa. This study provided the evidence that the invasive plant (B. pilosa var. radiata) has different chromosome numbers from the other two varieties and is unlikely to hybridize with the other two varieties.

A new twist on an old idea part 2: cyclosporine preserves normal mitochondrial but not cardiomyocyte function in mini‐swine with compensated heart failure

PubMed Central

Hiemstra, Jessica A.; Gutiérrez‐Aguilar, Manuel; Marshall, Kurt D.; McCommis, Kyle S.; Zgoda, Pamela J.; Cruz‐Rivera, Noelany; Jenkins, Nathan T.; Krenz, Maike; Domeier, Timothy L.; Baines, Christopher P.; Emter, Craig A.

2014-01-01

Abstract We recently developed a clinically relevant mini‐swine model of heart failure with preserved ejection fraction (HFpEF), in which diastolic dysfunction was associated with increased mitochondrial permeability transition (MPT). Early diastolic function is ATP and Ca2+‐dependent, thus, we hypothesized chronic low doses of cyclosporine (CsA) would preserve mitochondrial function via inhibition of MPT and subsequently maintain normal cardiomyocyte Ca2+ handling and contractile characteristics. Left ventricular cardiomyocytes were isolated from aortic‐banded Yucatan mini‐swine divided into three groups; control nonbanded (CON), HFpEF nontreated (HF), and HFpEF treated with CsA (HF‐CsA). CsA mitigated the deterioration of mitochondrial function observed in HF animals, including functional uncoupling of Complex I‐dependent mitochondrial respiration and increased susceptibility to MPT. Attenuation of mitochondrial dysfunction in the HF‐CsA group was not associated with commensurate improvement in cardiomyocyte Ca2+ handling or contractility. Ca2+ transient amplitude was reduced and transient time to peak and recovery (tau) prolonged in HF and HF‐CsA groups compared to CON. Alterations in Ca2+ transient parameters observed in the HF and HF‐CsA groups were associated with decreased cardiomyocyte shortening and shortening rate. Cellular function was consistent with impaired in vivo systolic and diastolic whole heart function. A significant systemic hypertensive response to CsA was observed in HF‐CsA animals, and may have played a role in the accelerated the development of heart failure at both the whole heart and cellular levels. Given the significant detriment to cardiac function observed in response to CsA, our findings suggest chronic CsA treatment is not a viable therapeutic option for HFpEF. PMID:24963034

[Effects of ciclosporin and tacrolimus on replication of hepatitis B virus in vitro: a comparative study].

PubMed

Xia, Wei-liang; Xie, Hai-yang; Shen, Yan; Wu, Li-ming; Zhang, Feng; Zheng, Shu-sen

2006-01-10

To investigate the effects of ciclosporin (CsA) and tacrolimus (FK506) on replication of hepatitis B virus (HBV) in vitro. HBV genome permanently transfected human liver cancer cells of the line HepG2.2.15 were cultured. CsA and FK506 at different concentrations were added into the culture fluid so as to identify the nontoxic concentrations by MTT method. Then the HepG2.2.15 cells were treated by CsA and FK506 at different nontoxic concentrations respectively for 4 days. ELISA was used to detect the HB surface antigen (HBsAg) and HB e antigen (HBeAg) in the supernatant. The relative replication level of HBV DNA was detected by slot blot analysis. MTT method confirmed that the nontoxic concentrations of CsA and FK506 were 0-40.0 microg/ml and 0-400 ng/ml respectively. After the treatment of CsA at the concentration of 1.3, 2.5, and 5.0 microg/ml, in comparison to the control group, the suppression rates of HBsAg expression in the HepG2.2.15 cells were 16.5% +/- 9.4%, 21.5% +/- 8.9%, and 33.1% +/- 5.3% respectively (all P < 0.05); the suppression rates of HBeAg expression in the HepG2.2.15 cells were 7.8% +/- 2.2%, 11.0% +/- 2.3%, and 20.8% +/- 1.5% respectively (all P < 0.05); and the HBV DNA replication levels were 56 +/- 16, 42 +/- 11, and 40 +/- 10 respectively (P > 0.05, P < 0.05, and P > 0.05). However, FK506 at different nontoxic concentrations showed no significant inhibitory effect on the levels of HBsAg, HBeAg, and HBV DNA. CsA dose-dependently inhibits the HBV replication in vitro, and FK506 does not exercise similar effects.

Rehabilitative ultrasound imaging of the supraspinatus muscle: Intra- and interrater reliability of thickness and cross-sectional area.

PubMed

Schneebeli, Alessandro; Egloff, Michele; Giampietro, Amelia; Clijsen, Ron; Barbero, Marco

2014-04-01

To examine intra- and interrater reliability of thickness and cross-sectional area (CSA) measurements of the supraspinatus muscle using rehabilitative ultrasound imaging (RUSI). Two physical therapists acquired b-mode images of the supraspinatus muscles in twenty-five healthy subjects. Thickness and CSA were measured. Intra- and interrater reliability were examined. Intrarater reliability for thickness was high, (ICC1.1 0.91) for rater 1 and (ICC1.1 0.92) for rater 2. Intrarater reliability for CSA was also high, (ICC1.1 0.90) for rater 1 and (ICC1.1 0.85) for rater 2. Interrater reliability for the thickness was high, (ICC3.1 0.86). For CSA, interrater reliability was moderate, (ICC3.1 0.70). Supraspinatus muscle thickness and CSA can be reliably measured by physical therapists in healthy subjects. These findings confirm that RUSI has an interesting potential for physiotherapy clinical practice, especially to assess morphometric changes in skeletal muscles. Further research is needed in subjects with shoulder disorders. Copyright © 2013 Elsevier Ltd. All rights reserved.

Sexual abuse and psychiatric disorder in England: results from the 2007 Adult Psychiatric Morbidity Survey.

PubMed

Jonas, S; Bebbington, P; McManus, S; Meltzer, H; Jenkins, R; Kuipers, E; Cooper, C; King, M; Brugha, T

2011-04-01

Evidence is accumulating that child sexual abuse (CSA) is associated with many psychiatric disorders in adulthood. This paper uses the detailed information available from the 2007 Adult Psychiatric Morbidity Survey of England (APMS 2007) to quantify links between CSA and a range of psychiatric conditions. The prevalence of psychiatric disorder was established in a random sample of the English household population (n=7403), which also provided sociodemographic and experiential information. We analyzed six types of common mental disorder, alcohol abuse and drug abuse, and people who screened positively for post-traumatic stress disorder (PTSD) and eating disorders. All were strongly and highly significantly associated with CSA, particularly if non-consensual sexual intercourse was involved, for which odds ratios (ORs) ranged from 3.7 to 12.1. These disorders were also related to adult sexual abuse (ASA), although the likelihood of reverse causality is then increased. Revictimization in adulthood was common, and increased the association of CSA with disorder. For several disorders, the relative odds were higher in females but formal tests for moderation by gender were significant only for common mental disorders and only in relation to non-consensual sexual intercourse. The population attributable fraction (PAF) was higher in females in all cases. The detailed and high-quality data in APMS 2007 provided important confirmation both of the strength of association of CSA with psychiatric disorder and of its relative non-specificity. Our results have major implications at the public health level and the individual level, in particular the need for better recognition and treatment of the sequelae of CSA.

Predicting suicide attempts in depressed adolescents: Clarifying the role of disinhibition and childhood sexual abuse.

PubMed

Stewart, Jeremy G; Kim, Judy C; Esposito, Erika C; Gold, Joseph; Nock, Matthew K; Auerbach, Randy P

2015-11-15

Suicide is the second leading cause of death among adolescents, and depressed youth are six times more likely to make suicide attempts as compared to non-depressed adolescents. The present study examined the unique and interactive effects of two well-established correlates of suicidality - childhood sexual abuse (CSA) and disinhibition - in predicting suicide attempts among depressed adolescents. Participants were 163 adolescents (125 females) aged 13-18 (M=15.60, SD=1.27) diagnosed with Major Depressive Disorder (n=95, 58.3%) and/or Dysthymia (n=69, 42.3%) recruited from an acute residential treatment service. Participants completed interviews assessing psychopathology and suicidality, self-report measures of depressive symptoms and CSA, and a computerized disinhibition task. Consistent with hypotheses, CSA moderated the association between disinhibition and adolescents' report of their past year and lifetime suicide attempts. Specifically, higher disinhibition was associated with a greater likelihood of having made a suicide attempt among adolescents with a history of CSA, but not among those without. The same pattern of results held in analyses of suicide attempt frequency. Primary findings were based on observational, cross-sectional data, and therefore, causal relationships cannot be inferred. The gender imbalance in the sample precluded stratifying our analyses by gender. CSA was ascertained by self-report; replication of the results with more objective measures is warranted. Our findings indicate that CSA and disinhibition may work together to predict elevated suicide risk, and these results have implications for early identification efforts in youth at high risk for suicide. Copyright © 2015 Elsevier B.V. All rights reserved.

Predicting Suicide Attempts in Depressed Adolescents: Clarifying the Role of Disinhibition and Childhood Sexual Abuse

PubMed Central

Stewart, Jeremy G.; Kim, Judy C.; Esposito, Erika C.; Gold, Joseph; Nock, Matthew K.; Auerbach, Randy P.

2015-01-01

Background Suicide is the second leading cause of death among adolescents, and depressed youth are six times more likely to make suicide attempts as compared to non-depressed adolescents. The present study examined the unique and interactive effects of two well-established correlates of suicidality – childhood sexual abuse (CSA) and disinhibition – in predicting suicide attempts among depressed adolescents. Method Participants were 163 adolescents (125 females) aged 13 to 18 (M = 15.60, SD = 1.27) diagnosed with Major Depressive Disorder (n = 95, 58.3%) and/or Dysthymia (n = 69, 42.3%) recruited from an acute residential treatment service. Participants completed interviews assessing psychopathology and suicidality, self-report measures of depressive symptoms and CSA, and a computerized disinhibition task. Results Consistent with hypotheses, CSA moderated the association between disinhibition and adolescents' report of their past year and lifetime suicide attempts. Specifically, higher disinhibition was associated with a greater likelihood of having made a suicide attempt among adolescents with a history of CSA, but not among those without. The same pattern of results held in analyses of suicide attempt frequency. Limitations Primary findings were based on observational, cross-sectional data, and therefore, causal relationships cannot be inferred. The gender imbalance in the sample precluded stratifying our analyses by gender. CSA was ascertained by self-report; replication of the results with more objective measures is warranted. Conclusions Our findings indicate that CSA and disinhibition may work together to predict elevated suicide risk, and these results have implications for early identification efforts in youth at high risk for suicide. PMID:26318268

Testing a multiple mediator model of the effect of childhood sexual abuse on adolescent sexual victimization.

PubMed

Bramsen, Rikke H; Lasgaard, Mathias; Koss, Mary P; Shevlin, Mark; Elklit, Ask; Banner, Jytte

2013-01-01

The present study modeled the direct relationship between child sexual abuse (CSA) and adolescent peer-to-peer sexual victimization (APSV) and the mediated effect via variables representing the number of sexual partners, sexual risk behavior, and signaling sexual boundaries. A cross-sectional study on the effect of CSA on APSV was conducted, utilizing a multiple mediator model. Mediated and direct effects in the model were estimated employing Mplus using bootstrapped percentile based confidence intervals to test for significance of mediated effects. The study employed 327 Danish female adolescents with a mean age of 14.9 years (SD = 0.5). The estimates from the mediational model indicated full mediation of the effect of CSA on APSV via number of sexual partners and sexual risk behavior. The current study suggests that the link between CSA and APSV was mediated by sexual behaviors specifically pertaining to situations of social peer interaction, rather than directly on prior experiences of sexual victimization. The present study identifies a modifiable target area for intervention to reduce adolescent sexual revictimization. © 2013 American Orthopsychiatric Association.

Detoxification of Benzoxazolinone Allelochemicals from Wheat by Gaeumannomyces graminis var. tritici, G. graminis var. graminis, G. graminis var. avenae, and Fusarium culmorum

PubMed Central

Friebe, A.; Vilich, V.; Hennig, L.; Kluge, M.; Sicker, D.

1998-01-01

The ability of phytopathogenic fungi to overcome the chemical defense barriers of their host plants is of great importance for fungal pathogenicity. We studied the role of cyclic hydroxamic acids and their related benzoxazolinones in plant interactions with pathogenic fungi. We identified species-dependent differences in the abilities of Gaeumannomyces graminis var. tritici, Gaeumannomyces graminis var. graminis, Gaeumannomyces graminis var. avenae, and Fusarium culmorum to detoxify these allelochemicals of gramineous plants. The G. graminis var. graminis isolate degraded benzoxazolin-2(3H)-one (BOA) and 6-methoxy-benzoxazolin-2(3H)-one (MBOA) more efficiently than did G. graminis var. tritici and G. graminis var. avenae. F. culmorum degraded BOA but not MBOA. N-(2-Hydroxyphenyl)-malonamic acid and N-(2-hydroxy-4-methoxyphenyl)-malonamic acid were the primary G. graminis var. graminis and G. graminis var. tritici metabolites of BOA and MBOA, respectively, as well as of the related cyclic hydroxamic acids. 2-Amino-3H-phenoxazin-3-one was identified as an additional G. graminis var. tritici metabolite of BOA. No metabolite accumulation was detected for G. graminis var. avenae and F. culmorum by high-pressure liquid chromatography. The mycelial growth of the pathogenic fungi was inhibited more by BOA and MBOA than by their related fungal metabolites. The tolerance of Gaeumannomyces spp. for benzoxazolinone compounds is correlated with their detoxification ability. The ability of Gaeumannomyces isolates to cause root rot symptoms in wheat (cultivars Rektor and Astron) parallels their potential to degrade wheat allelochemicals to nontoxic compounds. PMID:9647804

Characterization of five fungal endophytes producing Cajaninstilbene acid isolated from pigeon pea [Cajanus cajan (L.) Millsp].

PubMed

Gao, Yuan; Zhao, Jin Tong; Zu, Yuan Gang; Fu, Yu Jie; Wang, Wei; Luo, Meng; Efferth, Thomas

2011-01-01

Five fungal endophytes (K4, K5, K6, K9, K14) producing Cajaninstilbene acid (CSA, 3-hydroxy-4-prenyl-5-methoxystilbene-2-carboxylic acid) were isolated from the roots of pigeon pea [Cajanus cajan (L.) Millsp.]. CSA is responsible for the prominent pharmacological activities in pigeon pea. The amount of CSA in culture solution varied among the five fungal endophytes. K4 produced the highest levels of CSA (1037.13 µg/L) among the endophytes tested after incubation for five days. Both morphological characteristics and molecular methods were used for species identification of fungal endophytes. The five endophytic isolates were characterized by analyzing the internal transcribed spacer (ITS) rRNA and β-tubulin genes. The K4, K5, K9 and K14 strains isolated from pigeon pea roots were found to be closely related to the species Fusarium oxysporum. K6 was identified as Neonectria macrodidym. The present study is the first report on the isolation and identification of fungal endophytes producing CSA in pigeon pea. The study also provides a scientific base for large scale production of CSA.

Self-assembling colloidal system for the ocular administration of cyclosporine A.

PubMed

Luschmann, Christoph; Tessmar, Joerg; Schoeberl, Simon; Strauß, Olaf; Luschmann, Karl; Goepferich, Achim

2014-01-01

In this study, we developed a self-assembling micellar system to deliver cyclosporine A (CsA) in an aqueous solution to the cornea. Two nonionic surfactants of the poly(ethylene glycol)-fatty alcohol ether type (Sympatens AS and Sympatens ACS) were characterized in terms of micelle size, shape, and charge, and their encapsulation efficiency for CsA. In an in situ single dose bioavailability study, the corneal CsA levels were determined in an enucleated porcine eye model. A commercial formulation and a 2% CsA olive oil solution served as references. Both surfactants formed spherical micelles with a size of 9 to 12 nm in water. A concentration as low as 0.3% (wt/vol) Sympatens AS was sufficient to entrap therapeutic levels of at least 0.1% (wt/vol) CsA. In the porcine in situ model, exceptionally high drug levels in the cornea were obtained for the micellar CsA solution (1557 ± 407 ngCsA/gcornea). They were significantly higher than those of Restasis (545 ± 137 ngCsA/gcornea) or the olive oil solution (452 ± 142 ngCsA/gcornea). In conclusion, we have shown a promising simple and efficient approach for the application of CsA in an aqueous solution to the cornea to treat inflammatory corneal diseases.

A Two-Dimensional Variational Analysis Method for NSCAT Ambiguity Removal: Methodology, Sensitivity, and Tuning

NASA Technical Reports Server (NTRS)

Hoffman, R. N.; Leidner, S. M.; Henderson, J. M.; Atlas, R.; Ardizzone, J. V.; Bloom, S. C.; Atlas, Robert (Technical Monitor)

2001-01-01

In this study, we apply a two-dimensional variational analysis method (2d-VAR) to select a wind solution from NASA Scatterometer (NSCAT) ambiguous winds. 2d-VAR determines a "best" gridded surface wind analysis by minimizing a cost function. The cost function measures the misfit to the observations, the background, and the filtering and dynamical constraints. The ambiguity closest in direction to the minimizing analysis is selected. 2d-VAR method, sensitivity and numerical behavior are described. 2d-VAR is compared to statistical interpolation (OI) by examining the response of both systems to a single ship observation and to a swath of unique scatterometer winds. 2d-VAR is used with both NSCAT ambiguities and NSCAT backscatter values. Results are roughly comparable. When the background field is poor, 2d-VAR ambiguity removal often selects low probability ambiguities. To avoid this behavior, an initial 2d-VAR analysis, using only the two most likely ambiguities, provides the first guess for an analysis using all the ambiguities or the backscatter data. 2d-VAR and median filter selected ambiguities usually agree. Both methods require horizontal consistency, so disagreements occur in clumps, or as linear features. In these cases, 2d-VAR ambiguities are often more meteorologically reasonable and more consistent with satellite imagery.

Comparison of continuous spinal anaesthesia using a 32-gauge catheter with anaesthesia using a single-dose 24-gauge atraumatic needle in young patients.

PubMed

de Andrés, J; Bellver, J; Bolinches, R

1994-12-01

One hundred and twenty-eight ASA I-III patients less than 40 yr of age, undergoing orthopaedic or trauma lower limb surgery, were allocated randomly to receive either continuous spinal anaesthesia (CSA) using a 32-gauge polyimide microcatheter with a permanent stylet (Rusch/TFX Medical, Duluth, GA, USA) or single-dose spinal anaesthesia (SDSA) with a 24-gauge x 103-mm Sprotte spinal needle (Pajunk, Germany). Plain bupivacaine (0.5%) was used as the local anaesthetic. The initial doses were 1 ml (5 mg) of CSA and 3 ml (15 mg) of SDSA, while the re-injection doses were 1 ml (5 mg) in the CSA group. SDSA was quicker to perform: mean 4.4 (SD 1.6) min compared with 6.2 (2.6) min for CSA (P < 0.01). Times to onset and surgical anaesthesia were also significantly greater in the CSA group (P < 0.01). The quality of the block was better in the SDSA group (P < 0.05), but was associated with greater haemodynamic instability (P < 0.05). The segmental level of analgesia was significantly lower in the CSA group (median T10 (range T12-T8)) than in the SDSA group (T9 (T11-T5)) (P < 0.05). There were no significant differences in the incidence of postoperative complications, with two mild spinal headaches in both groups. We conclude that CSA using a microcatheter in young patients is difficult to perform and affords no advantages over SDSA with a small gauge atraumatic needle.

Identification of malaria parasite-infected red blood cell surface aptamers by inertial microfluidic SELEX (I-SELEX)

NASA Astrophysics Data System (ADS)

Birch, Christina M.; Hou, Han Wei; Han, Jongyoon; Niles, Jacquin C.

2015-07-01

Plasmodium falciparum malaria parasites invade and remodel human red blood cells (RBCs) by trafficking parasite-synthesized proteins to the RBC surface. While these proteins mediate interactions with host cells that contribute to disease pathogenesis, the infected RBC surface proteome remains poorly characterized. Here we use a novel strategy (I-SELEX) to discover high affinity aptamers that selectively recognize distinct epitopes uniquely present on parasite-infected RBCs. Based on inertial focusing in spiral microfluidic channels, I-SELEX enables stringent partitioning of cells (efficiency ≥ 106) from unbound oligonucleotides at high volume throughput (~2 × 106 cells min-1). Using an RBC model displaying a single, non-native antigen and live malaria parasite-infected RBCs as targets, we establish suitability of this strategy for de novo aptamer selections. We demonstrate recovery of a diverse set of aptamers that recognize distinct, surface-displayed epitopes on parasite-infected RBCs with nanomolar affinity, including an aptamer against the protein responsible for placental sequestration, var2CSA. These findings validate I-SELEX as a broadly applicable aptamer discovery platform that enables identification of new reagents for mapping the parasite-infected RBC surface proteome at higher molecular resolution to potentially contribute to malaria diagnostics, therapeutics and vaccine efforts.

Should conventional angiography be the gold standard for carotid stenosis?

PubMed

Zhang, Wayne W; Harris, Linda M; Dryjski, Maciej L

2006-12-01

To compare conventional angiography (CA) and rotational angiography (RA) to assess the degree of angiographically-measured stenosis versus cross-sectional area (CSA) stenosis in an in vitro carotid model. Various grades of stenosis were created by adhering different amounts of silicone rubber sealant onto the inner wall of clear, radiolucent tubes. Following 2- and 3-projection CA and 20-projection RA, the tubes were transected at the actual maximum stenosis. The cross-sectional areas were digitally photographed, and CSA stenosis was calculated using ImageJ planimeter software. The differences among CA, RA, and CSA stenosis measurements were compared statistically. There was no significant difference between RA and CSA stenosis measurements (p=0.46). Conventional angiography with 2 or 3 projections between 0 degrees and 90 degrees underestimated the severity of disease in 19 (63%) of 30 samples. The maximum stenosis percentage was significantly lower in CA versus RA (p<0.0001 in 2-projection, p<0.0003 in 3-projection) and in CA versus CSA stenosis (p<0.0004 in 2-projection, p<0.001 in 3-projection). The maximum stenosis percentages measured by RA were less than CSA stenosis in 5 (71.4%) of 7 tubes (p=NS) containing 50% to 69% stenoses. Eight tubes had mountain-shaped lesions, which was significantly overestimated by RA (11.5%+/-9.7%, p<0.012). CA with 2 or 3 projections significantly underestimates the maximum stenosis in an in vitro model. RA may overestimate disease in patients with mountain-shaped plaques and may underestimate disease if the stenosis is <70%. Our data suggest that CA should not be the gold standard for the qualification of carotid endarterectomy in asymptomatic patients, nor for vascular laboratory quality assurance analysis.

Cardiac resynchronization therapy and atrial overdrive pacing for the treatment of central sleep apnoea

PubMed Central

Lüthje, Lars; Renner, Bernd; Kessels, Roger; Vollmann, Dirk; Raupach, Tobias; Gerritse, Bart; Tasci, Selcuk; Schwab, Jörg O.; Zabel, Markus; Zenker, Dieter; Schott, Peter; Hasenfuss, Gerd; Unterberg-Buchwald, Christina; Andreas, Stefan

2009-01-01

Aims The combined therapeutic impact of atrial overdrive pacing (AOP) and cardiac resynchronization therapy (CRT) on central sleep apnoea (CSA) in chronic heart failure (CHF) so far has not been investigated. We aimed to evaluate the effect of CRT alone and CRT + AOP on CSA in CHF patients and to compare the influence of CRT on CHF between CSA positive and CSA negative patients. Methods and results Thirty patients with CRT indication underwent full night polysomnography, echocardiography, exercise testing, and neurohumoral evaluation before and 3 months after CRT implantation. In CSA positive patients (60%), two additional sleep studies were conducted after 3 months of CRT, with CRT alone or CRT + AOP, in random order. Cardiac resynchronization therapy resulted in significant improvements of NYHA class, left ventricular ejection fraction, N-terminal pro-brain natriuretic peptide, VO2max, and quality of life irrespective of the presence of CSA. Cardiac resynchronization therapy also reduced the central apnoea–hypopnoea index (AHI) (33.6 ± 14.3 vs. 23.8 ± 16.9 h−1; P < 0.01) and central apnoea index (17.3 ± 14.1 vs. 10.9 ± 13.9 h−1; P < 0.01) without altering sleep stages. Cardiac resynchronization therapy with atrial overdrive pacing resulted in a small but significant additional decrease of the central AHI (23.8 ± 16.9 vs. 21.5 ± 16.9 h−1; P < 0.01). Conclusion In this study, CRT significantly improved CSA without altering sleep stages. Cardiac resynchronization therapy with atrial overdrive pacing resulted in a significant but minor additional improvement of CSA. Positive effects of CRT were irrespective of the presence of CSA. PMID:19147446

Skeletal muscle hypertrophy and structure and function of skeletal muscle fibres in male body builders

PubMed Central

D'Antona, Giuseppe; Lanfranconi, Francesca; Pellegrino, Maria Antonietta; Brocca, Lorenza; Adami, Raffaella; Rossi, Rosetta; Moro, Giorgio; Miotti, Danilo; Canepari, Monica; Bottinelli, Roberto

2006-01-01

Needle biopsy samples were taken from vastus lateralis muscle (VL) of five male body builders (BB, age 27.4 ± 0.93 years; mean ±s.e.m.), who had being performing hypertrophic heavy resistance exercise (HHRE) for at least 2 years, and from five male active, but untrained control subjects (CTRL, age 29.9 ± 2.01 years). The following determinations were performed: anatomical cross-sectional area and volume of the quadriceps and VL muscles in vivo by magnetic resonance imaging (MRI); myosin heavy chain isoform (MHC) distribution of the whole biopsy samples by SDS-PAGE; cross-sectional area (CSA), force (Po), specific force (Po/CSA) and maximum shortening velocity (Vo) of a large population (n= 524) of single skinned muscle fibres classified on the basis of MHC isoform composition by SDS-PAGE; actin sliding velocity (Vf) on pure myosin isoforms by in vitro motility assays. In BB a preferential hypertrophy of fast and especially type 2X fibres was observed. The very large hypertrophy of VL in vivo could not be fully accounted for by single muscle fibre hypertrophy. CSA of VL in vivo was, in fact, 54% larger in BB than in CTRL, whereas mean fibre area was only 14% larger in BB than in CTRL. MHC isoform distribution was shifted towards 2X fibres in BB. Po/CSA was significantly lower in type 1 fibres from BB than in type 1 fibres from CTRL whereas both type 2A and type 2X fibres were significantly stronger in BB than in CTRL. Vo of type 1 fibres and Vf of myosin 1 were significantly lower in BB than in CTRL, whereas no difference was observed among fast fibres and myosin 2A. The findings indicate that skeletal muscle of BB was markedly adapted to HHRE through extreme hypertrophy, a shift towards the stronger and more powerful fibre types and an increase in specific force of muscle fibres. Such adaptations could not be fully accounted for by well known mechanisms of muscle plasticity, i.e. by the hypertrophy of single muscle fibre (quantitative mechanism) and by a regulation of contractile properties of muscle fibres based on MHC isoform content (qualitative mechanism). Two BB subjects took anabolic steroids and three BB subjects did not. The former BB differed from the latter BB mostly for the size of their muscles and muscle fibres. PMID:16339176

Soil organic phosphorus flows to water via critical and non-critical hydrological source areas

NASA Astrophysics Data System (ADS)

Wang, Ying; Surridge, Ben; Haygarth, Phil

2015-04-01

Soil organic phosphorus flows to water via critical and non-critical hydrological source areas Ying Wang, Ben W.J. Surridge, Philip M. Haygarth Lancaster Environment Centre, Lancaster University, LA1 4YQ, UK Critical source areas (CSAs) are zones in the landscape where easily connected hydrology coincides with a phosphorus (P) sources in the soil. The P export risks in CSAs are hypothesised to be higher compared with non-critical source areas (Non-CSAs) and specifically that the magnitudes of P forms in CSA areas were higher than Non-CSAs. Past research on CSAs has often neglected forms of organic P, such as DNA and phospholipids which are among the most potentially biodegradable organic P compounds. The objectives of this study were i) to quantify the magnitude of organic P compounds in agricultural soils and specifically determine whether these magnitudes differed significantly between CSAs and Non-CSAs; ii) determine the variation of P magnitude between and within individual fields; iii) identify the P delivery concentrations in soil solution after raining events in CSAs. The study focussed on soils collected from the Morland sub-catchment of the River Eden catchment in Cumbria, northern England. CSA and Non-CSA pairs were identified using the SCIMAP modelling and field assessment providing five CSA - Non-CSA pairs in total. The results showed that there are significant differences in the total P (TP) concentrations, the proportions of DNA-P, WETP (water extractable total P), WERP (water extractable reactive P) and WEUP (water extractable unreactive P) between CSA and Non-CSA. We also found that the concentrations of all the P forms showed distribution variation between fields or even within the same field. Liable organic P such as DNA-P and PLD-P was presented considerable proportions of total P in soil, especially DNA-P which had a good correlation with TP. DNA-P in the ten areas accounted for a considerable proportion of soil TP (4.9 to 16.6%). Given the potential lability and bioavailability of DNA and phospholipids, our data demonstrate that these soil organic P could be a potential pool to support plant nutrition and a potential contributor to water pollution problems. Furthermore, For a number of soil samples, comparisons were made between extraction of P within phospholipids and DNA and the results of 31 PNMR analyses, to provide further characterisation of the organic P fractions within these soils.Data of this study will also be presented concerning the forms and magnitudes of P fractions in runoff pathways across an agricultural catchment, including the prevalence of organic P in these pathways. Keywords: Organic P; Soil; CSA; DNA; Phospholipids

Association between vertebral cross-sectional area and lumbar lordosis angle in adolescents.

PubMed

Wren, Tishya A L; Aggabao, Patricia C; Poorghasamians, Ervin; Chavez, Thomas A; Ponrartana, Skorn; Gilsanz, Vicente

2017-01-01

Lumbar lordosis (LL) is more prominent in women than in men, but the mechanisms responsible for this discrepancy are poorly defined. A recent study indicates that newborn girls have smaller vertebral cross-sectional area (CSA) when compared to boys-a difference that persists throughout life and is independent of body size. We determined the relations between vertebral cross-sectional area (CSA) and LL angle and whether sex differences in lumbar lordosis are related to sex differences in vertebral CSA. Using multi-planar magnetic resonance imaging (MRI), we measured vertebral cross-sectional area (CSA) and vertebral height of the spine of 40 healthy boys and 40 girls, ages 9-13 years. Measures of the CSA of the lumbar vertebrae significantly differed between sexes (9.38 ± 1.46 vs. 7.93 ± 0.69 in boys and girls, respectively; P < 0.0001), while the degree of LL was significantly greater in girls than in boys (23.7 ± 6.1 vs. 27.6 ± 8.0 in boys and girls, respectively; P = 0.02). When all subjects were analyzed together, values for LL angle were negatively correlated to vertebral CSA (r = -0.47; P < 0.0001); this was also true when boys and girls were analyzed separately. Multivariate regression analysis indicated that vertebral CSA was independently associated with LL, even after accounting for sex, age, height or vertebral height, and weight. Similar negative relations were present when thoracic vertebrae were analyzed (Model P < 0.0001, R2 = 0.37, thoracic vertebral CSA slope P < 0.0001), suggesting that deficient vertebral cross-sectional dimensions are not merely the consequence of the anterior lumbar curvature. We conclude that vertebral CSA is negatively associated with LL, and that the greater degree of LL in females could, at least in part, be due to smaller vertebral cross-sectional dimensions. Studies are needed to examine the potential relations between vertebral CSA and spinal conditions known to be associated with increased LL, such as spondylolysis and spondylolisthesis.

Myoglobin plasma level related to muscle mass and fiber composition: a clinical marker of muscle wasting?

PubMed

Weber, Marc-André; Kinscherf, Ralf; Krakowski-Roosen, Holger; Aulmann, Michael; Renk, Hanna; Künkele, Annette; Edler, Lutz; Kauczor, Hans-Ulrich; Hildebrandt, Wulf

2007-08-01

Progressive muscle wasting is a central feature of cancer-related cachexia and has been recognized as a determinant of poor prognosis and quality of life. However, until now, no easily assessable clinical marker exists that allows to predict or to track muscle wasting. The present study evaluated the potential of myoglobin (MG) plasma levels to indicate wasting of large locomotor muscles and, moreover, to reflect the loss of MG-rich fiber types, which are most relevant for daily performance. In 17 cancer-cachectic patients (weight loss 22%) and 27 age- and gender-matched healthy controls, we determined plasma levels of MG and creatine kinase (CK), maximal quadriceps muscle cross-sectional area (CSA) by magnetic resonance imaging, muscle morphology and fiber composition in biopsies from the vastus lateralis muscle, body cell mass (BCM) by impedance technique as well as maximal oxygen uptake (VO(2)max). In cachectic patients, plasma MG, muscle CSA, BCM, and VO(2)max were 30-35% below control levels. MG showed a significant positive correlation to total muscle CSA (r = 0.65, p < 0.001) and to the CSA fraction formed by type 1 and 2a fibers (r = 0.80, p < 0.001). However, when adjusted for body height and age by multiple regression, MG yielded a largely improved prediction of total CSA (multiple r = 0.83, p < 0.001) and of fiber type 1 and 2a CSA (multiple r = 0.89, p < 0.001). The correlations between CK and these muscle parameters were weaker, and elevated CK values were observed in 20% of control subjects despite a prior abstinence from exercise for 5 days. In conclusion, plasma MG, when adjusted for anthropometric parameters unaffected by weight, may be considered as a novel marker of muscle mass (CSA) indicating best the mass of MG-rich type 1 and 2a fibers as well as VO(2)max as an important functional readout. CK plasma levels appear to be less reliable because prolonged increases are observed in even subclinical myopathies or after exercise. Notably, cancer-related muscle wasting was not associated with increases in plasma MG or CK in this study.

Systematics of Juniperus section Juniperus based on leaf essential oils and random amplified polymorphic DNAs (RAPDs).

PubMed

Adams

2000-07-01

The composition of the leaf essential oils of all the species of Juniperus in sect. Juniperus (=sect. Oxycedrus) are reported and compared (J. brevifolia, J. cedrus, J. communis, J. c. var. saxatilis, J. c. var. oblonga, J. formosana, J. oxycedrus, J. o. subsp. badia, J. o. subsp. macrocarpa, J. o. subsp. transtagana, J. rigida, J. r. subsp. conferta, J. sibirica, J. taxifolia and J. t. var. lutchuensis). In addition, DNA fingerprinting by RAPDs was utilized. Based on these data, several taxa remained at the same taxonomic level: J. brevifolia, J. cedrus, J. communis, J. c. var. saxatilis, J. formosana, J. oxycedrus, J. rigida, J. r. var. conferta, and J. taxifolia. However, several taxa exhibited considerable differentiation that warranted their recognition at the specific level: J. oblonga M.-Bieb. (=J. communis var. oblonga), J. badia H. Gay (=J. oxycedrus subsp. badia), J. macrocarpa Sibth. and Sm. (=J. oxycedrus subsp. macrocarpa), J. navicularis Gand. (=J. oxycedrus subsp. transtagana), J. sibirica Brugsd. (=J. communis var. saxatilis in part), and J. lutchuensis Koidz. (= J. taxifolia var. lutchuensis).

Lactoferrin derived resistance against plant pathogen in transgenic plants

USDA-ARS?s Scientific Manuscript database

Lactoferrin (LF) is a ubiquitous cationic iron-binding milk glycoprotein and it is known to exert a broad-spectrum primary defense activity against bacteria, fungi, protozoa and viruses in mammals. The Bovine lactoferrin gene was introduced to tobacco (Nicotiana tabacum var Xanthi), Arabidopsis (A. ...

Identification of cellular and viral factors related to anti-hepatitis C virus activity of cyclophilin inhibitor.

PubMed

Goto, Kaku; Watashi, Koichi; Inoue, Daisuke; Hijikata, Makoto; Shimotohno, Kunitada

2009-10-01

We have so far reported that an immunosuppressant cyclosporin A (CsA), a well-known cyclophilin (CyP) inhibitor (CPI), strongly suppressed hepatitis C virus (HCV) replication in cell culture, and that CyPB was a cellular cofactor for viral replication. To further investigate antiviral mechanisms of CPI, we here developed cells carrying CsA-resistant HCV replicons, by culturing the HCV subgenomic replicon cells for 4 weeks in the presence of CsA with G418. Transfection of total RNA from the isolated CsA-resistant cells to naïve Huh7 cells conferred CsA resistance, suggesting that the replicon RNA itself was responsible for the resistant phenotype. Of the identified amino acid mutations, D320E in NS5A conferred the CsA resistance. The replicon carrying the D320E mutation was sensitive to interferon-alpha, but was resistant to CsA and other CPIs including NIM811 and sanglifehrin A. Knockdown of individual CyP subtypes revealed CyP40, in addition to CyPA and CyPB, contributed to viral replication, and CsA-resistant replicons acquired independence from CyPA for efficient replication. These data provide important evidence on the mechanisms underlying the regulation of HCV replication by CyP and for designing novel and specific anti-HCV strategies with CPIs.

Investigation of the intestinal permeability of ciclosporin using the in situ technique in rats and the relevance of P-glycoprotein.

PubMed

Zakeri-Milani, Parvin; Valizadeh, Hadi; Islambulchilar, Ziba; Damani, Sanaz; Mehtari, Maryam

2008-01-01

The primary endpoint of this study was to determine the intestinal permeability of ciclosporin (cyclosporine A, CsA, CAS 59865-13-3) using the single-pass intestinal perfusion technique (SPIP) and a range of concentrations in rats. The second objective was to assess the quantitative contribution of P-glycoprotein (P-gp)-mediated efflux in limiting the oral bioavailability of CsA using erythromycin (Ery, CAS 114-07-8) as an inhibitor of P-gp efflux transporter. A solution containing CsA and phenol red either in the presence or in the absence of Ery as a P-gp inhibitor was perfused through a cannulated jejunal segment in rats. Outlet samples were collected every 10 min in micro tubes up to 90 min. Samples were analyzed using a modified reverse phase HPLC method. The mean effective permeability coefficients (Peff) of CsA in concentrations of 5, 10, 15 and 20 micromol/L in the perfusion solution were found to be 2.21 (+/- 0.26) x 10(-4) cm/s, 3.34 (+/- 1.29) x 10(-4) cm/s, 3.12 (+/- 0.23) x 10(-4) cm/s and 2.73 (+/- 0.28) x 10(-4) cm/s, respectively. The corresponding values in the presence of Ery were found to be 3.96 (+/- 1.04) x 10(-4) cm/s, 5.34 (+/- 1.29) x 10(-4) cm/s, 3.72 (+/- 0.21) x 10(-4) cm/s and 4.41 (+/- 0.89) x 10(-4) cm/s, respectively. The two-tailed Student's t-test showed that the intestinal permeability of CsA was significantly increased by Ery in all four CsA concentrations used (P < 0.05). However, there was no significant difference between the Peff values of CsA in different concentrations, indicating that the CsA permeation was independent of the concentration. Therefore it is concluded that at least some part of the observed clinical interaction between Ery and CsA is due to the interaction in absorption level.

Prevalence and predictors of Axis I disorders in a large sample of treatment-seeking victims of sexual abuse and incest

PubMed Central

McElroy, Eoin; Shevlin, Mark; Elklit, Ask; Hyland, Philip; Murphy, Siobhan; Murphy, Jamie

2016-01-01

Background Childhood sexual abuse (CSA) is a common occurrence and a robust, yet non-specific, predictor of adult psychopathology. While many demographic and abuse factors have been shown to impact this relationship, their common and specific effects remain poorly understood. Objective This study sought to assess the prevalence of Axis I disorders in a large sample of help-seeking victims of sexual trauma, and to examine the common and specific effects of demographic and abuse characteristics across these different diagnoses. Method The participants were attendees at four treatment centres in Denmark that provide psychological therapy for victims of CSA (N=434). Axis I disorders were assessed using the Millon Clinical Multiaxial Inventory-III (MCMI-III). Multivariate logistic regression analysis was used to examine the associations between CSA characteristics (age of onset, duration, number of abusers, number of abusive acts) and 10 adult clinical syndromes. Results There was significant variation in the prevalence of disorders and the abuse characteristics were differentially associated with the outcome variables. Having experienced sexual abuse from more than one perpetrator was the strongest predictor of psychopathology. Conclusions The relationship between CSA and adult psychopathology is complex. Abuse characteristics have both unique and shared effects across different diagnoses. Highlights of the article The prevalence of Axis I disorders were assessed in a large sample of sexual abuse and incest survivors. The impact of demographic and abuse characteristics were also examined. There was significant variation in the prevalence of disorders. Abuse characteristics were differentially associated with the disorders. Abuse from multiple perpetrators was the strongest overall predictor of psychopathology. PMID:27064976

Putting the past behind us: Social stress-induced urinary retention can be overcome.

PubMed

Weiss, Dana A; Butler, Stephan J; Fesi, Joanna; Long, Christopher J; Valentino, Rita J; Canning, Douglas A; Zderic, Stephen A

2015-08-01

To study the pathophysiology of dysfunctional voiding, we have previously developed a model of stress-induced voiding dysfunction. We have shown that cyclosporine A (CsA), an inhibitor of the Ca(2+)-calmodulin complex, can prevent social stress-induced urinary retention. However, treatment with cyclosporine has not had an effect on the increase in the stress peptide corticotrophin-releasing factor (CRF) in Barrington's nucleus, which is involved in the micturition pathway. We now investigate whether cyclosporine administered after stress can reverse the abnormal voiding phenotype, and whether it has effects on the bladder wall itself, or on the stress response within Barrington's nucleus. Six-week old Swiss-Webster mice were exposed to aggressor males for 1 h a day, followed by 23 h of barrier separation. In a long-term trial, 1 month of stress was followed by single-cage housing for 6 months. In a separate CsA reversal trial, mice either received CsA in drinking water or had plain drinking water during 1 month of single-cage housing during recovery. Bladder contractile function was examined on a Guth myograph. Nuclear translocation of myocyte enhancing factor (MEF)-2 and NFAT (nuclear factor of activated T cells) in the bladder was assessed using electrophoretic mobility shift assays (EMSAs). The expression of CRF was determined in Barrington's nucleus using in situ hybridization. Voiding dysfunction persisted for up to 6 months after stress exposure while mice recovered in single-cage housing. In the CsA reversal trial, voiding patterns improved when they received CsA in water during single-cage housing following stress, whereas those that underwent single-cage housing alone had persistent abnormal voiding (Fig. A). There was no difference between CRF levels in Barrington's nucleus between reversal groups (p = 0.42) (Fig. B), possibly indicating a direct effect on the bladder rather than a persistent stress effect. There were no differences in the contractility of bladder wall muscle. CsA decreased the nuclear translocation of MEF-2 and NFAT induced by stress (Fig. C,D). CsA reverses stress-induced urinary retention, but does not change the stress-induced CRF increase in Barrington's nucleus. Furthermore, bladder smooth muscle contractility is unchanged by CsA; however, there are changes in the levels of the downstream transcription factors MEF-2 and NFAT. We suspect that additional CsA responsive neural changes play a pivotal role in the abnormal voiding phenotype following social stress. Copyright © 2015 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

Is more lordosis associated with improved outcomes in cervical laminectomy and fusion when baseline alignment is lordotic?

PubMed

Sielatycki, John A; Armaghani, Sheyan; Silverberg, Arnold; McGirt, Matthew J; Devin, Clinton J; O'Neill, Kevin

2016-08-01

In cervical spondylotic myelopathy (CSM), cervical sagittal alignment (CSA) is associated with disease severity. Increased kyphosis and C2-C7 sagittal vertical axis (SVA) correlate with worse myelopathy and poor outcomes. However, when alignment is lordotic, it is unknown whether these associations persist. The study aimed to investigate the associations between CSA parameters and patient-reported outcomes (PROs) following posterior decompression and fusion for CSM when baseline lordosis is maintained. This is an analysis of a prospective surgical cohort at a single academic institution. The sample includes adult patients undergoing primary cervical laminectomy and fusion for CSM over a 3-year period. The PROs included EuroQol-5D, Short-Form-12 (SF-12) physical composite (PCS) and mental composite scales (MCS), Neck Disability Index, and the modified Japanese Orthopaedic Association scores. Radiographic CSA parameters measured included C1-C2 Cobb, C2-C7 Cobb, C1-C7 Cobb, C2-C7 SVA, C1-C7 SVA, and T1 slope. The PROs were recorded at baseline and at 3 and 12 months postoperatively. The CSA parameters were measured on standing radiographs in the neutral position at baseline and 3 months. Wilcoxon rank test was used to test for changes in PROs and CSA parameters, and Pearson correlation coefficients were calculated for CSA parameters and PROs preoperatively and at 12 months. No external sources of funding were used for this work. There were 45 patients included with an average age of 63 years who underwent posterior decompression and fusion of 3.7±1.3 levels. Significant improvements were found in all PROs except SF-12 MCS (p=.06). Small but statistically significant changes were found in C2-C7 Cobb (mean change: +3.6°; p=.03) and C2-C7 SVA (mean change: +3 mm; p=.01). At baseline, only C2-C7 SVA associated with worse SF-12 PCS scores (r=-0.34, p=.02). Postoperatively, there were no associations found between PROs and any CSA parameters. Similarly, no CSA parameters were associated with changes in PROs. Although creating more lordosis and decreasing SVA are associated with improved myelopathy and outcomes in patients with kyphosis, our study did not find such associationsin patients with lordosis undergoing posterior laminectomy and fusion for CSM. This suggests that any amount of lordosis may be sufficient. Copyright © 2016 Elsevier Inc. All rights reserved.

Evaluation of the in vitro activity of ceragenins against Trichomonas vaginalis.

PubMed

Polat, Zubeyde Akin; Cetin, Ali; Savage, Poul B

2016-03-01

Trichomonosis, caused by the protozoan parasite Trichomonas vaginalis, is a curable sexually transmitted disease that is most commonly encountered worldwide. Increasing importance of trichomoniasis and emerging of resistance against metronidazole lead to search for alternative drugs with different mode of activity. The purpose of this study was to determine in vitro activity of ceragenins (CSA-13, CSA-44, CSA-13, and CSA-138) against the metronidazole-susceptible (ATCC 30001) and metronidazole-resistant (ATCC 50138) strains of T. vaginalis. The effective concentrations were evaluated using two strains of T. vaginalis with different metronidazole susceptibilities (ATCC 30001 and ATCC 50138) in the presence of dilution series of ceragenins in 24-well microtitre assays. Overall, all the ceragenins killed the metronidazole-susceptible (ATCC 30001) and metronidazole-resistant (ATCC 50138) strains of T. vaginalis (p>0.05). With regard to the their effects against the studied strains of T. vaginalis, in order of effectiveness, overall, the ceragenins ordered as CSA-13 (the most effective), CSA-131 and CSA-138 (effective similarly), and CSA-44 (the least effective) (p<0.05). All of the ceragenins reduced the trophozoite numbers of both of studied strains of T. vaginalis with a time- and dose- dependent manner (p<0.05). Although all of the study ceragenins, CSA-13, CSA-44, CSA-13, and CSA-138, killed the studied strains of T. vaginalis. CSA-13 is the leading ceragenin as the most effective anti-trichomonas compound, followed by CSA-131 and CSA-138. They have a potential to have a place in the armemantarium of gynecologic and urologic practice for the management of sexually transmitted diseases.

Enhanced p122RhoGAP/DLC-1 Expression Can Be a Cause of Coronary Spasm

PubMed Central

Kinjo, Takahiko; Tanaka, Makoto; Osanai, Tomohiro; Shibutani, Shuji; Narita, Ikuyo; Tanno, Tomohiro; Nishizaki, Kimitaka; Ichikawa, Hiroaki; Kimura, Yoshihiro; Ishida, Yuji; Yokota, Takashi; Shimada, Michiko; Homma, Yoshimi; Tomita, Hirofumi; Okumura, Ken

2015-01-01

Background We previously showed that phospholipase C (PLC)-δ1 activity was enhanced by 3-fold in patients with coronary spastic angina (CSA). We also reported that p122Rho GTPase-activating protein/deleted in liver cancer-1 (p122RhoGAP/DLC-1) protein, which was discovered as a PLC-δ1 stimulator, was upregulated in CSA patients. We tested the hypothesis that p122RhoGAP/DLC-1 overexpression causes coronary spasm. Methods and Results We generated transgenic (TG) mice with vascular smooth muscle (VSM)-specific overexpression of p122RhoGAP/DLC-1. The gene and protein expressions of p122RhoGAP/DLC-1 were markedly increased in the aorta of homozygous TG mice. Stronger staining with anti-p122RhoGAP/DLC-1 in the coronary artery was found in TG than in WT mice. PLC activities in the plasma membrane fraction and the whole cell were enhanced by 1.43 and 2.38 times, respectively, in cultured aortic vascular smooth muscle cells from homozygous TG compared with those from WT mice. Immediately after ergometrine injection, ST-segment elevation was observed in 1 of 7 WT (14%), 6 of 7 heterozygous TG (84%), and 7 of 7 homozygous TG mice (100%) (p<0.05, WT versus TGs). In the isolated Langendorff hearts, coronary perfusion pressure was increased after ergometrine in TG, but not in WT mice, despite of the similar response to prostaglandin F2α between TG and WT mice (n = 5). Focal narrowing of the coronary artery after ergometrine was documented only in TG mice. Conclusions VSM-specific overexpression of p122RhoGAP/DLC-1 enhanced coronary vasomotility after ergometrine injection in mice, which is relevant to human CSA. PMID:26624289

Colon-targeted delivery of cyclosporine A using dual-functional Eudragit® FS30D/PLGA nanoparticles ameliorates murine experimental colitis.

PubMed

Naeem, Muhammad; Bae, Junhwan; Oshi, Murtada A; Kim, Min-Soo; Moon, Hyung Ryong; Lee, Bok Luel; Im, Eunok; Jung, Yunjin; Yoo, Jin-Wook

2018-01-01

Colon-targeted oral nanoparticles (NPs) have emerged as an ideal, safe, and effective therapy for ulcerative colitis (UC) owing to their ability to selectively accumulate in inflamed colonic mucosa. Cyclosporine A (CSA), an immunosuppressive agent, has long been used as rescue therapy in severe steroid-refractory UC. In this study, we developed CSA-loaded dual-functional polymeric NPs composed of Eudragit ® FS30D as a pH-sensitive polymer for targeted delivery to the inflamed colon, and poly(lactic-co-glycolic acid) (PLGA) as a sustained-release polymer. CSA-loaded Eudragit FS30D nanoparticles (ENPs), PLGA nanoparticles (PNPs), and Eudragit FS30D/PLGA nanoparticles (E/PNPs) were prepared using the oil-in-water emulsion method. Scanning electron microscope images and zeta size data showed successful preparation of CSA-loaded NPs. PNPs exhibited a burst drug release of >60% at pH 1.2 (stomach pH) in 0.5 h, which can lead to unwanted systemic absorption and side effects. ENPs effectively inhibited the burst drug release at pH 1.2 and 6.8 (proximal small intestine pH); however, nearly 100% of the CSA in ENPs was released rapidly at pH 7.4 (ileum-colon pH) owing to complete NP dissolution. In contrast to single-functional PNPs and ENPs, the dual-functional E/PNPs minimized burst drug release (only 18%) at pH 1.2 and 6.8, and generated a sustained release at pH 7.4 thereafter. Importantly, in distribution studies in the gastrointestinal tracts of mice, E/PNPs significantly improved CSA distribution to the colon compared with PNPs or ENPs. In a mouse model of colitis, E/PNP treatment improved weight loss and colon length, and decreased rectal bleeding, spleen weight, histological scoring, myeloperoxidase activity, macrophage infiltration, and expression of proinflammatory cytokines compared with PNPs or ENPs. Overall, this work confirms the benefits of CSA-loaded E/PNPs for efficiently delivering CSA to the colon, suggesting their potential for UC therapy.

Continuous spinal anaesthesia versus ultrasound-guided combined psoas compartment-sciatic nerve block for hip replacement surgery in elderly high-risk patients: a prospective randomised study.

PubMed

Aksoy, Mehmet; Dostbil, Aysenur; Ince, Ilker; Ahiskalioglu, Ali; Alici, Hacı Ahmet; Aydin, Ali; Kilinc, Osman Ozgur

2014-01-01

Our aim is to compare the hemodynamic effects of combined psoas compartment-sciatic nerve block (PCSNB) with continuous spinal anaesthesia (CSA) in elderly high-risk patients undergoing hip replacement surgery. Seventy patients over the age of 60 with ASA III or IV physical status were randomly allocated to two groups: In the PCSNB group, ultrasound-guided psoas compartment block was performed with modified Winnie technique using 30 mL of 0.25% bupivacaine with 1:200.000 epinephrine (5 μgr/mL) and iliac crest block was performed using the same local anaesthetic solution (5 mL). All patients in the PCSNB group needed continuing infusion of propofol (2 mg/kg/h) during operation. In the CSA group, CSA was performed in the L3-L4 interspaced with the patient in lateral decubitus position using 2.5 mg of isobaric bupivacaine 0.5%. When sensory block was not reached to the level of T12 within 10 minutes in the CSA group, additional 2.5 mg of isobaric bupivacaine 0.5% was administered through the catheter at 5-min intervals by limiting the total dose of 15 mg until a T12 level of the sensory block was achieved. The PCSNB group had significantly higher mean arterial blood pressure values at the beginning of surgery and at 5(th), 10(th) and 20(th) minutes of surgery compared to the CSA group (P = 0.038, P = 0.029, P = 0.012, P = 0.009 respectively). There were no significant differences between groups in terms of heart rate and peripheral oxygen saturation values during surgery and the postoperative period (P >0.05). Arterial hypotension required ephedrine was observed in 13 patients in the CSA and 4 patients in the PCSNB group (P =0.012). CSA and PCSNB produce satisfactory quality of anaesthesia in elderly high-risk patients with fewer hemodynamic changes in PCSNB cases compared with CSA cases. Australian New Zealand Clinical Trials Registry: ACTRN12614000658617, Registered 24 June 2014.

An exploration of associations between separation anxiety in childhood and complicated grief in later life.

PubMed

Vanderwerker, Lauren C; Jacobs, Selby C; Parkes, Colin Murray; Prigerson, Holly G

2006-02-01

Recent studies have suggested that the vulnerability to complicated grief (CG) may be rooted in insecure attachment styles developed in childhood. The aim of this study was to examine the etiologic relevance of childhood separation anxiety (CSA) to the onset of CG relative to major depressive disorder, posttraumatic stress disorder, and generalized anxiety disorder in bereaved individuals. The Structured Clinical Interview for the DSM-IV, Inventory of Complicated Grief-Revised, and CSA items from the Panic Agoraphobic Spectrum Questionnaire were administered to 283 recently bereaved community-dwelling residents at an average of 10.6 months postloss. CSA was significantly associated with CG (OR = 3.2; 95% CI, 1.2-8.9), adjusting for sex, level of education, kinship relationship to the deceased, prior history of psychiatric disorder, and history of childhood abuse. CSA was not significantly associated with major depressive disorder, posttraumatic stress disorder, or generalized anxiety disorder.

Formative assessment of GP trainees' clinical skills.

PubMed

Wiener-Ogilvie, Sharon; Begg, Drummond

2012-03-01

Clinical skill assessment (CSA) has been an integral part of the Royal College of General Practitioners' membership examination (MRCGP) since 2008. It is an expensive, high-stakes examination with first time pass rates ranging from 76.4 to 81.3. In this paper we describe the South East Scotland Deanery, NHS Education Scotland, pilot of a formative clinical skills assessment (fCSA) using the principles of formative assessment and OSCE. The purpose of the study was to assess the acceptability of the fCSA and to examine whether trainees, identified during the fCSA as 'at risk of failing the MRCGP CSA exam', are more likely to fail the MRCGP CSA exam later on in the year. Trainees were assessed in four clinical skills stations under exam conditions. After each station they were given verbal feedback and subsequently both trainee and their trainer received written feedback. We assessed the value of the exercise through written feedback from trainees and trainers. Each trainee's performance in fCSA was triangulated with trainer assessment to identify 'flagged trainees'. We compared flagged and non-flagged trainees' performance in MRCGP CSA. Both trainees and trainers highly rated the fCSA. Overall 97% of non-flagged trainees have passed the RCGP CSA exam by May of that year in comparison to 80% of flagged trainees who have passed the RCGP CSA (P = 0.005). Trainers and trainees rated the fCSA as excellent and useful. We were able to demonstrate that the fCSA can be used to identify those trainees likely to fail the RCGP CSA. Contrary to reservations about the potential to demoralise trainees, the fCSA was viewed as a useful and a positive experience by both trainees and trainers. In addition, we suggest that feedback from fCSA was useful in triggering appropriate educational interventions. Early intervention with trainees who are predicted to fail the CSA has the potential to reduce deaneries overall fail rate. Preventing one trainee failure could save over £30 000.

Best single time point correlations with AUC for cyclosporine and tacrolimus in HIV-infected kidney and liver transplant recipients.

PubMed

Frassetto, Lynda A; Tan-Tam, Clara C; Barin, Burc; Browne, Matt; Wolfe, Alan R; Stock, Peter G; Roland, Michelle; Benet, Leslie Z

2014-03-27

Interactions between antiretrovirals (ARVs) and transplant immunosuppressant agents (IS) among HIV-infected transplant recipients may lead to lack of efficacy or toxicity. In transplant recipients not infected with HIV, tacrolimus (TAC) trough levels (C0) or cyclosporine (CsA) drawn at C0 or 2 hours after dosing (C2) correlate with drug exposure (area under the curve [AUC]/dose) and outcomes. Because of ARV-IS interactions in HIV-infected individuals, and the high rate of rejection in these subjects, this study investigated the correlations between IS concentrations and exposure to determine the best method to monitor immunosuppressant levels. This study prospectively studied 50 HIV-infected transplant recipients undergoing kidney or liver transplantation evaluating the pharmacokinetics of the IS in 150 studies over time after transplantation (weeks 2 to 4, 12, 28, 52, and 104). IS levels were measured with liquid chromatography-tandem mass spectrometry and AUC calculated using WinNonlin 9.0. Correlation analyses were run on SAS 9.2. CsA concentration at C4 correlated better with AUC than C0 or C2, and over time TAC concentration correlated better at C0 or C2. It is suggested that C0 is acceptable for TAC monitoring, but poor predictability will occur at C0 with CsA. The low correlation of C0 with CsA AUC could be responsible for the higher rejection rates on CsA that has been reported in these subjects.

Psychiatric and physical sequelae of childhood physical and sexual abuse and forced sexual trauma among individuals with serious mental illness.

PubMed

Subica, Andrew M

2013-10-01

Trauma and posttraumatic stress disorder (PTSD) frequently co-occur with serious mental illness, yet the unique mental and physical health influences of childhood physical abuse (CPA), childhood sexual abuse (CSA), and forced sexual trauma on individuals with serious mental illness remain unevaluated. The present study of 172 individuals with serious mental illness investigated the adverse effects of CPA, CSA, and forced sexual trauma on severity of PTSD and depression, and overall mental and physical health functioning. Data analysis consisted of chi-square tests, independent t tests, bivariate odds ratios, and linear regressions. Prevalence of CPA (44.8%), CSA (29.1%), and forced sexual trauma (33.1%) were elevated, and nearly one third of participants (31.4%) reported clinical PTSD. Participants exposed to CSA or forced sexual trauma evidenced bivariate ORs ranging from 4.13 to 7.02 for PTSD, 2.44 to 2.50 for major depression, and 2.14 to 2.31 for serious physical illness/disability. Sexual trauma exposure associated with heightened PTSD and depression, and reduced mental and physical health functioning, with CSA uniquely predicting PTSD, depression, and physical health difficulties. CPA less significantly affected these clinical domains. Sexual traumas have profound negative effects on mental and physical health outcomes among individuals with serious mental illness; increased screening and treatment of sexual traumas is needed. Copyright © 2013 International Society for Traumatic Stress Studies.

Associations between body mass index, post-traumatic stress disorder, and child maltreatment in young women.

PubMed

Duncan, Alexis E; Sartor, Carolyn E; Jonson-Reid, Melissa; Munn-Chernoff, Melissa A; Eschenbacher, Michaela A; Diemer, Elizabeth W; Nelson, Elliot C; Waldron, Mary; Bucholz, Kathleen K; Madden, Pamela A F; Heath, Andrew C

2015-07-01

The objective of this study was to examine interrelationships between child maltreatment, post-traumatic stress disorder (PTSD) and body mass index (BMI) in young women. We used multinomial logistic regression models to explore the possibility that PTSD statistically mediates or moderates the association between BMI category and self-reported childhood sexual abuse (CSA), physical abuse (CPA), or neglect among 3,699 young women participating in a population-based twin study. Obese women had the highest prevalence of CSA, CPA, neglect, and PTSD (p<.001 for all). Although all three forms of child maltreatment were significantly, positively associated with overweight and obesity in unadjusted models, only CSA was significantly associated with obesity after adjusting for other forms of maltreatment and covariates (OR=2.21, 95% CI: 1.63, 3.00). CSA and neglect, but not CPA, were associated with underweight in unadjusted models; however, after adjusting for other forms of maltreatment and covariates, the associations were no longer statistically significant (OR=1.43, 95% CI: 0.90-2.28 and OR=2.16, 95% CI: 0.90-5.16 for CSA and neglect, respectively). Further adjustment for PTSD generally resulted in modest attenuation of effects across associations of child maltreatment forms with BMI categories, suggesting that PTSD may, at most, be only a weak partial mediator of these associations. Future longitudinal studies are needed to elucidate the mechanisms linking CSA and obesity and to further evaluate the role of PTSD in associations between child maltreatment and obesity. Copyright © 2015 Elsevier Ltd. All rights reserved.

Difficulties in estimating muscle forces from muscle cross-sectional area. An example using the psoas major muscle.

PubMed

Gatton, M L; Pearcy, M J; Pettet, G J

1999-07-15

Most biomechanical models use muscle cross-sectional area (CSA) as an indicator of maximum isometric muscle force. In general, there are multiple estimates of CSA for the same muscle. For example, numerous studies have estimated the CSA of the psoas major muscle using different subject populations and positions. However, few studies have combined the available information to obtain an overall estimate of CSA or investigated the effect different subject characteristics may have on CSA. In the present update, nine studies that reported psoas major CSA or physiologic CSA were compared with respect to subject characteristics, methodology, and results. Corrections to cadaveric data were made to adjust physiologic CSA to CSA. Comparison of reported values for living subjects indicated that females have smaller mean CSA than males for the psoas major muscle and that body size does not significantly influence muscle CSA in males. Areas derived from cadaveric data were smaller than similar studies on living subjects, possibly because of subject age, removal of tendinous and fatty components of fascicles, and lack of detailed data for fascicle angles in the supine position. Results indicate that researchers who use muscle CSA in biomechanical models should carefully assess the appropriateness of the data used, particularly in relation to potential sex differences and the influence of postural changes on CSA.

Prevalence of childhood sexual abuse and timing of disclosure in a representative sample of adults from Quebec.

PubMed

Hébert, Martine; Tourigny, Marc; Cyr, Mireille; McDuff, Pierre; Joly, Jacques

2009-09-01

Our study sought to explore patterns of disclosure of child sexual abuse (CSA) in a sample of adult men and women. A telephone survey conducted with a representative sample of adults (n = 804) from Quebec assessed the prevalence of CSA and disclosure patterns. Analyses were carried out to determine whether disclosure groups differed in terms of psychological distress and symptoms of posttraumatic stress, and a logistic regression was used to examine factors associated with prompt disclosure. Prevalence of CSA was 22.1% for women and 9.7% for men. About 1 survivor out of 5 had never disclosed the abuse, with men more likely not to have told anyone, than women. Only 21.2% of adults reported prompt disclosure (within a month of the first abusive event), while 57.5% delayed disclosure (more than 5 years after the first episode). CSA victims who never disclosed the abuse and those who delayed disclosure were more likely to obtain scores of psychological distress and posttraumatic stress achieving clinical levels, compared with adults without a history of CSA. In the multivariate analysis, experiencing CSA involving a perpetrator outside the immediate family and being female were factors independently associated with prompt disclosure. A significant number of adult women and men reported experiencing CSA, and most victims attested to either not disclosing or significantly delaying abuse disclosure.

Adults and Children in Low-Income Households that Participate in Cost-Offset Community Supported Agriculture Have High Fruit and Vegetable Consumption.

PubMed

Hanson, Karla L; Kolodinsky, Jane; Wang, Weiwei; Morgan, Emily H; Pitts, Stephanie B Jilcott; Ammerman, Alice S; Sitaker, Marilyn; Seguin, Rebecca A

2017-07-08

This paper examines fruit and vegetable intake (FVI) in low-income households that participated in a cost-offset (CO), or 50% subsidized, community-supported agriculture (CSA) program. CSA customers paid farms upfront for a share of the harvest, and received produce weekly throughout the growing season. A cohort of adults and children 2-12 y in a summer CO-CSA were surveyed online twice: August 2015 ( n = 41) and February 2016 ( n = 23). FVI was measured by the National Cancer Institute's (NCI) Fruit and Vegetable Screener (FVS) and an inventory of locally grown fruits and vegetables. FVI relative to United States (US) recommendations and averages, and across seasons, were tested with non-parametric tests and paired t -tests ( p < 0.05). Both adults and children in the CO-CSA had higher FVI than the US averages, and more often met recommendations for vegetables. Some summer fruits and vegetables were more often eaten when locally in-season. The CO-CSA model warrants further examination as an avenue for improving vegetable consumption among adults and children in low-income households. However, causality between CO-CSA participation and FVI cannot be inferred, as CO-CSA participants may be positive deviants with respect to FVI. A multi-state randomized controlled trial is currently underway to evaluate impacts of CO-CSAs on FVI and related outcomes.

Adults and Children in Low-Income Households That Participate in Cost-Offset Community Supported Agriculture Have High Fruit and Vegetable Consumption

PubMed Central

Hanson, Karla L.; Kolodinsky, Jane; Wang, Weiwei; Morgan, Emily H.; Jilcott Pitts, Stephanie B.; Ammerman, Alice S.; Sitaker, Marilyn; Seguin, Rebecca A.

2017-01-01

This paper examines fruit and vegetable intake (FVI) in low-income households that participated in a cost-offset (CO), or 50% subsidized, community-supported agriculture (CSA) program. CSA customers paid farms upfront for a share of the harvest, and received produce weekly throughout the growing season. A cohort of adults and children 2–12 y in a summer CO-CSA were surveyed online twice: August 2015 (n = 41) and February 2016 (n = 23). FVI was measured by the National Cancer Institute’s (NCI) Fruit and Vegetable Screener (FVS) and an inventory of locally grown fruits and vegetables. FVI relative to United States (US) recommendations and averages, and across seasons, were tested with non-parametric tests and paired t-tests (p < 0.05). Both adults and children in the CO-CSA had higher FVI than the US averages, and more often met recommendations for vegetables. Some summer fruits and vegetables were more often eaten when locally in-season. The CO-CSA model warrants further examination as an avenue for improving vegetable consumption among adults and children in low-income households. However, causality between CO-CSA participation and FVI cannot be inferred, as CO-CSA participants may be positive deviants with respect to FVI. A multi-state randomized controlled trial is currently underway to evaluate impacts of CO-CSAs on FVI and related outcomes. PMID:28698460

The ligand-binding profile of HARE: hyaluronan and chondroitin sulfates A, C, and D bind to overlapping sites distinct from the sites for heparin, acetylated low-density lipoprotein, dermatan sulfate, and CS-E.

PubMed

Harris, Edward N; Weigel, Paul H

2008-08-01

The hyaluronic acid receptor for endocytosis (HARE)/ Stabilin-2 is the primary systemic scavenger receptor for hyaluronan (HA), the chondroitin sulfates (CS), dermatan sulfate (DS), and nonglycosaminoglycan (GAG) ligands such as acetylated low-density lipoprotein (AcLDL), pro-collagen propeptides, and advanced glycation end products. We recently discovered that HARE is also a systemic scavenger receptor for heparin (Hep) (Harris EN, Weigel JA, Weigel PH. 2008. The human hyaluronan receptor for endocytosis [HARE/Stabilin-2] is a systemic clearance receptor for heparin. J Biol Chem. 283:17341-17350). Our goal was to map the binding sites of eight different ligands within HARE. We used biotinylated GAGs and radio-iodinated streptavidin or AcLDL to assess the binding activities of ligands directly or indirectly (by competition with unlabeled ligands) in endocytosis assays using stable cell lines expressing the 315 or 190 kDa HA receptor for endocytosis (315- or 190-HARE) isoforms, and ELISA-like assays, with purified recombinant soluble 190-HARE ecto-domain. For example, Hep binding to HARE was competed by DS, CS-E, AcLDL, and dextran sulfate, but not by other CS types, HA, dextran, or heparosan. (125)I-AcLDL binding to HARE was partially competed by Hep and dextran sulfate, but not competed by HA. Two ligands, DS and CS-E, competed with both Hep and HA to some degree. Hep and HA binding or endocytosis is mutually inclusive; binding of these two GAGs occurs with functionally separate, noncompetitive, and apparently noninteracting domains. Thus, HARE binds to HA and Hep simultaneously. Although the domain(s) responsible for Hep binding remains unknown, the Link domain was required for HARE binding to HA, CS-A, CS-C, and CS-D. These results enable us to outline, for the first time, a binding activity map for multiple ligands of HARE.

The ligand-binding profile of HARE: hyaluronan and chondroitin sulfates A, C, and D bind to overlapping sites distinct from the sites for heparin, acetylated low-density lipoprotein, dermatan sulfate, and CS-E

PubMed Central

Harris, Edward N.; Weigel, Paul H.

2008-01-01

The hyaluronic acid receptor for endocytosis (HARE)/ Stabilin-2 is the primary systemic scavenger receptor for hyaluronan (HA), the chondroitin sulfates (CS), dermatan sulfate (DS), and nonglycosaminoglycan (GAG) ligands such as acetylated low-density lipoprotein (AcLDL), pro-collagen propeptides, and advanced glycation end products. We recently discovered that HARE is also a systemic scavenger receptor for heparin (Hep) (Harris EN, Weigel JA, Weigel PH. 2008. The human hyaluronan receptor for endocytosis [HARE/Stabilin-2] is a systemic clearance receptor for heparin. J Biol Chem. 283:17341–17350). Our goal was to map the binding sites of eight different ligands within HARE. We used biotinylated GAGs and radio-iodinated streptavidin or AcLDL to assess the binding activities of ligands directly or indirectly (by competition with unlabeled ligands) in endocytosis assays using stable cell lines expressing the 315 or 190 kDa HA receptor for endocytosis (315- or 190-HARE) isoforms, and ELISA-like assays, with purified recombinant soluble 190-HARE ecto-domain. For example, Hep binding to HARE was competed by DS, CS-E, AcLDL, and dextran sulfate, but not by other CS types, HA, dextran, or heparosan. 125I-AcLDL binding to HARE was partially competed by Hep and dextran sulfate, but not competed by HA. Two ligands, DS and CS-E, competed with both Hep and HA to some degree. Hep and HA binding or endocytosis is mutually inclusive; binding of these two GAGs occurs with functionally separate, noncompetitive, and apparently noninteracting domains. Thus, HARE binds to HA and Hep simultaneously. Although the domain(s) responsible for Hep binding remains unknown, the Link domain was required for HARE binding to HA, CS-A, CS-C, and CS-D. These results enable us to outline, for the first time, a binding activity map for multiple ligands of HARE. PMID:18499864

Characterization of Five Fungal Endophytes Producing Cajaninstilbene Acid Isolated from Pigeon Pea [Cajanus cajan (L.) Millsp.

PubMed Central

Zu, Yuan Gang; Fu, Yu Jie; Wang, Wei; Luo, Meng; Efferth, Thomas

2011-01-01

Five fungal endophytes (K4, K5, K6, K9, K14) producing Cajaninstilbene acid (CSA, 3-hydroxy-4-prenyl-5-methoxystilbene-2-carboxylic acid) were isolated from the roots of pigeon pea [Cajanus cajan (L.) Millsp.]. CSA is responsible for the prominent pharmacological activities in pigeon pea. The amount of CSA in culture solution varied among the five fungal endophytes. K4 produced the highest levels of CSA (1037.13 µg/L) among the endophytes tested after incubation for five days. Both morphological characteristics and molecular methods were used for species identification of fungal endophytes. The five endophytic isolates were characterized by analyzing the internal transcribed spacer (ITS) rRNA and β-tubulin genes. The K4, K5, K9 and K14 strains isolated from pigeon pea roots were found to be closely related to the species Fusarium oxysporum. K6 was identified as Neonectria macrodidym. The present study is the first report on the isolation and identification of fungal endophytes producing CSA in pigeon pea. The study also provides a scientific base for large scale production of CSA. PMID:22102911

Cyclosporin A reduces matrix metalloproteinases and collagen expression in dermal fibroblasts from regenerative FOXN1 deficient (nude) mice

PubMed Central

2013-01-01

Background Cyclosporin A (CsA), an immunosuppressive agent modifies the wound healing process through an influence on extracellular matrix metabolism. We have compared the effects of CsA on dermal fibroblasts from nude (FOXN1 deficient) mice, a genetic model of skin scarless healing, and from control (C57BL/6 J (B6) mice to evaluate metabolic pathways that appear to have important roles in the process of scarless healing/regeneration. Results High levels of matrix metalloproteinases (MMPs) and collagen III expression in dermal fibroblasts from nude (regenerative) mice were down-regulated by CsA treatment to the levels observed in dermal fibroblasts from B6 (non-regenerative) mice. In contrast, dermal fibroblasts from control mice respond to CsA treatment with a minor reduction of Mmps mRNA and 2.5-fold increase expression of collagen I mRNA. An in vitro migratory assay revealed that CsA treatment profoundly delayed the migratory behavior of dermal fibroblasts from both nude and control mice. Conclusion The data suggest that by alternation of the accumulation of extracellular matrix components CsA treatment stimulates the transition from a scarless to a scar healing. PMID:23547542

[Effects of thymosin alpha1 on immune effector molecules of mouse].

PubMed

Li, Wei-ye; Lu, Hui-min; Guo, Qiang; Hu, Wei-ming; Zhang, Zhao-da

2014-05-01

To analysis the effects of Talpha1 on the immune effector molecules in mouse immune system. Sixty five BABL/c mice were divided into four groups: CsA group (n=20), Talpha1 group (n= 20), CsA+Talpha1 group (n=20) and control group (n=5). In the 3 experimental groups, 10 mg/kg CsA, 400 microg/ kg Talpha1, 10 mg/kg CsA+400 microg/kg Talpha1 were respectively administrated by intraperitoneal injection daily. Luminex was performed for cytokine detection at 1 d, 7 d, 14 d, 21 d day after the above treatments. Lymphocyte culture was prepared with the mouse spleen suspension, and then treated with 0. 25 mg/mL CsA, 10 microg/mL Talpha1 or 0.25 mg/mL CsA+10 microg/mL Talpha1 in vitro, respectively. Three days later, OD values of each treated lymphocyte culture and several cytokines in the culture were measured. Compared with other groups, CsA+Talpha1 group had significant lower IL-1alpha, IL-2, IL-6, IL-17, and significant higher IL-10 at 1 d, 7 d, 14 d, 21 d after the treatments (P < 0.05). Three days after the culture, OD value in the control group was significantly higher than that in Talppha1 group, CsA group, and CsA+ Talpha1 group (P < 0.05). IL-1alpa and IL-6 in the control group were significantly higher than those in the experiment groups (P < 0.05), while IL-10 in the control group was significantly lower than that in the experiment groups (P < 0.05). IL-2 and IL-17 were similar. Talpha1 show regulatory effect on the immune effector molecules which could promote Th1 cells transforming to Th2 cells.

Differences Between African-American and European-American Women in the Association of Childhood Sexual Abuse With Initiation of Marijuana Use and Progression to Problem Use.

PubMed

Sartor, Carolyn E; Agrawal, Arpana; Grant, Julia D; Duncan, Alexis E; Madden, Pamela A F; Lynskey, Michael T; Heath, Andrew C; Bucholz, Kathleen K

2015-07-01

Childhood sexual abuse (CSA) is associated with elevated risk of early marijuana use and cannabis use disorder (CUD). Both the prevalence of CSA and the course of marijuana use differ between African Americans and European Americans. The current study aimed to determine whether these differences manifest in racial/ ethnic distinctions in the association of CSA with early and problem use of marijuana. Data were derived from female participants in a female twin study and a high-risk family study of substance use (n = 4,193, 21% African-American). Cox proportional hazard regression analyses using CSA to predict initiation of marijuana use and progression to CUD symptom(s) were conducted separately by race/ethnicity. Sibling status on the marijuana outcome was used to adjust for familial influences. CSA was associated with both stages of marijuana use in African-American and European-American women. The association was consistent over the risk period (hazard ratio [HR] = 1.57, 95% confidence interval [CI] [1.37, 1.79] for initiation; HR = 1.51, 95% CI [1.21, 1.88] for CUD symptom onset) in European-American women. In African-American women, the HRs for initiation were 2.52 (95% CI [1.52, 4.18]) before age 15, 1.82 (95% CI [1.36, 2.44]) at ages 15-17, and nonsignificant after age 17. In the CUD symptom model, CSA predicted onset only at age 21 and older (HR = 2.17, 95% CI [1.31, 3.59]). The association of CSA with initiation of marijuana use and progression to problem use is stable over time in European-American women, but in African-American women, it varies by developmental period. Findings suggest the importance of considering race/ethnicity in prevention efforts with this high-risk population.

Differences Between African-American and European- American Women in the Association of Childhood Sexual Abuse With Initiation of Marijuana Use and Progression to Problem Use

PubMed Central

Sartor, Carolyn E.; Agrawal, Arpana; Grant, Julia D.; Duncan, Alexis E.; Madden, Pamela A. F.; Lynskey, Michael T.; Heath, Andrew C.; Bucholz, Kathleen K.

2015-01-01

Objective: Childhood sexual abuse (CSA) is associated with elevated risk of early marijuana use and cannabis use disorder (CUD). Both the prevalence of CSA and the course of marijuana use differ between African Americans and European Americans. The current study aimed to determine whether these differences manifest in racial/ ethnic distinctions in the association of CSA with early and problem use of marijuana. Method: Data were derived from female participants in a female twin study and a high-risk family study of substance use (n = 4,193, 21% African-American). Cox proportional hazard regression analyses using CSA to predict initiation of marijuana use and progression to CUD symptom(s) were conducted separately by race/ethnicity. Sibling status on the marijuana outcome was used to adjust for familial influences. Results: CSA was associated with both stages of marijuana use in African-American and European-American women. The association was consistent over the risk period (hazard ratio [HR] = 1.57, 95% confidence interval [CI] [1.37, 1.79] for initiation; HR = 1.51, 95% CI [1.21, 1.88] for CUD symptom onset) in European-American women. In African-American women, the HRs for initiation were 2.52 (95% CI [1.52, 4.18]) before age 15, 1.82 (95% CI [1.36, 2.44]) at ages 15–17, and nonsignificant after age 17. In the CUD symptom model, CSA predicted onset only at age 21 and older (HR = 2.17, 95% CI [1.31, 3.59]). Conclusions: The association of CSA with initiation of marijuana use and progression to problem use is stable over time in European-American women, but in African-American women, it varies by developmental period. Findings suggest the importance of considering race/ethnicity in prevention efforts with this high-risk population. PMID:26098032

Preservation of renal function during maintenance therapy with cyclosporine.

PubMed

Serón, D; Moreso, F

2004-03-01

During the last 20 years the management of cyclosporine (CsA) has improved due to the introduction of microemulsion technology, C2 monitoring, and combination with other new immunosuppressants. All these modifications have reduced the incidence of biopsy-proven acute rejection episodes to approximately 10%. However despite the wide experience, there are unanswered questions regarding CsA monitoring after the first year. Available clinical and histological data suggest that the therapeutic range to avoid nephrotoxicity or underimmunosuppression during the maintenance period is rather narrow. Furthermore, the combination of CsA with new immunosuppressants may modify the target CsA levels. Although the utility of C2 levels during the first year has been well characterized, there are few data on its utility for maintenance therapy, particularly the therapeutic range for C2 levels in patients receiving different immunosuppressive combinations. Since serum creatinine does not precisely reflect the progression of chronic allograft nephropathy, the efficacy of C2 monitoring during the maintenance period must be assessed not only by means of evaluation of renal function, but also histologic assessment using protocol biopsies.

CO 2 Dynamics in Pure and Mixed-Metal MOFs with Open Metal Sites

DOE PAGES

Marti, Robert M.; Howe, Joshua D.; Morelock, Cody R.; ...

2017-09-22

Metal–organic frameworks (MOFs), such as MOF-74, can have open metal sites to which adsorbates such as CO 2 preferentially bind. 13C NMR of 13CO 2 is highly informative about the binding sites present in Mg-MOF-74. We used this technique to investigate loadings between ~0.88 and 1.15 molecules of CO 2 per metal in Mg-MOF-74 at 295 K. 13C lineshapes recorded as a function of loading can be understood in terms of the dependence of the CO 2 NMR frequency on the angle (θ) with respect to the CO 2 axis and the channel of the MOF, reflected in the Legendremore » polynomial, P 2. In the fast motion limit, the NMR spectra reveal the time-averaged value of P 2, where θ is the angle between the instantaneous CO 2 axis and the channel axis. DFT calculations were used to determine a weighted average of P 2 in this regime and are in good agreement with experimental data. Static variable temperature 13C NMR from cryogenic temperatures to room temperature was used to investigate 13CO 2 binding in Mg-MOF-74 loaded at two levels (~0.88 and 1.08 molecules of CO 2 per metal), revealing temperature-dependent lineshapes. We have investigated the effect of partial substitution of Cd for Mg in Mg-MOF-74 on the 13CO 2 variable temperature NMR spectra. The chemical shift anisotropy (CSA) that leads to characteristic lineshapes of 13C indicates that incorporation of Cd leads to weaker binding energies for adsorbed CO 2.« less

CO 2 Dynamics in Pure and Mixed-Metal MOFs with Open Metal Sites

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marti, Robert M.; Howe, Joshua D.; Morelock, Cody R.

Metal–organic frameworks (MOFs), such as MOF-74, can have open metal sites to which adsorbates such as CO 2 preferentially bind. 13C NMR of 13CO 2 is highly informative about the binding sites present in Mg-MOF-74. We used this technique to investigate loadings between ~0.88 and 1.15 molecules of CO 2 per metal in Mg-MOF-74 at 295 K. 13C lineshapes recorded as a function of loading can be understood in terms of the dependence of the CO 2 NMR frequency on the angle (θ) with respect to the CO 2 axis and the channel of the MOF, reflected in the Legendremore » polynomial, P 2. In the fast motion limit, the NMR spectra reveal the time-averaged value of P 2, where θ is the angle between the instantaneous CO 2 axis and the channel axis. DFT calculations were used to determine a weighted average of P 2 in this regime and are in good agreement with experimental data. Static variable temperature 13C NMR from cryogenic temperatures to room temperature was used to investigate 13CO 2 binding in Mg-MOF-74 loaded at two levels (~0.88 and 1.08 molecules of CO 2 per metal), revealing temperature-dependent lineshapes. We have investigated the effect of partial substitution of Cd for Mg in Mg-MOF-74 on the 13CO 2 variable temperature NMR spectra. The chemical shift anisotropy (CSA) that leads to characteristic lineshapes of 13C indicates that incorporation of Cd leads to weaker binding energies for adsorbed CO 2.« less

Heavy metal contents of road-deposited sediment along the urban-rural gradient around Beijing and its potential contribution to runoff pollution.

PubMed

Zhao, Hongtao; Li, Xuyong; Wang, Xiaomei

2011-09-01

Understanding the contribution of road-deposited sediment (RDS) and its washoff process is essential for controlling urban runoff pollution. Ninety-seven RDS samples were collected along the urban-suburban-rural gradient from areas of five administrative units in the Beijing metropolitan region, including central urban (UCA), urban village (UVA), central suburban county (CSA), rural town (RTA), and rural village (RVA) areas. RDS washoff was evaluated with different particle sizes using a rainfall simulator. Heavy metal elements (i.e., Cr, Cu, Ni, Pb, and Zn) were estimated in both RDS and runoff samples. The RDS mass per unit area increased in the order UCA (21 ± 24 g/m(2)) ≈ CSA (20 ± 16 g/m(2)) < RTA (59 ± 63 g/m(2)) < RVA (147 ± 112 g/m(2)) ≈ UVA (147 ± 198 g/m(2)). Compared to RDS from the other administrative units, RDS from the UCA and CSA had higher metal concentrations and higher proportions of smaller particles, whereas that from the RVA and UVA had larger quantities of metals per unit area. UCA and CSA had lower potential runoff pollution contributions per unit area. Our findings imply that controlling the first flush in the UCA and CSA, and improving existing street cleaning methods and road surface conditions in the TRA, UVA, and RVA will be appropriate strategies for controlling runoff pollution from RDS.

A comparison between EDA-EnVar and ETKF-EnVar data assimilation techniques using radar observations at convective scales through a case study of Hurricane Ike (2008)

NASA Astrophysics Data System (ADS)

Shen, Feifei; Xu, Dongmei; Xue, Ming; Min, Jinzhong

2017-07-01

This study examines the impacts of assimilating radar radial velocity (Vr) data for the simulation of hurricane Ike (2008) with two different ensemble generation techniques in the framework of the hybrid ensemble-variational (EnVar) data assimilation system of Weather Research and Forecasting model. For the generation of ensemble perturbations we apply two techniques, the ensemble transform Kalman filter (ETKF) and the ensemble of data assimilation (EDA). For the ETKF-EnVar, the forecast ensemble perturbations are updated by the ETKF, while for the EDA-EnVar, the hybrid is employed to update each ensemble member with perturbed observations. The ensemble mean is analyzed by the hybrid method with flow-dependent ensemble covariance for both EnVar. The sensitivity of analyses and forecasts to the two applied ensemble generation techniques is investigated in our current study. It is found that the EnVar system is rather stable with different ensemble update techniques in terms of its skill on improving the analyses and forecasts. The EDA-EnVar-based ensemble perturbations are likely to include slightly less organized spatial structures than those in ETKF-EnVar, and the perturbations of the latter are constructed more dynamically. Detailed diagnostics reveal that both of the EnVar schemes not only produce positive temperature increments around the hurricane center but also systematically adjust the hurricane location with the hurricane-specific error covariance. On average, the analysis and forecast from the ETKF-EnVar have slightly smaller errors than that from the EDA-EnVar in terms of track, intensity, and precipitation forecast. Moreover, ETKF-EnVar yields better forecasts when verified against conventional observations.

Trajectories of Childhood Sexual Abuse and Early Adolescent HIV/AIDS Risk Behaviors: The Role of Other Maltreatment, Witnessed Violence, and Child Gender

PubMed Central

Jones, Deborah J.; Runyan, Desmond K.; Lewis, Terri; Litrownik, Alan J.; Black, Maureen M.; Wiley, Tisha; English, Diana E.; Proctor, Laura J.; Jones, Bobby L.; Nagin, Daniel S.

2013-01-01

Childhood sexual abuse (CSA) has been associated with HIV/AIDS risk behavior; however, much of this work is retrospective and focuses on women. The current study used semiparametric mixture modeling with youth (n = 844; 48.8% boys) from the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN) to examine the link between trajectories of CSA (2 to 12 y.o.) and HIV/AIDS risk behavior at age 14 (i.e., sexual intercourse & alcohol use). Trajectory analyses revealed a link between a history of CSA and the development of risky behavior. In addition, trajectories for physical and emotional abuse, but not neglect or witnessed violence, contributed to risky behavior over and above the role of CSA. Child gender did not moderate the findings. Findings highlight the signficance of CSA histories, as well as the broader context of maltreatment, for better understanding the development of risk behaviors in both girls and boys. PMID:20706919

Knockdown endogenous CypA with siRNA in U2OS cells results in disruption of F-actin structure and alters tumor phenotype.

PubMed

Calhoun, Colonya C; Lu, Ying-Chun; Song, Jun; Chiu, Robert

2009-01-01

Cyclophilin A (CypA) was originally identified as a cytosolic protein possessing peptidyl-prolyl isomerase activity. CypA has been shown to play a pivotal role in the immune response, but little is known about other molecular mechanisms of CypA-mediated biologic events. In our present study, we demonstrate that knockdown CypA expression using RNAi in U2OS cells resulted in disruption of the F-actin structure, as well as decreased anchorage-independent growth, proliferation, and migration. Wild-type U2OS cells treated with cyclosporine A (CsA), a peptidyl-prolyl isomerase inhibitor, displayed the same phenotype as knockdown CypA cells, suggesting that the isomerase activity of CypA is required to maintain a normal phenotype. In vitro and in vivo binding assays revealed that CypA binds to N-WASP, which functions in the nucleation of actin via the Arp2/3 complex. Pulse-chase labeling study indicated an enhanced degradation of N-WASP in cell lacking CypA, suggesting that CypA is required for stabilizing N-WASP to form a N-WASP/Arp2/3 complex for the nucleation/initiation of F-actin polymerization.

A novel bioerodible deep scleral lamellar cyclosporine implant for uveitis.

PubMed

Gilger, Brian C; Salmon, Jacklyn H; Wilkie, David A; Cruysberg, Lars P J; Kim, Jonghyeon; Hayat, Matt; Kim, Hyuncheol; Kim, Stephanie; Yuan, Peng; Lee, Susan S; Harrington, Susan M; Murray, Patrick R; Edelhauser, Henry F; Csaky, Karl G; Robinson, Michael R

2006-06-01

To determine the feasibility, safety, and effectiveness of an episcleral or deep scleral lamellar sustained release cyclosporine (CsA) device in a naturally occurring animal model of uveitis. A two-compartment perfusion chamber was used to assess in vitro human and equine scleral permeability of fluorescein, dexamethasone-fluorescein, or CsA. A biodegradable, matrix-reservoir CsA implant was designed, and release rates of CsA were determined in vitro. Tissue CsA levels were measured in eyes with the implant. Horses with equine recurrent uveitis (ERU) received episcleral or deep scleral lamellar CsA implants and were monitored for up to 3 years. Dexamethasone-fluorescein and CsA penetrated the in vitro equine sclera poorly; however, low but detectable levels of CsA were detected intraocularly in vivo. The implant placed episclerally failed to control inflammatory episodes in ERU. CsA implants placed in the deep sclera adjacent to the suprachoroidal space resulted in high levels of CsA in most ocular tissues. In clinical equine patients with ERU, frequency of uveitic flare-ups was significantly decreased after implantation of a deep scleral lamellar CsA implant. Diffusion of CsA across the sclera from the episcleral space was not a feasible method of drug delivery to the equine eye. However, placing a deep scleral lamellar CsA implant adjacent to the suprachoroidal space was effective in achieving therapeutic ocular drug concentrations and controlling uveitis in horses with ERU.

Pharmacological Cyclophilin Inhibitors Prevent Intoxication of Mammalian Cells with Bordetella pertussis Toxin.

PubMed

Ernst, Katharina; Eberhardt, Nina; Mittler, Ann-Katrin; Sonnabend, Michael; Anastasia, Anna; Freisinger, Simon; Schiene-Fischer, Cordelia; Malešević, Miroslav; Barth, Holger

2018-05-01

The Bordetella pertussis toxin (PT) is one important virulence factor causing the severe childhood disease whooping cough which still accounted for approximately 63,000 deaths worldwide in children in 2013. PT consists of PTS1, the enzymatically active (A) subunit and a non-covalently linked pentameric binding/transport (B) subunit. After endocytosis, PT takes a retrograde route to the endoplasmic reticulum (ER), where PTS1 is released into the cytosol. In the cytosol, PTS1 ADP-ribosylates inhibitory alpha subunits of trimeric GTP-binding proteins (Giα) leading to increased cAMP levels and disturbed signalling. Here, we show that the cyclophilin (Cyp) isoforms CypA and Cyp40 directly interact with PTS1 in vitro and that Cyp inhibitors cyclosporine A (CsA) and its tailored non-immunosuppressive derivative VK112 both inhibit intoxication of CHO-K1 cells with PT, as analysed in a morphology-based assay. Moreover, in cells treated with PT in the presence of CsA, the amount of ADP-ribosylated Giα was significantly reduced and less PTS1 was detected in the cytosol compared to cells treated with PT only. The results suggest that the uptake of PTS1 into the cytosol requires Cyps. Therefore, CsA/VK112 represent promising candidates for novel therapeutic strategies acting on the toxin level to prevent the severe, life-threatening symptoms caused by PT.

Trypsin inhibitors from Capsicum baccatum var. pendulum leaves involved in Pepper yellow mosaic virus resistance.

PubMed

Moulin, M M; Rodrigues, R; Ribeiro, S F F; Gonçalves, L S A; Bento, C S; Sudré, C P; Vasconcelos, I M; Gomes, V M

2014-11-07

Several plant organs contain proteinase inhibitors, which are produced during normal plant development or are induced upon pathogen attack to suppress the enzymatic activity of phytopathogenic microorganisms. In this study, we examined the presence of proteinase inhibitors, specifically trypsin inhibitors, in the leaf extract of Capsicum baccatum var. pendulum inoculated with PepYMV (Pepper yellow mosaic virus). Leaf extract from plants with the accession number UENF 1624, which is resistant to PepYMV, was collected at 7 different times (0, 24, 48, 72, 96, 120, and 144 h). Seedlings inoculated with PepYMV and control seedlings were grown in a growth chamber. Protein extract from leaf samples was partially purified by reversed-phase chromatography using a C2/C18 column. Residual trypsin activity was assayed to detect inhibitors followed by Tricine-SDS-PAGE analysis to determine the N-terminal peptide sequence. Based on trypsin inhibitor assays, trypsin inhibitors are likely constitutively synthesized in C. baccatum var. pendulum leaf tissue. These inhibitors are likely a defense mechanism for the C. baccatum var. pendulum- PepYMV pathosystem.

Shortened Time to Identify Staphylococcus Species from Blood Cultures and Methicillin Resistance Testing Using CHROMAgar

PubMed Central

Chihara, Shingo; Hayden, Mary K.; Minogue-Corbett, Eileen; Singh, Kamaljit

2009-01-01

The ability to rapidly differentiate coagulase-negative staphylococcus (CoNS) from Staphylococcus aureus and to determine methicillin resistance is important as it affects the decision to treat empiric antibiotic selection. The objective of this study was to evaluate CHROMagar S. aureus and CHROMagar MRSA (Becton Dickinson) for rapid identification of Staphylococcus spp. directly from blood cultures. Consecutive blood culture bottles (BacT Alert 3D SA and SN, bioMérieux) growing gram-positive cocci in clusters were evaluated. An aliquot was plated onto CHROMagar MRSA (C-MRSA) and CHROMagar S. aureus (C-SA) plates, which were read at 12 to 16 hours. C-SA correctly identified 147/147 S. aureus (100% sensitivity); 2 CoNS were misidentified as S. aureus (98% specificity). C-MRSA correctly identified 74/77 MRSA (96% sensitivity). None of the MSSA isolates grew on C-MRSA (100% specificity). In conclusion, CHROMagar is a rapid and sensitive method to distinguish MRSA, MSSA, and coagulase-negative Staphylococcus and may decrease time of reporting positive results. PMID:20016679

Selective training-induced thigh muscles hypertrophy in professional road cyclists.

PubMed

Hug, François; Marqueste, Tanguy; Le Fur, Yann; Cozzone, Patrick J; Grélot, Laurent; Bendahan, David

2006-07-01

Muscular adaptations linked to a high volume and intensity of training have been scarcely reported. We aimed at documenting, using MRI, the cross-sectional area changes associated with a high volume and intensity of training in 11 thigh muscles of a population of professional road cyclists as compared with sport science students. We were also interested in determining, whether selective muscle hypertrophy in professional road cyclists, if any, was correlated to selective exercise-induced T (2) changes during a pedaling exercise on a cycloergometer. Cross-sectional area of 11 thigh muscles was quantified in sixteen subjects (i.e. eight professional road cyclists and eight sport science students) using MRI. In addition, transverse relaxation times (T (2)) were measured before and just after a maximal standardized constant-load exercise in order to investigate exercise-related T (2) changes in these muscles. Professional road cyclists had a significantly higher relative amount of muscle (including the whole set of thigh muscles, 90.5+/-3.3%) as compared to controls (81.6+/-7.3%). Regarding relative values expressed with respect to the total thigh muscles CSA, Vastus lateralis and Biceps femoris CSA were significantly larger in cyclists whereas CSA of the Vastus intermedius was smaller. However, this selective hypertrophy was not correlated to the exercise-induced T (2)-increase. We have reported, for the first time, a selective hypertrophy of Vastus lateralis and Biceps femoris in professional road cyclists confirming their involvement in pedaling task and suggesting a possible cause-effect relationship between muscle activation and hypertrophy, associated with a specific pedaling skill.

78 FR 79423 - Energy Efficiency Program for Industrial Equipment: Petition of CSA Group for Classification as a...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-30

.... Evaluation and Testing CSA Group with the manufacturer's assistance prepares a motor control list...-0053] Energy Efficiency Program for Industrial Equipment: Petition of CSA Group for Classification as a...: This notice announces receipt of a petition from CSA Group (CSA) seeking classification as a nationally...

Association between vertebral cross-sectional area and lumbar lordosis angle in adolescents

PubMed Central

Aggabao, Patricia C.; Poorghasamians, Ervin; Chavez, Thomas A.

2017-01-01

Lumbar lordosis (LL) is more prominent in women than in men, but the mechanisms responsible for this discrepancy are poorly defined. A recent study indicates that newborn girls have smaller vertebral cross-sectional area (CSA) when compared to boys—a difference that persists throughout life and is independent of body size. We determined the relations between vertebral cross-sectional area (CSA) and LL angle and whether sex differences in lumbar lordosis are related to sex differences in vertebral CSA. Using multi-planar magnetic resonance imaging (MRI), we measured vertebral cross-sectional area (CSA) and vertebral height of the spine of 40 healthy boys and 40 girls, ages 9–13 years. Measures of the CSA of the lumbar vertebrae significantly differed between sexes (9.38 ± 1.46 vs. 7.93 ± 0.69 in boys and girls, respectively; P < 0.0001), while the degree of LL was significantly greater in girls than in boys (23.7 ± 6.1 vs. 27.6 ± 8.0 in boys and girls, respectively; P = 0.02). When all subjects were analyzed together, values for LL angle were negatively correlated to vertebral CSA (r = -0.47; P < 0.0001); this was also true when boys and girls were analyzed separately. Multivariate regression analysis indicated that vertebral CSA was independently associated with LL, even after accounting for sex, age, height or vertebral height, and weight. Similar negative relations were present when thoracic vertebrae were analyzed (Model P < 0.0001, R2 = 0.37, thoracic vertebral CSA slope P < 0.0001), suggesting that deficient vertebral cross-sectional dimensions are not merely the consequence of the anterior lumbar curvature. We conclude that vertebral CSA is negatively associated with LL, and that the greater degree of LL in females could, at least in part, be due to smaller vertebral cross-sectional dimensions. Studies are needed to examine the potential relations between vertebral CSA and spinal conditions known to be associated with increased LL, such as spondylolysis and spondylolisthesis. PMID:28245271

Human skeletal muscle fibre contractile properties and proteomic profile: adaptations to 3 weeks of unilateral lower limb suspension and active recovery.

PubMed

Brocca, Lorenza; Longa, Emanuela; Cannavino, Jessica; Seynnes, Olivier; de Vito, Giuseppe; McPhee, Jamie; Narici, Marco; Pellegrino, Maria Antonietta; Bottinelli, Roberto

2015-12-15

It is generally assumed that muscle fibres go through atrophy following disuse with a loss of specific force and an increase in unloaded shortening velocity. However, the underlying mechanisms remain to be clarified. Most studies have focused on events taking place during the development of disuse, whereas the subsequent recovery phase, which is equally important, has received little attention. Our findings support the hypotheses that the specific force of muscle fibres decreased following unilateral lower limb suspension (ULLS) and returned to normal after 3 weeks of active recovery as a result of a loss and recovery of myosin and actin content. Furthermore, muscle fibres went through extensive qualitative changes in muscle protein pattern following ULLS, and these were reversed by active recovery. Resistance training was very effective in restoring both muscle mass and qualitative muscle changes, indicating that long-term ULLS did not prevent the positive effect of exercise on human muscle. Following disuse, muscle fibre function goes through adaptations such as a loss of specific force (PO /CSA) and an increase in unloaded shortening velocity, which could be a result of both quantitative changes (i.e. atrophy) and qualitative changes in protein pattern. The underlying mechanisms remain to be clarified. In addition, little is known about the recovery of muscle mass and strength following disuse. In the present study, we report an extensive dataset describing, in detail,the functional and protein content adaptations of skeletal muscle in response to both disuse and re-training. Eight young healthy subjects were subjected to 3 weeks of unilateral lower limb suspension (ULLS), a widely used human model of disuse skeletal muscle atrophy. Needle biopsies samples were taken from the vastus lateralis muscle Pre-ULLS, Post-ULLS and after 3 weeks of recovery during which heavy resistance training was performed. After disuse, cross-sectional area (CSA), PO /CSA and myosin concentration (MC) decreased in both type 1 and 2A skinned muscle fibres. After recovery, CSA and MC returned to levels comparable to those observed before disuse, whereas Po/CSA and unloaded shortening velocity reached a higher level. Myosin heavy chain isoform composition of muscle samples did not differ among the experimental groups. To study the mechanisms underlying such adaptations, a two-dimensional proteomic analysis was performed. ULLS induced a reduction of myofibrillar, metabolic (glycolytic and oxidative) and anti-oxidant defence system protein content. Resistance training was very effective in counteracting ULLS-induced alterations, indicating that long-term ULLS did not prevent the positive effect of exercise on human muscle. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Semi-nonparametric VaR forecasts for hedge funds during the recent crisis

NASA Astrophysics Data System (ADS)

Del Brio, Esther B.; Mora-Valencia, Andrés; Perote, Javier

2014-05-01

The need to provide accurate value-at-risk (VaR) forecasting measures has triggered an important literature in econophysics. Although these accurate VaR models and methodologies are particularly demanded for hedge fund managers, there exist few articles specifically devoted to implement new techniques in hedge fund returns VaR forecasting. This article advances in these issues by comparing the performance of risk measures based on parametric distributions (the normal, Student’s t and skewed-t), semi-nonparametric (SNP) methodologies based on Gram-Charlier (GC) series and the extreme value theory (EVT) approach. Our results show that normal-, Student’s t- and Skewed t- based methodologies fail to forecast hedge fund VaR, whilst SNP and EVT approaches accurately success on it. We extend these results to the multivariate framework by providing an explicit formula for the GC copula and its density that encompasses the Gaussian copula and accounts for non-linear dependences. We show that the VaR obtained by the meta GC accurately captures portfolio risk and outperforms regulatory VaR estimates obtained through the meta Gaussian and Student’s t distributions.

[Local cyclosporin A therapy of nummuli after epidemic keratoconjunctivitis--case report].

PubMed

Reinhard, T; Sundmacher, R

1997-03-01

Steroid therapy for persistent or recurrent nummular adenoviral keratoconjunctivitis (AK) has little benefit because of the frequent recurrences, and mostly "offers" only serious steroid side effects. Since January 1995, we have treated different patients with nummuli after AK with topical Ciclosporin A (CSA) in an attempt to achieve at least the same symptomatic effect as with steroids, however, without side effects. Here, we report about our experiences in a very severe case with longterm treatment. The patient was sent to our clinic 4 months after AK with confluent nummuli and Descemet folds, more severe in the right than in the left eye. Best corrected visual acuity was 0.05 in the right and 0.5 in the left eye. Topical CSA 2% 4 times daily was first administered only in the right eye. When after 6 weeks a reduction of nummuli was noted in the right eye, the left eye, which had not improved, was started on the same regime. Therapy was tapered and finally stopped after 12 months in the right and 10 months in the left eye, when only minor changes were left in the corneae. A prompt recurrence of nummuli in both eyes within 4 weeks forced us to resume CSA therapy. At present, both corneae are clear with full vision, and this result is stable with 1 drop of CSA daily. No side effects of CSA therapy have been noted. The disappearance of nummuli with topical CSA and even more the reappearance of nummuli after cessation of CSA therapy show that topical CSA is about as effective as topical steroids in the symptomatic treatment of non-scarred nummuli after KE without the serious steroid side effects. Topical CSA treatment of nummuli after KE is, therefore, a very recommendable alternative for the potentially dangerous steroid therapy. Generally valid data on risk of recurrences, dosage and general effectiveness could only be learned from prospective studies with large numbers of AK patients, which, however, are not available outside epidemics.

Muscle Torque Relative to Cross-Sectional Area and the Functional Muscle-Bone Unit in Children and Adolescents with Chronic Disease

PubMed Central

Lee, Dale Y.; Wetzsteon, Rachel J.; Zemel, Babette S.; Shults, Justine; Organ, Jason M.; Foster, Bethany J.; Herskovitz, Rita M.; Foerster, Debbie L.; Leonard, Mary B.

2015-01-01

Measures of muscle mass or size are often used as surrogates of forces acting on bone. However, chronic diseases may be associated with abnormal muscle force relative to muscle size. The muscle-bone unit was examined in 64 children and adolescents with new-onset Crohn’s disease (CD), 54 with chronic kidney disease (CKD), 51 treated with glucocorticoids for nephrotic syndrome (NS), and 264 healthy controls. Muscle torque was assessed by isometric ankle dynamometry. Calf muscle cross-sectional area (CSA) and tibia cortical section modulus (Zp) were assessed by quantitative CT. Log-linear regression was used to determine the relations among muscle CSA, muscle torque, and Zp, adjusted for tibia length, age, Tanner stage, sex, and race. Muscle CSA and muscle torque-relative-to-muscle CSA were significantly lower than controls in advanced CKD (CSA −8.7%, p = 0.01; torque −22.9%, p < 0.001) and moderate-to-severe CD (CSA −14.1%, p < 0.001; torque −7.6%, p = 0.05), but not in NS. Zp was 11.5% lower in advanced CKD (p = 0.005) compared to controls, and this deficit was attenuated to 6.7% (p = 0.05) with adjustment for muscle CSA. With additional adjustment for muscle torque and body weight, Zp was 5.9% lower and the difference with controls was no longer significant (p = 0.09). In participants with moderate-to-severe CD, Zp was 6.8% greater than predicted (p = 0.01) given muscle CSA and torque deficits (R2=0.92), likely due to acute muscle loss in newly diagnosed patients. Zp did not differ in NS, compared with controls. In conclusion, muscle torque relative to muscle CSA was significantly lower in CKD and CD, compared with controls, and was independently associated with Zp. Future studies are needed to determine if abnormal muscle strength contributes to progressive bone deficits in chronic disease, independent of muscle area. PMID:25264231

[The impact of childhood sexual abuse on the development of AIDS related high risk behaviors and psychological appearances among men who have sex with men].

PubMed

Yu, Zeng-Zhao; Zhang, Bei-Chuan; Li, Xiu-Fang; Wang, Ning; Shi, Tong-Xin; Chu, Quan-Sheng

2009-01-01

To study the AIDS related high risk behaviors and psychological appearances among men who have sex with men (MSM) who ever experienced childhood sexual abuse (CSA). Target sampling for a cross-sectional study was developed and valid anonymous questionnaires were adopted to compare the differences of high risk behaviors related to AIDS and psychological appearances between those with or without CSA experiences among 2147 MSM from nine cities. Compared to corresponding ones without CSA experience, CSA group had a significant larger numbers in the following events: total sexual partners, anal sex episodes with same sex, female sexual partners and anal sex in the previous six months, with the figures of median as 20.0, 10.0, 3.0, 3.0 respectively. In the previous year, 30.8% of them had ever participated in 'group sex', 19.2% ever exchanged money for sex, 36.7% bled while having sexual intercourse, 37.3% had sex with male partners away from his own region. All the above said figures were higher than non-CSA group, with significant differences. It also appeared that CSA experience had an impact on significant lower rate of condom use (67.3%) in the last anal sex. Those with CSA experience had more psychological problems which appeared as: 75.6% considered they would suffer from serious discrimination if their sexual orientation ever disclosed, 34.7% had a strong intention of suicide and 24.3% ever having had suicidal attempts. The differences of the two groups showed statistical significance. CSA experience not only increased the number of AIDS related high risk behaviors in adulthood, but also had negative impact on their psychological appearances. It is of urgent need to carry out psychological intervention approaches to target on MSM with CSA experiences while childhood sexual education and rights assurance towards juvenile population should also not be neglected.

[Treatment of transfusion-dependent nonsevere aplastic anemia with cyclosporine A plus ATG/ALG versus cyclosporine A plus androgens: a retrospective single center study].

PubMed

Song, L; Peng, G X; Wu, Z J; Zhang, L; Jing, L P; Zhou, K; Li, Y; Li, Y; Ye, L; Li, J P; Fan, H H; Zhao, X; Yang, W R; Yang, Y; Zhang, F K

2016-11-14

Objective: To determine whether cyclosporine A (CsA) plus androgens was as effective as the current standard immunosuppressive therapy (IST) for transfusion-dependent nonsevere aplastic anemia (TD-NSAA). Methods: The records of 125 consecutive TD-NSAA patients who were treated between Aug. 2007 and Sept. 2014, with either CsA plus androgen or ALG/ATG plus CsA regimen were reviewed. The 3-month and 6-month hematologic responses and survival were evaluated. Results: There were 125 TD-NSAA patients (70 were male and 55 female, 1.25∶1). Median age was 27 (6-66) years. There was no significant difference in early mortality between 48 treated by ATG/ALG plus CsA and 77 by CsA plus androgen patients (1/48 vs 0/77, P =0.384). Both the total hematologic response and the better hematological response rates at 3-month (70.8% vs 45.5%, P =0.006 and 27.1% vs 10.4%, P =0.015, respectively) and 6-month (75.0% vs 55.8%, P =0.031 and 41.7% vs 22.1% P =0.020, respectively) after treatment were much higher in the standard IST group than that in CsA plus androgen group. The median time to transfusion independent of 36.5 (0-149) days in the standard IST group was significantly shorter than 98 (14-180) days in CsA plus androgen group ( P <0.001). Survival was comparable between the two groups (97.9% vs 100.0%, P =0.227). It was superior (71.2% vs 59.5%) but not significantly ( P =0.227) in event-free survival in standard IST group. Conclusions: CsA plus androgen was inferior to the standard IST of ATG/ALG and CsA regimen in treating TD-NSAA in terms of the hematologic response and the quality of response, despite of comparable short-term survival.

Childhood sexual abuse and HIV-related risks among men who have sex with men in Washington, DC.

PubMed

Phillips, Gregory; Magnus, Manya; Kuo, Irene; Rawls, Anthony; Peterson, James; Montanez, Luz; West-Ojo, Tiffany; Jia, Yujiang; Opoku, Jenevieve; Greenberg, Alan E

2014-05-01

Childhood sexual abuse (CSA) has been reported to be disproportionately higher among men who have sex with men (MSM) than among heterosexual men; it has also been found to be significantly positively associated with HIV status and HIV risk factors, including unprotected anal intercourse. The purpose of this study was to assess the correlates of CSA in a sample of community-recruited MSM, investigate race as a potential effect modifier, and describe the independent association between CSA and HIV infection in Washington, DC. A total of 500 MSM were recruited by venue-based sampling in 2008 as part of the National HIV Behavioral Surveillance. More than one-half of MSM identified as White, while one-third identified as Black. CSA was reported by 17.5 % of the 451 MSM, with the first instance of abuse occurring at a median age of 8.3 (interquartile range = 5.0, 11.0). In multivariable analysis, HIV-positive men were significantly more likely to report a history of CSA compared to HIV-negative men after adjusting for intimate partner violence in the last 12 months, having been arrested in the last 12 months, and depressive symptoms. HIV-positive MSM had more than four times the odds of reporting CSA after controlling for other correlates (aOR = 4.19; 95 % CI 2.26, 7.75). Despite hypothesizing that race modified the effect of CSA on HIV infection we found this was not the case in this sample. More research is needed to investigate the potential pathway between a history of CSA and HIV infection, and how this contributes to driving the HIV epidemic among MSM in Washington, DC.

Amorphous solid dispersion of cyclosporine A prepared with fine droplet drying process: Physicochemical and pharmacokinetic characterization.

PubMed

Suzuki, Hiroki; Moritani, Tatsuru; Morinaga, Tadahiko; Seto, Yoshiki; Sato, Hideyuki; Onoue, Satomi

2017-03-15

The present study aimed to develop an amorphous solid dispersion (ASD) of cyclosporine A (CsA) by a fine droplet drying (FDD) process for improvement in oral absorption of CsA. CsA and hydroxypropyl cellulose-SSL were dissolved in 1,4-dioxane, and the solution was powdered by the FDD process to obtain the ASD formulation of CsA (ASD/CsA). The ASD/CsA was characterized in terms of morphology, particle size distribution, crystallinity, dissolution behavior, physicochemical stability, and pharmacokinetic behavior in rats. The ASD/CsA was obtained in the form of uniform spherical particles, and the span factor was calculated to be ca. 0.4. CsA in the formulation existed in an amorphous state. The ASD/CsA exhibited a higher dissolution behavior of CsA than amorphous CsA, whereas storage of the ASD/CsA under accelerated conditions led to impairment in the dissolution behavior. The constant release of CsA from non-aged ASD/CsA was observed during dissolution testing. After oral administration of CsA samples (10mg-CsA/kg) in rats, the ASD/CsA showed a high and sustained plasma concentration of CsA as evidenced by a 18-fold increase in the oral bioavailability of CsA compared with amorphous CsA. From these findings, the FDD process might be an efficacious option for the ASD formulation of CsA with enhanced biopharmaceutics properties. Copyright © 2017 Elsevier B.V. All rights reserved.

Sprinting performance on the Woodway Curve 3.0 is related to muscle architecture.

PubMed

Mangine, Gerald T; Fukuda, David H; Townsend, Jeremy R; Wells, Adam J; Gonzalez, Adam M; Jajtner, Adam R; Bohner, Jonathan D; LaMonica, Michael; Hoffman, Jay R; Fragala, Maren S; Stout, Jeffrey R

2015-01-01

To determine if unilateral measures of muscle architecture in the rectus femoris (RF) and vastus lateralis (VL) were related to (and predictive of) sprinting speed and unilateral (and bilateral) force (FRC) and power (POW) during a 30 s maximal sprint on the Woodway Curve 3.0 non-motorized treadmill. Twenty-eight healthy, physically active men (n = 14) and women (n = 14) (age = 22.9 ± 2.4 years; body mass = 77.1 ± 16.2 kg; height = 171.6 ± 11.2 cm; body-fa t = 19.4 ± 8.1%) completed one familiarization and one 30-s maximal sprint on the TM to obtain maximal sprinting speed, POW and FRC. Muscle thickness (MT), cross-sectional area (CSA) and echo intensity (ECHO) of the RF and VL in the dominant (DOM; determined by unilateral sprinting power) and non-dominant (ND) legs were measured via ultrasound. Pearson correlations indicated several significant (p < 0.05) relationships between sprinting performance [POW (peak, DOM and ND), FRC (peak, DOM, ND) and sprinting time] and muscle architecture. Stepwise regression indicated that POW(DOM) was predictive of ipsilateral RF (MT and CSA) and VL (CSA and ECHO), while POW(ND) was predictive of ipsilateral RF (MT and CSA) and VL (CSA); sprinting power/force asymmetry was not predictive of architecture asymmetry. Sprinting time was best predicted by peak power and peak force, though muscle quality (ECHO) and the bilateral percent difference in VL (CSA) were strong architectural predictors. Muscle architecture is related to (and predictive of) TM sprinting performance, while unilateral POW is predictive of ipsilateral architecture. However, the extent to which architecture and other factors (i.e. neuromuscular control and sprinting technique) affect TM performance remains unknown.

Diverse Functional Outcomes of Plasmodium falciparum Ligation of EPCR: Potential Implications for Malarial Pathogenesis

PubMed Central

Gillrie, Mark R.; Avril, Marion; Brazier, Andrew J.; Davis, Shevaun P.; Stins, Monique F.; Smith, Joseph D.; Ho, May

2015-01-01

Summary P. falciparum-infected erythrocytes (IRBC) expressing the domain cassettes (DC) 8 and 13 of the cytoadherent ligand PfEMP1 adhere to the endothelial protein C receptor (EPCR). By interfering with EPCR anti-coagulant and pro-endothelial barrier functions, IRBC adhesion could promote coagulation and vascular permeability that contribute to the pathogenesis of cerebral malaria. In this study, we examined adhesion of DC8- and DC13-expressing parasite lines to endothelial cells from different microvasculature, and the consequences of EPCR engagement on endothelial cell function. We found that IRBC from IT4var19 (DC8) and IT4var07 (DC13) parasite lines adhered to human brain, lung, and dermal endothelial cells under shear stress. However, the relative contribution of EPCR to parasite cytoadherence on the different types of endothelial cell varied. We also observed divergent functional outcomes for DC8 CIDRα1.1 and DC13 CIDRα1.4 domains. IT4var07 CIDRα1.4 inhibited generation of activated protein C (APC) on lung and dermal endothelial cells and blocked the APC-EPCR binding interaction on brain endothelial cells. IT4var19 CIDRα1.1 inhibited thrombin-induced endothelial barrier dysfunction in lung endothelial cells, while IT4var07 CIDRα1.4- inhibited the protective effect of APC on thrombin-induced permeability. Overall, these findings reveal a much greater complexity of how CIDRα1-expressing parasites may modulate malaria pathogenesis through EPCR adhesion. PMID:26119044

Parental Discussion of Child Sexual Abuse: Is It Associated with the Parenting Practices of Involvement, Monitoring, and General Communication?

PubMed

Rudolph, Julia; Zimmer-Gembeck, Melanie J; Shanley, Dianne C; Walsh, Kerrryann; Hawkins, Russell

2018-01-01

We investigated whether parents who reported more positive parenting practices (i.e., monitoring, involvement, and communication) reported more discussion of child sexual abuse (CSA) with their children. Parents from Australia and the UK (N = 248), with children aged 6 to 11 years, completed an online survey. About half of parents reported directly discussing CSA, whereas 35% reported telling their children that CSA perpetrators may be family members. Rates of discussion were higher for other CSA-related topics such as body integrity and abduction. Correlational analyses showed that parents who reported speaking to their children about CSA also reported more positive parenting practices, more discussion of other sensitive topics, and assessed CSA risk for children (in general) to be higher. Discussion of CSA risk was not associated with parents' CSA knowledge, confidence or appraisal of own-child risk. Parents higher in positive parenting believed their children to be at less CSA risk. Parents who appraised higher own-child risk reported less positive parenting practices and were less confident about their parenting and their ability to protect their children from CSA. The findings are the first to report on the associations of parenting practices with parents' CSA discussion with their children.

Prevalence of childhood sexual abuse in a community sample of Australian women.

PubMed

Fleming, J M

1997-01-20

To ascertain the prevalence of childhood sexual abuse (CSA) in a community sample of Australian women. Retrospective study, done in 1994, of cross-sectional data on the prevalence of CSA, collected as part of a larger two-stage case-control study of the possible relationship between CSA and alcohol abuse. Data were appropriately weighted to adjust for the different selection probabilities of cases and controls. 710 Women randomly selected from Australian federal electoral rolls. One hundred and forty-four women (20%) had experienced CSA. In 14 of these 144 women (10%), the abuse involved either vaginal or anal intercourse (i.e., 2% of the sample population experienced such abuse). The mean age at first episode of CSA was 10 years, and most (71%) of the women were aged under 12 years at the time. Perpetrators of the abuse were usually male (98%) and usually known to the child; 41% were relatives. The mean age of abusers was 34 years, with a median age difference of 24 years from that of the abused individual. Only 10% of CSA experiences were ever reported to the police, a doctor or a helping agency (e.g., community organisations, such as sexual assault services). The high rates of CSA (estimated to be 20% of all women) and low rates of reporting (10%) indicate the need for general practitioners and other health professionals to be aware that a history of such abuse may be common in women in the general population.

Prediction of warmed-over flavour development in cooked chicken by colorimetric sensor array.

PubMed

Kim, Su-Yeon; Li, Jinglei; Lim, Na-Ri; Kang, Bo-Sik; Park, Hyun-Jin

2016-11-15

The aim of this study was to develop a simple and rapid method based on colorimetric sensor array (CSA) for evaluation of warmed-over flavour (WOF) in cooked chicken. All samples were classified according to storage time by CSA coupled with principle component analysis (PCA) or hierarchical cluster analysis (HCA). The CSA data were used to establish prediction models with thiobarbituric acid reactive substances (TBARS), pentanal, hexanal, or heptanal associated with WOF by partial least square regression (PLSR). For the TBARS model, the coefficient of determination (rp(2)) was 0.9997 in the prediction range of 0.28-0.69mg/kg. In each of the models for pentanal, hexanal, and heptanal, all rp(2) were higher than 0.960 in the range of 0.58-2.10mg/kg, 5.50-11.69mg/kg, and 0.09-0.16mg/kg, respectively. These results demonstrate that the CSA was able to predict WOF development and to distinguish between each storage time. Copyright © 2016 Elsevier Ltd. All rights reserved.

Phytochemical characterization of several hawthorn (Crataegus spp.) species sampled from the Eastern Mediterranean region of Turkey.

PubMed

Calişkan, Oğuzhan; Gündüz, Kazim; Serçe, Sedat; Toplu, Celil; Kamiloğlu, Onder; Sengül, Memnune; Ercişli, Sezai

2012-01-01

We evaluated the total phenolic content, antioxidant capacity as well as antioxidant activity of five Crataegus species (A1, A2, Y1, Y2, Y4 accessions of Crataegus aronia var. aronia; B2, B3, B5, B6, B7, B9, Y5 accessions of C. aronia var. dentata; B10 accession of C. aronia var. minuta; Y3 accession of Crataegus orientalis var. orientalis and A3 accession of Crataegus monogyna subsp. azarella). Antioxidant activity and total phenolic content of fruits were determined by β-carotene bleaching and Folin-Ciocalteu assays. Antioxidant capacity was determined by using 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. C. monogyna subsp. azarella had the highest total phenol, antioxidant activity and antioxidant capacity of 55.2 mg gallic acid equivalents (GAE)/g dry weight (DW), 81.9% and 31.2%, respectively. C. aronia var. aronia was found to have the lowest total phenolic content (35.7 mg GAE/g DW). The antioxidant activities of fruit extracts increased in the order of C. orientalis var. orientalis < C. aronia var. minuta < C. aronia var. dentata < C. aronia var. aronia < C. monogyna subsp. azarella according to β-carotene/linoleic acid assay. In recent years, C. aronia var. dentata has gained importance as a commercial species in this region. B3 and B7 accessions had fruit weight more than 14 g, and considerable total phenol content, antioxidant activity and antioxidant capacity. This investigation shows the potential value of hawthorn fruit species as a good source of natural antioxidants and that consumption of hawthorn fruit or its products may contribute substantial amounts of antioxidants to the diet.

Phytochemical characterization of several hawthorn (Crataegus spp.) species sampled from the Eastern Mediterranean region of Turkey

PubMed Central

Çalişkan, Oğuzhan; Gündüz, Kazim; Serçe, Sedat; Toplu, Celil; Kamiloğlu, Önder; Şengül, Memnune; Ercişli, Sezai

2012-01-01

Background: We evaluated the total phenolic content, antioxidant capacity as well as antioxidant activity of five Crataegus species (A1, A2, Y1, Y2, Y4 accessions of Crataegus aronia var. aronia; B2, B3, B5, B6, B7, B9, Y5 accessions of C. aronia var. dentata; B10 accession of C. aronia var. minuta; Y3 accession of Crataegus orientalis var. orientalis and A3 accession of Crataegus monogyna subsp. azarella). Materials and Methods: Antioxidant activity and total phenolic content of fruits were determined by β-carotene bleaching and Folin–Ciocalteu assays. Antioxidant capacity was determined by using 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. Results: C. monogyna subsp. azarella had the highest total phenol, antioxidant activity and antioxidant capacity of 55.2 mg gallic acid equivalents (GAE)/g dry weight (DW), 81.9% and 31.2%, respectively. C. aronia var. aronia was found to have the lowest total phenolic content (35.7 mg GAE/g DW). The antioxidant activities of fruit extracts increased in the order of C. orientalis var. orientalis < C. aronia var. minuta < C. aronia var. dentata < C. aronia var. aronia < C. monogyna subsp. azarella according to β-carotene/linoleic acid assay. In recent years, C. aronia var. dentata has gained importance as a commercial species in this region. B3 and B7 accessions had fruit weight more than 14 g, and considerable total phenol content, antioxidant activity and antioxidant capacity. Conclusion: This investigation shows the potential value of hawthorn fruit species as a good source of natural antioxidants and that consumption of hawthorn fruit or its products may contribute substantial amounts of antioxidants to the diet. PMID:22438658

Effect of a new functional CYP3A4 polymorphism on calcineurin inhibitors' dose requirements and trough blood levels in stable renal transplant patients.

PubMed

Elens, Laure; van Schaik, Ron H; Panin, Nadtha; de Meyer, Martine; Wallemacq, Pierre; Lison, Dominique; Mourad, Michel; Haufroid, Vincent

2011-10-01

CYP3A4 is involved in the oxidative metabolism of many drugs and xenobiotics including the immunosuppressants tacrolimus (Tac) and cyclosporine (CsA). The objective of the study was to assess the potential influence of a new functional SNP in CYP3A4 on the pharmacokinetic parameters assessed by dose requirements and trough blood levels of both calcineurin inhibitors (CNI) in stable renal transplant patients. A total of 99 stable renal transplant patients receiving either Tac (n = 49) or CsA (n = 50) were genotyped for the CYP3A4 intron 6 C>T (rs35599367) and CYP3A5*3 SNPs. Trough blood levels ([Tac](0) or [CsA](0) in ng/ml), dose-adjusted [Tac](0) or [CsA](0) (ng/ml per mg/kg bodyweight) as well as doses (mg/kg bodyweight) required to achieve target concentrations were compared among patients according to allelic status for CYP3A4 and CYP3A5. Dose-adjusted concentrations were 2.0- and 1.6-fold higher in T-variant allele carriers for the CYP3A4 intron 6 C>T SNP compared with homozygous CC for Tac and CsA, respectively. When CYP3A4/CYP3A5 genotypes were combined, the difference was even more striking as the so-defined CYP3A poor metabolizer group presented dose-adjusted concentration 1.6- and 4.1-fold higher for Tac, and 1.5- and 2.2-fold higher for CsA than the intermediate metabolizer and extensive metabolizer groups, respectively. Multiple linear regression analysis revealed that, taken together, both CYP3A4 intron 6 and CYP3A5*3 SNPs explained more than 60 and 20% of the variability observed in dose-adjusted [Tac](0) and [CsA](0), respectively. The CYP3A4 intron 6 C>T polymorphism is associated with altered Tac and CsA metabolism. CYP3A4 intron 6 C>T along with CYP3A5*3 (especially for Tac) pharmacogenetic testing performed just before transplantation may help identifying patients at risk of CNI overexposure and contribute to limit CNI-related nephrotoxicity by refining the starting dose according to their genotype. Original submitted 5 May 2011; Revision submitted 29 June 2011.

Fat Attenuation at CT in Anorexia Nervosa

PubMed Central

Gill, Corey M.; Torriani, Martin; Murphy, Rachel; Harris, Tamara B.; Miller, Karen K.; Klibanski, Anne

2016-01-01

Purpose To investigate the composition, cross-sectional area (CSA), and hormonal correlates of different fat depots in women with anorexia nervosa (AN) and control subjects with normal weights to find out whether patients with AN have lower fat CSA but higher attenuation than did control subjects and whether these changes may be mediated by gonadal steroids, cortisol, and thyroid hormones. Materials and Methods This study was institutional review board approved and HIPAA compliant. Written informed consent was obtained. Forty premenopausal women with AN and 40 normal-weight women of comparable age (mean age ± standard deviation, 26 years ± 5) were studied. All individuals underwent computed tomography of the abdomen and thigh with a calibration phantom. Abdominal subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), thigh SAT, and thigh intermuscular adipose tissue CSA and attenuation were quantified. Serum estradiol, thyroid hormones, and urinary free cortisol levels were assessed. Variables were compared by using analysis of variance. Associations were examined by using linear regression analysis. Results Women with AN had higher fat attenuation than did control subjects (−100.1 to −46.7 HU vs −117.6 to −61.8 HU, P < .0001), despite lower fat CSA (2.0–62.8 cm2 vs 5.5–185.9 cm2, P < .0001). VAT attenuation but not CSA was inversely associated with lowest prior lifetime body mass index in AN (r = −0.71, P = .006). Serum estradiol levels were inversely associated with fat attenuation (r = −0.34 to −0.61, P = .03 to <.0001) and were positively associated with fat CSA of all compartments (r = 0.42–0.64, P = .007 to <.0001). Thyroxine levels and urinary free cortisol levels were positively associated with thigh SAT attenuation (r = 0.64 [P = .006] and r = 0.68 [P = .0004], respectively) and were inversely associated with abdominal SAT and VAT CSA (r = −0.44 to −0.58, P = .04 to .02). Conclusion Women with AN have differences in fat composition, with higher fat attenuation than that of control subjects, as well as low fat mass. VAT attenuation but not CSA is inversely associated with lowest prior lifetime body mass index, suggesting that fat attenuation may serve as a biomarker of prior and current disease status in AN. © RSNA, 2015 PMID:26509295

Skeletal muscle stem cell characteristics and myonuclei content in patients with rheumatoid arthritis: a cross-sectional study.

PubMed

Boutrup, Rasmus Jentoft; Farup, Jean; Vissing, Kristian; Kjaer, Michael; Mikkelsen, Ulla Ramer

2018-06-01

To investigate satellite cells (SCs) and myonuclei characteristics in patients with rheumatoid arthritis (RA). Resting biopsies from m. vastus lateralis were obtained from thirteen RA patients and thirteen matched healthy controls (CON). Muscle biopsies were immunohistochemically stained and analyzed for fiber type specific content of SCs (Pax7 + ), proliferating SCs (Pax7 + /MyoD + ) and differentiating SCs (myogenin + ). Furthermore, we quantified fiber type specific content of myonuclei and myofiber cross-sectional area (CSA). Finally, newly formed/regenerating fibers expressing neonatal MHC (nMHC + ) were determined. The fiber type specific number of SCs did not differ between RA patients and CON, nor did the content of proliferating or differentiating SCs. In contrast, the content of myonuclei per fiber was higher in RA patients than CON for both type I (2.01 ± 0.41 vs. 1.42 ± 0.40 myonuclei/fiber, p < 0.01) and type II fibers (2.01 ± 0.41 vs. 1.37 ± 0.32 myonuclei/fiber, p < 0.01). No differences were observed in fiber composition, fiber type specific CSA or content of nMHC + fibers. Our results indicate an increased propensity for myogenic differentiation of SC leading to an elevated myonuclear content in the skeletal muscle of RA patients. It is hypothesized that this could be a compensatory regulatory response related to the chronic inflammation in these patients.

Sleep-disordered breathing in patients with atrial fibrillation and normal systolic left ventricular function.

PubMed

Bitter, Thomas; Langer, Christoph; Vogt, Jürgen; Lange, Mathias; Horstkotte, Dieter; Oldenburg, Olaf

2009-03-01

Obstructive sleep apnea (OSA) is more common in patients with atrial fibrillation (AFib). Recently, an additional association between central sleep apnea/Cheyne-Stokes respiration (CSA/CSR) and AFib has been described. The aim of this study was to investigate the prevalence and type of sleep-disordered breathing in patients with AFib and normal systolic left ventricular function. 150 patients (110 men and 40 women, aged 66.1 +/- 1.7 years) underwent cardiorespiratory polygraphy, capillary blood gas analysis, measurement of NT-proBNP, and echocardiography to determine the diameter of the left atrium (LAD) and the peak systolic pulmonary artery pressure (PAP). Sleep-disordered breathing was documented in 74% of all patients with AFib (43% had OSA and 31% had CSA/CSR). Patients with CSA/CSR had a higher PAP, a higher apnea-hypopnea index, a greater LAD, and a lower capillary blood pCO(2) than patients with OSA. Patients with AFib were found to have not only a high prevalence of obstructive sleep apnea, as has been described previously, but also a high prevalence of CSA/CSR. It remains unknown whether CSA/CSR is more common in AFib because of diastolic dysfunction or whether phenomena associated with CSA/CSR predispose to AFib. Further research on this question is needed.

Administration of cyclosporin A to recipients improves the potential of mouse somatic cell nuclear-transferred oocytes to develop to fetuses.

PubMed

Tsuji, Yuta; Kato, Yoko; Tsunoda, Yukio

2012-08-01

Somatic cell nuclear-transferred (SCNT) oocytes have a high potential for development in vitro, but a large proportion of embryos that are transferred to recipients is aborted before parturition. The precise mechanism for the high abortion rate is unknown, but abnormal placenta formation is frequently observed in SCNT-cloned pregnancies. The present study examined the effects of treating the recipients with cyclosporin A (CsA), an immunoprotectant, on the proportion of fetuses resulting from SCNT-cloned pregnancies. Cloned embryos developed from enucleated oocytes and receiving cumulus cells from F1 (C57BL/6 × DBA, H-2b/d) females were transferred to outbred ICR (in which the H-2 complex was not fixed) recipient females. Each recipient received an intraperitoneal injection of CsA or vehicle. Compared with vehicle, administration of CsA to recipients on day 4.5 of pregnancy significantly increased the proportion of fetuses observed on day 10.5. The proportion of fetuses at day 18.5 of pregnancy in recipients receiving CsA treatment was slightly higher than that in controls. This study is the first to report that CsA administration increases the proportion of fetuses resulting from SCNT-cloned pregnancies.

Sleep apnea and cardiovascular risk.

PubMed

Floras, John S

2014-01-01

Sleep apnea is evident in approximately 10% of adults in the general population, but in certain cardiovascular diseases, and in particular those characterized by sodium and water retention, its prevalence can exceed 50%. Although sleep apnea is not as yet integrated into formal cardiovascular risk assessment algorithms, there is increasing awareness of its importance in the causation or promotion of hypertension, coronary artery disease, heart failure, atrial arrhythmias, and stroke, and thus, not surprisingly, as a predictor of premature cardiovascular death. Sleep apnea manifests as two principal phenotypes, both characterized by respiratory instability: obstructive (OSA), which arises when sleep-related withdrawal of respiratory drive to the upper airway dilator muscles is superimposed upon a narrow and highly compliant airway predisposed to collapse, and central (CSA), which occurs when the partial pressure of arterial carbon dioxide falls below the apnea threshold, resulting in withdrawal of central drive to respiratory muscles. The present objectives are to: (1) review the epidemiology and patho-physiology of OSA and CSA, with particular emphasis on the role of renal sodium retention in initiating and promoting these processes, and on population studies that reveal the long-term consequences of untreated OSA and CSA; (2) illustrate mechanical, autonomic, chemical, and inflammatory mechanisms by which OSA and CSA can increase cardiovascular risk and event rates by initiating or promoting hypertension, atherosclerosis, coronary artery disease, heart failure, arrhythmias, and stroke; (3) highlight insights from randomized trials in which treating sleep apnea was the specific target of therapy; (4) emphasize the present lack of evidence that treating sleep apnea reduces cardiovascular risk and the current clinical equipoise concerning treatment of asymptomatic patients with sleep apnea; and (5) consider clinical implications and future directions of clinical research and practice. Copyright © 2013. Published by Elsevier Ltd.

(R)-[¹¹C]Emopamil as a novel tracer for imaging enhanced P-glycoprotein function.

PubMed

Toyohara, Jun; Okamoto, Mayumi; Aramaki, Hiroki; Zaitsu, Yuto; Shimizu, Isao; Ishiwata, Kiichi

2016-01-01

2-Isopropyl-5-[methyl-(2-phenylethyl)amino]-2-phenylpentanenitrile (emopamil; EMP) is a calcium channel blocker of the phenylalkylamine class, with weak substrate properties for P-glycoprotein (P-gp). A weak substrate for P-gp would be suitable for measuring enhanced P-gp function. This study was performed to synthesise (R)- and (S)-[(11)C]EMP and characterise their properties as P-gp tracers. We synthesised (R)- and (S)-[(11)C]EMP and compared their biodistribution, peripheral metabolism, and effects of the P-gp inhibitor cyclosporine A (CsA, 50 mg/kg). We compared the brain pharmacokinetics of (R)-[(11)C]EMP and (R)-[(11)C]verapamil [(R)-[(11)C]VER] at baseline and CsA pretreatment with small animal positron emission tomography (PET). (R)- and (S)-[(11)C]EMP were synthesised from (R)- and (S)-noremopamil, respectively, by methylation with [(11)C]methyl triflate in the presence of NaOH at room temperature. (R)- and (S)-[(11)C]EMP yields were ~30%, with specific activity>74 GBq/μmol and radiochemical purity>99%. (R)-[(11)C]EMP showed significantly greater uptake in the mouse brain than (S)-[(11)C]EMP. Both showed homogeneous non-stereoselective regional brain distributions. (R)- and (S)-[(11)C]EMP were rapidly metabolised to hydrophilic metabolites. Unchanged plasma (S)-[(11)C]EMP level was significantly lower than that of (R)-[(11)C]EMP 15 minutes post-injection, whilst>88% of radioactivity in the brain was intact at 15 minutes post-injection and was non-stereoselective. CsA pretreatment increased brain activity ~3-fold in mice, but was non-stereoselective. The baseline area-under-the-curve (AUC) of brain radioactivity (0-60 minutes) of (R)-[(11)C]EMP was 2-fold higher than that of (R)-[(11)C]VER, but their AUCs after CsA pretreatment were comparable. (R)-[(11)C]EMP is a novel tracer for imaging P-gp function with higher baseline uptake than (R)-[(11)C]VER. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of stabilization training on multifidus muscle cross-sectional area among young elite cricketers with low back pain.

PubMed

Hides, Julie A; Stanton, Warren R; McMahon, Shaun; Sims, Kevin; Richardson, Carolyn A

2008-03-01

A single-blinded, pretreatment-posttreatment assessment. To investigate, using ultrasound imaging, the cross-sectional area (CSA) of the lumbar multifidus muscle at 4 vertebral levels (L2, L3, L4, L5) in elite cricketers with and without low back pain (LBP) and (2) to document the effect of a staged stabilization training program on multifidus muscle CSA. Despite high fitness levels and often intensive strength training programs, athletes still suffer LBP. The incidence of LBP among Australian cricketers is 8% and as high as 14% among fast bowlers. Previous researchers have found that the multifidus muscle contributes to segmental stability of the lumbopelvic region; however, the CSA of this muscle has not been previously assessed in elite cricketers. CSAs of the multifidus muscles were assessed at rest on the left and right sides for 4 vertebral levels at the start and completion of a 13-week cricket training camp. Participants who reported current or previous LBP were placed in a rehabilitation group. The stabilization program involved voluntary contraction of the multifidus, transversus abdominis, and pelvic floor muscles, with real-time feedback from rehabilitative ultrasound imaging (RUSI), progressed from non-weight-bearing to weight-bearing positions and movement training. Pain scores (using a visual analogue scale) were also collected from those with LBP. The CSAs of the multifidus muscles at the L5 vertebral level increased for the 7 cricketers with LBP who received the stabilization training, compared with the 14 cricketers without LBP who did not receive rehabilitation (P = .004). In addition, the amount of muscle asymmetry among those with LBP significantly decreased (P = .029) and became comparable to cricketers without LBP. These effects were not evident for the L2, L3, and L4 vertebral levels. There was also a 50% decrease in the mean reported pain level among the cricketers with LBP. Multifidus muscle atrophy can exist in highly active, elite athletes with LBP. Specific retraining resulted in an improvement in multifidus muscle CSA and this was concomitant with a decrease in pain. Therapy, level 2b.

Mitochondria-targeted therapies for acute kidney injury.

PubMed

Tábara, Luis Carlos; Poveda, Jonay; Martin-Cleary, Catalina; Selgas, Rafael; Ortiz, Alberto; Sanchez-Niño, Maria D

2014-08-08

Acute kidney injury (AKI) is a serious clinical condition with no effective treatment. Tubular cells are key targets in AKI. Tubular cells and, specifically, proximal tubular cells are extremely rich in mitochondria and mitochondrial changes had long been known to be a feature of AKI. However, only recent advances in understanding the molecules involved in mitochondria biogenesis and dynamics and the availability of mitochondria-targeted drugs has allowed the exploration of the specific role of mitochondria in AKI. We now review the morphological and functional mitochondrial changes during AKI, as well as changes in the expression of mitochondrial genes and proteins. Finally, we summarise the current status of novel therapeutic strategies specifically targeting mitochondria such as mitochondrial permeability transition pore (MPTP) opening inhibitors (cyclosporine A (CsA)), quinone analogues (MitoQ, SkQ1 and SkQR1), superoxide dismutase (SOD) mimetics (Mito-CP), Szeto-Schiller (SS) peptides (Bendavia) and mitochondrial division inhibitors (mdivi-1). MitoQ, SkQ1, SkQR1, Mito-CP, Bendavia and mdivi-1 have improved the course of diverse experimental models of AKI. Evidence for a beneficial effect of CsA on human cardiac ischaemia-reperfusion injury derives from a clinical trial; however, CsA is nephrotoxic. MitoQ and Bendavia have been shown to be safe for humans. Ongoing clinical trials are testing the efficacy of Bendavia in AKI prevention following renal artery percutaneous transluminal angioplasty.

Selected aspects of modelling monetary transmission mechanism by BVAR model

NASA Astrophysics Data System (ADS)

Vaněk, Tomáš; Dobešová, Anna; Hampel, David

2013-10-01

In this paper we use the BVAR model with the specifically defined prior to evaluate data including high-lag dependencies. The results are compared to both restricted and common VAR model. The data depicts the monetary transmission mechanism in the Czech Republic and Slovakia from January 2002 to February 2013. The results point to the inadequacy of the common VAR model. The restricted VAR model and the BVAR model appear to be similar in the sense of impulse responses.

Exploring the nature of the relationship between child sexual abuse and substance use among women.

PubMed

Jarvis, T J; Copeland, J; Walton, L

1998-06-01

This study investigated whether child abuse (CSA) was associated with earlier substance use and greater severity of substance dependence and what aspects of CSA might predict substance abuse. The study compared (a) drug and alcohol treatment clients with and without a history of CSA and (b) CSA survivors outside drug and alcohol treatment who did or did not have current substance abuse. Semi-structured interviews took place at participants' homes, treatment agencies or the research centre. Volunteer participants included 100 women recruited from drug and alcohol treatment programmes and 80 CSA survivors recruited through CSA counseling services and medial advertising. The results focus on data from the Opiate Treatment Index, Severity of Alcohol Dependence Questionnaire, Substance Dependence Scale, Self-Esteem Inventory and self-reported histories of CSA. There were no differences between CSA survivors and other drug and alcohol treatment clients in their severity of dependence. Women with a history of CSA more frequently identified stimulants as their main problem drug and reported an earlier age of first intoxication and earlier use of inhalants. Among abused CSA survivors outside drug and alcohol treatment, women with current substance abuse had typically been abused during adolescence by someone outside the family, whereas those without current substance abuse were typically abused by family members before adolescence. The results suggest that adolescence is a crucial time for the influence of CSA experiences on substance abuse.

Vector autoregressive model approach for forecasting outflow cash in Central Java

NASA Astrophysics Data System (ADS)

hoyyi, Abdul; Tarno; Maruddani, Di Asih I.; Rahmawati, Rita

2018-05-01

Multivariate time series model is more applied in economic and business problems as well as in other fields. Applications in economic problems one of them is the forecasting of outflow cash. This problem can be viewed globally in the sense that there is no spatial effect between regions, so the model used is the Vector Autoregressive (VAR) model. The data used in this research is data on the money supply in Bank Indonesia Semarang, Solo, Purwokerto and Tegal. The model used in this research is VAR (1), VAR (2) and VAR (3) models. Ordinary Least Square (OLS) is used to estimate parameters. The best model selection criteria use the smallest Akaike Information Criterion (AIC). The result of data analysis shows that the AIC value of VAR (1) model is equal to 42.72292, VAR (2) equals 42.69119 and VAR (3) equals 42.87662. The difference in AIC values is not significant. Based on the smallest AIC value criteria, the best model is the VAR (2) model. This model has satisfied the white noise assumption.

Intra-dialytic blood oxygen saturation (SO2): association with dialysis hypotension (the SOGLIA Study).

PubMed

Mancini, E; Perazzini, C; Gesualdo, L; Aucella, F; Limido, A; Scolari, F; Savoldi, S; Tramonti, M; Corazza, L; Atti, M; Severi, S; Bolasco, P; Santoro, A

2017-12-01

Intradialytic hypotension (IDH) has a dramatic impact on the main outcomes of dialysis patients. Early warning of hemodynamic worsening during dialysis would enable preventive measures to be taken. Blood oxygen saturation (SO 2 ) is used for hemodynamic monitoring in the critical care setting and may provide useful information about IDH onset. To evaluate whether short- and medium-term variations in the SO 2 signal (ST-SO 2var , MT-SO 2var ,) during dialysis are a predictor of IDH. In this 3-month observational cohort study, 51 hypotension-prone chronic hemodialysis (HD) patients, with vascular access by arteriovenous fistula (AVF) or central venous catheter (CVC), were enrolled. Continuous non-invasive blood SO 2 was monitored (fc = 0.2 Hz) by an optical sensor on the arterial line of the extracorporeal circulation; blood pressure (every 30 min), symptoms and their time of appearance were noted. Predictive power of IDH was expressed by the area under curve (AUC) sensitivity and specificity based on intradialytic variations in SO 2 . A total of 1290 HD sessions were analyzed. Overall, off-line ST-SO 2var analysis proved able to correctly predict IDH in 67 % of the sessions where IDH occurred. The best predictive performance was found in the presence of highly arterialized AVF (SO 2  > 95 %) (75 % sensitivity; AUC 0.825; p < 0.05). On the contrary, in sessions with CVC, IDH prediction proved more efficient by MT-SO 2var (AUC 0.575; p = 0.01). Intradialytic SO 2 variability could be a valid parameter to detect in advance the hemodynamic worsening that precedes IDH. Appropriate timely intervention could help prevent IDH onset.

Hydration studies of calcium sulfoaluminate cements blended with fly ash

DOE Office of Scientific and Technical Information (OSTI.GOV)

García-Maté, M.; De la Torre, A.G.; León-Reina, L.

The main objective of this work is to study the hydration and properties of calcium sulfoaluminate cement pastes blended with fly ash (FA) and the corresponding mortars at different hydration ages. Laboratory X-ray powder diffraction, rheological studies, thermal analysis, porosimetry and compressive strength measurements were performed. The analysis of the diffraction data by Rietveld method allowed quantifying crystalline phases and overall amorphous contents. The studied parameters were: i) FA content, 0, 15 and 30 wt.%; and ii) water addition, water-to-CSA mass ratio (w/CSA = 0.50 and 0.65), and water-to-binder mass ratio (w/b = 0.50). Finally, compressive strengths after 6 monthsmore » of 0 and 15 wt.% FA [w/CSA = 0.50] mortars were similar: 73 ± 2 and 72 ± 3 MPa, respectively. This is justified by the filler effect of the FA as no strong evidences of reactivity of FA with CSA were observed. These results support the partial substitution of CSA cements with FA with the economic and environmental benefits.« less

Linking vegetable preferences, health and local food systems through community-supported agriculture.

PubMed

Wilkins, Jennifer L; Farrell, Tracy J; Rangarajan, Anusuya

2015-09-01

The objective of the present study was to explore the influence of participation in community-supported agriculture (CSA) on vegetable exposure, vegetable intake during and after the CSA season, and preference related to locally produced vegetables acquired directly from CSA growers. Quantitative surveys were administered at three time points in two harvest seasons to four groups of CSA participants: new full-paying, returning full-paying, new subsidized and returning subsidized members. Questionnaires included a vegetable frequency measure and measures of new and changed vegetable preference. Comparisons were made between new and returning CSA members and between those receiving subsidies and full-paying members. The research was conducted in a rural county in New York, USA. CSA members who agreed to participate in the study. Analysis was based on 151 usable questionnaires. CSA participants reported higher intake of eleven different vegetables during the CSA season, with a sustained increase in some winter vegetables. Over half of the respondents reported trying at least one, and up to eleven, new vegetables. Sustained preferences for CSA items were reported. While those who choose to join a CSA may be more likely to acquire new and expanded vegetable preferences than those who do not, the CSA experience has the potential to enhance vegetable exposure, augment vegetable preference and increase overall vegetable consumption. Dietary patterns encouraged through CSA participation can promote preferences and consumer demand that support local production and seasonal availability. Emphasis on fresh and fresh stored locally produced vegetables is consistent with sustainable community-based food systems.

Comparison of muscle cross-sectional areas between weight lifters and wrestlers.

PubMed

Kanehisa, H; Ikegawa, S; Fukunaga, T

1998-05-01

The purpose of this study was to investigate the difference in the magnitude of muscular development between Olympic weight lifters and wrestlers through the measurements of fat-free mass (FFM) and limb muscle cross-sectional area (CSA). Subjects were college Olympic weight lifters (N = 34, age = 20.0 +/- 1.3 years, stature = 1.67 +/- 0.07 m, body mass = 70.1 +/- 10.2 kg, X +/- SD) and wrestlers (N = 33,20.3 +/- 1.2 years, 1.69 +/- 0.06 m, 71.0 +/- 1.8 kg) who had identical range of body mass. Body density and the CSAs of reciprocal muscle groups in the forearm, upper arm, lower leg and thigh were measured by underwater weighing and B-mode ultrasound methods, respectively. No significant difference was found in body density between the weight lifters (1.077 +/- 0.007 g x ml(-3)) and wrestlers (1.076 +/- 0.008 g x ml(-3)). Moreover, FFM and the CSA values of all muscle groups tested were similar in the two groups of weight-classified athletes, with an exception that the wrist flexor CSA was significantly larger in wrestlers than in weight lifters, and the knee extensor and thigh (extensors + flexors) CSAs were larger in weight lifters than in wrestlers. The total muscle CSA of every site was significantly correlated to FFM2/3 in the separate groups; r = 0.714 to 0.815 (p < 0.05) in weight lifters and r = 0.769 to 0.919 (p < 0.05) in wrestlers. While the CSA-to-FFM2/3 ratios of the upper arm and wrist flexor muscles were significantly higher in wrestlers than in weight lifters, those of the thigh and knee extensor muscles were higher in weight lifters than in wrestlers. Thus, the present results suggest that an event-related difference exists in the magnitude of limb muscle CSA between competitive weight lifters and wrestlers of similar FFM.

Celecoxib, but not indomethacin, ameliorates the hypertensive and perivascular fibrotic actions of cyclosporine in rats: Role of endothelin signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

El-Mas, Mahmoud M., E-mail: mahelm@hotmail.com; Helmy, Maged W.; Ali, Rabab M.

The immunosuppressant drug cyclosporine (CSA) is used with nonsteroidal antiinflammatory drugs (NSAIDs) in arthritic conditions. In this study, we investigated whether NSAIDs modify the deleterious hypertensive action of CSA and the role of endothelin (ET) receptors in this interaction. Pharmacologic, protein expression, and histopathologic studies were performed in rats to investigate the roles of endothelin receptors (ET{sub A}/ET{sub B}) in the hemodynamic interaction between CSA and two NSAIDs, indomethacin and celecoxib. Tail-cuff plethysmography measurements showed that CSA (20 mg kg{sup −1} day{sup −1}, 10 days) increased systolic blood pressure (SBP) and heart rate (HR). CSA hypertension was associated with renalmore » perivascular fibrosis and divergent changes in immunohistochemical signals of renal arteriolar ET{sub A} (increases) and ET{sub B} (decreases) receptors. While these effects of CSA were preserved in rats treated concomitantly with indomethacin (5 mg kg{sup −1} day{sup −1}), celecoxib (10 mg kg{sup −1} day{sup −1}) abolished the pressor, tachycardic, and fibrotic effects of CSA and normalized the altered renal ET{sub A}/ET{sub B} receptor expressions. Selective blockade of ET{sub A} receptors by atrasentan (5 mg kg{sup −1} day{sup −1}) abolished the pressor response elicited by CSA or CSA plus indomethacin. Alternatively, BQ788 (ET{sub B} receptor blocker, 0.1 mg kg{sup −1} day{sup −1}) caused celecoxib-sensitive elevations in SBP and potentiated the pressor response evoked by CSA. Together, the improved renovascular fibrotic and endothelin receptor profile (ET{sub A} downregulation and ET{sub B} upregulation) mediate, at least partly, the protective effect of celecoxib against the hypertensive effect of CSA. Clinically, the use of celecoxib along with CSA in the management of arthritic conditions might provide hypertension-free regimen. - Highlights: • Chronic CSA causes hypertension and renal perivascular fibrosis in rats. • CSA increased and decreased renal ET{sub A} and ET{sub B} receptor expression, respectively. • CSA effects were abolished after co-treatment with celecoxib but not indomethacin. • ET{sub B} receptor blockade caused celecoxib-sensitive elevations in SBP. • Celecoxib protects against CSA hypertension via rectifying altered ET receptors.« less

Characteristics and circadian distribution of cardiac arrhythmias in patients with heart failure and sleep-disordered breathing.

PubMed

Omran, Hazem; Bitter, Thomas; Horstkotte, Dieter; Oldenburg, Olaf; Fox, Henrik

2018-05-08

Cardiac arrhythmias and sleep-disordered breathing (SDB) are common comorbidities in heart failure with reduced ejection fraction (HFrEF). However, understanding of the association between arrhythmias and SDB is poor. This study assessed the occurrence and circadian distribution of ventricular arrhythmias in HFrEF patients with and without SDB. This retrospective analysis included HFrEF patients admitted for unattended overnight cardiorespiratory polygraphy and 24-h Holter-ECG recording. Holter-ECG data (events/h) were categorized by time of day: morning, 06:00-13:59; afternoon, 14:00-21:59; nighttime, 22:00-05:59. Respiratory events were expressed using the apnea-hypopnea index (AHI) and an AHI ≥ 15/h was categorized as moderate to severe SDB. 167 patients were included (82% male, age 65 ± 10.4 years, left ventricular ejection fraction 30.9 ± 7.9%); SDB was predominantly central sleep apnea (CSA) in 45.5%, obstructive sleep apnea (OSA) in 23.9% or none/mild (nmSDB) in 17.4%. Morning premature ventricular contractions (PVCs) were detected significantly more frequently in CSA versus nmSDB patients (44.4/h versus 1.8/h; p = 0.02). Non-sustained VT was more frequent in patients with CSA versus versus OSA or nmSDB (17.9 versus 3.2 or 3.2%/h; p = 0.003 and p = 0.005, respectively). There was no significant variation in VT occurrence by time of day in HFrEF patients with CSA (p = 0.3). CSA was an independent predictor of VT occurrence in HFrEF in multivariate logistic regression analysis (odds ratio 4.1, 95% confidence interval 1.5-11.4, p = 0.007). CSA was associated with VT occurrence irrespective of sleep/wake status in HFrEF patients, and independently predicted the occurrence of VT. This association may contribute to chances by which CSA increases sudden death risk in HFrEF patients.

Resistance to cyclosporin A derives from mutations in hepatitis C virus nonstructural proteins.

PubMed

Arai, Masaaki; Tsukiyama-Kohara, Kyoko; Takagi, Asako; Tobita, Yoshimi; Inoue, Kazuaki; Kohara, Michinori

2014-05-23

Cyclosporine A (CsA) is an immunosuppressive drug that targets cyclophilins, cellular cofactors that regulate the immune system. Replication of hepatitis C virus (HCV) is suppressed by CsA, but the molecular basis of this suppression is still not fully understood. To investigate this suppression, we cultured HCV replicon cells (Con1, HCV genotype 1b, FLR-N cell) in the presence of CsA and obtained nine CsA-resistant FLR-N cell lines. We determined full-length HCV sequences for all nine clones, and chose two (clones #6 and #7) of the nine clones that have high replication activity in the presence of CsA for further analysis. Both clones showed two consensus mutations, one in NS3 (T1280V) and the other in NS5A (D2292E). Characterization of various mutants indicated that the D2292E mutation conferred resistance to high concentrations of CsA (up to 2 μM). In addition, the missense mutation T1280V contributed to the recovery of colony formation activity. The effects of these mutations are also evident in two established HCV replicon cell lines-HCV-RMT ([1], genotype 1a) and JFH1 (genotype 2a). Moreover, three other missense mutations in NS5A-D2303H, S2362G, and E2414K-enhanced the resistance to CsA conferred by D2292E; these double or all quadruple mutants could resist approximately 8- to 25-fold higher concentrations of CsA than could wild-type Con1. These four mutations, either as single or combinations, also made Con1 strain resistant to two other cyclophilin inhibitors, N-methyl-4-isoleucine-cyclosporin (NIM811) or Debio-025. Interestingly, the changes in IC50 values that resulted from each of these mutations were the lowest in the Debio-025-treated cells, indicating its highest resistant activity against the adaptive mutation. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Assessing Chronic Stress, Coping Skills, and Mood Disorders through Speech Analysis: A Self-Assessment 'Voice App' for Laptops, Tablets, and Smartphones.

PubMed

Braun, Silke; Annovazzi, Chiara; Botella, Cristina; Bridler, René; Camussi, Elisabetta; Delfino, Juan P; Mohr, Christine; Moragrega, Ines; Papagno, Costanza; Pisoni, Alberto; Soler, Carla; Seifritz, Erich; Stassen, Hans H

2016-01-01

Computerized speech analysis (CSA) is a powerful method that allows one to assess stress-induced mood disturbances and affective disorders through repeated measurements of speaking behavior and voice sound characteristics. Over the past decades CSA has been successfully used in the clinical context to monitor the transition from 'affectively disturbed' to 'normal' among psychiatric patients under treatment. This project, by contrast, aimed to extend the CSA method in such a way that the transition from 'normal' to 'affected' can be detected among subjects of the general population through 10-20 self-assessments. Central to the project was a normative speech study of 5 major languages (English, French, German, Italian, and Spanish). Each language comprised 120 subjects stratified according to gender, age, and education with repeated assessments at 14-day intervals (total n = 697). In a first step, we developed a multivariate model to assess affective state and stress-induced bodily reactions through speaking behavior and voice sound characteristics. Secondly, we determined language-, gender-, and age-specific thresholds that draw a line between 'natural fluctuations' and 'significant changes'. Thirdly, we implemented the model along with the underlying methods and normative data in a self-assessment 'voice app' for laptops, tablets, and smartphones. Finally, a longitudinal self-assessment study of 36 subjects was carried out over 14 days to test the performance of the CSA method in home environments. The data showed that speaking behavior and voice sound characteristics can be quantified in a reproducible and language-independent way. Gender and age explained 15-35% of the observed variance, whereas the educational level had a relatively small effect in the range of 1-3%. The self-assessment 'voice app' was realized in modular form so that additional languages can simply be 'plugged in' once the respective normative data become available. Results of the longitudinal self-assessment study in home environments demonstrated that CSA methods work well under most circumstances. We have successfully developed and tested a self-assessment CSA method that can monitor transitions from 'normal' to 'affected' in subjects of the general population in the broader context of mood disorders. Our easy-to-use 'voice app' evaluates sequences of 10-20 repeated assessments and watches for affect- and stress-induced deviations from baseline that exceed language-, gender-, and age-specific thresholds. Specifically, the 'voice app' provides users with stress-related 'biofeedback' and can help to identify that 10-15% subgroup of the general population that exhibits insufficient coping skills under chronic stress and may benefit from early detection and intervention prior to developing clinically relevant symptoms. © 2016 S. Karger AG, Basel.

42 CFR 23.9 - What must an entity to which National Health Service Corps personnel are assigned (i.e., a...

Code of Federal Regulations, 2011 CFR

2011-10-01

... with annual incomes at or below the “CSA Income Poverty Guidelines” (45 CFR 1060.2). However, no... has an annual income above the “CSA Income Poverty Guidelines,” but whose income does not exceed 200...

42 CFR 23.9 - What must an entity to which National Health Service Corps personnel are assigned (i.e., a...

Code of Federal Regulations, 2014 CFR

2014-10-01

... with annual incomes at or below the “CSA Income Poverty Guidelines” (45 CFR 1060.2). However, no... has an annual income above the “CSA Income Poverty Guidelines,” but whose income does not exceed 200...

42 CFR 23.9 - What must an entity to which National Health Service Corps personnel are assigned (i.e., a...

Code of Federal Regulations, 2012 CFR

2012-10-01

... with annual incomes at or below the “CSA Income Poverty Guidelines” (45 CFR 1060.2). However, no... has an annual income above the “CSA Income Poverty Guidelines,” but whose income does not exceed 200...

42 CFR 23.9 - What must an entity to which National Health Service Corps personnel are assigned (i.e., a...

Code of Federal Regulations, 2013 CFR

2013-10-01

... with annual incomes at or below the “CSA Income Poverty Guidelines” (45 CFR 1060.2). However, no... has an annual income above the “CSA Income Poverty Guidelines,” but whose income does not exceed 200...

42 CFR 23.9 - What must an entity to which National Health Service Corps personnel are assigned (i.e., a...

Code of Federal Regulations, 2010 CFR

2010-10-01

... with annual incomes at or below the “CSA Income Poverty Guidelines” (45 CFR 1060.2). However, no... has an annual income above the “CSA Income Poverty Guidelines,” but whose income does not exceed 200...

Evaluation of Freehand B-Mode and Power-Mode 3D Ultrasound for Visualisation and Grading of Internal Carotid Artery Stenosis.

PubMed

Pelz, Johann Otto; Weinreich, Anna; Karlas, Thomas; Saur, Dorothee

2017-01-01

Currently, colour-coded duplex sonography (2D-CDS) is clinical standard for detection and grading of internal carotid artery stenosis (ICAS). However, unlike angiographic imaging modalities, 2D-CDS assesses ICAS by its hemodynamic effects rather than luminal changes. Aim of this study was to evaluate freehand 3D ultrasound (3DUS) for direct visualisation and quantification of ICAS. Thirty-seven patients with 43 ICAS were examined with 2D-CDS as reference standard and with freehand B-mode respectively power-mode 3DUS. Stenotic value of 3D reconstructed ICAS was calculated as distal diameter respectively distal cross-sectional area (CSA) reduction percentage and compared with 2D-CDS. There was a trend but no significant difference in successful 3D reconstruction of ICAS between B-mode and power mode (examiner 1 {Ex1} 81% versus 93%, examiner 2 {Ex2} 84% versus 88%). Inter-rater agreement was best for power-mode 3DUS and assessment of stenotic value as distal CSA reduction percentage (intraclass correlation coefficient {ICC} 0.90) followed by power-mode 3DUS and distal diameter reduction percentage (ICC 0.81). Inter-rater agreement was poor for B-mode 3DUS (ICC, distal CSA reduction 0.36, distal diameter reduction 0.51). Intra-rater agreement for power-mode 3DUS was good for both measuring methods (ICC, distal CSA reduction 0.88 {Ex1} and 0.78 {Ex2}; ICC, distal diameter reduction 0.83 {Ex1} and 0.76 {Ex2}). In comparison to 2D-CDS inter-method agreement was good and clearly better for power-mode 3DUS (ICC, distal diameter reduction percentage: Ex1 0.85, Ex2 0.78; distal CSA reduction percentage: Ex1 0.63, Ex2 0.57) than for B-mode 3DUS (ICC, distal diameter reduction percentage: Ex1 0.40, Ex2 0.52; distal CSA reduction percentage: Ex1 0.15, Ex2 0.51). Non-invasive power-mode 3DUS is superior to B-mode 3DUS for imaging and quantification of ICAS. Thereby, further studies are warranted which should now compare power-mode 3DUS with the angiographic gold standard imaging modalities for quantification of ICAS, i.e. with CTA or CE-MRA.

Characterization of the regulatory network of BoMYB2 in controlling anthocyanin biosynthesis in purple cauliflower

USDA-ARS?s Scientific Manuscript database

Purple cauliflower (Brassica oleracea L. var. botrytis) Graffiti represents a unique mutant in conferring ectopic anthocyanin biosynthesis, which is caused by the tissue specific activation of BoMYB2, an ortholog of Arabidopsis PAP2 or MYB113. To gain a better understanding of the regulatory network...

Association of visceral fat area with abdominal skeletal muscle distribution in overweight Japanese adults.

PubMed

Tanaka, Noriko I; Murakami, Haruka; Ohmori, Yumi; Aiba, Naomi; Morita, Akemi; Watanabe, Shaw; Miyachi, Motohiko

2016-07-20

Quantitative evaluation of visceral fat mass and skeletal muscle mass is important for health promotion. Recently, some studies suggested the existence of adipocyte-myocyte negative crosstalk. If so, abdominal skeletal muscles may easily and negatively affected not only by the age but also the visceral fat because age-related reduction in abdominal region is greater compared with limbs. We cross-sectionally examined the existence of quantitative associations between visceral fat area and abdominal skeletal muscle distribution in overweight people. A total of 230 Japanese males and females who aged 40-64 years and whose body mass index (BMI) was 28.0-44.8kg/m 2 participated in this study. The cross-sectional area (CSA) of the visceral fat, subcutaneous fat, and abdominal skeletal muscles, namely, the rectus abdominis, abdominal oblique, erector spinae, and iliopsoas muscles were measured by the computed tomography images. Stepwise regression analyses revealed the existence of sex difference in the relation between visceral fat CSA and other morphological variables. In males, BMI was a positive, and the iliopsoas muscle group CSA was a negative contributor of the visceral fat CSA. In females, both age and BMI were selected as positive contributors. These data suggested that the visceral fat CSA may negatively associated with iliopsoas muscle group CSA in males. In females, the visceral fat CSA was not significantly related to the distribution of the abdominal skeletal muscle groups. Copyright © 2016 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Central Sleep Apnoea Is Related to the Severity and Short-Term Prognosis of Acute Coronary Syndrome.

PubMed

Florés, Marina; de Batlle, Jordi; Sánchez-de-la-Torre, Alicia; Sánchez-de-la-Torre, Manuel; Aldomá, Albina; Worner, Fernando; Galera, Estefanía; Seminario, Asunción; Torres, Gerard; Dalmases, Mireia; Montserrat, Josep M; Garmendia, Onintza; Barbé, Ferran

2016-01-01

To evaluate the relation of central sleep apnoea (CSA) to the severity and short-term prognosis of patients who experience acute coronary syndrome (ACS). Observational study with cross-sectional and longitudinal analyses. Patients acutely admitted to participating hospitals because of ACS underwent respiratory polygraphy during the first 24 to 72 h. CSA was defined as an apnoea-hypopnoea index (AHI) >15 events•h-1 (>50% of central apnoeas). ACS severity (Killip class, ejection fraction, number of diseased vessels and peak plasma troponin) was evaluated at baseline, and short-term prognosis (length of hospitalization, complications and mortality) was evaluated at discharge. A total of 68 CSA patients (AHI 31±18 events•h-1, 64±12 years, 87% males) and 92 controls (AHI 7±5 events•h-1, 62±12 years, 84% males) were included in the analyses. After adjusting for age, body mass index, hypertension and smoking status, patients diagnosed with CSA spent more days in the coronary unit compared with controls (3.7±2.9 vs. 1.5±1.7; p<0.001) and had a worse Killip class (Killip I: 16% vs. 96%; p<0.001). No differences were observed in ejection fraction estimates. CSA patients exhibited increased ACS severity as indicated by their Killip classification. These patients had a worse prognosis, with longer lengths of stay in the coronary care units. Our results highlight the relevance of CSA in patients suffering ACS episodes and suggest that diagnosing CSA may be a useful strategy to improve the management of certain ACS patients.

Identification of a novel cyclosporin-sensitive element in the human tumor necrosis factor alpha gene promoter

PubMed Central

1993-01-01

Tumor necrosis factor alpha (TNF-alpha), a cytokine with pleiotropic biological effects, is produced by a variety of cell types in response to induction by diverse stimuli. In this paper, TNF-alpha mRNA is shown to be highly induced in a murine T cell clone by stimulation with T cell receptor (TCR) ligands or by calcium ionophores alone. Induction is rapid, does not require de novo protein synthesis, and is completely blocked by the immunosuppressant cyclosporin A (CsA). We have identified a human TNF-alpha promoter element, kappa 3, which plays a key role in the calcium-mediated inducibility and CsA sensitivity of the gene. In electrophoretic mobility shift assays, an oligonucleotide containing kappa 3 forms two DNA protein complexes with proteins that are present in extracts from unstimulated T cells. These complexes appear in nuclear extracts only after T cell stimulation. Induction of the inducible nuclear complexes is rapid, independent of protein synthesis, and blocked by CsA, and thus, exactly parallels the induction of TNF-alpha mRNA by TCR ligands or by calcium ionophore. Our studies indicate that the kappa 3 binding factor resembles the preexisting component of nuclear factor of activated T cells. Thus, the TNF-alpha gene is an immediate early gene in activated T cells and provides a new model system in which to study CsA-sensitive gene induction in activated T cells. PMID:8376940

RAF and Authorities

DTIC Science & Technology

2015-02-01

with other nations.2 By May 2012, General Raymond T. Odierno, Chief of Staff of the Army (CSA) had expanded the concept of Regionally Aligned Brigades...includes the Reserve Components (RC), which consists of the Army Reserve (AR) and the National Guard (NG). Army civilians may also be included.9 Each...force component may deal in different ways with various general and specific authorizations. Title 10 of United States Code provides the legal basis

Caregiver perceptions about mental health services after child sexual abuse.

PubMed

Fong, Hiu-fai; Bennett, Colleen E; Mondestin, Valerie; Scribano, Philip V; Mollen, Cynthia; Wood, Joanne N

2016-01-01

The objective of this study was to describe caregiver perceptions about mental health services (MHS) after child sexual abuse (CSA) and to explore factors that affected whether their children linked to services. We conducted semi-structured, in-person interviews with 22 non-offending caregivers of suspected CSA victims<13 years old seen at a child advocacy center in Philadelphia. Purposive sampling was used to recruit caregivers who had (n=12) and had not (n=10) linked their children to MHS. Guided by the Health Belief Model framework, interviews assessed perceptions about: CSA severity, the child's susceptibility for adverse outcomes, the benefits of MHS, and the facilitators and barriers to MHS. Interviews were audio-recorded, transcribed, coded, and analyzed using modified grounded theory. Recruitment ended when thematic saturation was reached. Caregivers expressed strong reactions to CSA and multiple concerns about adverse child outcomes. Most caregivers reported that MHS were generally necessary for children after CSA. Caregivers who had not linked to MHS, however, believed MHS were not necessary for their children, most commonly because they were not exhibiting behavioral symptoms. Caregivers described multiple access barriers to MHS, but caregivers who had not linked reported that they could have overcome these barriers if they believed MHS were necessary for their children. Caregivers who had not linked to services also expressed concerns about MHS being re-traumatizing and stigmatizing. Interventions to increase MHS linkage should focus on improving communication with caregivers about the specific benefits of MHS for their children and proactively addressing caregiver concerns about MHS. Copyright © 2015 Elsevier Ltd. All rights reserved.

Skeletal muscle weakness in osteogenesis imperfecta mice.

PubMed

Gentry, Bettina A; Ferreira, J Andries; McCambridge, Amanda J; Brown, Marybeth; Phillips, Charlotte L

2010-09-01

Exercise intolerance, muscle fatigue and weakness are often-reported, little-investigated concerns of patients with osteogenesis imperfecta (OI). OI is a heritable connective tissue disorder hallmarked by bone fragility resulting primarily from dominant mutations in the proα1(I) or proα2(I) collagen genes and the recently discovered recessive mutations in post-translational modifying proteins of type I collagen. In this study we examined the soleus (S), plantaris (P), gastrocnemius (G), tibialis anterior (TA) and quadriceps (Q) muscles of mice expressing mild (+/oim) and moderately severe (oim/oim) OI for evidence of inherent muscle pathology. In particular, muscle weight, fiber cross-sectional area (CSA), fiber type, fiber histomorphology, fibrillar collagen content, absolute, relative and specific peak tetanic force (P(o), P(o)/mg and P(o)/CSA respectively) of individual muscles were evaluated. Oim/oim mouse muscles were generally smaller, contained less fibrillar collagen, had decreased P(o) and an inability to sustain P(o) for the 300-ms testing duration for specific muscles; +/oim mice had a similar but milder skeletal muscle phenotype. +/oim mice had mild weakness of specific muscles but were less affected than their oim/oim counterparts which demonstrated readily apparent skeletal muscle pathology. Therefore muscle weakness in oim mice reflects inherent skeletal muscle pathology. Copyright © 2010 Elsevier B.V. All rights reserved.

Isolation and characterization of a J domain protein that interacts with ARC1 from ornamental kale (Brassica oleracea var. acephala).

PubMed

Lan, Xingguo; Yang, Jia; Cao, Mingming; Wang, Yanhong; Kawabata, Saneyuki; Li, Yuhua

2015-05-01

A novel J domain protein, JDP1, was isolated from ornamental kale. The C-terminus of JDP1 specifically interacted with ARC1, which has a conserved role in self-incompatibility signaling. Armadillo (ARM)-repeat containing 1 (ARC1) plays a conserved role in self-incompatibility signaling across the Brassicaceae and functions downstream of the S-locus receptor kinase. Here, we identified a J domain protein 1 (JDP1) that interacts with ARC1 using a yeast two-hybrid screen against a stigma cDNA library from ornamental kale (Brassica oleracea var. acephala). JDP1, a 38.4-kDa protein with 344 amino acids, is a member of the Hsp40 family. Fragment JDP1(57-344), originally isolated from a yeast two-hybrid cDNA library, interacted specifically with ARC1 in yeast two-hybrid assays. The N-terminus of JDP1 (JDP1(1-68)) contains a J domain, and the C-terminus of JDP1 (JDP1(69-344)) contains an X domain of unknown function. However, JDP1(69-344) was required and sufficient for interaction with ARC1 in yeast two-hybrid assays and in vitro binding assays. Moreover, JDP1(69-344) regulated the trafficking of ARC1 from the cytoplasm to the plasma membrane by interacting with ARC1 in Arabidopsis mesophyll protoplasts. Finally, Tyr(8) in the JDP1 N-terminal region was identified to be the specific site for regulating the interaction between JDP1 and BoARC1 in yeast two-hybrid assays. Possible roles of JDP1 as an interactor with ARC1 in Brassica are discussed.

Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome.

PubMed

Laugel, V; Dalloz, C; Durand, M; Sauvanaud, F; Kristensen, U; Vincent, M C; Pasquier, L; Odent, S; Cormier-Daire, V; Gener, B; Tobias, E S; Tolmie, J L; Martin-Coignard, D; Drouin-Garraud, V; Heron, D; Journel, H; Raffo, E; Vigneron, J; Lyonnet, S; Murday, V; Gubser-Mercati, D; Funalot, B; Brueton, L; Sanchez Del Pozo, J; Muñoz, E; Gennery, A R; Salih, M; Noruzinia, M; Prescott, K; Ramos, L; Stark, Z; Fieggen, K; Chabrol, B; Sarda, P; Edery, P; Bloch-Zupan, A; Fawcett, H; Pham, D; Egly, J M; Lehmann, A R; Sarasin, A; Dollfus, H

2010-02-01

Cockayne syndrome is an autosomal recessive multisystem disorder characterized principally by neurological and sensory impairment, cachectic dwarfism, and photosensitivity. This rare disease is linked to mutations in the CSB/ERCC6 and CSA/ERCC8 genes encoding proteins involved in the transcription-coupled DNA repair pathway. The clinical spectrum of Cockayne syndrome encompasses a wide range of severity from severe prenatal forms to mild and late-onset presentations. We have reviewed the 45 published mutations in CSA and CSB to date and we report 43 new mutations in these genes together with the corresponding clinical data. Among the 84 reported kindreds, 52 (62%) have mutations in the CSB gene. Many types of mutations are scattered along the whole coding sequence of both genes, but clusters of missense mutations can be recognized and highlight the role of particular motifs in the proteins. Genotype-phenotype correlation hypotheses are considered with regard to these new molecular and clinical data. Additional cases of molecular prenatal diagnosis are reported and the strategy for prenatal testing is discussed. Two web-based locus-specific databases have been created to list all identified variants and to allow the inclusion of future reports (www.umd.be/CSA/ and www.umd.be/CSB/). (c) 2009 Wiley-Liss, Inc.

Bearing and gear steels for aerospace applications

NASA Technical Reports Server (NTRS)

Zaretsky, Erwin V.

1990-01-01

Research in metallurgy and processing for bearing and gear steels has resulted in improvements in rolling-element bearing and gear life for aerospace application by a factor of approximately 200 over that obtained in the early 1940's. The selection and specification of a bearing or gear steel is dependent on the integration of multiple metallurgical and physical variables. For most aerospace bearings, through-hardened VIM-VAR AISI M-50 steel is the material of preference. For gears, the preferential material is case-carburized VAR AISI 9310. However, the VAR processing for this material is being replaced by VIM-VAR processing. Since case-carburized VIM-VAR M-50NiL incorporates the desirable qualities of both the AISI M-50 and AISI 9310 materials, optimal life and reliability can be achieved in both bearings and gears with a single steel. Hence, this material offers the promise of a common steel for both bearings and gears for future aerospace applications.

The effect of partial acclimatization to high altitude on loop gain and central sleep apnoea severity.

PubMed

Andrews, Gareth; Ainslie, Philip N; Shepherd, Kelly; Dawson, Andrew; Swart, Marianne; Lucas, Samuel; Burgess, Keith R

2012-07-01

Loop gain is an engineering term that predicts the stability of a feedback control system, such as the control of breathing. Based on earlier studies at lower altitudes, it was hypothesized that acclimatization to high altitude would lead to a reduction in loop gain and thus central sleep apnoea (CSA) severity. This study used exposure to very high altitude to induce CSA in healthy subjects to investigate the effect of partial acclimatization on loop gain and CSA severity. Measurements were made on 12 subjects (age 30 ± 10 years, body mass index 22.8 ± 1.9, eight males, four females) at an altitude of 5050 m over a 2-week period upon initial arrival (days 2-4) and following partial acclimatization (days 12-14). Sleep was studied by full polysomnography, and resting arterial blood gases were measured. Loop gain was measured by the 'duty cycle' method (duration of hyperpnoea/cycle length). Partial acclimatization to high-altitude exposure was associated with both an increase in loop gain (duty cycle fell from 0.60 ± 0.05 to 0.55 ± 0.06 (P = 0.03)) and severity of CSA (apnoea-hypopnoea index increased from 76.8 ± 48.8 to 115.9 ± 20.2 (P = 0.01)), while partial arterial carbon dioxide concentration fell from 29 ± 3 to 26 ± 2 (P = 0.01). Contrary to the results at lower altitudes, at high-altitude loop gain and severity of CSA increased. © 2012 The Authors. Respirology © 2012 Asian Pacific Society of Respirology.

Factors protecting against the development of adjustment difficulties in young adults exposed to childhood sexual abuse.

PubMed

Lynskey, M T; Fergusson, D M

1997-12-01

The aims of this study were to identify the factors which discriminated young people exposed to childhood sexual abuse (CSA) who developed psychiatric disorder or adjustment difficulties in young adulthood from those young people exposed to CSA who did not develop psychiatric disorder or adjustment difficulties by age 18. Data were gathered on a birth cohort of 1,025 New Zealand children studied from birth to the age of 18 on (a) exposure to CSA; (b) patterns of psychiatric disorder and adjustment difficulties at age 18 years; (c) factors that may have influenced responses to CSA including characteristics of the abuse, parental bonding, parental characteristics, and adolescent peer affiliations. Just over 10% of the cohort reported CSA. Those reporting CSA were at increased risks of a range of difficulties at age 18 (depression, anxiety, conduct disorder, alcohol abuse/dependence, other substance abuse/dependence, post sexual abuse trauma, attempted suicide). However, not all of those exposed to CSA developed difficulties and approximately a quarter of those exposed to CSA did not meet criteria for any adjustment difficulty. Further analysis suggested that the extent of adjustment difficulties in those exposed to CSA was influenced by two additional factors: (a) the extent of affiliations with delinquent or substance using peers in adolescence; and (b) the extent of paternal care or support in childhood. The findings of this study suggest that while young people exposed to CSA are at increased risks of psychiatric disorder and adjustment difficulties in young adulthood, not all individuals exposed to CSA will develop adjustment difficulties. Important factors protecting against the development of adjustment difficulties in young people experiencing CSA appear to be the nature and quality of peer and family relationships.

Exploring the role of child sexual abuse and posttraumatic stress disorder symptoms in gay and bisexual men reporting compulsive sexual behavior.

PubMed

Blain, Leah M; Muench, Fred; Morgenstern, Jon; Parsons, Jeffrey T

2012-05-01

Compulsive sexual behavior (CSB) is an impairing yet understudied clinical phenomenon. The experience of child sexual abuse (CSA) has been implicated as an etiological factor in the development of some cases of CSB (Kuzma & Black, 2008); however, research regarding the role of CSA and related psychopathology in CSB symptomatology has been limited in the literature. The present study aimed to examine the uniqueness of the association of CSA with CSB as compared to other experiences of child maltreatment; the role of posttraumatic stress disorder (PTSD) symptomatology in CSB symptoms for individuals reporting CSA; and clinical differences between individuals with and without histories of CSA. Hypotheses were tested using data from a sample of 182 gay and bisexual men reporting CSB symptoms. CSA prevalence was high in the tested sample (39%). CSA severity was a unique predictor of CSB symptoms, above child physical and emotional abuse, and poly-victimization status was not significantly related to CSB symptoms. Contrary to hypotheses, PTSD symptoms did not significantly mediate the role of CSA severity, although PTSD symptoms explained additional variance in CSB symptoms, with the final model accounting for over a quarter of the variance in CSB symptoms (27%). Finally, men with a history of CSA reported more CSB, depressive, and anxious symptoms than those without a history of CSA. Findings from the present study support the hypothesis that CSA may be uniquely related to CSB symptoms, above other forms of child maltreatment, and indicate that men with a CSA history are likely to present more severe clinical comorbidities. Clinical implications and future research directions are discussed. Copyright © 2012 Elsevier Ltd. All rights reserved.

Methodologic Considerations for the Study of Childhood Sexual Abuse in Sexual Health Outcome Research: A Comprehensive Review.

PubMed

Kilimnik, Chelsea D; Pulverman, Carey S; Meston, Cindy M

2018-04-01

Childhood sexual abuse (CSA) has been a topic of interest in sexual health research for decades, yet literature on the sexual health correlates of CSA has been hindered by methodologic inconsistencies that have resulted in discrepant samples and mixed results. To review the major methodologic inconsistencies in the field, explore the scientific and clinical impact of these inconsistencies, and propose methodologic approaches to increase consistency and generalizability to the general population of women with CSA histories. A comprehensive literature review was conducted to assess the methodologic practices used in examining CSA and sexual health outcomes. Methodologic decisions of researchers examining sexual health outcomes of CSA. There are a number of inconsistencies in the methods used to examine CSA in sexual health research across the domains of CSA operationalization, recruitment language, and measurement approaches to CSA experiences. The examination of CSA and sexual health correlates is an important research endeavor that needs rigorous methodologic approaches. We propose recommendations to increase the utility of CSA research in sexual health. We recommend the use of a developmentally informed operationalization of childhood and adolescence, rather than age cutoffs. Researchers are encouraged to use a broad operationalization of sexual abuse such that different abuse characteristics can be measured, reported, and examined in the role of sexual health outcomes. We recommend inclusive recruitment approaches to capture the full range of CSA experiences and transparency in reporting these methods. The field also could benefit from the validation of existing self-report instruments for assessing CSA and detailed reporting of the instruments used in research studies. The use of more consistent research practices could improve the state of knowledge on the relation between CSA and sexual health. Kilimnik CD, Pulverman CS, Meston CM. Methodologic Considerations for the Study of Childhood Sexual Abuse in Sexual Health Outcome Research: A Comprehensive Review. Sex Med Rev 2018;6:176-187. Copyright © 2018 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Enhanced absorption of cyclosporin A by complexation with dimethyl-beta-cyclodextrin in bile duct-cannulated and -noncannulated rats.

PubMed

Miyake, K; Arima, H; Irie, T; Hirayama, F; Uekama, K

1999-01-01

The enhancing effects of dimethyl-beta-cyclodextrin (DM-beta-CyD) on the absorption of cyclosporin A (CsA) after oral administration to rats under bile duct-cannulated and -noncannulated conditions were investigated. The dissolution rate of CsA was markedly augmented by complexation with DM-beta-CyD. In a closed loop in situ study, DM-beta-CyD considerably increased the cumulative amounts of CsA in the mesenteric venous blood after injection of the aqueous CsA suspension into the small intestinal sac of rats. In addition, the cumulative amount ratio of M1, the dominant metabolite of CsA in rats, to CsA in the mesenteric venous blood for up to 40 min after the injection of the CsA-DM-beta-CyD suspension into the sac was lower than that of the CsA suspension alone. DM-beta-CyD inhibited the bioconversion of CsA in the small intestinal microsomes of rats. These results indicate that the bioconversion of CsA was abated by complexation with DM-beta-CyD. An in vivo study revealed that DM-beta-CyD increased the transfer of CsA to blood, not lymph, with low variability in the absorption after oral administration of the CsA suspension to rats. The variability of bioavailability of DM-beta-CyD complex was lower than that of Sandimmune, although the extent of bioavailability of DM-beta-CyD was only a little higher than that of Sandimmune. The bioavailability of CsA or its DM-beta-CyD complex was appreciably decreased by the cannulation of the bile duct of rats, and the extent of the lowering in the bioavailability in the presence of DM-beta-CyD was much less serious than that of CsA alone. The present results suggest that DM-beta-CyD is particularly useful in designing oral preparations of CsA with an enhanced bioavailability and a reduced variability in absorption.

Muscle Damage After Total Hip Arthroplasty Through the Direct Anterior Approach for Developmental Dysplasia of the Hip.

PubMed

Kawasaki, Masashi; Hasegawa, Yukiharu; Okura, Toshiaki; Ochiai, Satoshi; Fujibayashi, Takayoshi

2017-08-01

Total hip arthroplasty (THA) through the direct anterior approach (DAA) is known to cause less muscle damage than other surgical approaches. However, more complex primary cases, such as developmental dysplasia of the hip (DDH), might often cause muscle damage. The objective of the present study was to clarify the muscle damage observed 1 year after THA through the DAA for DDH using magnetic resonance imaging. We prospectively compared the muscle cross-sectional area (M-CSA) and fatty atrophy (FA) in muscles by magnetic resonance imaging and the Harris hip score before and at 1-year follow-up after THA through the DAA in 3 groups: 37 patients with Crowe group 1 DDH (D1), 13 patients with Crowe group 2 and 3 DDH (D2 + 3), and 12 patients with osteonecrosis as a control. THA through the DAA for D1 displayed significantly decreased M-CSA and significantly increased FA in the gluteus minimus (Gmini), the tensor fasciae latae (TFL), and the obturator internus (OI). Patients with D2 + 3 group did not have decreased M-CSA in the TFL or increased FA in the Gmini. Postoperatively, a significant negative correlation was observed between the M-CSA and FA for the OI in patients with D1 and D2 + 3. THA through the DAA for DDH caused the damage in the Gmini, the TFL, and the OI; severe damage was observed in the OI, showing increased FA with decreased M-CSA in patients with both D1 and D2 + 3. Copyright © 2017 Elsevier Inc. All rights reserved.

H2 haplotype at chromosome 17q21.31 protects against childhood sexual abuse-associated risk for alcohol consumption and dependence

PubMed Central

Nelson, Elliot C.; Agrawal, Arpana; Pergadia, Michele L.; Wang, Jen C.; Whitfield, John B.; Saccone, F. Scott; Kern, Jason; Grant, Julia D.; Schrage, Andrew J.; Rice, John P.; Montgomery, Grant W.; Heath, Andrew C.; Goate, Alison M.; Martin, Nicholas G.; Madden, Pamela A.F.

2011-01-01

Animal research supports a central role for corticotropin releasing factor (CRF) in actions of ethanol on brain function. An examination of alcohol consumption in adolescents reported a significant genotype × environment (G × E) interaction involving rs1876831, a CRHR1 polymorphism, and negative events. CRHR1 and at least 4 other genes are located at 17q21.31 in an extremely large block of high linkage disequilibrium resulting from a local chromosomal inversion; the minor allele of rs1876831 is contained within the H2 haplotype. Here we examine whether G × E interactions involving this haplotype and childhood sexual abuse (CSA) are associated with risk for alcohol consumption and dependence in Australian participants (N=1128 respondents from 476 families) of the Nicotine Addiction Genetics project. Telephone interviews provided data on DSM-IV alcohol dependence diagnosis and CSA and enabled calculation of lifetime alcohol consumption factor score (ACFS) from 4 indices of alcohol consumption. Individuals reporting a history of CSA had significantly higher ACFS and increased risk for alcohol dependence. A significant G × E interaction was found for ACFS involving the H2 haplotype and CSA (p<0.017). A similar G × E interaction was associated with protective effects against alcohol dependence risk (odds ratio 0.42; 95%CI 0.20 – 0.89). For each outcome, no significant CSA-associated risk was observed in H2 haplotype carriers. These findings support conducting further investigation of the H2 haplotype to determine the gene(s) responsible. Our results also suggest that severe early trauma may prove to be an important clinical covariate in the treatment of alcohol dependence. PMID:19878140

Beta 2-agonist fenoterol has greater effects on contractile function of rat skeletal muscles than clenbuterol.

PubMed

Ryall, James G; Gregorevic, Paul; Plant, David R; Sillence, Martin N; Lynch, Gordon S

2002-12-01

Potential treatments for skeletal muscle wasting and weakness ideally possess both anabolic and ergogenic properties. Although the beta(2)-adrenoceptor agonist clenbuterol has well-characterized effects on skeletal muscle, less is known about the therapeutic potential of the related beta(2)-adrenoceptor agonist fenoterol. We administered an equimolar dose of either clenbuterol or fenoterol to rats for 4 wk to compare their effects on skeletal muscle and tested the hypothesis that fenoterol would produce more powerful anabolic and ergogenic effects. Clenbuterol treatment increased fiber cross-sectional area (CSA) by 6% and maximal isometric force (P(o)) by 20% in extensor digitorum longus (EDL) muscles, whereas fiber CSA in soleus muscles decreased by 3% and P(o) was unchanged, compared with untreated controls. In the EDL muscles, fenoterol treatment increased fiber CSA by 20% and increased P(o) by 12% above values achieved after clenbuterol treatment. Soleus muscles of fenoterol-treated rats exhibited a 13% increase in fiber CSA and a 17% increase in P(o) above that of clenbuterol-treated rats. These data indicate that fenoterol has greater effects on the functional properties of rat skeletal muscles than clenbuterol.

Nuclear spin relaxation due to chemical shift anisotropy of gas-phase 129Xe.

PubMed

Hanni, Matti; Lantto, Perttu; Vaara, Juha

2011-08-14

Nuclear spin relaxation provides detailed dynamical information on molecular systems and materials. Here, first-principles modeling of the chemical shift anisotropy (CSA) relaxation time for the prototypic monoatomic (129)Xe gas is carried out, both complementing and predicting the results of NMR measurements. Our approach is based on molecular dynamics simulations combined with pre-parametrized ab initio binary nuclear shielding tensors, an "NMR force field". By using the Redfield relaxation formalism, the simulated CSA time correlation functions lead to spectral density functions that, for the first time, quantitatively determine the experimental spin-lattice relaxation times T(1). The quality requirements on both the Xe-Xe interaction potential and binary shielding tensor are investigated in the context of CSA T(1). Persistent dimers Xe(2) are found to be responsible for the CSA relaxation mechanism in the low-density limit of the gas, completely in line with the earlier experimental findings.

Porous mannitol carrier for pulmonary delivery of cyclosporine A nanoparticles.

PubMed

Leung, Sharon Shui Yee; Wong, Jennifer; Guerra, Heloisa Victorino; Samnick, Kevin; Prud'homme, Robert K; Chan, Hak-Kim

2017-03-01

This study employed the ultrasonic spray-freeze-drying technique to prepare porous mannitol carriers that incorporated hydrophobic cyclosporine A (CsA) nanoparticles (NPs) for pulmonary delivery. Two nanosuspension stabilization systems, (1) a combination of lecithin and lactose system and (2) a D-α-tocopheryl polyethylene glycol succinate (TPGS) system, were investigated. The ability of the lecithin and TPGS in anchoring the hydrophobic CsA NPs to the porous hydrophilic mannitol structure was first reported. Formulations stabilized by TPGS provided a much better dose uniformity, suggesting that TPGS is a better anchoring agent compared with lecithin. The effects of mannitol carrier density and CsA loading (4.9-27%) on aerosol performance and dissolution profiles were assessed. The fine particle fraction (FPF) increased from 44 to 63% as the mannitol concentration decreased from 1 to 5%. All formulations achieved full dissolution within an hour without significant influence from the mannitol content and CsA loading. The initial dissolution rates of the present formulations were almost double than that of the spray-dried counterpart, with 90% of the drug dissolved in 10 min. Overall, the CsA NPs were successfully incorporated into the porous mannitol which demonstrated good aerosol performance and enhanced dissolution profiles. These spray-freeze-drying (SFD) powders were stable after 2-year storage under desiccation at 20 ± 3°C.

Approaches to the implementation of the Water Framework Directive: targeting mitigation measures at critical source areas of diffuse phosphorus in Irish catchments.

PubMed

Doody, D G; Archbold, M; Foy, R H; Flynn, R

2012-01-01

The Water Framework Directive (WFD) has initiated a shift towards a targeted approach to implementation through its focus on river basin districts as management units and the natural ecological characteristics of waterbodies. Due to its role in eutrophication, phosphorus (P) has received considerable attention, resulting in a significant body of research, which now forms the evidence base for the programme of measures (POMs) adopted in WFD River Basin Management Plans (RBMP). Targeting POMs at critical sources areas (CSAs) of P could significantly improve environmental efficiency and cost effectiveness of proposed mitigation strategies. This paper summarises the progress made towards targeting mitigation measures at CSAs in Irish catchments. A review of current research highlights that knowledge related to P export at field scale is relatively comprehensive however; the availability of site-specific data and tools limits widespread identification of CSA at this scale. Increasing complexity of hydrological processes at larger scales limits accurate identification of CSA at catchment scale. Implementation of a tiered approach, using catchment scale tools in conjunction with field-by-field surveys could decrease uncertainty and provide a more practical and cost effective method of delineating CSA in a range of catchments. Despite scientific and practical uncertainties, development of a tiered CSA-based approach to assist in the development of supplementary measures would provide a means of developing catchment-specific and cost-effective programmes of measures for diffuse P. The paper presents a conceptual framework for such an approach, which would have particular relevance for the development of supplementary measures in High Status Waterbodies (HSW). The cost and resources necessary for implementation are justified based on HSWs' value as undisturbed reference condition ecosystems. Copyright © 2011 Elsevier Ltd. All rights reserved.

The Neuropsychology of Adolescent Sexual Offending: Testing an Executive Dysfunction Hypothesis.

PubMed

Morais, Hugo B; Joyal, Christian C; Alexander, Apryl A; Fix, Rebecca L; Burkhart, Barry R

2016-12-01

Although executive dysfunctions are commonly hypothesized to contribute to sexual deviance or aggression, evidence of this relationship is scarce and its specificity is unproven, especially among adolescents. The objective of this study was to compare the executive functioning (EF) of adolescents with sexual offense convictions (ASOC) to that of non-sex-delinquents (NSD). A secondary goal was to assess the relationship among specific sexual offense characteristics (i.e., victim age), history of childhood sexual abuse (CSA), and EF. It was hypothesized that as a group, ASOC would present similar EF profiles as NSD. It was further hypothesized that ASOC with child victims would present significantly higher rates of CSA and more severe impairment of EF than ASOC with peer-aged or older victims and NSD. A total of 183 male adolescents (127 ASOC and 56 NSD) were interviewed to collect demographic information, sexual development history, history of CSA, an assessment of living conditions, and history of delinquency and sexual offending. Participants were administered the Delis-Kaplan Executive Functioning System and the Hare Psychopathy Checklist-Youth Version. In accord with the first hypothesis, ASOC and NSD presented similar EF scores, well below normative values. Thus, EF deficits may not characterize the profiles of adolescents with sexual behavior problems. Contrarily to our second hypothesis, however, offending against children and or experiencing CSA were not associated with poorer EF performance. On the contrary, ASOC with child victims obtained significantly higher scores on measures of higher order EF than both ASOC with peer-aged or older victims and NSD. Implications of these results and future directions are discussed. © The Author(s) 2015.

Compressed spectral arrays of patients with fulminant hepatic failure in hepatic coma undergoing liver transplantation.

PubMed

Takeichi, Takayuki; Asonuma, Katsuhiro; Kim, Ildeok; Inomata, Yukihiro; Kasahara, Mureo; Ohwada, Susumu; Morishita, Yasuo; Tanaka, Koichi

2002-08-01

Assessing the coma status of patients with fulminant hepatic failure (FHF) is important for determining the reversibility of brain damage and for properly timing liver transplantation. The compressed spectral array (CSA) method is a frequency analysis technique that processes electroencephalogram signals by computer to facilitate on-line interpretation. This method has been used to monitor the consciousness levels of neurointensive care unit patients. In this study, we determined whether CSA could be used to assess the coma status of patients with FHF, and whether CSA provided information that was useful in deciding when to proceed with liver transplantation. CSA recording was carried out in 17 FHF patients with encephalopathy (coma grade III-IV) who underwent living-related liver transplantation between August 1997 and May 1999. Recording was performed with a Neuromonitor OEE-72044 (NIHON KOHDEN, Osaka, Japan) every 24 h before and after transplantation, until the patients regained consciousness. The CSAs of healthy controls were distributed almost equally between 0 and 16 Hz. The CSAs of FHF patients in hepatic coma were classified into three patterns. Eight of the 17 patients showed very prominent slow waves of about 2 Hz (group A), and seven patients showed strongly suppressed rapid waves between 8 and 16 Hz (group B). The remaining two patients showed CSA patterns that were similar to those of healthy controls, even though these patients were comatose (group C). Abnormal CSA patterns were observed in 15 of the 17 patients (88%). Group B patients seemed to have higher coma grades than did group A patients. Sixteen patients underwent liver transplantation, completely recovered from hepatic encephalopathy, and subsequently showed CSA patterns similar to those of healthy controls. One patient died without regaining consciousness. These results suggest that CSA is useful in assessing the coma status of FHF patients and in evaluating electrophysiological recovery from hepatic coma after liver transplantation.

Is There an Association Between the “Critical Shoulder Angle” and Clinical Outcome After Rotator Cuff Repair?

PubMed Central

Kirsch, Jacob M.; Nathani, Amit; Robbins, Christopher B.; Gagnier, Joel J.; Bedi, Asheesh; Miller, Bruce S.

2017-01-01

Background: Variations in scapular morphology have been associated with the development of atraumatic rotator cuff tears (RCTs). The critical shoulder angle (CSA) accounts for both glenoid inclination and lateral extension of the acromion. The impact of the CSA on outcomes after rotator cuff repair (RCR) has not been investigated previously. Hypothesis: Our hypothesis was that individuals with smaller CSAs will have better patient-reported outcome scores over time compared with those with larger CSAs. Theoretically, a smaller CSA minimizes the biomechanical forces favoring superior translation of the humeral head, which may be advantageous after RCR. This is the first study to examine the relationship between the CSA and clinical outcomes after RCR. Study Design: Cohort study; Level of evidence, 2. Methods: Fifty-three patients (mean age, 61 years) with atraumatic full-thickness RCTs who underwent arthroscopic RCR were prospectively evaluated. Demographic data as well as the Western Ontario Rotator Cuff Index (WORC) score, American Shoulder and Elbow Surgeons (ASES) score, and a visual analog scale (VAS) for pain were prospectively collected at various time points up to 24 months postoperatively. Statistical analysis included longitudinal multilevel regression modeling to investigate the association between the CSA and the WORC, ASES, and VAS scores. Results: The overall clinical outcome, as measured by the WORC, ASES, and VAS, improved significantly (P < .0001). Controlling for demographic and clinical characteristics, a multilevel regression analysis demonstrated that the CSA was not a significant independent predictor for change in WORC (P = .581), ASES (P = .458), or VAS (P = .859) scores at 24 months after arthroscopic RCR. Interobserver and intraobserver reliability for CSA measurements resulted in interclass correlation coefficients of 0.986 and 0.982, respectively (P < .001), indicating excellent agreement. Conclusion: The CSA did not appear to be a significant predictor of patient-reported outcomes after arthroscopic repair of atraumatic full-thickness RCTs. PMID:28451621

Response of human renal tubular cells to cyclosporine and sirolimus: A toxicogenomic study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pallet, Nicolas; Rabant, Marion; Xu-Dubois, Yi-Chun

The molecular mechanisms involved in the potentially nephrotoxic response of tubular cells to immunosuppressive drugs remain poorly understood. Transcriptional profiles of human proximal tubular cells exposed to cyclosporine A (CsA), sirolimus (SRL) or their combination, were established using oligonucleotide microarrays. Hierarchical clustering of genes implicated in fibrotic processes showed a clear distinction between expression profiles with CsA and CsA + SRL treatments on the one hand and SRL treatment on the other. Functional analysis found that CsA and CsA + SRL treatments preferentially alter biological processes located at the cell membrane, such as ion transport or signal transduction, whereas SRLmore » modifies biological processes within the nucleus and related to transcriptional activity. Genome wide expression analysis suggested that CsA may induce an endoplasmic reticulum (ER) stress in tubular cells in vitro. Moreover we found that CsA exposure in vivo is associated with the upregulation of the ER stress marker BIP in kidney transplant biopsies. In conclusion, this toxicogenomic study highlights the molecular interaction networks that may contribute to the tubular response to CsA and SRL. These results may also offer a new working hypothesis for future research in the field of CsA nephrotoxicity. Further studies are needed to evaluate if ER stress detection in tubular cells in human biopsies can predict CsA nephrotoxicity.« less

Immunogenicity and safety of measles-mumps-rubella and varicella vaccines coadministered with a fourth dose of Haemophilus influenzae type b and Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine in toddlers: a pooled analysis of randomized trials.

PubMed

Bryant, Kristina; McVernon, Jodie; Marchant, Colin; Nolan, Terry; Marshall, Gary; Richmond, Peter; Marshall, Helen; Nissen, Michael; Lambert, Stephen; Aris, Emmanuel; Mesaros, Narcisa; Miller, Jacqueline

2012-08-01

A pooled analysis was conducted of 1257 toddlers who received a fourth dose of Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine (HibMenCY-TT) or Hib conjugate vaccine (Hib polysaccharide conjugated to N. meningitidis outer membrane protein) coadministered with measles-mumps-rubella (MMR) and varicella (VAR) vaccines (NCT00134719/NCT00289783). Noninferiority of immunological responses to MMR and VAR was demonstrated between groups and incidences of MMR- and VAR-specific solicited symptoms were similar, indicating that HibMenCY-TT can be coadministered with MMR and VAR.

An Empirical Case Study of a Child Sexual Abuse Prevention Initiative in Georgia

ERIC Educational Resources Information Center

Schober, Daniel J.; Fawcett, Stephen B.; Thigpen, Sally; Curtis, Anna; Wright, Renee

2012-01-01

Objective: This empirical case study describes Prevent Child Abuse Georgia's effort to prevent child sexual abuse (CSA) by educating communities throughout the state on supporting preventive behaviour. The initiative consisted of three major components: (1) dissemination of CSA prevention messages and materials; (2) a statewide helpline that…

77 FR 31066 - Improvements to the Compliance, Safety, Accountability (CSA) Motor Carrier Safety Measurement...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-24

... intervention resources and made available to the public on the SMS public Web site in July 2012. However, based... addressing industry biases; (2) Better applications of SMS results for Agency interventions by more... hauling hazardous materials (HM)), so that such firms can be selected for CSA interventions at more...

Action potential amplitude as a noninvasive indicator of motor unit-specific hypertrophy.

PubMed

Pope, Zachary K; Hester, Garrett M; Benik, Franklin M; DeFreitas, Jason M

2016-05-01

Skeletal muscle fibers hypertrophy in response to strength training, with type II fibers generally demonstrating the greatest plasticity in regards to cross-sectional area (CSA). However, assessing fiber type-specific CSA in humans requires invasive muscle biopsies. With advancements in the decomposition of surface electromyographic (sEMG) signals recorded using multichannel electrode arrays, the firing properties of individual motor units (MUs) can now be detected noninvasively. Since action potential amplitude (APSIZE) has a documented relationship with muscle fiber size, as well as with its parent MU's recruitment threshold (RT) force, our purpose was to examine if MU APSIZE, as a function of its RT (i.e., the size principle), could potentially be used as a longitudinal indicator of MU-specific hypertrophy. By decomposing the sEMG signals from the vastus lateralis muscle of 10 subjects during maximal voluntary knee extensions, we noninvasively assessed the relationship between MU APSIZE and RT before and immediately after an 8-wk strength training intervention. In addition to significant increases in muscle size and strength (P < 0.02), our data show that training elicited an increase in MU APSIZE of high-threshold MUs. Additionally, a large portion of the variance (83.6%) in the change in each individual's relationship between MU APSIZE and RT was explained by training-induced changes in whole muscle CSA (obtained via ultrasonography). Our findings suggest that the noninvasive, electrophysiological assessment of longitudinal changes to MU APSIZE appears to reflect hypertrophy specific to MUs across the RT continuum. Copyright © 2016 the American Physiological Society.

Children's knowledge of sexual abuse prevention in El Salvador.

PubMed

Hurtado, Alicia; Katz, Craig L; Ciro, Dianne; Guttfreund, Daniel; Nosike, Digna

2014-01-01

Child sexual abuse (CSA) remains a global health problem that must be addressed. In a country with limited resources such as El Salvador, we sought an alternative way to disseminate CSA prevention information to elementary school children. The aim of this study was to evaluate the effectiveness of a child sexual abuse (CSA) prevention exhibit at a children's museum. We asked 189 children to answer a questionnaire about CSA prevention before entering a museum exhibit on the subject and then asked 59 different children to answer the questionnaire after visiting the exhibit. Children's knowledge scores on CSA prevention significantly improved after visiting the exhibit (P < .012). A museum exhibit that addresses CSA prevention is an effective way of communicating CSA prevention to children. Copyright © 2014 Icahn School of Medicine at Mount Sinai. Published by Elsevier Inc. All rights reserved.

When the face reveals what words do not: facial expressions of emotion, smiling, and the willingness to disclose childhood sexual abuse.

PubMed

Bonanno, George A; Keltner, Dacher; Noll, Jennie G; Putnam, Frank W; Trickett, Penelope K; LeJeune, Jenna; Anderson, Cameron

2002-07-01

For survivors of childhood sexual abuse (CSA), verbal disclosure is often complex and painful. The authors examined the voluntary disclosure-nondisclosure of CSA in relation to nonverbal expressions of emotion in the face. Consistent with hypotheses derived from recent theorizing about the moral nature of emotion, CSA survivors who did not voluntarily disclose CSA showed greater facial expressions of shame, whereas CSA survivors who voluntarily disclosed CSA expressed greater disgust. Expressions of disgust also signaled sexual abuse accompanied by violence. Consistent with recent theorizing about smiling behavior, CSA nondisclosers made more polite smiles, whereas nonabused participants expressed greater genuine positive emotion. Discussion addressed the implications of these findings for the study of disclosure of traumatic events, facial expression, and the links between morality and emotion.

Atmospheric effects on the mapping of Martian thermal inertia and thermally derived albedo

NASA Technical Reports Server (NTRS)

Hayashi, Joan N.; Jakosky, Bruce M.; Haberle, Robert M.

1995-01-01

We examine the effects of a dusty CO2 atmosphere on the thermal inertia and thermally derived albedo of Mars and we present a new map of thermal inertias. This new map was produced using a coupled surface atmosphere (CSA) model, dust opacities from Viking infrared thermal mapper (IRTM) data, and CO2 columns based on topography. The CSA model thermal inertias are smaller than the 2% model thermal inertias, with the difference largest at large thermal inertia. Although the difference between the thermal inertias obtained with the two models is moderate for much of the region studied, it is largest in regions of either high dust opacity or of topographic lows, including the Viking Lander 1 site and some geologically interesting regions. The CSA model thermally derived albedos do not acurately predict the IRTM measured albedos and are very similar to the thermally derived albedos obtained with models making the 2% assumption.

Vector Autoregressive (VAR) Models and Granger Causality in Time Series Analysis in Nursing Research: Dynamic Changes Among Vital Signs Prior to Cardiorespiratory Instability Events as an Example

PubMed Central

Bose, Eliezer; Hravnak, Marilyn; Sereika, Susan M.

2016-01-01

Background Patients undergoing continuous vital sign monitoring (heart rate [HR], respiratory rate [RR], pulse oximetry [SpO2]) in real time display inter-related vital sign changes during situations of physiologic stress. Patterns in this physiological cross-talk could portend impending cardiorespiratory instability (CRI). Vector autoregressive (VAR) modeling with Granger causality tests is one of the most flexible ways to elucidate underlying causal mechanisms in time series data. Purpose The purpose of this article is to illustrate development of patient-specific VAR models using vital sign time series (VSTS) data in a sample of acutely ill, monitored, step-down unit (SDU) patients, and determine their Granger causal dynamics prior to onset of an incident CRI. Approach CRI was defined as vital signs beyond stipulated normality thresholds (HR = 40–140/minute, RR = 8–36/minute, SpO2 < 85%) and persisting for 3 minutes within a 5-minute moving window (60% of the duration of the window). A 6-hour time segment prior to onset of first CRI was chosen for time series modeling in 20 patients using a six-step procedure: (a) the uniform time series for each vital sign was assessed for stationarity; (b) appropriate lag was determined using a lag-length selection criteria; (c) the VAR model was constructed; (d) residual autocorrelation was assessed with the Lagrange Multiplier test; (e) stability of the VAR system was checked; and (f) Granger causality was evaluated in the final stable model. Results The primary cause of incident CRI was low SpO2 (60% of cases), followed by out-of-range RR (30%) and HR (10%). Granger causality testing revealed that change in RR caused change in HR (21%) (i.e., RR changed before HR changed) more often than change in HR causing change in RR (15%). Similarly, changes in RR caused changes in SpO2 (15%) more often than changes in SpO2 caused changes in RR (9%). For HR and SpO2, changes in HR causing changes in SpO2 and changes in SpO2 causing changes in HR occurred with equal frequency (18%). Discussion Within this sample of acutely ill patients who experienced a CRI event, VAR modeling indicated that RR changes tend to occur before changes in HR and SpO2. These findings suggest that contextual assessment of RR changes as the earliest sign of CRI is warranted. Use of VAR modeling may be helpful in other nursing research applications based on time series data. PMID:27977564

Feline coronavirus replication is affected by both cyclophilin A and cyclophilin B.

PubMed

Tanaka, Yoshikazu; Sato, Yuka; Sasaki, Takashi

2017-02-01

Feline coronavirus (FCoV) causes the fatal disease feline infectious peritonitis, which is currently incurable by drug treatment, and no effective vaccines are available. Cyclosporin A (CsA), a cyclophilin (Cyp) inhibitor, inhibits the replication of FCoV in vitro and in vivo as well as the replication of human and animal coronaviruses. However, the mechanism underlying the regulation of coronavirus replication by CsA is unknown. In this study, we analysed the role of Cyps in FCoV replication using knockdown and knockout cells specific to Cyps. Inhibition of CypA and CypB reduced FCoV replication, with replication in knockout cells being much less than that in knockdown cells. Furthermore, the proteins expressed by CypA and CypB harbouring mutations in their respective predicted peptidyl-prolyl cis-transisomerase active sites, which also alter the affinities between Cyps and CsA, inhibited FCoV replication. These findings indicate that the peptidyl-prolyl cis-transisomerase active sites of Cyps might be required for FCoV replication.

Flavonoids with DNA strand-scission activity from Rhus javanica var. roxburghiana.

PubMed

Lin, Chun-Nan; Chen, Hui-Ling; Yen, Ming-Hong

2008-01-01

The flavonoids isolated from the stems of Rhus javanica var. roxburghiana, taxifolin (1), fisetin (2), fustin (3), 3,7,4'-trihydroxyflavanone (4) and 3,7,4'-trihydroxyflavone (5) caused breakage of supercoiled plasmid pBR322 DNA in the presence of Cu(II). Cu(I) was shown to be an essential intermediate by using the Cu(I)-specific sequestering reagent neocuproine. The Cu(II)-mediated DNA scissions induced by 1, 2, 3 and 5 were inhibited by the addition of catalase and exhibited DNA strand break by the addition of KI and superoxide dimutase (SOD), while in the Cu(II)-mediated DNA scissions induced by 4 was inhibited by the addition of KI, SOD, and catalase. It is concluded that 1, 2, 3, and 5 can induce H2O2 and superoxide anion, while 4 can induce OH* and H2O2 and subsequent oxidative damage of DNA in the presence of Cu(II).

Critical role of free cytosolic calcium, but not uncoupling, in mitochondrial permeability transition and cell death induced by diclofenac oxidative metabolites in immortalized human hepatocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lim, M.S.; Lim, Priscilla L.K.; Gupta, Rashi

2006-12-15

Diclofenac is a widely used nonsteroidal anti-inflammatory drug that has been associated with rare but serious hepatotoxicity. Experimental evidence indicates that diclofenac targets mitochondria and induces the permeability transition (mPT) which leads to apoptotic cell death in hepatocytes. While the downstream effector mechanisms have been well characterized, the more proximal pathways leading to the mPT are not known. The purpose of this study was to explore the role of free cytosolic calcium (Ca{sup 2+} {sub c}) in diclofenac-induced cell injury in immortalized human hepatocytes. We show that exposure to diclofenac caused time- and concentration-dependent cell injury, which was prevented bymore » the specific mPT inhibitor cyclosporin A (CsA, 5 {mu}M). At 8 h, diclofenac caused increases in [Ca{sup 2+}]{sub c} (Fluo-4 fluorescence), which was unaffected by CsA. Combined exposure to diclofenac/BAPTA (Ca{sup 2+} chelator) inhibited cell injury, indicating that Ca{sup 2+} plays a critical role in precipitating mPT. Diclofenac decreased the mitochondrial membrane potential, {delta}{psi}{sub m} (JC-1 fluorescence), even in the presence of CsA or BAPTA, indicating that mitochondrial depolarization was not a consequence of the mPT or elevated [Ca{sup 2+}]{sub c}. The CYP2C9 inhibitor sulphaphenazole (10 {mu}M) protected from diclofenac-induced cell injury and prevented increases in [Ca{sup 2+}]{sub c}, while it had no effect on the dissipation of the {delta}{psi}{sub m}. Finally, diclofenac exposure greatly increased the mitochondria-selective superoxide levels secondary to the increases in [Ca{sup 2+}]{sub c}. In conclusion, these data demonstrate that diclofenac has direct depolarizing effects on mitochondria which does not lead to cell injury, while CYP2C9-mediated bioactivation causes increases in [Ca{sup 2+}]{sub c}, triggering the mPT and precipitating cell death.« less

10 CFR 431.447 - Department of Energy recognition of nationally recognized certification programs.

Code of Federal Regulations, 2013 CFR

2013-01-01

... IEEE Std 112-2004 Test Methods A and B, IEEE Std 114-2010, CSA C390-10, and CSA C747 (incorporated by... IEEE Std 112-2004 Test Methods A and B, IEEE Std 114-2010, CSA C390-10, and CSA C747- (incorporated by...

10 CFR 431.447 - Department of Energy recognition of nationally recognized certification programs.

Code of Federal Regulations, 2014 CFR

2014-01-01

... IEEE Std 112-2004 Test Methods A and B, IEEE Std 114-2010, CSA C390-10, and CSA C747 (incorporated by... IEEE Std 112-2004 Test Methods A and B, IEEE Std 114-2010, CSA C390-10, and CSA C747- (incorporated by...

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qi Xinming; Cai Yan; Gong Likun

Aristolochic acid (AA), a natural nephrotoxin and carcinogen, can induce a progressive tubulointerstitial nephropathy. However, the mechanism by which AA causes renal injury remains largely unknown. Here we reported that the mitochondrial permeability transition (MPT) plays an important role in the renal injury induced by aristolochic acid I (AAI). We found that in the presence of Ca{sup 2+}, AAI caused mitochondrial swelling, leakage of Ca{sup 2+}, membrane depolarization, and release of cytochrome c in isolated kidney mitochondria. These alterations were suppressed by cyclosporin A (CsA), an agent known to inhibit MPT. Culture of HK-2 cell, a human renal tubular epithelialmore » cell line for 24 h with AAI caused a decrease in cellular ATP, mitochondrial membrane depolarization, cytochrome c release, and increase of caspase 3 activity. These toxic effects of AAI were attenuated by CsA and bongkrekic acid (BA), another specific MPT inhibitor. Furthermore, AAI greatly inhibited the activity of mitochondrial adenine nucleotide translocator (ANT) in isolated mitochondria. We suggested that ANT may mediate, at least in part, the AAI-induced MPT. Taken together, these results suggested that MPT plays a critical role in the pathogenesis of HK-2 cell injury induced by AAI and implied that MPT might contribute to human nephrotoxicity of aristolochic acid.« less

Monoacylglycerol lipase (MGLL) polymorphism rs604300 interacts with childhood adversity to predict cannabis dependence symptoms and amygdala habituation: Evidence from an endocannabinoid system-level analysis

PubMed Central

Carey, Caitlin E.; Agrawal, Arpana; Zhang, Bo; Conley, Emily D.; Degenhardt, Louisa; Heath, Andrew C.; Li, Daofeng; Lynskey, Michael T.; Martin, Nicholas G.; Montgomery, Grant W.; Wang, Ting; Bierut, Laura J.; Hariri, Ahmad R.; Nelson, Elliot C.; Bogdan, Ryan

2015-01-01

Despite evidence for heritable variation in cannabis involvement and the discovery of cannabinoid receptors and their endogenous ligands, no consistent patterns have emerged from candidate endocannabinoid (eCB) genetic association studies of cannabis involvement. Given interactions between eCB and stress systems and associations between childhood stress and cannabis involvement, it may be important to consider childhood adversity in the context of eCB-related genetic variation. We employed a system-level gene-based analysis of data from the Comorbidity and Trauma Study (N = 1,558) to examine whether genetic variation in 6 eCB genes (anabolism: DAGLA, DAGLB, NAPEPLD, catabolism: MGLL, FAAH, binding: CNR1; SNPs N = 65) and childhood sexual abuse (CSA) predicts cannabis dependence symptoms. Significant interactions with CSA emerged for MGLL at the gene-level (p = .009), and for rs604300 within MGLL (ΔR2 = .007, p < .001), the latter of which survived SNP-level Bonferroni correction and was significant in an additional sample with similar directional effects (N = 859; ΔR2 = .005, p = .026). Furthermore, in a third sample (N = 312), there was evidence that rs604300 genotype interacts with early life adversity to predict threat-related basolateral amygdala habituation, a neural phenotype linked to the eCB system and addiction (ΔR2 = .013, p = .047). Rs604300 may be related to epigenetic modulation of MGLL expression. These results are consistent with rodent models implicating 2-arachidonoylglycerol (2-AG), an endogenous cannabinoid metabolized by the enzyme encoded by MGLL, in the etiology of stress adaptation related to cannabis dependence, but require further replication. PMID:26595473

The effect of cyclosporin-A on peri-operative myocardial injury in adult patients undergoing coronary artery bypass graft surgery: a randomised controlled clinical trial

PubMed Central

Hausenloy, DJ; Kunst, G; Boston-Griffiths, E; Kolvekar, S; Chaubey, S; John, L; Desai, J; Yellon, DM

2014-01-01

Objective Cyclosporin-A (CsA) has been reported to reduce myocardial infarct size in both the experimental and clinical settings. This protective effect is dependent on its ability to prevent the opening of the mitochondrial permeability transition pore, a critical determinant of cell death in the setting of acute ischaemia-reperfusion injury. Whether CsA can reduce the extent of peri-operative myocardial injury (PMI) in patients undergoing coronary artery bypass graft (CABG) surgery is unknown, and is investigated in this randomised controlled clinical trial. Methods 78 adult patients undergoing elective CABG surgery were randomised to receive either an intravenous bolus of CsA (2.5 mg/kg) or placebo administered after induction of anaesthesia and prior to sternotomy. PMI was assessed by measuring serum cardiac enzymes, troponin T (cTnT) and CK-MB at 0, 6, 12, 24, 48 and 72 h after surgery. Results There was no significant difference in mean peak cTnT levels between control (n=43) and CsA treatment (n=40) patients (0.56±0.06 ng/mL with control vs 0.35±0.05 ng/mL with CsA; p=0.07). However, in higher-risk patients with longer cardiopulmonary bypass times, there was a significant reduction in PMI with CsA therapy (p=0.049), with a reduced postoperative cTnT rise by 0.03 ng/mL for every 10 min, when compared with control. Conclusions In patients with longer cardiopulmonary bypass times, a single intravenous bolus of CsA administered prior to CABG surgery reduced the extent of PMI. PMID:24488610

Effects of expressive writing on sexual dysfunction, depression, and PTSD in women with a history of childhood sexual abuse: Results from a randomized clinical trial

PubMed Central

Meston, Cindy M.; Lorenz, Tierney A.; Stephenson, Kyle R.

2013-01-01

Introduction Women with a history of childhood sexual abuse (CSA) have high rates of depression, post-traumatic stress disorder, and sexual problems in adulthood. Aim We tested an expressive writing based intervention for its effects on psychopathology, sexual function, satisfaction and distress in women who have a history of CSA. Main Outcome measures Validated self-report measures of psychopathology and sexual function were conducted at post-treatment, 2 weeks, one month, and six months. Methods Seventy women with CSA histories completed five 30-minute sessions of expressive writing, either with a trauma focus or a sexual schema focus. Results Women in both writing interventions exhibited improved symptoms of depression and posttraumatic stress disorder (PTSD). Women who were instructed to write about the impact of the abuse on their sexual schema were significantly more likely to recover from sexual dysfunction. Conclusions Expressive writing may improve depressive and PTSD symptoms in women with CSA histories. Sexual schema-focused expressive writing in particular appears to improve sexual problems, especially for depressed women with CSA histories. Both treatments are accessible, cost-effective, and acceptable to patients. PMID:23875721

Effects of expressive writing on sexual dysfunction, depression, and PTSD in women with a history of childhood sexual abuse: results from a randomized clinical trial.

PubMed

Meston, Cindy M; Lorenz, Tierney A; Stephenson, Kyle R

2013-09-01

Women with a history of childhood sexual abuse (CSA) have high rates of depression, posttraumatic stress disorder, and sexual problems in adulthood. We tested an expressive writing-based intervention for its effects on psychopathology, sexual function, satisfaction, and distress in women who have a history of CSA. Seventy women with CSA histories completed five 30-minute sessions of expressive writing, either with a trauma focus or a sexual schema focus. Validated self-report measures of psychopathology and sexual function were conducted at posttreatment: 2 weeks, 1 month, and 6 months. Women in both writing interventions exhibited improved symptoms of depression and posttraumatic stress disorder (PTSD). Women who were instructed to write about the impact of the abuse on their sexual schema were significantly more likely to recover from sexual dysfunction. Expressive writing may improve depressive and PTSD symptoms in women with CSA histories. Sexual schema-focused expressive writing in particular appears to improve sexual problems, especially for depressed women with CSA histories. Both treatments are accessible, cost-effective, and acceptable to patients. © 2013 International Society for Sexual Medicine.