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Sample records for replication clinical progression

  1. Regulation of replication fork progression through histone supply and demand

    DEFF Research Database (Denmark)

    Groth, Anja; Corpet, Armelle; Cook, Adam J L

    2007-01-01

    DNA replication in eukaryotes requires nucleosome disruption ahead of the replication fork and reassembly behind. An unresolved issue concerns how histone dynamics are coordinated with fork progression to maintain chromosomal stability. Here, we characterize a complex in which the human histone...... chaperone Asf1 and MCM2-7, the putative replicative helicase, are connected through a histone H3-H4 bridge. Depletion of Asf1 by RNA interference impedes DNA unwinding at replication sites, and similar defects arise from overproduction of new histone H3-H4 that compromises Asf1 function. These data link Asf......1 chaperone function, histone supply, and replicative unwinding of DNA in chromatin. We propose that Asf1, as a histone acceptor and donor, handles parental and new histones at the replication fork via an Asf1-(H3-H4)-MCM2-7 intermediate and thus provides a means to fine-tune replication fork...

  2. Replication fork progression is paused in two large chromosomal zones flanking the DNA replication origin in Escherichia coli.

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    Akiyama, Masahiro Tatsumi; Oshima, Taku; Chumsakul, Onuma; Ishikawa, Shu; Maki, Hisaji

    2016-08-01

    Although the speed of nascent DNA synthesis at individual replication forks is relatively uniform in bacterial cells, the dynamics of replication fork progression on the chromosome are hampered by a variety of natural impediments. Genome replication dynamics can be directly measured from an exponentially growing cell population by sequencing newly synthesized DNA strands that were specifically pulse-labeled with the thymidine analogue 5-bromo-2'-deoxyuridine (BrdU). However, a short pulse labeling with BrdU is impracticable for bacteria because of poor incorporation of BrdU into the cells, and thus, the genomewide dynamics of bacterial DNA replication remain undetermined. Using a new thymidine-requiring Escherichia coli strain, eCOMB, and high-throughput sequencing, we succeeded in determining the genomewide replication profile in bacterial cells. We also found that fork progression is paused in two ~200-kb chromosomal zones that flank the replication origin in the growing cells. This origin-proximal obstruction to fork progression was overcome by an increased thymidine concentration in the culture medium and enhanced by inhibition of transcription. These indicate that DNA replication near the origin is sensitive to the impediments to fork progression, namely a scarcity of the DNA precursor deoxythymidine triphosphate and probable conflicts between replication and transcription machineries.

  3. DNA copy-number control through inhibition of replication fork progression

    NARCIS (Netherlands)

    J.T. Nordman (Jared T.); E. Kozhevnikova (Elena); C.P. Verrijzer (Peter); A.V. Pindyurin (Alexey); E.N. Andreyeva (Evgeniya); V.V. Shloma (Victor); I.F. Zhimulev (Igor); T. Orr-Weaver (T.)

    2014-01-01

    textabstractProper control of DNA replication is essential to ensure faithful transmission of genetic material and prevent chromosomal aberrations that can drive cancer progression and developmental disorders. DNA replication is regulated primarily at the level of initiation and is under strict

  4. DNA copy-number control through inhibition of replication fork progression

    NARCIS (Netherlands)

    J.T. Nordman (Jared T.); E. Kozhevnikova (Elena); C.P. Verrijzer (Peter); A.V. Pindyurin (Alexey); E.N. Andreyeva (Evgeniya); V.V. Shloma (Victor); I.F. Zhimulev (Igor); T. Orr-Weaver (T.)

    2014-01-01

    textabstractProper control of DNA replication is essential to ensure faithful transmission of genetic material and prevent chromosomal aberrations that can drive cancer progression and developmental disorders. DNA replication is regulated primarily at the level of initiation and is under strict cell

  5. DNA copy-number control through inhibition of replication fork progression

    NARCIS (Netherlands)

    J.T. Nordman (Jared T.); E. Kozhevnikova (Elena); C.P. Verrijzer (Peter); A.V. Pindyurin (Alexey); E.N. Andreyeva (Evgeniya); V.V. Shloma (Victor); I.F. Zhimulev (Igor); T. Orr-Weaver (T.)

    2014-01-01

    textabstractProper control of DNA replication is essential to ensure faithful transmission of genetic material and prevent chromosomal aberrations that can drive cancer progression and developmental disorders. DNA replication is regulated primarily at the level of initiation and is under strict cell

  6. [Mechanisms of inhibition of viral replication in plants]. Progress report

    Energy Technology Data Exchange (ETDEWEB)

    1992-09-01

    Progress is described concerning genetic mapping CMV movement genes for CMV coat protein in squash and ToMV gene in tomato. These gene products appear to be involved in resistance to squash and tomato mosaic viruses respectively.

  7. MMSET is dynamically regulated during cell-cycle progression and promotes normal DNA replication.

    Science.gov (United States)

    Evans, Debra L; Zhang, Haoxing; Ham, Hyoungjun; Pei, Huadong; Lee, SeungBaek; Kim, JungJin; Billadeau, Daniel D; Lou, Zhenkun

    2016-01-01

    The timely and precise duplication of cellular DNA is essential for maintaining genome integrity and is thus tightly-regulated. During mitosis and G1, the Origin Recognition Complex (ORC) binds to future replication origins, coordinating with multiple factors to load the minichromosome maintenance (MCM) complex onto future replication origins as part of the pre-replication complex (pre-RC). The pre-RC machinery, in turn, remains inactive until the subsequent S phase when it is required for replication fork formation, thereby initiating DNA replication. Multiple myeloma SET domain-containing protein (MMSET, a.k.a. WHSC1, NSD2) is a histone methyltransferase that is frequently overexpressed in aggressive cancers and is essential for normal human development. Several studies have suggested a role for MMSET in cell-cycle regulation; however, whether MMSET is itself regulated during cell-cycle progression has not been examined. In this study, we report that MMSET is degraded during S phase in a cullin-ring ligase 4-Cdt2 (CRL4(Cdt2)) and proteasome-dependent manner. Notably, we also report defects in DNA replication and a decreased association of pre-RC factors with chromatin in MMSET-depleted cells. Taken together, our results suggest a dynamic regulation of MMSET levels throughout the cell cycle, and further characterize the role of MMSET in DNA replication and cell-cycle progression.

  8. Human ribonuclease H1 resolves R-loops and thereby enables progression of the DNA replication fork.

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    Parajuli, Shankar; Teasley, Daniel C; Murali, Bhavna; Jackson, Jessica; Vindigni, Alessandro; Stewart, Sheila A

    2017-09-15

    Faithful DNA replication is essential for genome stability. To ensure accurate replication, numerous complex and redundant replication and repair mechanisms function in tandem with the core replication proteins to ensure DNA replication continues even when replication challenges are present that could impede progression of the replication fork. A unique topological challenge to the replication machinery is posed by RNA-DNA hybrids, commonly referred to as R-loops. Although R-loops play important roles in gene expression and recombination at immunoglobulin sites, their persistence is thought to interfere with DNA replication by slowing or impeding replication fork progression. Therefore, it is of interest to identify DNA-associated enzymes that help resolve replication-impeding R-loops. Here, using DNA fiber analysis, we demonstrate that human ribonuclease H1 (RNH1) plays an important role in replication fork movement in the mammalian nucleus by resolving R-loops. We found that RNH1 depletion results in accumulation of RNA-DNA hybrids, slowing of replication forks, and increased DNA damage. Our data uncovered a role for RNH1 in global DNA replication in the mammalian nucleus. Because accumulation of RNA-DNA hybrids is linked to various human cancers and neurodegenerative disorders, our study raises the possibility that replication fork progression might be impeded, adding to increased genomic instability and contributing to disease. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication

    Science.gov (United States)

    Sacramento, Carolina Q.; de Melo, Gabrielle R.; de Freitas, Caroline S.; Rocha, Natasha; Hoelz, Lucas Villas Bôas; Miranda, Milene; Fintelman-Rodrigues, Natalia; Marttorelli, Andressa; Ferreira, André C.; Barbosa-Lima, Giselle; Abrantes, Juliana L.; Vieira, Yasmine Rangel; Bastos, Mônica M.; de Mello Volotão, Eduardo; Nunes, Estevão Portela; Tschoeke, Diogo A.; Leomil, Luciana; Loiola, Erick Correia; Trindade, Pablo; Rehen, Stevens K.; Bozza, Fernando A.; Bozza, Patrícia T.; Boechat, Nubia; Thompson, Fabiano L.; de Filippis, Ana M. B.; Brüning, Karin; Souza, Thiago Moreno L.

    2017-01-01

    Zika virus (ZIKV) is a member of the Flaviviridae family, along with other agents of clinical significance such as dengue (DENV) and hepatitis C (HCV) viruses. Since ZIKV causes neurological disorders during fetal development and in adulthood, antiviral drugs are necessary. Sofosbuvir is clinically approved for use against HCV and targets the protein that is most conserved among the members of the Flaviviridae family, the viral RNA polymerase. Indeed, we found that sofosbuvir inhibits ZIKV RNA polymerase, targeting conserved amino acid residues. Sofosbuvir inhibited ZIKV replication in different cellular systems, such as hepatoma (Huh-7) cells, neuroblastoma (SH-Sy5y) cells, neural stem cells (NSC) and brain organoids. In addition to the direct inhibition of the viral RNA polymerase, we observed that sofosbuvir also induced an increase in A-to-G mutations in the viral genome. Together, our data highlight a potential secondary use of sofosbuvir, an anti-HCV drug, against ZIKV. PMID:28098253

  10. Clinical Trials: Key to Medical Progress

    Science.gov (United States)

    Skip Navigation Bar Home Current Issue Past Issues Clinical Trials: Key to Medical Progress Past Issues / Summer 2008 ... this page please turn Javascript on. Photo iStock Clinical trials are research studies that test how well new ...

  11. The XNA world: progress towards replication and evolution of synthetic genetic polymers.

    Science.gov (United States)

    Pinheiro, Vitor B; Holliger, Philipp

    2012-08-01

    Life's diversity is built on the wide range of properties and functions that can be encoded in natural biopolymers such as polypeptides and nucleic acids. However, despite their versatility, the range of chemical functionalities is limited, particularly in the case of nucleic acids. Chemical modification of nucleic acids can greatly increase their functional diversity but access to the full phenotypic potential of such polymers requires a system of replication. Here we review progress in the chemical and enzymatic synthesis, replication and evolution of unnatural nucleic acid polymers, which promises to enable the exploration of a vast sequence space not accessible to nature and deliver ligands, catalysts and materials based on this new class of biopolymers. Copyright © 2012 Elsevier Ltd. All rights reserved.

  12. Unligated Okazaki Fragments Induce PCNA Ubiquitination and a Requirement for Rad59-Dependent Replication Fork Progression.

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    Hai Dang Nguyen

    Full Text Available Deficiency in DNA ligase I, encoded by CDC9 in budding yeast, leads to the accumulation of unligated Okazaki fragments and triggers PCNA ubiquitination at a non-canonical lysine residue. This signal is crucial to activate the S phase checkpoint, which promotes cell cycle delay. We report here that a pol30-K107 mutation alleviated cell cycle delay in cdc9 mutants, consistent with the idea that the modification of PCNA at K107 affects the rate of DNA synthesis at replication forks. To determine whether PCNA ubiquitination occurred in response to nicks or was triggered by the lack of PCNA-DNA ligase interaction, we complemented cdc9 cells with either wild-type DNA ligase I or a mutant form, which fails to interact with PCNA. Both enzymes reversed PCNA ubiquitination, arguing that the modification is likely an integral part of a novel nick-sensory mechanism and not due to non-specific secondary mutations that could have occurred spontaneously in cdc9 mutants. To further understand how cells cope with the accumulation of nicks during DNA replication, we utilized cdc9-1 in a genome-wide synthetic lethality screen, which identified RAD59 as a strong negative interactor. In comparison to cdc9 single mutants, cdc9 rad59Δ double mutants did not alter PCNA ubiquitination but enhanced phosphorylation of the mediator of the replication checkpoint, Mrc1. Since Mrc1 resides at the replication fork and is phosphorylated in response to fork stalling, these results indicate that Rad59 alleviates nick-induced replication fork slowdown. Thus, we propose that Rad59 promotes fork progression when Okazaki fragment processing is compromised and counteracts PCNA-K107 mediated cell cycle arrest.

  13. Excess Cdt1 inhibits nascent strand elongation by repressing the progression of replication forks in Xenopus egg extracts.

    Science.gov (United States)

    Nakazaki, Yuta; Tsuyama, Takashi; Seki, Masayuki; Takahashi, Mikiko; Enomoto, Takemi; Tada, Shusuke

    2016-02-01

    Cdt1 is a protein essential for initiation of DNA replication; it recruits MCM helicase, a core component of the replicative DNA helicase, onto replication origins. In our previous study, we showed that addition of excess Cdt1 inhibits nascent strand elongation during DNA replication in Xenopus egg extracts. In the present study, we investigated the mechanism behind the inhibitory effect of Cdt1. We found that addition of recombinant Cdt1 inhibited nascent DNA synthesis in a reinitiation-independent manner. To identify the mechanism by which Cdt1 inhibits nascent strand elongation, the effect of Cdt1 on loading of Mcm4 and Rpa70 onto chromatin was examined. The results showed that Cdt1 suppressed the excessive Rpa70 binding caused by extensive, aphidicolin-induced DNA unwinding; this unwinding occurs between stalled DNA polymerases and advancing replication forks. These findings suggested that excess Cdt1 suppressed the progression of replication forks.

  14. Replicative nature of Indian research, essence of scientific temper, and future of scientific progress

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    Ajai R. Singh

    2004-05-01

    Full Text Available A lot of Indian research is replicative in nature. This is because originality is at a premium here and mediocrity is in great demand. But replication has its merit as well because it helps in corroboration. And that is the bedrock on which many a fancied scientific hypothesis or theory stands, or falls. However, to go from replicative to original research will involve a massive effort to restructure the Indian psyche and an all round effort from numerous quarters. The second part of this paper deals with the essence of scientific temper,which need not have any basic friendship, or animosity, with religion, faith, superstition and other such entities. A true scientist follows two cardinal rules. He is never unwilling to accept the worth of evidence, howsoever damning to the most favourite of his theories. Second, and perhaps more important, for want of evidence, he withholds comment. He says neither yes nor no. Where will Science ultimately lead Man is the third part of this essay. One argument is that the conflict between Man and Science will continue tilleither of them is exhausted or wiped out. The other believes that it is Science which has to be harnessed for Man and not Man used for Science. And with the numerous checks and balances in place, Science will remain an effective tool for man's progress. The essential value-neutrality of Science will have to be supplemented by the values that man has upheld for centuries as fundamental, and which religious thought and moral philosophy have continuously professed.

  15. 3D replicon distributions arise from stochastic initiation and domino-like DNA replication progression.

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    Löb, D; Lengert, N; Chagin, V O; Reinhart, M; Casas-Delucchi, C S; Cardoso, M C; Drossel, B

    2016-04-07

    DNA replication dynamics in cells from higher eukaryotes follows very complex but highly efficient mechanisms. However, the principles behind initiation of potential replication origins and emergence of typical patterns of nuclear replication sites remain unclear. Here, we propose a comprehensive model of DNA replication in human cells that is based on stochastic, proximity-induced replication initiation. Critical model features are: spontaneous stochastic firing of individual origins in euchromatin and facultative heterochromatin, inhibition of firing at distances below the size of chromatin loops and a domino-like effect by which replication forks induce firing of nearby origins. The model reproduces the empirical temporal and chromatin-related properties of DNA replication in human cells. We advance the one-dimensional DNA replication model to a spatial model by taking into account chromatin folding in the nucleus, and we are able to reproduce the spatial and temporal characteristics of the replication foci distribution throughout S-phase.

  16. Clinical neurorestorative progress in amyotrophic lateral sclerosis

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    Chen L

    2015-08-01

    Full Text Available Lin Chen,1,2,5 Hongyun Huang,3 Haitao Xi,4,5 Gengsheng Mao3 1Medical Center, Tsinghua University, 2Tsinghua University Yuquan Hospital, 3General Hospital of Chinese People's Armed Police Forces, 4Beijing Rehabilitation Hospital of Capital Medical University, 5Beijing Hongtianji Neuroscience Academy, Beijing, People’s Republic of China Abstract: Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease characterized by progressive paralysis and motor neuron death. In addition to symptomatic managements such as ventilation and nutritional support, neurorestorative therapies have demonstrated anti-neurodegenerative potential and may improve quality of life for patients. Currently, clinical neurorestorative strategies include pharmacological management (granulocyte colony stimulating factor, neuromodulatory intervention (repetitive transcranial magnetic and cortical stimulation, cell transplantation (bone marrow stromal cells, olfactory ensheathing cells, granulocyte colony stimulating factor-mobilized peripheral blood stromal cells, hematopoietic stem and progenitor cells, neural stem/progenitor cells, CD133+ cells and CD34+ cells, bioengineering and tissue engineering therapy, and combined neurorehabilitative treatment. In this review, we describe the latest progress in clinical neurorestorative management of amyotrophic lateral sclerosis and discuss the underlying evidence base. Keywords: amyotrophic lateral sclerosis, neurorestorative treatment, cell transplantation, clinical trial

  17. Hybrid antibiotics - clinical progress and novel designs.

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    Parkes, Alastair L; Yule, Ian A

    2016-07-01

    There is a growing need for new antibacterial agents, but success in development of antibiotics in recent years has been limited. This has led researchers to investigate novel approaches to finding compounds that are effective against multi-drug resistant bacteria, and that delay onset of resistance. One such strategy has been to link antibiotics to produce hybrids designed to overcome resistance mechanisms. The concept of dual-acting hybrid antibiotics was introduced and reviewed in this journal in 2010. In the present review the authors sought to discover how clinical candidates described had progressed, and to examine how the field has developed. In three sections the authors cover the clinical progress of hybrid antibiotics, novel agents produced from hybridisation of two or more small-molecule antibiotics, and novel agents produced from hybridisation of antibiotics with small-molecules that have complementary activity. Many key questions regarding dual-acting hybrid antibiotics remain to be answered, and the proposed benefits of this approach are yet to be demonstrated. While Cadazolid in particular continues to progress in the clinic, suggesting that there is promise in hybridisation through covalent linkage, it may be that properties other than antibacterial activity are key when choosing a partner molecule.

  18. Body mass index, weight change, and clinical progression in mild cognitive impairment and Alzheimer disease.

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    Besser, Lilah M; Gill, Dawn P; Monsell, Sarah E; Brenowitz, Willa; Meranus, Dana H; Kukull, Walter; Gustafson, Deborah R

    2014-01-01

    The speed and severity of clinical progression after Alzheimer disease (AD) diagnosis varies and depends on multiple factors, most not well elucidated. We assessed whether body mass index (BMI) and 1-year weight change (WC) are associated with clinical progression in amnestic mild cognitive impairment (aMCI) and early-stage AD. Longitudinal data comprising 2268 aMCI and 1506 AD participants in the National Alzheimer's Coordinating Center's Uniform Data Set were used to examine nuances of clinical progression by BMI and WC, as well as potential variations in associations by age, sex, BMI (WC model), or apolipoprotein E genotype. In aMCI, high BMI (vs. moderate BMI) was associated with slower progression; weight loss (vs. no WC) was associated with faster progression. In AD, no significant differences were observed in clinical progression by BMI or WC. The association between BMI and clinical progression varied significantly by apolipoprotein E genotype in AD, and the association between WC and clinical progression varied significantly by sex and BMI in aMCI. Baseline BMI and 1-year WC in late life may serve as early prognostic indicators in aMCI and early-stage AD. If replicated, these results may help in counseling patients on anticipated clinical progression and suggest windows of opportunity for intervention.

  19. Genome-wide alterations of the DNA replication program during tumor progression

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    Arneodo, A.; Goldar, A.; Argoul, F.; Hyrien, O.; Audit, B.

    2016-08-01

    Oncogenic stress is a major driving force in the early stages of cancer development. Recent experimental findings reveal that, in precancerous lesions and cancers, activated oncogenes may induce stalling and dissociation of DNA replication forks resulting in DNA damage. Replication timing is emerging as an important epigenetic feature that recapitulates several genomic, epigenetic and functional specificities of even closely related cell types. There is increasing evidence that chromosome rearrangements, the hallmark of many cancer genomes, are intimately associated with the DNA replication program and that epigenetic replication timing changes often precede chromosomic rearrangements. The recent development of a novel methodology to map replication fork polarity using deep sequencing of Okazaki fragments has provided new and complementary genome-wide replication profiling data. We review the results of a wavelet-based multi-scale analysis of genomic and epigenetic data including replication profiles along human chromosomes. These results provide new insight into the spatio-temporal replication program and its dynamics during differentiation. Here our goal is to bring to cancer research, the experimental protocols and computational methodologies for replication program profiling, and also the modeling of the spatio-temporal replication program. To illustrate our purpose, we report very preliminary results obtained for the chronic myelogeneous leukemia, the archetype model of cancer. Finally, we discuss promising perspectives on using genome-wide DNA replication profiling as a novel efficient tool for cancer diagnosis, prognosis and personalized treatment.

  20. Deep-Sequence Identification and Role in Virus Replication of a JC Virus Quasispecies in Patients with Progressive Multifocal Leukoencephalopathy.

    Science.gov (United States)

    Takahashi, Kenta; Sekizuka, Tsuyoshi; Fukumoto, Hitomi; Nakamichi, Kazuo; Suzuki, Tadaki; Sato, Yuko; Hasegawa, Hideki; Kuroda, Makoto; Katano, Harutaka

    2017-01-01

    JC virus (JCV) is a DNA virus causing progressive multifocal leukoencephalopathy (PML) in immunodeficient patients. In the present study, 22 genetic quasispecies with more than 1.5% variant frequency were detected in JCV genomes from six clinical samples of PML by next-generation sequencing. A mutation from A to C at nucleotide (nt) 3495 in JCV Mad1 resulting in a V-to-G amino acid substitution at amino acid (aa) position 392 of the large T antigen (TAg) was identified in all six cases of PML at 3% to 19% variant frequencies. Transfection of JCV Mad1 DNA possessing the V392G substitution in TAg into IMR-32 and human embryonic kidney 293 (HEK293) cells resulted in dramatically decreased production of JCV-encoded proteins. The virus DNA copy number was also reduced in supernatants of the mutant virus-transfected cells. Transfection of the IMR-32 and HEK293 cells with a virus genome containing a revertant mutation recovered viral production and protein expression. Cotransfection with equal amounts of wild-type genome and mutated JCV genome did not reduce the expression of viral proteins or viral replication, suggesting that the mutation did not have any dominant-negative function. Finally, immunohistochemistry demonstrated that TAg was expressed in all six pathological samples in which the quasispecies were detected. In conclusion, the V392G amino acid substitution in TAg identified frequently in PML lesions has a function in suppressing JCV replication, but the frequency of the mutation was restricted and its role in PML lesions was limited.

  1. [Ear keloid and clinical research progress].

    Science.gov (United States)

    Du, Guangyuan; Zhu, Jiang

    2014-04-01

    Keloid refers to the damaged skin due to excessive fibroblast proliferation. Ear is one predilection site. The pathogenesis of ear keloid is not very clear, and the treatment is also varied. Surgery, postoperative radiotherapy and laser treatment, steroid hormones, pressure therapy are the basic treatment methods. Integrated application of a variety of treatments, classification research and new materials using revealed the prospect for the treatment of the disease. This thesis reviews literature about ear keloid in recent 10 years, and introduces this disease and clinical research progress.

  2. HIV Replication at Low Copy Number and its Correlation with the HIV Reservoir: A Clinical Perspective.

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    Sarmati, Loredana; D'Ettorre, Gabriella; Parisi, Saverio Giuseppe; Andreoni, Massimo

    2015-01-01

    The efficacy of combination therapy (antiretroviral therapy--ARV) is demonstrated by the high rates of viral suppression achieved in most treated HIV patients. Whereas contemporary treatments may continuously suppress HIV replication, they do not eliminate the latent reservoir, which can reactivate HIV infection if ARV is discontinued. The persistence of HIV proviral DNA and infectious viruses in CD4+ T cells and others cells has long been considered a major obstacle in eradicating the HIV virus in treated patients. Moreover, recent studies have demonstrated the persistence of HIV replication at low copies in most patients on suppressive ARV. The source of this 'residual viraemia' and whether it declines over years of therapy remain unknown. Similarly, little is known regarding the biological relationships between the HIV reservoir and viral replication at low copies. The question of whether this 'residual viraemia' represents active replication or the release of non-productive virus from the reservoir has not been adequately resolved. From a clinical perspective, both the quantification of the HIV reservoir and the detection of low levels of replication in full-responder patients on prolonged ARV may provide important information regarding the effectiveness of treatment and the eradication of HIV. To date, the monitoring of these two parameters has been conducted only for research purposes; the routine use of standardised tests procedure is lacking. This review aims to assess the current data regarding the correlation between HIV replication at low copies and the HIV reservoir and to provide useful information for clinicians.

  3. Clinical neurorestorative progress in traumatic brain injury

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    Huang H

    2015-03-01

    Full Text Available Huiling Huang,1 Lin Chen,2,3 Hongyun Huang4–61Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Huanhu Hospital, Tianjin Neurosurgical Institute, Tianjin, People's Republic of China; 2Medical Center, Tsinghua University, Beijing, People's Republic of China; 3Tsinghua University Yuquan Hospital, Beijing, People's Republic of China; 4General Hospital of Chinese people's Armed Police Forces, 5Beijing Rehabilitation Hospital of Capital Medical University, Beijing, People's Republic of China; 6Beijing Hongtianji Neuroscience Academy, Beijing, People's Republic of ChinaAbstract: Traumatic brain injury (TBI is a leading cause of death and disability from trauma to the central nervous system. Besides the surgical interventions and symptomatic management, the conventional therapies for TBI and its sequelae are still limited. Recently emerging evidence suggests that some neurorestorative treatments appear to have a potential therapeutic role for TBI and improving the patient's quality of life. The current clinical neurorestorative strategies available in TBI include pharmacological treatments (recombinant human interleukin-1 receptor antagonist, amantadine, lithium, and valproate, the neuromodulation treatments (repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and low-level laser therapy, cell transplantation (bone marrow stromal cells and umbilical cord stromal cells, and combined neurorehabilitation. In this review, we summarize the recent clinical neurorestorative progress in the management of neurodegeneration as well as cognitive and motor deficits after TBI; indeed further clinical trials are required to provide more robust evidence.Keywords: brain trauma, neurorestorative treatment, cell transplantation, clinical study

  4. Pfh1 Is an Accessory Replicative Helicase that Interacts with the Replisome to Facilitate Fork Progression and Preserve Genome Integrity.

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    Karin R McDonald

    2016-09-01

    Full Text Available Replicative DNA helicases expose the two strands of the double helix to the replication apparatus, but accessory helicases are often needed to help forks move past naturally occurring hard-to-replicate sites, such as tightly bound proteins, RNA/DNA hybrids, and DNA secondary structures. Although the Schizosaccharomyces pombe 5'-to-3' DNA helicase Pfh1 is known to promote fork progression, its genomic targets, dynamics, and mechanisms of action are largely unknown. Here we address these questions by integrating genome-wide identification of Pfh1 binding sites, comprehensive analysis of the effects of Pfh1 depletion on replication and DNA damage, and proteomic analysis of Pfh1 interaction partners by immunoaffinity purification mass spectrometry. Of the 621 high confidence Pfh1-binding sites in wild type cells, about 40% were sites of fork slowing (as marked by high DNA polymerase occupancy and/or DNA damage (as marked by high levels of phosphorylated H2A. The replication and integrity of tRNA and 5S rRNA genes, highly transcribed RNA polymerase II genes, and nucleosome depleted regions were particularly Pfh1-dependent. The association of Pfh1 with genomic integrity at highly transcribed genes was S phase dependent, and thus unlikely to be an artifact of high transcription rates. Although Pfh1 affected replication and suppressed DNA damage at discrete sites throughout the genome, Pfh1 and the replicative DNA polymerase bound to similar extents to both Pfh1-dependent and independent sites, suggesting that Pfh1 is proximal to the replication machinery during S phase. Consistent with this interpretation, Pfh1 co-purified with many key replisome components, including the hexameric MCM helicase, replicative DNA polymerases, RPA, and the processivity clamp PCNA in an S phase dependent manner. Thus, we conclude that Pfh1 is an accessory DNA helicase that interacts with the replisome and promotes replication and suppresses DNA damage at hard-to-replicate

  5. Clinical research progress of tuberculous meningitis

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    Zhan-yun MA

    2014-08-01

    Full Text Available Tuberculous meningitis is an infectious disease of central nervous system caused by Mycobacterium tuberculosis. It mainly invades into brain meninges and parenchyma, and may spread to the spinal cord and spinal meninges. The disability rate and mortality rate of this disease are very high. In recent years, incidence of tuberculosis increased significantly due to the increase of drug-resistant tuberculosis cases, population mobility, acquired immunodeficiency syndrome (AIDS epidemic and other factors. Tuberculosis is still a worldwide serious threat to human life and health, especially in the underdeveloped and developing countries. China is the world's largest developing country with large population, so tuberculosis prevention and control is still a quite severe problem. In this paper, the clinical manifestations, diagnosis and differential diagnosis, treatment progress of tuberculous meningitis were reviewed systematically. doi: 10.3969/j.issn.1672-6731.2014.08.004

  6. Clinical neurorestorative progress in Parkinson's disease

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    Chen L

    2015-06-01

    Full Text Available Lin Chen,1,2 Hongyun Huang,3–5 Wei-Ming Duan,6 Gengsheng Mao3 1Department of Neurosurgery, Yuquan Hospital, Tsinghua University, 2Department of Neurosurgery, Medical Center, Tsinghua University, 3Department of Neurosurgery, General Hospital of Chinese People's Armed Police Forces, 4Center of Cell Research, Beijing Rehabilitation Hospital of Capital Medical University, 5Beijing Hongtianji Neuroscience Academy, 6Department of Anatomy, Capital Medical University, Beijing, People's Republic of China Abstract: Parkinson’s disease (PD is one of the common neurodegenerative diseases. Besides the symptomatic therapies, the increasing numbers of neurorestorative therapies have shown the potential therapeutic value of reversing the neurodegenerative process and improving the patient's quality of life. Currrently available novel clinical neurorestorative strategies include pharmacological managements (glial cell-line derived neurotrophic factor, selegiline, recombinant human erythropoietin, neuromodulation intervention (deep brain stimulation, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, tissue and cell transplantation (fetal ventral mesencephalic tissue, sympathetic neurons, carotid body cells, bone marrow stromal cells, retinal pigment epithelium cells, gene therapy, and neurorehabilitative therapy. Herein, we briefly review the progress in this field and describe the neurorestorative mechanisms of the above-mentioned therapies for PD. Keywords: Parkinson’s disease, clinical study, neurorestorative treatment, cell transplantation, neuromodulation

  7. Progress in Clinical Encapsulated Islet Xenotransplantation.

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    Cooper, David K C; Matsumoto, Shinichi; Abalovich, Adrian; Itoh, Takeshi; Mourad, Nizar I; Gianello, Pierre R; Wolf, Eckhard; Cozzi, Emanuele

    2016-11-01

    At the 2015 combined congress of the Cell Transplant Society, International Pancreas and Islet Transplant Association, and International Xenotransplantation Association, a symposium was held to discuss recent progress in pig islet xenotransplantation. The presentations focused on 5 major topics - (1) the results of 2 recent clinical trials of encapsulated pig islet transplantation, (2) the inflammatory response to encapsulated pig islets, (3) methods to improve the secretion of insulin by pig islets, (4) genetic modifications to the islet-source pigs aimed to protect the islets from the primate immune and/or inflammatory responses, and (5) regulatory aspects of clinical pig islet xenotransplantation. Trials of microencapsulated porcine islet transplantation to treat unstable type 1 diabetic patients have been associated with encouraging preliminary results. Further advances to improve efficacy may include (1) transplantation into a site other than the peritoneal cavity, which might result in better access to blood, oxygen, and nutrients; (2) the development of a more biocompatible capsule and/or the minimization of a foreign body reaction; (3) pig genetic modification to induce a greater secretion of insulin by the islets, and/or to reduce the immune response to islets released from damaged capsules; and (4) reduction of the inflammatory response to the capsules/islets by improvements in the structure of the capsules and/or in genetic engineering of the pigs and/or in some form of drug therapy. Ethical and regulatory frameworks for islet xenotransplantation are already available in several countries, and there is now a wider international perception of the importance of developing an internationally harmonized ethical and regulatory framework.

  8. Effects of ethanol on hepatic cellular replication and cell cycle progression

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Ethanol is a hepatotoxin. It appears that the liver is the target of ethanol induced toxicity primarily because it is the major site of ethanol metabolism. Metabolism of ethanol results in a number of biochemical changes that are thought to mediate the toxicity associated with ethanol abuse. These include the production of acetaldehyde and reactive oxygen species, as well as an accumulation of nicotinamide adenine dinucleotide(NADH). These biochemical changes are associated with the accumulation of fat and mitochondrial dysfunction in the liver. If these changes are severe enough they can themselves cause hepatotoxicity, or they can sensitize the liver to more severe damage by other hepatotoxins.Whether liver damage is the result of ethanol metabolism or some other hepatotoxin, recovery of the liver from damage requires replacement of cells that have been destroyed. It is now apparent that ethanol metabolism not only causes hepatotoxicity but also impairs the replication of normal hepatocytes. This impairment has been shown to occur at both the G1/S, and the G2/M transitions of the cell cycle. These impairments may be the result of activation of the checkpoint kinases, which can mediate cell cycle arrest at both of these transitions.Conversely, because ethanol metabolism results in a number of biochemical changes, there may be a number of mechanisms by which ethanol metabolism impairs cellular replication. It is the goal of this article to review the mechanisms by which ethanol metabolism mediates impairment of hepatic replication.

  9. Slx5/Slx8 Promotes Replication Stress Tolerance by Facilitating Mitotic Progression

    Directory of Open Access Journals (Sweden)

    Yee Mon Thu

    2016-05-01

    Full Text Available Loss of minichromosome maintenance protein 10 (Mcm10 causes replication stress. We uncovered that S. cerevisiae mcm10-1 mutants rely on the E3 SUMO ligase Mms21 and the SUMO-targeted ubiquitin ligase complex Slx5/8 for survival. Using quantitative mass spectrometry, we identified changes in the SUMO proteome of mcm10-1 mutants and revealed candidates regulated by Slx5/8. Such candidates included subunits of the chromosome passenger complex (CPC, Bir1 and Sli15, known to facilitate spindle assembly checkpoint (SAC activation. We show here that Slx5 counteracts SAC activation in mcm10-1 mutants under conditions of moderate replication stress. This coincides with the proteasomal degradation of sumoylated Bir1. Importantly, Slx5-dependent mitotic relief was triggered not only by Mcm10 deficiency but also by treatment with low doses of the alkylating drug methyl methanesulfonate. Based on these findings, we propose a model in which Slx5/8 allows for passage through mitosis when replication stress is tolerable.

  10. Progress on systems of DNA modified colloidal particles for self-replication

    Science.gov (United States)

    Chaikin, Paul; Leunissen, Mirjam; Dreyfus, Remi; Sha, Roujie; Seeman, Nadrian; Grier, David; Pine, David

    2008-03-01

    Our goal is to create new materials that can self-replicate and self-assemble. For this, we modify the interactions between micrometer-sized colloids by coating them with single-stranded DNA `sticky ends', which specifically recognize complementary sequences on other colloids. We find that the aggregation-dissociation behavior is fully reversible for at least tens of temperature cycles. Using magnetic beads or optical tweezers, we form a chain-like `seed' structure, which acts as a template to assemble copies of itself from a soup of singlets. To determine what are the preferred binding sites, we studied the interactions between the singlets and their complementary particles in the seed. Important in our replication scheme is that each particle has two different types of sticky ends: one for `longitudinal' bonding along the chain and another for `transverse' bonding between seed and daughter chains. Contrary to the transverse linkers, the longitudinal linkers form AT/TA bonds, which can be crosslinked with an intercalator and UV irradiation. In this way, we permanently fix the seed and its copies.

  11. The 2008 National Assessment of Educational Progress (NAEP): A Visual Arts Replication Study

    Science.gov (United States)

    Heid, Karen

    2016-01-01

    The 2008 National Assessment of Educational Progress (NAEP) Arts Assessment was administered to selected 8th grade students throughout the nation, and in 2009 the results from that administration were publicly reported. In the spring of 2010, building on the format and structure of the 2008 national assessment, the researcher administered a…

  12. Clinical trials: innovation, progress and controversy

    Directory of Open Access Journals (Sweden)

    Martin GS

    2011-08-01

    Full Text Available Greg S MartinDepartment of Pulmonary, Allergy and Critical Care, Emory University, Atlanta, Georgia, USAThe Open Access Journal of Clinical Trials began in 2009 with the goal of being an authoritative, open access source for international, peer-reviewed publications in the field of human research and clinical trials. Since then, the Open Access Journal of Clinical Trials has published approximately 30 high-quality articles on original research, innovative reviews, and critical commentaries. These articles have spanned many aspects of clinical trials wonderfully, including trial design and management; legal, ethical and regulatory issues of clinical trials; subject participation and retention in clinical trials; and data collection and data management.

  13. Estimating Typical Multiple Sclerosis Disability Progression Speed from Clinical Observations

    OpenAIRE

    Brown, Murray G.; Mark Asbridge; Vern Hicks; Sarah Kirby; Murray, Thomas J.; Pantelis Andreou; Dong Lin

    2014-01-01

    INTRODUCTION: Multiple sclerosis (MS) is a chronic disease of the central nervous system. Estimates of MS natural history (NH) disability progression speed from clinical observations vary worldwide. This may reflect, in part, variance in censoring-bias) (missing observations) and assumptions about when irreversible disability progression events occurred. We test whether estimates of progression speed which assume midpoint survival time at irreversible disability endpoints are significantly fa...

  14. HRV biofeedback for pediatric irritable bowel syndrome and functional abdominal pain: a clinical replication series.

    Science.gov (United States)

    Stern, Mark J; Guiles, Robert A F; Gevirtz, Richard

    2014-12-01

    Irritable bowel syndrome (IBS) and Functional Abdominal Pain (FAP) are among the most commonly reported Functional Gastrointestinal Disorders. Both have been associated with varying autonomic dysregulation. Heart Rate Variability Biofeedback (HRVB) has recently begun to show efficacy in the treatment of both IBS and FAP. The purpose of this multiple clinical replication series was to analyze the clinical outcomes of utilizing HRVB in a clinical setting. Archival data of twenty-seven consecutive pediatric outpatients diagnosed with IBS or FAP who received HRVB were analyzed. Clinical outcomes were self-report and categorized as full or remission with patient satisfaction, or no improvement. Qualitative reports of patient experiences were also noted. Full remission was achieved by 69.2 % and partial remission was achieved by 30.8 % of IBS patients. Full remission was achieved by 63.6 % and partial remission was achieved by 36.4 % of FAP patients. No patients in either group did not improve to a level of patient satisfaction or >50 %. Patient's commonly reported feeling validated in their discomfort as a result of psychophysiological education. Results suggest that HRVB is a promising intervention for pediatric outpatients with IBS or FAP. Randomized controlled trials are necessary to accurately determine clinical efficacy of HRVB in the treatment of IBS and FAP.

  15. Clinical Investigation Program. Annual Research Progress Report.

    Science.gov (United States)

    1980-09-30

    Stereoscope 79/118 $6149.00 Ion Generator 78/116 $5000.00 Poultry Cages 79/301 $2929.00 Microtome/Cryostat 79/304 $5494.72 Tissue Embedder 79/300... Mycology : Assessment of bacteriologic and seroligic parameters of clinically-important mycoses normal and immunologic comprised host. Presented: American

  16. Progress testing 2.0: clinical skills meets necessary science

    Science.gov (United States)

    Gold, Jonathan; DeMuth, Robin; Mavis, Brian; Wagner, Dianne

    2015-01-01

    Introduction Progress testing has been widely used in medical schools to test scientific knowledge but has not been reported for assessing clinical skills. Development We designed a novel progress examination that included assessments of both clinical performance and underlying basic and social science knowledge. This Progress Clinical Skills Examination (PCSE) was given to 21 early medical students at the beginning and end of a 6-week pilot test of a new medical school curriculum. Implementation This examination was feasible for early students, easy to map to curricular objectives, and easy to grade using a combination of assessment strategies. Future directions Use of a PCSE is feasible for early medical students. As medical schools integrate clinical experience with underlying knowledge, this type of examination holds promise. Further data are needed to validate this examination as an accurate measure of clinical performance and knowledge. PMID:25948045

  17. Progress testing 2.0: clinical skills meets necessary science

    Directory of Open Access Journals (Sweden)

    Jonathan Gold

    2015-05-01

    Full Text Available Introduction: Progress testing has been widely used in medical schools to test scientific knowledge but has not been reported for assessing clinical skills. Development: We designed a novel progress examination that included assessments of both clinical performance and underlying basic and social science knowledge. This Progress Clinical Skills Examination (PCSE was given to 21 early medical students at the beginning and end of a 6-week pilot test of a new medical school curriculum. Implementation: This examination was feasible for early students, easy to map to curricular objectives, and easy to grade using a combination of assessment strategies. Future directions: Use of a PCSE is feasible for early medical students. As medical schools integrate clinical experience with underlying knowledge, this type of examination holds promise. Further data are needed to validate this examination as an accurate measure of clinical performance and knowledge.

  18. Clinical Progress on Moxibustion Treatment of Asthma

    Institute of Scientific and Technical Information of China (English)

    WU Yao-chi; SHI Yin; HUANG Guo-qi

    2004-01-01

    In the treatment of asthma, there are the commonly-used external therapies of scarring moxibustion, ginger-insulated moxibustion and acupoint herb-applying method, etc, with better clinical effects. But, strict recruitment standard was lacked and the designs of clinical studies were not complete in some reports. Therefore, the design of clinical study on moxibustion therapy and acupoint herb-applying method in the treatment of asthma needs to be strict and complete in the future studies.%治疗哮喘的常用外治法有化脓灸,隔姜灸和穴位贴敷等,均有较好的临床效果,但部分报道缺乏严格的纳入标准,而且临床研究设计不完善,有待于在以后的研究中严格与完善灸法和穴位贴敷防治哮喘的临床研究设计.

  19. Clinical neurorestorative progresses in cerebral palsy

    Directory of Open Access Journals (Sweden)

    Sharma A

    2017-02-01

    Full Text Available Alok Sharma,1 Tongchao Geng,2 Hemangi Sane,3 Pooja Kulkarni3 1Department of Medical Services & Clinical Research, NeuroGen Brain and Spine Institute, Mumbai, India; 2Department of Neurology, Yuquan Hospital, Tsinghua University, Beijing, People’s Republic of China; 3Department of Research and Development, Neurogen Brain and Spine Institute, Mumbai, India Abstract: Cerebral palsy (CP, group of permanent nonprogressive clinical disorders in children, is caused by damage to the immature brain. Conventionally available treatments for CP are mainly targeted toward management of its symptoms. With the upcoming field of neurorestorative strategies, we are now able to repair the core brain damage in CP. There are various drugs, stem cells, etc, which have been implicated to have neurorestorative properties. Autologous bone marrow stem cells, umbilical cord stem cells, neural stem cells, and olfactory ensheathing cells have shown the safety and efficacy in preliminary studies. Here, we review the different medicines and cell types that have shown beneficial effects in clinical studies. We propose that combination strategies may be the future of neurorestoration. Keywords: stem cell therapy, bone marrow, umbilical cord, neural cells, regenerative medicine, brain

  20. Progress in clinical research of asteroid hyalosis

    Directory of Open Access Journals (Sweden)

    Xiao-Xue Liu

    2017-08-01

    Full Text Available Asteroid Hyalosis(AHis a common clinical disease, which has been considered a benign disorder as it rarely impairs visual acuity. It was often discovered when the patient was treated for other eye diseases. The mechanism was unclear. Its characteristic B-ultrasound property makes the B-ultrasound a very helpful diagnostic technique. In the case of the patients with other fundus diseases associated with AH, optical coherence tomography(OCTand fluorescein angiography(FAmay be used to reduce the interference from asteroid bodies, therefore improve the fundus visibility. Recent studies have shown that AH can incorporate with many other eye diseases. For example, in patients with cataracts, asteroid hyalosis can cause surface calcification of silicone plate intraocular lenses, which in most cases may lead to the need for explantation of the calcified intraocular lenses. The efficacy of pars plana vitrectomy(PPV, the removal of some, or all, of the eye's vitreous humor for AH remains controversial. In this paper, we provide a review of the recent literature on AH disease: the etiology, diagnosis and treatment. We hope to thus improve the awareness and outcomes of AH disease.

  1. Evidence for clinical progression of unipolar and bipolar disorders

    DEFF Research Database (Denmark)

    Kessing, L. V.; Andersen, P. K.

    2016-01-01

    ) the risk of recurrence of episodes, (ii) probability of recovery from episodes, (iii) severity of episodes, (iv) the threshold for developing episodes, and (v) progression of cognitive deficits in unipolar and bipolar disorders. Method: A systematic review comprising an extensive literature search...... severity of episodes, (iv) decreasing threshold for developing episodes, and (v) increasing risk of developing dementia. Conclusion: Although the course of illness is heterogeneous, there is evidence for clinical progression of unipolar and bipolar disorders....

  2. Host factors and HIV-1 replication: clinical evidence and potential therapeutic approaches

    Directory of Open Access Journals (Sweden)

    Mariana eSanta-Marta

    2013-10-01

    Full Text Available HIV and human defense mechanisms have co-evolved to counteract each other. In the process of infection, HIV takes advantage of cellular machinery and blocks the action of the host restriction factors. A small subset of HIV+ individuals control HIV infection and progression to AIDS in the absence of treatment. These individuals known, as long-term non-progressors (LNTPs exhibit genetic and immunological characteristics that confer upon them an efficient resistance to infection and/or disease progression. The identification of some of these host factors led to the development of therapeutic approaches that attempted to mimic the natural control of HIV infection. Some of these approaches are currently being tested in clinical trials. While there are many genes which carry mutations and polymorphisms associated with non-progression, this review will be specifically focused on HIV host restriction factors (RF including both the main chemokine receptors and chemokines as well as intracellular restriction factors including, APOBEC, TRIM, tetherin and SAMHD1. The understanding of molecular profiles and mechanisms present in LTNPs should provide new insights to control HIV infection and contribute to the development of novel therapies against AIDS.

  3. Can genetic pleiotropy replicate common clinical constellations of cardiovascular disease and risk?

    Directory of Open Access Journals (Sweden)

    Omri Gottesman

    Full Text Available The relationship between obesity, diabetes, hyperlipidemia, hypertension, kidney disease and cardiovascular disease (CVD is established when looked at from a clinical, epidemiological or pathophysiological perspective. Yet, when viewed from a genetic perspective, there is comparatively little data synthesis that these conditions have an underlying relationship. We sought to investigate the overlap of genetic variants independently associated with each of these commonly co-existing conditions from the NHGRI genome-wide association study (GWAS catalog, in an attempt to replicate the established notion of shared pathophysiology and risk. We used pathway-based analyses to detect subsets of pleiotropic genes involved in similar biological processes. We identified 107 eligible GWAS studies related to CVD and its established comorbidities and risk factors and assigned genes that correspond to the associated signals based on their position. We found 44 positional genes shared across at least two CVD-related phenotypes that independently recreated the established relationship between the six phenotypes, but only if studies representing non-European populations were included. Seven genes revealed pleiotropy across three or more phenotypes, mostly related to lipid transport and metabolism. Yet, many genes had no relationship to each other or to genes with established functional connection. Whilst we successfully reproduced established relationships between CVD risk factors using GWAS findings, interpretation of biological pathways involved in the observed pleiotropy was limited. Further studies linking genetic variation to gene expression, as well as describing novel biological pathways will be needed to take full advantage of GWAS results.

  4. Age, CAG repeat length, and clinical progression in Huntington's disease.

    Science.gov (United States)

    Rosenblatt, Adam; Kumar, Brahma V; Mo, Alisa; Welsh, Claire S; Margolis, Russell L; Ross, Christopher A

    2012-02-01

    The objective of this study was to further explore the effect of CAG repeat length on the rate of clinical progression in patients with Huntington's disease. The dataset included records for 569 subjects followed prospectively at the Baltimore Huntington's Disease Center. Participants were seen for a mean of 7.1 visits, with a mean follow-up of 8.2 years. Subjects were evaluated using the Quantified Neurologic Examination and its Motor Impairment subscale, the Mini-Mental State Examination, and the Huntington's disease Activities of Daily Living Scale. By itself, CAG repeat length showed a statistically significant but small effect on the progression of all clinical measures. Contrary to our previous expectations, controlling for age of onset increased the correlation between CAG repeat length and progression of all variables by 69% to 159%. Graphical models further supported the idea that individuals with smaller triplet expansions experience a more gradual decline. CAG repeat length becomes an important determinant of clinical prognosis when accounting for age of onset. This suggests that the aging process itself influences clinical outcomes in Huntington's disease. Inconsistent results in prior studies examining CAG repeat length and progression may indeed reflect a lack of age adjustment.

  5. Ultrasound clinical progress monitoring: Who, where and how?

    Science.gov (United States)

    Harrison, Gill

    2015-11-01

    Prior to assessment of final ultrasound clinical competency it is important to monitor clinical progress, provide high quality feedback and encourage skills development. The role of the supervisor, mentor and assessor are fundamental to the on-going progress monitoring of ultrasound trainees. This article forms the second part of a larger project which was to elicit ultrasound practitioners' opinions on how progress should be monitored, where and by whom. An on-line questionnaire was used to gain opinions from ultrasound practitioners. Totally, 116 responses were received from professionals with an interest in ultrasound assessment. Results suggested that experienced, qualified ultrasound practitioners should undertake the role of supervisor and assessor, having been prepared for that role by the training centre. Formative monitoring should take place both within the clinical department and possibly the training centre, using a range of methods. Following completion of the training, practitioners should have a preceptorship period to consolidate their knowledge and skills for 3 to 6 months or until further competencies have been demonstrated. Formative progress monitoring should be a recognised part of ultrasound training. Essentially, staff undertaking supervision and assessor roles should be supported and trained to ensure a high quality, consistent learning experience for ultrasound trainees. Additionally, they should provide appropriate feedback to the trainee and education centre.

  6. Surgical treatment for progressive prostate cancer: A clinical case

    Directory of Open Access Journals (Sweden)

    E. I. Veliev

    2014-01-01

    Full Text Available In spite of its existing standards, the treatment of patients with progressive prostate cancer (PC remains a matter of debate. Ensuring that the patients have good quality of life is also relevant. The paper describes a clinical case of a patient with progressive PC after hormone therapy, brachytherapy, salvage prostatectomy, enucleation of the testicular parenchyma, and salvage lymphadenectomy. A phallic prosthesis and an artificial urinary sphincter have been implanted to improve quality of life. The results of preoperative examination and the technological features of surgical interventions are given.

  7. Estimating Typical Multiple Sclerosis Disability Progression Speed from Clinical Observations

    Science.gov (United States)

    Brown, Murray G.; Asbridge, Mark; Hicks, Vern; Kirby, Sarah; Murray, Thomas J.; Andreou, Pantelis; Lin, Dong

    2014-01-01

    Introduction Multiple sclerosis (MS) is a chronic disease of the central nervous system. Estimates of MS natural history (NH) disability progression speed from clinical observations vary worldwide. This may reflect, in part, variance in censoring-bias) (missing observations) and assumptions about when irreversible disability progression events occurred. We test whether estimates of progression speed which assume midpoint survival time at irreversible disability endpoints are significantly faster than estimates which assume maximum survival time, and are more stable across study groups and time periods. Methods Our Nova Scotia NH study population includes 2,240 definite relapsing-onset multiple sclerosis (R-MS) natural history patients with 18,078 Expanded Disability Status Scale (EDSS) clinical observations in study period 1979–2010. Progression speed is measured by rate-of-change in range EDSS 0–6 and by survival time at irreversible endpoints EDSS 1–9. Midpoint censoring-bias-reduction methods are applied to clinical observations. Findings Typical EDSS increase per year in range EDSS 0–6, assuming midpoint survival time, is estimated to be 0.168 for all R-MS, 0.204 for eventually-DMD-treated patients and 0.155 for never-DMD-treated patients. Estimates assuming midpoint rather than maximum survival time are significantly faster: 16% faster for all R-MS natural history patients, 6% faster for eventually-DMD-treated patients, and 21% faster for never-DMD-treated patients. The variability of estimates across study groups and time periods decreased when midpoint survival time was assumed. Conclusions Estimates of typical disease progression speed from 1979–2010 Nova Scotia clinical observations are sensitive to censoring-bias and to analysts’ survival time assumptions. Censoring-bias-adjusted estimates of typical natural history disability progression speed in relapsing-onset multiple sclerosis patients are significantly faster, and less variable within

  8. Estimating typical multiple sclerosis disability progression speed from clinical observations.

    Directory of Open Access Journals (Sweden)

    Murray G Brown

    Full Text Available INTRODUCTION: Multiple sclerosis (MS is a chronic disease of the central nervous system. Estimates of MS natural history (NH disability progression speed from clinical observations vary worldwide. This may reflect, in part, variance in censoring-bias (missing observations and assumptions about when irreversible disability progression events occurred. We test whether estimates of progression speed which assume midpoint survival time at irreversible disability endpoints are significantly faster than estimates which assume maximum survival time, and are more stable across study groups and time periods. METHODS: Our Nova Scotia NH study population includes 2,240 definite relapsing-onset multiple sclerosis (R-MS natural history patients with 18,078 Expanded Disability Status Scale (EDSS clinical observations in study period 1979-2010. Progression speed is measured by rate-of-change in range EDSS 0-6 and by survival time at irreversible endpoints EDSS 1-9. Midpoint censoring-bias-reduction methods are applied to clinical observations. FINDINGS: Typical EDSS increase per year in range EDSS 0-6, assuming midpoint survival time, is estimated to be 0.168 for all R-MS, 0.204 for eventually-DMD-treated patients and 0.155 for never-DMD-treated patients. Estimates assuming midpoint rather than maximum survival time are significantly faster: 16% faster for all R-MS natural history patients, 6% faster for eventually-DMD-treated patients, and 21% faster for never-DMD-treated patients. The variability of estimates across study groups and time periods decreased when midpoint survival time was assumed. CONCLUSIONS: Estimates of typical disease progression speed from 1979-2010 Nova Scotia clinical observations are sensitive to censoring-bias and to analysts' survival time assumptions. Censoring-bias-adjusted estimates of typical natural history disability progression speed in relapsing-onset multiple sclerosis patients are significantly faster, and less variable

  9. Clinical value of the VMI supplemental tests: a modified replication study.

    Science.gov (United States)

    Avi-Itzhak, Tamara; Obler, Doris Richard

    2008-10-01

    To carry out a modified replication of the study performed by Kulp and Sortor evaluating the clinical value of the information provided by Beery's visual-motor supplemental tests of Visual Perception (VP) and Motor Coordination (MC) in normally developed children. The objectives were to (a) estimate the correlations among the three tests scores; (b) assess the predictive power of the VP and MC scores in explaining the variance in Visual-Motor Integration (VMI) scores; and (c) examine whether poor performance on the VMI is related to poor performance on VP or MC. METHODS.: A convenience sample of 71 children ages 4 and 5 years (M = 4.62 +/- 0.43) participated in the study. The supplemental tests significantly (F = 9.59; dF = 2; p VMI performance. Only VP was significantly related to VMI (beta = 0.39; T = 3.49) accounting for the total amount of explained variance. Using the study population norms, 11 children (16% of total sample) did poorly on the VMI; of those 11, 73% did poorly on the VP, and none did poorly on the MC. None of these 11 did poorly on both the VP and MC. Nine percent of total sample who did poorly on the VP performed within the norm on the VMI. Thirteen percent who performed poorly on the MC performed within the norm on the VMI. Using the VMI published norms, 14 children (20% of total sample) who did poorly on the VP performed within the norm on the VMI. Forty-eight percent who did poorly on MC performed within the norm on the VMI. Findings supported Kulp and Sortor's conclusions that each area should be individually evaluated during visual-perceptual assessment of children regardless of performance on the VMI.

  10. African Green Monkeys Recapitulate the Clinical Experience with Replication of Live Attenuated Pandemic Influenza Virus Vaccine Candidates

    Science.gov (United States)

    Matsuoka, Yumiko; Suguitan, Amorsolo; Orandle, Marlene; Paskel, Myeisha; Boonnak, Kobporn; Gardner, Donald J.; Feldmann, Friederike; Feldmann, Heinz; Marino, Michael; Jin, Hong; Kemble, George

    2014-01-01

    ABSTRACT Live attenuated cold-adapted (ca) H5N1, H7N3, H6N1, and H9N2 influenza vaccine viruses replicated in the respiratory tract of mice and ferrets, and 2 doses of vaccines were immunogenic and protected these animals from challenge infection with homologous and heterologous wild-type (wt) viruses of the corresponding subtypes. However, when these vaccine candidates were evaluated in phase I clinical trials, there were inconsistencies between the observations in animal models and in humans. The vaccine viruses did not replicate well and immune responses were variable in humans, even though the study subjects were seronegative with respect to the vaccine viruses before vaccination. Therefore, we sought a model that would better reflect the findings in humans and evaluated African green monkeys (AGMs) as a nonhuman primate model. The distribution of sialic acid (SA) receptors in the respiratory tract of AGMs was similar to that in humans. We evaluated the replication of wt and ca viruses of avian influenza (AI) virus subtypes H5N1, H6N1, H7N3, and H9N2 in the respiratory tract of AGMs. All of the wt viruses replicated efficiently, while replication of the ca vaccine viruses was restricted to the upper respiratory tract. Interestingly, the patterns and sites of virus replication differed among the different subtypes. We also evaluated the immunogenicity and protective efficacy of H5N1, H6N1, H7N3, and H9N2 ca vaccines. Protection from wt virus challenge correlated well with the level of serum neutralizing antibodies. Immune responses were slightly better when vaccine was delivered by both intranasal and intratracheal delivery than when it was delivered intranasally by sprayer. We conclude that live attenuated pandemic influenza virus vaccines replicate similarly in AGMs and human subjects and that AGMs may be a useful model to evaluate the replication of ca vaccine candidates. IMPORTANCE Ferrets and mice are commonly used for preclinical evaluation of influenza

  11. Polyomavirus JC in the Context of Immunosuppression: A Series of Adaptive, DNA Replication-Driven Recombination Events in the Development of Progressive Multifocal Leukoencephalopathy

    Directory of Open Access Journals (Sweden)

    Edward M. Johnson

    2013-01-01

    Full Text Available Polyomavirus JC (JCV is the etiological agent of progressive multifocal leukoencephalopathy (PML, a demyelinating infection of oligodendrocytes in the brain. PML, a frequently fatal opportunistic infection in AIDS, has also emerged as a consequence of treatment with several new immunosuppressive therapeutic agents. Although nearly 80% of adults are seropositive, JCV attains an ability to infect glial cells in only a minority of people. Data suggest that JCV undergoes sequence alterations that accompany this ability, and these changes can be derived from an archetype strain by mutation, deletion, and duplication. While the introductory source and primary tissue reservoir of JCV remain unknown, lymphoid cells have been identified as potential intermediaries in progression of JCV to the brain. This review is focused on sequence changes in the noncoding control region (NCCR of the virus. We propose an adaptive mechanism that involves a sequential series of DNA replication-driven NCCR recombination events involving stalled DNA replication forks at NCCR palindromic secondary structures. We shall describe how the NCCR sequence changes point to a model in which viral DNA replication drives NCCR recombination, allowing JCV adaptation to different cell types in its progression to neurovirulence.

  12. Tumor-selective replication herpes simplex virus-based technology significantly improves clinical detection and prognostication of viable circulating tumor cells

    DEFF Research Database (Denmark)

    Zhang, Wen; Bao, Li; Yang, Shaoxing;

    2016-01-01

    Detection of circulating tumor cells remains a significant challenge due to their vast physical and biological heterogeneity. We developed a cell-surface-marker-independent technology based on telomerase-specific, replication-selective oncolytic herpes-simplex-virus-1 that targets telomerase......Search, our method detected significantly higher positive rates in 40 NSCLC in all stages, including N0M0, N+M0 and M1, and was less affected by chemotherapy. This simple, robust and clinically-applicable technology detects viable CTCs from solid and hematopoietic malignancies in early to late stages...... blood samples from patients with 6 different solid organ carcinomas and lymphomas. Significantly, CTC-positive rates increased remarkably with tumor progression from N0M0, N+M0 to M1 in each of 5 tested cancers (lung, colon, liver, gastric and pancreatic cancer, and glioma). Among 21 non-small cell lung...

  13. Proteomic analysis of mitochondria: biological and clinical progresses in cancer.

    Science.gov (United States)

    Wang, Yang; Zhang, Jing; Li, Bin; He, Qing-Yu

    2017-10-01

    Mitochondria play important roles in regulating multiple biological processes and signalling pathways in eukaryotic cells, and mitochondrial dysfunction may result in a wide range of serious diseases, including cancer. With improvements in the identification of mitochondrial proteins, mitochondrial proteomics has made great achievements. In particular, this approach has been widely used to compare tumour cells at different stages of malignancy. Therefore, there is an urgent need to identify and characterize the function of mitochondrial proteins in cancer progression and to determine the involved mechanisms. Areas covered: We provide an overview of recent progress related to mitochondrial proteomics in cancer and the application of comparative mitochondrial proteomics in various biological processes, including apoptosis, necroptosis, autophagy and metastasis, as well as clinical progress in cancer. Proteomics-related reports were found using PubMed and Google Scholar databases. Expert commentary: Understanding both post-translational modification and post-translational processing is important in the comprehensive characterization of protein function. The application of comparative mitochondrial proteomics to investigate clinical samples and cancer cells will contribute to our understanding of the molecular interplay of mitochondrial proteins in the development of cancer. This approach will mine more biomarkers for diagnosis and prognosis and improve therapeutic outcomes among cancer patients.

  14. Replication of clinical hepatitis B virus isolate and its application for selecting antiviral agents for chronic hepatitis B patients

    Institute of Scientific and Technical Information of China (English)

    Yin-ping Lu; Tao Guo; Bao-Ju Wang; Ji-Hua Dong; Jian-Fang Zhu; Zhao Liu; Meng-Ji Lu; Dong-Liang Yang

    2008-01-01

    AIM: To establish a cell model harboring replicative clinical hepatitis B virus (HBV) isolates and evaluate its application in individualized selection of anti-HBV agents for chronic hepatitis B (CHB) Patients.METHODS: The full-length HBV genomic DNA from 8 CHB patients was amplified by polymerase chain reaction (PCR). All the patients were treated with lamivudine for at least seven months and finally became resistant to lamivudine. The amplified HBV DNA fragments were inserted into pHY106 vectors by Sap digestion. The recombinant plasmids containing 1.1 copies of HBV genome were transiently transfected into Huh7 cell line, and the levels of HBsAg, HBeAg and intercellular HBV replicative intermediates were determined by ELISA and Southern blot analysis, respectively, with or without lamivudine and adefovir treatment. The antiviral treatment with adefovir was administered to the patients and analyzed in parallel.RESULTS: A total of 25 independent HBV isolates were obtained from the sera of 8 patients, each patient had at least two isolates. One isolate from each individual was selected and subcloned into pHY106 vector, including 5 isolates with YVDD mutation and 3 isolates with YIDD mutation. All recombinant plasmids harboring HBV isolates were transfected into Huh7 cells. The results indicated that HBV genome carried in HBV replicons of clinical HBV isolates could effectively replicate and express in Huh7 cells. Adefovir, but not lamivudine, inhibited HBV replication both in vitro and in vivo, and in vitro inhibition was dose-dependent.CONCLUSION: The novel method described herein enables individualized selection of anti-HBV agents in clinic and is useful in future studies of antiviral therapy for CHB.

  15. Alzheimer's Disease Neuroimaging Initiative 2 Clinical Core: Progress and plans.

    Science.gov (United States)

    Aisen, Paul S; Petersen, Ronald C; Donohue, Michael; Weiner, Michael W

    2015-07-01

    This article reviews the current status of the Clinical Core of the Alzheimer's Disease Neuroimaging Initiative (ADNI), and summarizes planning for the next stage of the project. Clinical Core activities and plans were synthesized based on discussions among the Core leaders and external advisors. The longitudinal data in ADNI-2 provide natural history data on a clinical trials population and continue to inform refinement and standardization of assessments, models of trajectories, and clinical trial methods that have been extended into sporadic preclinical Alzheimer's disease (AD). Plans for the next phase of the ADNI project include maintaining longitudinal follow-up of the normal and mild cognitive impairment cohorts, augmenting specific clinical cohorts, and incorporating novel computerized cognitive assessments and patient-reported outcomes. A major hypothesis is that AD represents a gradually progressive disease that can be identified precisely in its long presymptomatic phase, during which intervention with potentially disease-modifying agents may be most useful. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  16. Progress in clinical diagnosis of amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    YANG Qiong

    2012-06-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disease, mainly involving the pyramidal tract, brain stem and spinal cord anterior horn cells, manifests as progressive muscle atrophy, weakness and cramps, as well as cognitive impairment, and may overlap with frontotemporal dementia. ALS is familial in 5% of cases, whose clinical manifestations are similar to sporadic. The diagnosis is made mainly based on clinical manifestations, using internationally recognized consensus standard, after rule out conditions that can mimic ALS. Genetic testing provides a new way to accelerate the diagnostic process for early intervention. Part of the gene mutations are associated with specific phenotypes. According to this, prognosis assessment and genetic counseling are able to carry out.

  17. Heart Xenotransplantation: Historical Background, Experimental Progress, and Clinical Prospects.

    Science.gov (United States)

    Murthy, Raghav; Bajona, Pietro; Bhama, Jay K; Cooper, David K C

    2016-04-01

    If pig hearts could be transplanted successfully into patients with end-stage cardiac failure, the critical shortage of hearts from deceased human donors would be overcome. The several attempts at cardiac xenotransplantation carried out in the 20th century, usually with hearts from nonhuman primates (NHPs), are reviewed, as are the surgical techniques used in experimental heart transplantation in animals. For a number of reasons, the pig has been selected as the potential source of organs for clinical transplantation. The major pathobiological barriers that the pig presents, and progress in overcoming these barriers either by genetic engineering of the pig or by the administration of novel immunosuppressive agents, are described. Currently, non-life-supporting pig heterotopic heart transplantation in NHPs has extended to more than 2 years in 1 case, with life-supporting orthotopic heart transplantation of almost 2 months. Future approaches to resolve the remaining problems and the selection of patients for the initial clinical trials are briefly discussed.

  18. Glenohumeral arthritis after Latarjet procedure: Progression and it's clinical significance.

    Science.gov (United States)

    Kee, Young Moon; Kim, Hwan Jin; Kim, Jung Youn; Rhee, Yong Girl

    2017-09-01

    The risk factors of glenohumeral arthritis after the Latarjet procedure remain relatively unexplored. The purposes of this study are to evaluate the clinical significance of glenohumeral arthritis after the Latarjet procedure, and to investigate risk factors associated with arthritis progression. We evaluated 110 patients (110 shoulders) who underwent the Latarjet procedure for recurrent anterior shoulder instability. Patients had a mean age of 23.8 years (range, 14-52 years) at the time of the operation, and the mean duration of follow-up was 31 months (range, 24-111 months). At the last follow-up, the mean Visual Analog Scale (VAS), Rowe and University of California at Los Angeles (UCLA) scores significantly improved from 3.1, 36.5 and 23.6 points preoperatively to 1.6, 87.6 and 32.6 points (all P Latarjet procedure was in 20 shoulders (18.2%). At the final, overall prevalence of arthritis was 23.6% (26 shoulders). The non-arthritis group showed significantly better functional outcomes (VAS score: 0.9, Rowe Score: 89.3, UCLA score: 33.5) than the arthritis group (2.1, 84.9, 29.2; all P Latarjet procedure yielded satisfactory functional outcomes with low recurrent rate at mid-term follow-up. Development or progression of arthritis was observed in 18.2% of patients, postoperatively. Glenohumeral arthritis after the Latarjet procedure had an adverse effect on clinical outcome. Generalized laxity and lateral overhang should be considered as risk factors of progression to glenohumeral arthritis after the Latarjet procedure. Copyright © 2017 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

  19. Clinical scales in progressive MS: predicting long-term disability.

    Science.gov (United States)

    Bosma, Libertje V A E; Kragt, Jolijn J; Knol, Dirk L; Polman, Chris H; Uitdehaag, Bernard M J

    2012-03-01

    To determine which short-term changes on clinical scales including the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg test (9HPT) and Guy's Neurological Disability Scale (GNDS) are most predictive of long-term outcome of disability as rated by the EDSS in progressive multiple sclerosis (MS). From a longitudinal database, all progressive patients, both primary (PP) and secondary (SP), were selected on the basis of at least two complete examinations being available within a time interval of 1-2 years (short-term change). All patients who fulfilled the selection criteria were invited for a third visit after an interval of at least 3 years (long-term outcome). We used ordinal logistic regression to see which early changes were most predictive of the long-term EDSS. 181 patients fulfilled the selection criteria. Early change on EDSS and T25FW were the best predictors of long-term EDSS; both were significant predictors in a 'single predictor' model. Early EDSS change was a slightly stronger single predictor (R(2) 0.38, Wald χ(2) 42.65, p EDSS change in a 'combined predictor' model improved prediction (p = 0.036). Both early change on EDSS and T25FW predict long-term EDSS with comparable strength. Early change on T25FW adds significant independent information and improves the prediction model with early EDSS change only. Therefore we support the use of early T25FW examinations in future clinical trials in progressive MS.

  20. An ADAM33 polymorphism associates with progression of preschool wheeze into childhood asthma: a prospective case-control study with replication in a birth cohort study.

    Directory of Open Access Journals (Sweden)

    Ester M M Klaassen

    Full Text Available The influence of asthma candidate genes on the development from wheeze to asthma in young children still needs to be defined.To link genetic variants in asthma candidate genes to progression of wheeze to persistent wheeze into childhood asthma.In a prospective study, children with recurrent wheeze from the ADEM (Asthma DEtection and Monitoring study were followed until the age of six. At that age a classification (transient wheeze or asthma was based on symptoms, lung function and medication use. In 198 children the relationship between this classification and 30 polymorphisms in 16 asthma candidate genes was assessed by logistic regression. In case of an association based on a p<0.10, replication analysis was performed in an independent birth cohort study (KOALA study, n = 248 included for the present analysis.In the ADEM study, the minor alleles of ADAM33 rs511898 and rs528557 and the ORMDL3/GSDMB rs7216389 polymorphisms were negatively associated, whereas the minor alleles of IL4 rs2243250 and rs2070874 polymorphisms were positively associated with childhood asthma. When replicated in the KOALA study, ADAM33 rs528557 showed a negative association of the CG/GG-genotype with progression of recurrent wheeze into childhood asthma (0.50 (0.26-0.97 p = 0.04 and no association with preschool wheeze.Polymorphisms in ADAM33, ORMDL3/GSDMB and IL4 were associated with childhood asthma in a group of children with recurrent wheeze. The replication of the negative association of the CG/GG-genotype of rs528557 ADAM33 with childhood asthma in an independent birth cohort study confirms that a compromised ADAM33 gene may be implicated in the progression of wheeze into childhood asthma.

  1. Progress in Rett Syndrome: from discovery to clinical trials.

    Science.gov (United States)

    Percy, Alan K

    2016-09-01

    Fifty years ago, Andreas Rett described a disorder in 22 females featuring prominent regression of fine motor and communication skills, cognitive impairment, stereotypic movements, periodic breathing, and gait abnormalities. This disorder became known as Rett syndrome (RTT) following the report of Hagberg et al. in 1983. Although RTT was scarcely recognized at that time in the United States, here the efforts of Rett and Hagberg led to rapid progress in recognition and diagnosis, a clearer understanding of its clinical and pathological underpinnings, and, ultimately, identification of mutations in the methyl-CpG-binding protein 2 (MECP2) gene as the primary cause of this unique and challenging neurodevelopmental disorder. Thereafter, a natural history study and critical translational research in animal models paved the way for potential disease-modifying agents to be assessed in human clinical trials. To be successful, the energies of the international community at all levels, including researchers in clinical and basic science, funding agencies, pharmaceutical companies, patient advocates, and, above all, parents and their children are essential. Otherwise, hopes for effective treatment, if not, a cure, will remain unfulfilled.

  2. Dissecting the Syndrome of Schizophrenia: Progress toward Clinically Useful Biomarkers

    Directory of Open Access Journals (Sweden)

    Brian Dean

    2011-01-01

    Full Text Available The search for clinically useful biomarkers has been one of the holy grails of schizophrenia research. This paper will outline the evolving notion of biomarkers and then outline outcomes from a variety of biomarkers discovery strategies. In particular, the impact of high-throughput screening technologies on biomarker discovery will be highlighted and how new or improved technologies may allow the discovery of either diagnostic biomarkers for schizophrenia or biomarkers that will be useful in determining appropriate treatments for people with the disorder. History tells those involved in biomarker research that the discovery and validation of useful biomarkers is a long process and current progress must always be viewed in that light. However, the approval of the first biomarker screen with some value in predicting responsiveness to antipsychotic drugs suggests that biomarkers can be identified and that these biomarkers that will be useful in diagnosing and treating people with schizophrenia.

  3. Dissecting the Syndrome of Schizophrenia: Progress toward Clinically Useful Biomarkers.

    Science.gov (United States)

    Dean, Brian

    2011-01-01

    The search for clinically useful biomarkers has been one of the holy grails of schizophrenia research. This paper will outline the evolving notion of biomarkers and then outline outcomes from a variety of biomarkers discovery strategies. In particular, the impact of high-throughput screening technologies on biomarker discovery will be highlighted and how new or improved technologies may allow the discovery of either diagnostic biomarkers for schizophrenia or biomarkers that will be useful in determining appropriate treatments for people with the disorder. History tells those involved in biomarker research that the discovery and validation of useful biomarkers is a long process and current progress must always be viewed in that light. However, the approval of the first biomarker screen with some value in predicting responsiveness to antipsychotic drugs suggests that biomarkers can be identified and that these biomarkers that will be useful in diagnosing and treating people with schizophrenia.

  4. Cauda equina syndrome: a review of clinical progress

    Institute of Scientific and Technical Information of China (English)

    MA Bin; WU Hong; JIA Lian-shun; YUAN Wen; SHI Guo-dong; SHI Jian-gang

    2009-01-01

    Objective To review the literature on the clinical progress in cauda equina syndrome (CES), including the epidemic history, pathogenesis, diagnosis, treatment policy and prognosis.Data sources All reports on CES in the literature were searched in PubMed, Ovid, Springer, Elsevier, and the Chinese Biomedical Literature Disk using the key terms "cauda equina syndrome", "diagnosis", "treatment', "prognosis" and "evidence-based medicine".Study selection Original milestone articles and critical reviews wdtten by major pioneer investigators about the cauda equina syndrome were selected.Results CES is rare, both atraumatically and traumatically. Males and females are equally affected. The incidence of CES is variable, depending on the etiology of the syndrome. The most common cause of CES is herniation of a lumbar intervertebral disc. CES symptoms may have sudden onset and evolve rapidly or sometimes chronic ally. Each type of CES has different typical signs and symptoms. Low back pain may be the most significant symptoms, accompanied by sciatica, lower extremities weakness, saddle or perianal hypoesthesia, sexual impotence, and sphincter dysfunction. MRI is usually the preferred investigation approach. Patients who have had CES are difficult to return to a normal status.Conclusions The diagnosis of CES is primarily based on a careful history inquiry and clinical examination, assisted by elective radiologic investigations. Early diagnosis and early surgical decompression are crucial for a favorable outcome in most CES cases.

  5. Detection and measurement of clinically meaningful visual field progression in clinical trials for glaucoma.

    Science.gov (United States)

    De Moraes, C Gustavo; Liebmann, Jeffrey M; Levin, Leonard A

    2017-01-01

    Glaucomatous visual field progression has both personal and societal costs and therefore has a serious impact on quality of life. At the present time, intraocular pressure (IOP) is considered to be the most important modifiable risk factor for glaucoma onset and progression. Reduction of IOP has been repeatedly demonstrated to be an effective intervention across the spectrum of glaucoma, regardless of subtype or disease stage. In the setting of approval of IOP-lowering therapies, it is expected that effects on IOP will translate into benefits in long-term patient-reported outcomes. Nonetheless, the effect of these medications on IOP and their associated risks can be consistently and objectively measured. This helps to explain why regulatory approval of new therapies in glaucoma has historically used IOP as the outcome variable. Although all approved treatments for glaucoma involve IOP reduction, patients frequently continue to progress despite treatment. It would therefore be beneficial to develop treatments that preserve visual function through mechanisms other than lowering IOP. The United States Food and Drug Administration (FDA) has stated that they will accept a clinically meaningful definition of visual field progression using Glaucoma Change Probability criteria. Nonetheless, these criteria do not take into account the time (and hence, the speed) needed to reach significant change. In this paper we provide an analysis based on the existing literature to support the hypothesis that decreasing the rate of visual field progression by 30% in a trial lasting 12-18 months is clinically meaningful. We demonstrate that a 30% decrease in rate of visual field progression can be reliably projected to have a significant effect on health-related quality of life, as defined by validated instruments designed to measure that endpoint.

  6. Clinical Application of Variation in Replication Kinetics During Episodes of Post-transplant Cytomegalovirus Infections

    DEFF Research Database (Denmark)

    Lodding, I P; Sengeløv, Henrik; da Cunha-Bang, C

    2015-01-01

    of the first CMV infection in the first year post-transplant could be calculated for 193 recipients of haematopoietic stem cell or solid organ transplantation. Factors determining the proportion of recipients with a high diagnostic CMV viral load (≥ 18,200 IU/mL) were explored using mathematical simulation......BACKGROUND: Cytomegalovirus (CMV) infection in transplant recipients is reported to replicate with a doubling time of 1.2-2 days, and weekly screening is recommended for early diagnosis. We re-evaluated these features in our cohort of transplant recipients. METHODS: The CMV doubling time....... FINDINGS: The overall median doubling time was 4.3 days (IQR 2.5-7.8) and was not influenced by prior CMV immunity, or type of transplantation (p > 0.4). Assuming a fixed doubling time of 1.3 days and screening intervals of 7 or 10 days, 11.1% and 33.3% were projected to have a high CMV viral load...

  7. Bilirubin and Progression of Nephropathy in Type 2 Diabetes : A Post Hoc Analysis of RENAAL With Independent Replication in IDNT

    NARCIS (Netherlands)

    Riphagen, Ineke J.; Deetman, Petronella E.; Bakker, Stephan J. L.; Navis, Gerarda; Cooper, Mark E.; Lewis, Julia B.; de Zeeuw, Dick; Lambers Heerspink, Hiddo

    2014-01-01

    Bilirubin, a potent endogenous antioxidant, was found to protect against the development of diabetic nephropathy (DN) in rodents. In humans, cross-sectional studies found an inverse relation between bilirubin and DN. We prospectively investigated whether bilirubin is associated with progression of D

  8. Clinical features of progressive supranuclear palsy in 105 Chinese patients

    Institute of Scientific and Technical Information of China (English)

    Jing Hou; Ruibiao Guo; Tong Chen; Xiaohong Zhang; Weiping Wu; Zhenfu Wang

    2011-01-01

    OBJECTIVE: To thoroughly investigate clinical characteristics of progressive supranuclear palsy (PSP) in a Chinese population.METHODS: Computer-based online searches through China National Knowledge Infrastructure and Weipu Periodical Database were performed to collect case reports of PSP published between 1980 and 2009. Clinical characteristics were analyzed.RESULTS: A total of 58 studies comprising 105 patients (76 males and 29 females) were included. All cases were sporadic and free of family history. The mean age at onset was 60.6 ± 9.1 years, and the mean course from onset of symptoms to diagnosis was 3.4 ± 2.4 years. The male-to-female ratio was approximately 3: 1. Onset was characterized by akinetic-rigid features and accounted for 34.3% of all cases, followed by early postural instability (25.5%), pseudobulbar palsy (9.8%), cognitive impairment (9.8%), and vertical supranuclear ophthalmoplegia (7.8%). With disease progression, vertical supranuclear ophthalmoplegia was reported in 95.1% of cases, followed by akinetic-rigid features (83.3%), pseudobulbar palsy (82.4%), axial dystonia (75.5%), cognitive impairment (72.5%), and early postural instability (69.6%). A total of 70.5% of patients exhibited abnormal electroencephalograms, and 21.4% exhibited mild abnormalities in cerebrospinal fluid. Brain CT scanning results of 37 patients showed 37.8% with midbrain and concurrent cerebral hemisphere atrophy, and 5.4% and 24.3% with midbrain and cerebral hemisphere atrophy, respectively. Brain MRI scanning results of 55 patients revealed a total of 16.4% patients with midbrain atrophy, 23.6% with midbrain and concurrent cerebral hemisphere atrophy, 32.7% with cerebral hemisphere atrophy, and 11% with brainstem atrophy. The percentage of midbrain atrophy revealed by MRI was greater than by CT. All 11 patients subjected to Mini-Mental State Examination scored < 23. A total of 10 patients underwent brain electrophysiological examination, and 80% presented with

  9. Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives.

    Science.gov (United States)

    Ontaneda, Daniel; Fox, Robert J; Chataway, Jeremy

    2015-02-01

    Progressive multiple sclerosis is characterised clinically by the gradual accrual of disability independent of relapses and can occur with disease onset (primary progressive) or can be preceded by a relapsing disease course (secondary progressive). An effective disease-modifying treatment for progressive multiple sclerosis has not yet been identified, and so far the results of clinical trials have generally been disappointing. Ongoing advances in the knowledge of pathogenesis, in the identification of novel targets for neuroprotection, and in improved outcome measures could lead to effective treatments for progressive multiple sclerosis. In this Series paper, we summarise the lessons learned from completed clinical trials and perspectives from trials in progress in progressive multiple sclerosis. We review promising clinical, imaging, and biological markers, along with novel designs, for clinical trials. The use of more refined outcomes and truly neuroprotective drugs, coupled with more efficient trial design, has the capacity to deliver a new era of therapeutic discovery in this challenging area.

  10. Case of Rapid Progression of Hemiatrophy on the Face: A New Clinical Entity?

    Directory of Open Access Journals (Sweden)

    Hisashi Nomura

    2015-01-01

    Full Text Available A lot of diseases, including lupus profundus, morphea, lipodystrophy, and Parry-Romberg syndrome, may manifest progressive hemifacial atrophy. These diseases usually progress slowly and rapid progression of atrophy is extremely rare. We report a case of elderly-onset rapid progression of hemifacial atrophy only in three weeks. Our case did not meet variable differential diagnoses. We discuss the clinical character of the patient against the past of literature and suppose it may be a new clinical entity.

  11. Evaluation of the William S. Hall Psychiatric Institute Clinical Psychology Internship: a replication and extension.

    Science.gov (United States)

    Stader, Sandra R; Myers, DeRosset; Forand, Angela Q; Holmes, George R; McNulty, George F; Frey, Linda; Bolton, Staci S

    2010-12-01

    This study extends three earlier investigations involving participants who completed their predoctoral clinical psychology internship at the William S. Hall Psychiatric Institute. Intern graduates (N = 37) evaluated how effectively their internship training prepared them for seven aspects of their current work as practicing psychologists. Participants also rated the relevancy of 24 different internship training experiences to their current work and how much these experiences contributed to their development as clinical psychologists. The present study, in conjunction with the three previous studies, covers most of the 40-year period since the inception of the internship program. Analysis of the current data indicates the internship has improved over time and was deemed an exceptional training experience by its graduates. Findings may be of particular interest to internship directors and faculty interested in improving their training program and those who plan to conduct a self-study to maintain their accreditation for clinical psychology internship.

  12. Heart Failure in Patients with Preserved Ejection Fraction: Questions Concerning Clinical Progression

    Directory of Open Access Journals (Sweden)

    George E. Louridas

    2016-09-01

    Full Text Available Over the last two decades, important advances have been made in explaining some pathophysiological aspects of heart failure with preserved ejection fraction (HFpEF with repercussions for the successful clinical management of the syndrome. Despite these gains, our knowledge for the natural history of clinical progression from the pre-clinical diastolic dysfunction (PDD until the final clinical stages is significantly limited. The subclinical progression of PDD to the clinical phenotype of HFpEF and the further clinical progression to some more complex clinical models with multi-organ involvement, similar to heart failure with reduced ejection fraction (HFrEF, continue to be poorly understood. Prospective studies are needed to elucidate the natural history of clinical progression in patients with HFpEF and to identify the exact left ventricular remodeling mechanism that underlies this progression.

  13. Clinical characteristics and progression of liver abscess caused by toxocara

    Institute of Scientific and Technical Information of China (English)

    Kyung; Ho; Ha; Jung; Eun; Song; Byung; Seok; Kim; Chang; Hyeong; Lee

    2016-01-01

    AIM: To evaluate the clinical characteristics and progression of liver abscess caused by toxocara.METHODS: We retrospectively reviewed the medical records of patients with serum Ig G antibody to Toxocara canis and liver abscess diagnosed using abdominal computed tomography between February 2010 and February 2015. Among 84 patients exhibiting serum Ig G antibody to Toxocara canis, 34 patients were diagnosed with liver asbscess and treated with albendazole. A follow-up period of 1 year was conducted. RESULTS: Mean patient age was 53(34-79) years, with 26(76.5%) patients being male. Twenty-one(61.7%) patients were moderate or heavy drinkers, 23(67.6%) patients had a history of eating raw meat or liver and 6(17.6%) patients owned pet dogs or cats. Main patient symptoms consisted of right upper quadrant pain, fever, and fatigue; 18(52.9%) patients, however, presented with no symptoms. Lung involvement was detected in 444(11.7%) patients. The eosinophil count increased in 29(85.3%) patients at initial diagnosis, and decreased in most patients after albendazole treatment. The initial serum Ig E level increased in 25(73.5%) patients, but exhibited various response levels after albendazole treatment. Liver abscess formation improved in all patients.CONCLUSION: The liver abscess was improved with albendazole treatment.

  14. Characterization of the effects of Escherichia coli replication terminator protein (Tus) on transcription reveals dynamic nature of the tus block to transcription complex progression.

    Science.gov (United States)

    Guajardo, R; Sousa, R

    1999-01-01

    We have characterized the blocks to progression of T7 and T3 RNA polymerase transcription complexes created when a Tus protein is bound to the template. The encounter with Tus impedes the progress of the transcription complexes of either enzyme. The duration of the block depends on which polymerase is used and the orientation of Tus on the DNA. Both genuine termination (dissociation of the transcription complex) and halting followed by continued progression after the block is abrogated are observed. The fraction of complexes that terminates depends on which polymerase is used and on the orientation of the Tus molecule. The efficiency of the block to transcription increases as the Tus concentration is increased, even if the concentration of Tus is already many times in excess of what is required to saturate its binding sites on the template in the absence of transcription. The block to transcription is rapidly abrogated if an excess of a DNA containing a binding site for Tus is added to a transcription reaction in which Tus and template have been preincubated. Finally, we find that transcription will rapidly displace Tus from a template under conditions that generate persistent blocks to transcription. These observations reveal that during the encounter with the transcription complex Tus rapidly dissociates from the template but that at sufficiently high concentrations Tus usually rebinds before the transcription complex can move forward. The advantage of a mechanism which can create a persistent block to transcription or replication complex progression, which can nevertheless be rapidly abrogated in response to down regulation of the blocking protein, is suggested. PMID:10373601

  15. Minimal clinically important difference in radiological progression of joint damage. A definition based on patient perspective.

    NARCIS (Netherlands)

    Welsing, P.M.J.; Borm, G.F.; Riel, P.L.C.M. van

    2006-01-01

    OBJECTIVE: To estimate a threshold for minimal clinically important radiological progression of joint damage using its longitudinal relation with functional disability in patients with rheumatoid arthritis (RA). To validate existing estimates of minimal clinically important difference (MCID) using

  16. [Clinical types of FTLD: progressive nonfluent aphasia; comparative discussions on the associated clinical presentations].

    Science.gov (United States)

    Fukui, Toshiya

    2009-11-01

    Progressive nonfluent aphasia (PNFA) is one of the 3 clinical presentations of frontotemporal lobar degeneration (FTLD), the other 2 being frontotemporal dementia and semantic dementia (SD). PNFA and SD, both representing relentlessly progressive language impairment in the realm of FTLD, may share a large part with primary progressive aphasia (PPA). A salient distinction between PPA and PNFA or SD is that PPA includes another clinical type, namely, logopenic/phonemic aphasia (LPA), which is not represented in FTLD. This is primarily because LPA is usually caused by Alzheimer's disease (AD) and the brunt of the lesion is localized at the left temporo-parietal region of the brain. Further, PNFA/SD should be limited to the clinical consequencies of FTLD while PPA is more generous with regard to its causal pathology. By definition, PNFA is an expressive language impairment which is characterized by effortful speech, phonemic errors, grammatical impairment, and word-finding difficulties. Reading and writing may be comparatively impaired. Comprehension of single word meaning is normal, while comprehension of sentencies may sometimes be impaired. PNFA should be differentiated from SD, LPA, and pure progressive apraxia of speech (AOS or alternatively referred to as aphemia or anarthria). SD may be distinguished from PNFA by virtue of its fluency, characteristic loss of word meaning and absence of agrammatism. LPA is similar to PNFA, yet differs in that there is preservation of grammatical skills and speech motor function that is devoid of AOS and/or dysarthria. AOS is an impairment at the level of speech motor programming without language impairment. Thus, there may be a double dissociation between AOS and PNFA i. e., PNFA may or may not accompany AOS and vice versa. PNFA is associated with a localized lesion in the left frontotemporal area of the brain. Immunohistochemical investigations have revealed that ubiquitin/TAR DNA binding protein-43 (TDA-43) positive and tau

  17. Stem cells: progressions and applications in clinical medicine

    Directory of Open Access Journals (Sweden)

    Ali Hosseini Bereshneh

    2016-05-01

    of them in transferring gene into different cells. Today, this method have had considerable progress in the treatment of many disease. In this review study, some aspect of stem cells like types and characteristic, origin, derivation techniques, storage conditions and differentiation to target tissues, current clinical usage and their therapeutic capabilities will be discussed.

  18. Replicating animal mitochondrial DNA

    Directory of Open Access Journals (Sweden)

    Emily A. McKinney

    2013-01-01

    Full Text Available The field of mitochondrial DNA (mtDNA replication has been experiencing incredible progress in recent years, and yet little is certain about the mechanism(s used by animal cells to replicate this plasmid-like genome. The long-standing strand-displacement model of mammalian mtDNA replication (for which single-stranded DNA intermediates are a hallmark has been intensively challenged by a new set of data, which suggests that replication proceeds via coupled leading-and lagging-strand synthesis (resembling bacterial genome replication and/or via long stretches of RNA intermediates laid on the mtDNA lagging-strand (the so called RITOLS. The set of proteins required for mtDNA replication is small and includes the catalytic and accessory subunits of DNA polymerase y, the mtDNA helicase Twinkle, the mitochondrial single-stranded DNA-binding protein, and the mitochondrial RNA polymerase (which most likely functions as the mtDNA primase. Mutations in the genes coding for the first three proteins are associated with human diseases and premature aging, justifying the research interest in the genetic, biochemical and structural properties of the mtDNA replication machinery. Here we summarize these properties and discuss the current models of mtDNA replication in animal cells.

  19. Vitamin D and clinical disease progression in HIV infection

    DEFF Research Database (Denmark)

    Viard, Jean-Paul; Souberbielle, Jean-Claude; Kirk, Ole

    2011-01-01

    BACKGROUND:: We examined the association between vitamin D [25(OH)D] level and disease progression in HIV infection. METHODS:: Within the EuroSIDA study, 2000 persons were randomly selected for 25(OH)D measurement in stored plasma samples closest to study entry. 25(OH)D results were stratified...

  20. Mycobacterium tuberculosis modulates the gene interactions to activate the HIV replication and faster disease progression in a co-infected host.

    Science.gov (United States)

    Toor, Jaideep S; Singh, Sukhvinder; Sharma, Aman; Arora, Sunil K

    2014-01-01

    Understanding of the chronic immune activation, breakdown of immune defense and synergistic effect between HIV and Mycobacterium tuberculosis (Mtb) may provide essential information regarding key factors involved in the pathogenesis of HIV disease. In this study, we aimed to highlight a few of the immunological events that may influence and accelerate the progression of HIV disease in the presence of co-infecting Mtb. A cross-sectional study was performed on cohorts, including anti-tubercular therapy (ATT) naïve active pulmonary tuberculosis (PTB) patients, antiretroviral therapy (ART) naïve HIV-1 infected individuals at different stages of disease, ATT and ART naïve HIV-PTB co-infected individuals and healthy controls. A significantly higher T-regulatory cell (Treg) frequency coupled with the high FoxP3 expression in the CD4 T-cells indicated an immunosuppressive environment in the advance stage of HIV-1 infection. This is further substantiated by high HO-1 expression favoring TB co-infection. Functionally, this change in Treg frequency in HIV-1 infected individuals correlated well with suppression of T-cell proliferation. Mtb infection seems to facilitate the expansion of the Treg pool along with increased expression of FoxP3, specifically the variant-1, as evident from the data in HIV-1 co-infected as well as in patients with only PTB. A significantly lower expression of HO-1 in co-infected individuals compared to patients with only HIV-infection having comparable CD4 count correlated well with increased expression of CCR5 and CxCR4 as well as NF-κB and inflammatory cytokines IL-6 and TNF-α, which collectively may contribute to enhanced viral replication and increased cell death, hence faster disease progression in co-infected individuals.

  1. Mycobacterium tuberculosis modulates the gene interactions to activate the HIV replication and faster disease progression in a co-infected host.

    Directory of Open Access Journals (Sweden)

    Jaideep S Toor

    Full Text Available Understanding of the chronic immune activation, breakdown of immune defense and synergistic effect between HIV and Mycobacterium tuberculosis (Mtb may provide essential information regarding key factors involved in the pathogenesis of HIV disease. In this study, we aimed to highlight a few of the immunological events that may influence and accelerate the progression of HIV disease in the presence of co-infecting Mtb. A cross-sectional study was performed on cohorts, including anti-tubercular therapy (ATT naïve active pulmonary tuberculosis (PTB patients, antiretroviral therapy (ART naïve HIV-1 infected individuals at different stages of disease, ATT and ART naïve HIV-PTB co-infected individuals and healthy controls. A significantly higher T-regulatory cell (Treg frequency coupled with the high FoxP3 expression in the CD4 T-cells indicated an immunosuppressive environment in the advance stage of HIV-1 infection. This is further substantiated by high HO-1 expression favoring TB co-infection. Functionally, this change in Treg frequency in HIV-1 infected individuals correlated well with suppression of T-cell proliferation. Mtb infection seems to facilitate the expansion of the Treg pool along with increased expression of FoxP3, specifically the variant-1, as evident from the data in HIV-1 co-infected as well as in patients with only PTB. A significantly lower expression of HO-1 in co-infected individuals compared to patients with only HIV-infection having comparable CD4 count correlated well with increased expression of CCR5 and CxCR4 as well as NF-κB and inflammatory cytokines IL-6 and TNF-α, which collectively may contribute to enhanced viral replication and increased cell death, hence faster disease progression in co-infected individuals.

  2. The relationship between CAG repeat length and clinical progression in Huntington's disease.

    Science.gov (United States)

    Ravina, Bernard; Romer, Megan; Constantinescu, Radu; Biglan, Kevin; Brocht, Alicia; Kieburtz, Karl; Shoulson, Ira; McDermott, Michael P

    2008-07-15

    The objective of this study was to examine the relationship between CAG repeat length (CAGn) and clinical progression in patients with Huntington's disease (HD). There are conflicting reports about the relationship between CAGn and clinical progression of HD. We conducted an analysis of data from the Coenzyme Q10 and Remacemide Evaluation in Huntington's Disease (CARE-HD) clinical trial. We modeled progression over 30 months on the Unified Huntington's Disease Rating Scale (UHDRS) and supplemental neuropsychological and behavioral tests using multiple linear regression. Mean subject age was 47.9 +/- 10.5 years and mean CAGn was 45.0 +/- 4.1. Multiple linear regression revealed statistically significant associations between CAGn and worsening on several motor, cognitive, and functional outcomes, but not behavioral outcomes. Many effects were clinically important; 10 additional CAG repeats were associated with an 81% increase in progression on the Independence Scale. These associations were not observed in the absence of age adjustment. Age at the time of assessment confounds the association between CAGn and progression. Adjusting for age shows that longer CAGn is associated with greater clinical progression of HD. This finding may account for the variable results from previous studies examining CAGn and progression. Adjusting for CAGn may be important for clinical trials.

  3. Progress through Collaboration - Office of Cancer Clinical Proteomics Research

    Science.gov (United States)

    The National Cancer Institute (NCI), through the Office of Cancer Clinical Proteomics Research (OCCPR), has signed two Memorandums of Understanding (MOUs) in the areas of sharing proteomics reagents and protocols and also in regulatory science.

  4. [Progress of orthodontics in the clinical and basic research].

    Science.gov (United States)

    Zhao, Zhi-He

    2008-06-01

    In recent years, clinical diagnostic and treatment techniques of orthodontics have been developed rapidly. The orthopedic mechanism of malocclusion has been the hot spot of basic research of orthodontics.

  5. CtrA response regulator binding to the Caulobacter chromosome replication origin is required during nutrient and antibiotic stress as well as during cell cycle progression.

    Science.gov (United States)

    Bastedo, D Patrick; Marczynski, Gregory T

    2009-04-01

    The Caulobacter crescentus chromosome replication origin (Cori) has five binding sites for CtrA, an OmpR/PhoB family 'response regulator'. CtrA is degraded in replicating 'stalked' cells but is abundant in the non-replicating 'swarmer' cells, where it was proposed to repress replication by binding to Cori. We systematically mutated all Cori CtrA binding sites, and examined their consequences in the contexts of autonomous Cori-plasmid replication and in the natural chromosome locus. Remarkably, the C. crescentus chromosome tolerates severe mutations in all five CtrA binding sites, demonstrating that CtrA is not essential for replication. Further physiological and cell cycle experiments more rigorously supported the original hypothesis that CtrA represses replication. However, our experiments argued against another hypothesis that residual and/or replenished CtrA protein in stalked cells might prevent extra or unscheduled chromosome replication before cell division. Surprisingly, we also demonstrated that Cori CtrA binding sites are very advantageous and can become essential when cells encounter nutrients and antibiotics. Therefore, the CtrA cell cycle regulator co-ordinates replication with viable cell growth in stressful and rapidly changing environments. We argue that this new role for CtrA provided the primary selective pressure for evolving control by CtrA.

  6. Database Replication

    CERN Document Server

    Kemme, Bettina

    2010-01-01

    Database replication is widely used for fault-tolerance, scalability and performance. The failure of one database replica does not stop the system from working as available replicas can take over the tasks of the failed replica. Scalability can be achieved by distributing the load across all replicas, and adding new replicas should the load increase. Finally, database replication can provide fast local access, even if clients are geographically distributed clients, if data copies are located close to clients. Despite its advantages, replication is not a straightforward technique to apply, and

  7. Clinical Progress on Acupuncture Treatment of Prostatic Hyperplasia

    Institute of Scientific and Technical Information of China (English)

    李丽会; 张淑静; 徐名一; 黄国琪

    2009-01-01

    @@ Prostatic hyperplasia, also termed benign prostatic hyperplasia (BPH), is a commonly encountered disease in middle-aged and old males. This condition is known as "Retention of Urine" and "Urination Syndrome" in Chinese medicine. Now, the literature from 1998 to 2008 on acupuncture treatment of prostatic hyperplasia are abstracted and reviewed, in order to understand the clinical status of acupuncture treatment for this disease.

  8. Assessment of competence and progressive independence in postgraduate clinical training.

    NARCIS (Netherlands)

    Dijksterhuis, M.G.; Voorhuis, M.; Teunissen, P.W.; Schuwirth, L.W.; Cate, O.T.J. ten; Braat, D.D.M.; Scheele, F.

    2009-01-01

    CONTEXT: At present, competency-based, outcome-focused training is gradually replacing more traditional master-apprentice teaching in postgraduate training. This change requires a different approach to the assessment of clinical competence, especially given the decisions that must be made about the

  9. SURGICAL TREATMENT OF PROGRESSIVE DYSPLASTIC COXARTROSIS IN CHILDREN (CLINICAL CASE

    Directory of Open Access Journals (Sweden)

    Иван Иванович Кужеливский

    2017-03-01

    Full Text Available Dysplastic coxarthrosis is dominate among children orthopedic cases, and its surgical alignment continues to be peracute. Despite the application of advanced therapies and medical treatment, the patients of surgical state case constitute a significant percentage of the total patient number, i. e. from 19 to 35 %. In this article a detailed literature review of surgical alignment methods for deficiency acetabular roof by applying different implants has been described. The authors have proposed applying titanium nickelide materials in the surgical alignment method, as such materials possess the following properties: high corrosion stability, full compatibility with the body tissues, as well as, sufficient porosis providing radial border structure regeneration of acetabular roof, which in its turn, improves the support ability of extermity. In the event of progression of coxarthrosis iliac segment is reserved for the upcoming replacement.

  10. Viral replication rate regulates clinical outcome and CD8 T cell responses during highly pathogenic H5N1 influenza virus infection in mice.

    Directory of Open Access Journals (Sweden)

    Yasuko Hatta

    2010-10-01

    Full Text Available Since the first recorded infection of humans with H5N1 viruses of avian origin in 1997, sporadic human infections continue to occur with a staggering mortality rate of >60%. Although sustained human-to-human transmission has not occurred yet, there is a growing concern that these H5N1 viruses might acquire this trait and raise the specter of a pandemic. Despite progress in deciphering viral determinants of pathogenicity, we still lack crucial information on virus/immune system interactions pertaining to severe disease and high mortality associated with human H5N1 influenza virus infections. Using two human isolates of H5N1 viruses that differ in their pathogenicity in mice, we have defined mechanistic links among the rate of viral replication, mortality, CD8 T cell responses, and immunopathology. The extreme pathogenicity of H5N1 viruses was directly linked to the ability of the virus to replicate rapidly, and swiftly attain high steady-state titers in the lungs within 48 hours after infection. The remarkably high replication rate of the highly pathogenic H5N1 virus did not prevent the induction of IFN-β or activation of CD8 T cells, but the CD8 T cell response was ineffective in controlling viral replication in the lungs and CD8 T cell deficiency did not affect viral titers or mortality. Additionally, BIM deficiency ameliorated lung pathology and inhibited T cell apoptosis without affecting survival of mice. Therefore, rapidly replicating, highly lethal H5N1 viruses could simply outpace and overwhelm the adaptive immune responses, and kill the host by direct cytopathic effects. However, therapeutic suppression of early viral replication and the associated enhancement of CD8 T cell responses improved the survival of mice following a lethal H5N1 infection. These findings suggest that suppression of early H5N1 virus replication is key to the programming of an effective host response, which has implications in treatment of this infection in humans.

  11. Viral replication rate regulates clinical outcome and CD8 T cell responses during highly pathogenic H5N1 influenza virus infection in mice.

    Science.gov (United States)

    Hatta, Yasuko; Hershberger, Karen; Shinya, Kyoko; Proll, Sean C; Dubielzig, Richard R; Hatta, Masato; Katze, Michael G; Kawaoka, Yoshihiro; Suresh, M

    2010-10-07

    Since the first recorded infection of humans with H5N1 viruses of avian origin in 1997, sporadic human infections continue to occur with a staggering mortality rate of >60%. Although sustained human-to-human transmission has not occurred yet, there is a growing concern that these H5N1 viruses might acquire this trait and raise the specter of a pandemic. Despite progress in deciphering viral determinants of pathogenicity, we still lack crucial information on virus/immune system interactions pertaining to severe disease and high mortality associated with human H5N1 influenza virus infections. Using two human isolates of H5N1 viruses that differ in their pathogenicity in mice, we have defined mechanistic links among the rate of viral replication, mortality, CD8 T cell responses, and immunopathology. The extreme pathogenicity of H5N1 viruses was directly linked to the ability of the virus to replicate rapidly, and swiftly attain high steady-state titers in the lungs within 48 hours after infection. The remarkably high replication rate of the highly pathogenic H5N1 virus did not prevent the induction of IFN-β or activation of CD8 T cells, but the CD8 T cell response was ineffective in controlling viral replication in the lungs and CD8 T cell deficiency did not affect viral titers or mortality. Additionally, BIM deficiency ameliorated lung pathology and inhibited T cell apoptosis without affecting survival of mice. Therefore, rapidly replicating, highly lethal H5N1 viruses could simply outpace and overwhelm the adaptive immune responses, and kill the host by direct cytopathic effects. However, therapeutic suppression of early viral replication and the associated enhancement of CD8 T cell responses improved the survival of mice following a lethal H5N1 infection. These findings suggest that suppression of early H5N1 virus replication is key to the programming of an effective host response, which has implications in treatment of this infection in humans.

  12. From selection hits to clinical leads: progress in aptamer discovery

    Directory of Open Access Journals (Sweden)

    Keith E Maier

    2016-01-01

    Full Text Available Aptamers were discovered more than 25 years ago, yet only one has been approved by the US Food and Drug Administration to date. With some noteworthy advances in their chemical design and the enzymes we use to make them, aptamers and aptamer-based therapeutics have seen a resurgence in interest. New aptamer drugs are being approved for clinical evaluation, and it is certain that we will see increasingly more aptamers and aptamer-like drugs in the future. In this review, we will discuss the production of aptamers with an emphasis on the advances and modifications that enabled early aptamers to succeed in clinical trials as well as those that are likely to be important for future generations of these drugs.

  13. Clinical Investigation Program. Annual Progress Report. Volume 1

    Science.gov (United States)

    1994-01-20

    conducting, and publishing ethical, scientific inquiry into clinical health problems of beneficiaries of the military health care system, to include... Acromegaly and 173 Intermediate Markers of Neoplasia (5/90) 1417 Wong, Roy COL MC. Incidence of Gastric Mucosal Injury in 174 Patients Ingesting Liquid Versus... Respiratory 225 Control Mechanisms and Nocturnal Desaturation in Diffuse Pulmonary Fibrosis (2/81) 1714 Dillard, Thomas LTC MC. Mechanisms Limiting Exercise

  14. Progressing the utilisation of pharmacogenetics and pharmacogenomics into clinical care.

    Science.gov (United States)

    Trent, Ronald J; Cheong, Pak Leng; Chua, Eng Wee; Kennedy, Martin A

    2013-06-01

    Understanding human genetic variation and how it impacts on gene function is a major focus in genomic-based research. Translation of this knowledge into clinical care is exemplified by pharmacogenetics/pharmacogenomics. The identification of particular gene variants that might influence drug uptake, metabolism, distribution or excretion promises a more effective personalised medicine approach in choosing the right drug or its dose for any particular individual. Adverse drug responses can then be avoided or mitigated. An understanding of germline or acquired (somatic) DNA mutations can also be used to identify drugs that are more likely to be therapeutically beneficial. This represents an area of growing interest in the treatment of cancer.

  15. Application progress of temozolomide in clinical tumor chemotherapy

    Directory of Open Access Journals (Sweden)

    ZHONG Cheng

    2013-12-01

    Full Text Available Temozolomide is an imidazotetrazine derivative of the alkylating agent, which is used to treat central nervous system tumors, especially malignant brain gliomas. It is a milestone in brain giloma chemotherapy. Recently, some researchers used temozolomide for the treatment of other tumors, including melanoma, intracranial metastatic tumors, lymphomas, refractory leukaemia, pituitary tumors, lung cancer, and so on. Some results are encouraging in clinical trials. Here, this paper makes a review on the antineoplastic mechanisms of temozolomide, its indications in gliomas and some unusual indications.

  16. Editorial: Process to progress? Investigative trials, mechanism and clinical science.

    Science.gov (United States)

    Green, Jonathan

    2015-01-01

    In 2002 Helena Kraemer and colleagues published an important article on the analysis of clinical trials in mental health, which advocated a planned focus on mechanisms to investigate the processes behind treatment effects. Kraemer et al. considered not only new approaches to mediation analysis, but also a theoretical approach to factors, both pre-treatment and during treatment, that might moderate this mediation. Trials should not just be about whether a treatment 'worked', but how it worked; with the results informing modification of the intervention for the next trial by discarding aspects that were not effective and reinforcing aspects that were - an iterative procedure towards greater effectiveness. Can we enjoy similar ambitions for complex interventions within mental health? It is not so long ago when the received wisdom within the clinical and much of the research community was that it was simply impossible in practice to mount randomised controlled trials relevant to the kind of psychosocial interventions we use in child and adolescent mental health (CAMHS). How different the situation is now, with burgeoning interest in a systematic evidence base for psychological treatment and the possibilities for unexpected advances (as well as unexpected harms). Nevertheless it is probably still fair to say that the systematic use of process and mechanism study within trials in our field is the exception rather than the rule. What are the possibilities and implications for our field?

  17. National Comorbidity Survey Replication Adolescent Supplement (NCS-A): III. Concordance of DSM-IV/CIDI Diagnoses with Clinical Reassessments

    Science.gov (United States)

    Kessler, Ronald C.; Avenevoli, Shelli; Green, Jennifer; Gruber, Michael J.; Guyer, Margaret; He, Yulei; Jin, Robert; Kaufman, Joan; Sampson, Nancy A.; Zaslavsky, Alan M.; Merikangas, Kathleen R.

    2009-01-01

    The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnoses that was based on the World Health Organization's Composite International Diagnostic Interview (CIDI) and implemented in the National comorbidity survey replication adolescent supplement is found to have good individual-level concordance with diagnosis based on blinded…

  18. Dynamics of Escherichia coli Chromosome Segregation during Multifork Replication

    DEFF Research Database (Denmark)

    Nielsen, Henrik Jørck; Youngren, Brenda; Hansen, Flemming G.

    2007-01-01

    Slowly growing Escherichia coli cells have a simple cell cycle, with replication and progressive segregation of the chromosome completed before cell division. In rapidly growing cells, initiation of replication occurs before the previous replication rounds are complete. At cell division...

  19. Platelet Function Tests: A Review of Progresses in Clinical Application

    Directory of Open Access Journals (Sweden)

    Jae-Lim Choi

    2014-01-01

    Full Text Available The major goal of traditional platelet function tests has been to screen and diagnose patients who present with bleeding problems. However, as the central role of platelets implicated in the etiology of arterial thrombotic diseases such as myocardial infarction and stroke became widely known, platelet function tests are now being promoted to monitor the efficacy of antiplatelet drugs and also to potentially identify patients at increased risk of thrombosis. Beyond hemostasis and thrombosis, an increasing number of studies indicate that platelets play an integral role in intercellular communication, are mediators of inflammation, and have immunomodulatory activity. As new potential biomarkers and technologies arrive at the horizon, platelet functions testing appears to take on a new aspect. This review article discusses currently available clinical application of platelet function tests, placing emphasis on essential characteristics.

  20. Overview summary of clinical heavier-ion progress in Japan

    Science.gov (United States)

    Matsufuji, N.

    2017-06-01

    Swift ion beams such as carbon has unique characteristics suitable for treating deep-seated tumours. In Japan, carbon-ion radiotherapy was started in 1994 at Heavy Ion Medical Accelerator in Chiba (HIMAC) at National Institute of Radiological Sciences and more than 10,000 patients have been treated by Aug. 2016. Clinical outcomes show superior efficacy of carbon ions even against radioresistant tumour while keeping the quality of life at high level, and also the usefulness of hypofractionated irradiation down to the completion of the course of lung-cancer treatment in 1 day. During the decades, the improvement of hardware and software technology such as 3D scanning technique, superconducting rotating gantry or biology model have been carried out aiming at further optimized ion-beam radiotherapy as well as reducing the cost of the facility. The developed technology has been transferred to the following facilities. As of 2016, 5 carbon ion radiotherapy facilities are in operation in Japan.

  1. Solving the Telomere Replication Problem

    Science.gov (United States)

    Maestroni, Laetitia; Matmati, Samah; Coulon, Stéphane

    2017-01-01

    Telomeres are complex nucleoprotein structures that protect the extremities of linear chromosomes. Telomere replication is a major challenge because many obstacles to the progression of the replication fork are concentrated at the ends of the chromosomes. This is known as the telomere replication problem. In this article, different and new aspects of telomere replication, that can threaten the integrity of telomeres, will be reviewed. In particular, we will focus on the functions of shelterin and the replisome for the preservation of telomere integrity. PMID:28146113

  2. Pseudotumour cerebri in children: Aetiology, clinical features, and progression.

    Science.gov (United States)

    Mosquera Gorostidi, A; Iridoy Zulet, M; Azcona Ganuza, G; Gembero Esarte, E; Yoldi Petri, M E; Aguilera Albesa, S

    2017-01-09

    The definition, associated aetiologies, diagnosis, and treatment of idiopathic intracranial hypertension, or pseudotumour cerebri (PTC), are constantly being revised in the paediatric population. Our study included children younger than 15 years old with PTC and attended at a reference hospital in the past 12 years. We analysed the clinical and epidemiological features of our sample and the diagnostic and treatment approaches. PTC was defined as presence of intracranial hypertension (CSF opening pressure>25cmH2O) and absence of space-occupying lesions in brain MR images. A total of 12 children with PTC were included; mean age was 10 years and 90% were girls. Weight was normal in all patients. Eighty-two percent of the patients had symptoms: headache (66%), diplopia (8%), and visual loss (8%). All of them displayed papilloedema (17% unilaterally). Lumbar puncture (LP) provided the diagnosis in all cases and 91% showed no relevant MRI findings. A potential cause of PTC was identified in 5 cases: pharmacological treatment in 2 and infection (Mycoplasma pneumoniae [M. pneumoniae]) in 3. Ninety-one per cent of the patients received treatment: 75% underwent several LPs and 42% received acetazolamide and/or prednisone. Outcomes were favourable in all cases. The incidence of PTC was estimated at approximately 1 case per 100 000 children/years, in line with data reported by previous studies. Overweight was not found to be a risk factor for PTC in this population. M. pneumoniae infection may trigger PTC and cause recurrences at later stages. The absence of symptoms seems to be independent from the degree of intracranial hypertension. Acetazolamide treatment is effective in most cases, and it represents a viable alternative to repeated LP. Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  3. Psychology, replication & beyond.

    Science.gov (United States)

    Laws, Keith R

    2016-06-01

    Modern psychology is apparently in crisis and the prevailing view is that this partly reflects an inability to replicate past findings. If a crisis does exists, then it is some kind of 'chronic' crisis, as psychologists have been censuring themselves over replicability for decades. While the debate in psychology is not new, the lack of progress across the decades is disappointing. Recently though, we have seen a veritable surfeit of debate alongside multiple orchestrated and well-publicised replication initiatives. The spotlight is being shone on certain areas and although not everyone agrees on how we should interpret the outcomes, the debate is happening and impassioned. The issue of reproducibility occupies a central place in our whig history of psychology.

  4. Non-progressive cerebellar ataxia and previous undetermined acute cerebellar injury: a mysterious clinical condition

    Directory of Open Access Journals (Sweden)

    Wladimir Bocca Vieira de Rezende Pinto

    2015-01-01

    Full Text Available Cerebellar ataxias represent a wide group of neurological diseases secondary to dysfunctions of cerebellum or its associated pathways, rarely coursing with acute-onset acquired etiologies and chronic non-progressive presentation. We evaluated patients with acquired non-progressive cerebellar ataxia that presented previous acute or subacute onset. Clinical and neuroimaging characterization of adult patients with acquired non-progressive ataxia were performed. Five patients were identified with the phenotype of acquired non-progressive ataxia. Most patients presented with a juvenile to adult-onset acute to subacute appendicular and truncal cerebellar ataxia with mild to moderate cerebellar or olivopontocerebellar atrophy. Establishing the etiology of the acute triggering events of such ataxias is complex. Non-progressive ataxia in adults must be distinguished from hereditary ataxias.

  5. Non-progressive cerebellar ataxia and previous undetermined acute cerebellar injury: a mysterious clinical condition

    Directory of Open Access Journals (Sweden)

    Wladimir Bocca Vieira de Rezende Pinto

    2015-10-01

    Full Text Available Cerebellar ataxias represent a wide group of neurological diseases secondary to dysfunctions of cerebellum or its associated pathways, rarely coursing with acute-onset acquired etiologies and chronic non-progressive presentation. We evaluated patients with acquired non-progressive cerebellar ataxia that presented previous acute or subacute onset. Clinical and neuroimaging characterization of adult patients with acquired non-progressive ataxia were performed. Five patients were identified with the phenotype of acquired non-progressive ataxia. Most patients presented with a juvenile to adult-onset acute to subacute appendicular and truncal cerebellar ataxia with mild to moderate cerebellar or olivopontocerebellar atrophy. Establishing the etiology of the acute triggering events of such ataxias is complex. Non-progressive ataxia in adults must be distinguished from hereditary ataxias.

  6. Renal Morphology, Clinical Findings, and Progression Rate in Mesoamerican Nephropathy.

    Science.gov (United States)

    Wijkström, Julia; González-Quiroz, Marvin; Hernandez, Mario; Trujillo, Zulma; Hultenby, Kjell; Ring, Anneli; Söderberg, Magnus; Aragón, Aurora; Elinder, Carl-Gustaf; Wernerson, Annika

    2017-05-01

    Mesoamerican nephropathy (MeN) is a chronic kidney disease affecting rural inhabitants in Central America. We have previously described the renal morphology in 8 patients from El Salvador. To confirm the renal pathology, we have studied kidney biopsies from patients with MeN in Nicaragua. Follow-up urine and blood samples from both biopsy studies were collected to investigate the natural history. Case series. In the kidney biopsy study, 19 male sugarcane workers in Nicaragua with suspected MeN were investigated with questionnaires, kidney biopsies, and blood and urine analysis. Inclusion criteria were age 20 to 65 years and plasma creatinine level of 1.13 to 2.49mg/dL or estimated glomerular filtration rate (eGFR) of 30 to 80mL/min/1.73m(2). Exclusion criteria were proteinuria with protein excretion > 3g/24 h, uncontrolled hypertension, diabetes mellitus, or other known kidney disease. In the follow up-study, blood and urine from the kidney biopsy study in Nicaragua (n=18) and our previous biopsy study of MeN cases in El Salvador (n=7) were collected 1 to 1.5 and 2 to 2.5 years after biopsy, respectively. Renal morphology, clinical, and biochemical characteristics, change in eGFR per year. eGFR was calculated using the CKD-EPI creatinine (eGFRcr), cystatin C (eGFRcys), and creatinine-cystatin C (eGFRcr-cys) equations. In the kidney biopsy study, participants had a mean eGFRcr of 57 (range, 33-96) mL/min/1.73m(2). 47% had low plasma sodium and 21% had low plasma potassium levels. 16 kidney biopsies were representative and showed glomerulosclerosis (mean, 38%), glomerular hypertrophy, and signs of chronic glomerular ischemia. Mild to moderate tubulointerstitial damage and mostly mild vascular changes were seen. In the follow up-study, median duration of follow-up was 13 (range, 13-27) months. Mean change in eGFRcr was -4.4±8.4 (range, -27.7 to 10.2) mL/min/1.73m(2) per year. Most patients had stopped working with sugarcane cultivation. 3 biopsy specimens had 4 or

  7. Modeling and Predicting AD Progression by Regression Analysis of Sequential Clinical Data

    KAUST Repository

    Xie, Qing

    2016-02-23

    Alzheimer\\'s Disease (AD) is currently attracting much attention in elders\\' care. As the increasing availability of massive clinical diagnosis data, especially the medical images of brain scan, it is highly significant to precisely identify and predict the potential AD\\'s progression based on the knowledge in the diagnosis data. In this paper, we follow a novel sequential learning framework to model the disease progression for AD patients\\' care. Different from the conventional approaches using only initial or static diagnosis data to model the disease progression for different durations, we design a score-involved approach and make use of the sequential diagnosis information in different disease stages to jointly simulate the disease progression. The actual clinical scores are utilized in progress to make the prediction more pertinent and reliable. We examined our approach by extensive experiments on the clinical data provided by the Alzheimer\\'s Disease Neuroimaging Initiative (ADNI). The results indicate that the proposed approach is more effective to simulate and predict the disease progression compared with the existing methods.

  8. From inhibition of radiographic progression to maintaining structural integrity: a methodological framework for radiographic progression in rheumatoid arthritis and psoriatic arthritis clinical trials.

    Science.gov (United States)

    Landewé, Robert; Strand, Vibeke; van der Heijde, Désirée

    2013-07-01

    Usually, a clinical trial in rheumatoid arthritis and psoriatic arthritis aiming to demonstrate that a new antirheumatic drug treatment can inhibit progression of structural damage has a 'superiority design': The new treatment is compared to placebo or to another active treatment. Currently, many new drug treatments have shown to be able to completely suppress progression (progression rates close to zero). For largely unknown reasons, during the last 10 years, radiographic progression rates in clinical trials have gradually decreased, so that progression rates in the comparator groups are often too low to demonstrate meaningful inhibition, and thus superiority of the new treatment. We here propose an alternative framework to demonstrate that new treatments have the ability to 'preserve structural integrity' rather than to 'inhibit radiographic progression'. Anno 2013, preserving structural integrity is conceptually more realistic than inhibiting radiographic progression.

  9. Modeling inhomogeneous DNA replication kinetics.

    Directory of Open Access Journals (Sweden)

    Michel G Gauthier

    Full Text Available In eukaryotic organisms, DNA replication is initiated at a series of chromosomal locations called origins, where replication forks are assembled proceeding bidirectionally to replicate the genome. The distribution and firing rate of these origins, in conjunction with the velocity at which forks progress, dictate the program of the replication process. Previous attempts at modeling DNA replication in eukaryotes have focused on cases where the firing rate and the velocity of replication forks are homogeneous, or uniform, across the genome. However, it is now known that there are large variations in origin activity along the genome and variations in fork velocities can also take place. Here, we generalize previous approaches to modeling replication, to allow for arbitrary spatial variation of initiation rates and fork velocities. We derive rate equations for left- and right-moving forks and for replication probability over time that can be solved numerically to obtain the mean-field replication program. This method accurately reproduces the results of DNA replication simulation. We also successfully adapted our approach to the inverse problem of fitting measurements of DNA replication performed on single DNA molecules. Since such measurements are performed on specified portion of the genome, the examined DNA molecules may be replicated by forks that originate either within the studied molecule or outside of it. This problem was solved by using an effective flux of incoming replication forks at the model boundaries to represent the origin activity outside the studied region. Using this approach, we show that reliable inferences can be made about the replication of specific portions of the genome even if the amount of data that can be obtained from single-molecule experiments is generally limited.

  10. [Top ten progressions of clinical research in fundus diseases in China].

    Science.gov (United States)

    2014-11-01

    Ten research items in the past five years representing the progression of clinical research in fundus diseases in China were voted by specialists from the Ocular Fundus Disease Group of Ophthalmology Society of Chinese Medical Association. Choroidal neovascular disease, pediatric retinal disease, polypoidal choroidal vasculopathy, intraocular malignant tumor, and intraocular infection caused by specific pathogens are covered. Novel treatment, like anti-VEGF medication, PDT, minimally invasive vitrectomy, and intraocular injection, establishment of the Clinical Research Center of New Drug Development, and the epidemiologic study of fundus diseases are also included. These landmark research progressions represent the power and influence of Chinese fundus disease scholars in the world.

  11. A Probabilistic Reasoning Method for Predicting the Progression of Clinical Findings from Electronic Medical Records.

    Science.gov (United States)

    Goodwin, Travis; Harabagiu, Sanda M

    2015-01-01

    In this paper, we present a probabilistic reasoning method capable of generating predictions of the progression of clinical findings (CFs) reported in the narrative portion of electronic medical records. This method benefits from a probabilistic knowledge representation made possible by a graphical model. The knowledge encoded in the graphical model considers not only the CFs extracted from the clinical narratives, but also their chronological ordering (CO) made possible by a temporal inference technique described in this paper. Our experiments indicate that the predictions about the progression of CFs achieve high performance given the COs induced from patient records.

  12. Exploiting replicative stress to treat cancer

    DEFF Research Database (Denmark)

    Dobbelstein, Matthias; Sørensen, Claus Storgaard

    2015-01-01

    DNA replication in cancer cells is accompanied by stalling and collapse of the replication fork and signalling in response to DNA damage and/or premature mitosis; these processes are collectively known as 'replicative stress'. Progress is being made to increase our understanding of the mechanisms...

  13. Disease Progression/Clinical Outcome Model for Castration-Resistant Prostate Cancer in Patients Treated with Eribulin

    NARCIS (Netherlands)

    Van Hasselt, J. G C; Gupta, A.; Hussein, Z.; Beijnen, J. H.; Schellens, J. H M; Huitema, A. D R

    2015-01-01

    Frameworks that associate cancer dynamic disease progression models with parametric survival models for clinical outcome have recently been proposed to support decision making in early clinical development. Here we developed such a disease progression clinical outcome model for castration-resistant

  14. Disease Progression/Clinical Outcome Model for Castration-Resistant Prostate Cancer in Patients Treated with Eribulin

    NARCIS (Netherlands)

    Van Hasselt, J. G C; Gupta, A.; Hussein, Z.; Beijnen, J. H.; Schellens, J. H M; Huitema, A. D R

    2015-01-01

    Frameworks that associate cancer dynamic disease progression models with parametric survival models for clinical outcome have recently been proposed to support decision making in early clinical development. Here we developed such a disease progression clinical outcome model for castration-resistant

  15. Clinical outcomes after autologous haematopoietic stem cell transplantation in patients with progressive multiple sclerosis

    Institute of Scientific and Technical Information of China (English)

    XU Juan; JI Bing-xin; SU Li; DONG Hui-qing; SUN Xue-jing; LIU Cong-yan

    2006-01-01

    Background Multiple sclerosis (MS) is a continuously disabling disease and it is unresponsive to high dose steroid and immunomodulation with disease progression. The autologous haematopoietic stem cell transplantation (ASCT) has been introduced in the treatment of refractory forms of multiple sclerosis. In this study, the clinical outcomes followed by ASCT were evaluated for patients with progressive MS.Methods Twenty-two patients with secondary progressive MS were treated with ASCT. Peripheral blood stem cells were obtained by leukapheresis after mobilization with granulocyte colony stimulating factor. Etoposide,melphalan, carmustin and cytosine arabinoside were administered as conditioning regimen. Outcomes were evaluated by the expanded disability status scale and progression free survival. No maintenance treatment was administered during a median follow-up of 39 months (range, 6 to 59 months).Results No death occurred following the treatment. The overall confirmed progression free survival rate was77% up to 59 months after transplantation which was significantly higher compared with pre-transplantation (P=0.000). Thirteen patients (59%) had remarkable improvement in neurological manifestations, four (18%)stabilized their disability status and five (23%) showed clinical recurrence of active symptoms.Conclusions ASCT as a therapy is safe and available. It can improve or stabilize neurological manifestations in most patients with progressive MS following failure of conventional therapy.

  16. Glaucoma Monitoring in a Clinical Setting Glaucoma Progression Analysis vs Nonparametric Progression Analysis in the Groningen Longitudinal Glaucoma Study

    NARCIS (Netherlands)

    Wesselink, Christiaan; Heeg, Govert P.; Jansonius, Nomdo M.

    Objective: To compare prospectively 2 perimetric progression detection algorithms for glaucoma, the Early Manifest Glaucoma Trial algorithm (glaucoma progression analysis [GPA]) and a nonparametric algorithm applied to the mean deviation (MD) (nonparametric progression analysis [NPA]). Methods:

  17. CE: Original Research: Creating an Evidence-Based Progression for Clinical Advancement Programs.

    Science.gov (United States)

    Burke, Kathleen G; Johnson, Tonya; Sites, Christine; Barnsteiner, Jane

    2017-05-01

    : Background: The Institute of Medicine (IOM) and the Quality and Safety Education for Nurses (QSEN) project have identified six nursing competencies and supported their integration into undergraduate and graduate nursing curricula nationwide. But integration of those competencies into clinical practice has been limited, and evidence for the progression of competency proficiency within clinical advancement programs is scant. Using an evidence-based approach and building on the competencies identified by the IOM and QSEN, a team of experts at an academic health system developed eight competency domains and 186 related knowledge, skills, and attitudes (KSAs) for professional nursing practice. The aim of our study was to validate the eight identified competencies and 186 related KSAs and determine their developmental progression within a clinical advancement program. Using the Delphi technique, nursing leadership validated the newly identified competency domains and KSAs as essential to practice. Clinical experts from 13 Magnet-designated hospitals with clinical advancement programs then participated in Delphi rounds aimed at reaching consensus on the developmental progression of the 186 KSAs through four levels of clinical advancement. Two Delphi rounds resulted in consensus by the expert participants. All eight competency domains were determined to be essential at all four levels of clinical practice. At the novice level of practice, the experts identified a greater number of KSAs in the domains of safety and patient- and family-centered care. At more advanced practice levels, the experts identified a greater number of KSAs in the domains of professionalism, teamwork, technology and informatics, and continuous quality improvement. Incorporating the eight competency domains and the 186 KSAs into a framework for clinical advancement programs will likely result in more clearly defined role expectations; enhance accountability; and elevate and promote nursing practice

  18. Clinical progression of lobaplatin in combination chemotherapy for patients with recurrence or metastatic cancer

    Institute of Scientific and Technical Information of China (English)

    Yu Peng; Jiangkui Liu; Qiang Lin

    2014-01-01

    The-platinum-based-combination-chemotherapy-has-become-one-of-the-major-modalities-in-anti-cancer-treatment.-After-the-first-line-chemotherapy,-many-patients-need-further-chemotherapy-because-of-recurrence-or-metastasis.-Lobaplatin-is-one-of-the-third-generation-platinum-drugs,and-this-article-briefly-reviews-the-clinical-progression-of-lobaplatin-in-combination-chemotherapy-for-patients-with-recurrence-or-metastatic-cancer.

  19. 3-Hydroxy kynurenine treatment controls T. cruzi replication and the inflammatory pathology preventing the clinical symptoms of chronic Chagas disease.

    Directory of Open Access Journals (Sweden)

    Carolina P Knubel

    Full Text Available BACKGROUND: 3-Hydroxy Kynurenine (3-HK administration during the acute phase of Trypanosoma. cruzi infection decreases the parasitemia of lethally infected mice and improves their survival. However, due to the fact that the treatment with 3-HK is unable to eradicate the parasite, together with the known proapoptotic and immunoregulatory properties of 3-HK and their downstream catabolites, it is possible that the 3-HK treatment is effective during the acute phase of the infection by controlling the parasite replication, but at the same time suppressed the protective T cell response before pathogen clearance worsening the chronic phase of the infection. Therefore, in the present study, we investigated the effect of 3-HK treatment on the development of chronic Chagas' disease. PRINCIPAL FINDINGS: In the present study, we treated mice infected with T. cruzi with 3-HK at day five post infection during 5 consecutive days and investigated the effect of this treatment on the development of chronic Chagas disease. Cardiac functional (electrocardiogram and histopathological studies were done at 60 dpi. 3-HK treatment markedly reduced the incidence and the severity of the electrocardiogram alterations and the inflammatory infiltrates and fibrosis in heart and skeletal muscle. 3-HK treatment modulated the immune response at the acute phase of the infection impairing the Th1- and Th2-type specific response and inducing TGF-β-secreting cells promoting the emergence of regulatory T cells and long-term specific IFN-γ secreting cells. 3-HK in vitro induced regulatory phenotype in T cells from T. cruzi acutely infected mice. CONCLUSIONS: Our results show that the early 3-HK treatment was effective in reducing the cardiac lesions as well as altering the pattern of the immune response in experimental Chagas' disease. Thus, we propose 3-HK as a novel therapeutic treatment able to control both the parasite replication and the inflammatory response.

  20. Is modified clinical activity score an accurate indicator of diplopia progression in Graves' orbitopathy patients?

    Science.gov (United States)

    Kim, Ji Won; Woo, Young Jun; Yoon, Jin Sook

    2016-12-30

    The aim of this study is to describe characteristics of Graves' orbitopathy (GO) patients with progressive diplopia and to consider whether modified clinical activity score (CAS) is a useful indicator for prediction of diplopia progression. Medical records and images of GO patients with progressive diplopia were retrospectively reviewed. Clinical parameters (e.g., modified CAS, modified NOSPECS score, exophthalmometry results, score of diplopia, and prevalence of optic neuropathy) were evaluated. Thyroid stimulating hormone receptor autoantibody (TRAb) values were determined. Maximum recti muscle diameters and extraocular muscle (EOM) indices were evaluated. Sixty-three of the 435 GO patients had progressive diplopia; 44.4% (28/63) of these patients had a low CAS (diplopia, prevalence of optic neuropathy and the positive rate and level of TRAb were not significantly different between groups. There were no differences in maximum recti muscle diameters or EOM indices between the two groups. Diplopia may progress even in patients with a low modified CAS. CAS may not reflect the inflammatory activity of myopathy, especially in mild to moderate GO with low NOSPECS and exophthalmos values. Careful patient follow-up using subjective and objective measures for diplopia should be performed.

  1. In vitro measurement of cytotoxic T cell activity does not predict clinical progression in paediatric HIV disease—two case studies

    Science.gov (United States)

    FROEBEL, K S; MOK, J Y Q; ALDHOUS, M C; ARMITAGE, M P; ARNOTT, M; REYNOLDS, L M; PEUTHERER, J F; BURNS, S M

    1997-01-01

    Cytotoxic T cells are believed to be an important immune response in HIV infection, both in the initial response to viraemia, and in controlling HIV replication and maintaining clinical stability. We report here the detailed findings in two vertically infected children, from the Edinburgh perinatal cohort. Both were clinically stable for the first 7 years of life. One had vigorous HIV-specific cytotoxic T lymphocyte (CTL) responses, and non-lytic suppression, measured in vitro, while the second had no CTL activity against HIV. Despite her HIV-specific immunity, the first child had a declining CD4 count, and a high and fluctuating viral load, whereas the second child maintained a stable CD4 count, a low viral load and had a virus which could not be cultured in peripheral blood mononuclear cells (PBMC) in vitro. The first child subsequently progressed to AIDS and has now died, while the second remains clinically well. More detailed investigations showed the clinically stable child to be heterozygous for the CCR5 receptor, and to be HLA-B49—both of which markers have been associated with slow HIV disease progression. These findings question the role of CTL in maintaining stable HIV disease, and stress the need for immunological investigations to be considered in the light of the genetic make-up of the patient. They may also reflect a different immunopathogenesis of HIV disease in children compared with adults. PMID:9353143

  2. In vitro measurement of cytotoxic T cell activity does not predict clinical progression in paediatric HIV disease--two case studies.

    Science.gov (United States)

    Froebel, K S; Mok, J Y; Aldhous, M C; Armitage, M P; Arnott, M; Reynolds, L M; Peutherer, J F; Burns, S M

    1997-10-01

    Cytotoxic T cells are believed to be an important immune response in HIV infection, both in the initial response to viraemia, and in controlling HIV replication and maintaining clinical stability. We report here the detailed findings in two vertically infected children, from the Edinburgh perinatal cohort. Both were clinically stable for the first 7 years of life. One had vigorous HIV-specific cytotoxic T lymphocyte (CTL) responses, and non-lytic suppression, measured in vitro, while the second had no CTL activity against HIV. Despite her HIV-specific immunity, the first child had a declining CD4 count, and a high and fluctuating viral load, whereas the second child maintained a stable CD4 count, a low viral load and had a virus which could not be cultured in peripheral blood mononuclear cells (PBMC) in vitro. The first child subsequently progressed to AIDS and has now died, while the second remains clinically well. More detailed investigations showed the clinically stable child to be heterozygous for the CCR5 receptor, and to be HLA-B49--both of which markers have been associated with slow HIV disease progression. These findings question the role of CTL in maintaining stable HIV disease, and stress the need for immunological investigations to be considered in the light of the genetic make-up of the patient. They may also reflect a different immunopathogenesis of HIV disease in children compared with adults.

  3. Dynamics of Escherichia coli chromosome segregation during multifork replication.

    Science.gov (United States)

    Nielsen, Henrik J; Youngren, Brenda; Hansen, Flemming G; Austin, Stuart

    2007-12-01

    Slowly growing Escherichia coli cells have a simple cell cycle, with replication and progressive segregation of the chromosome completed before cell division. In rapidly growing cells, initiation of replication occurs before the previous replication rounds are complete. At cell division, the chromosomes contain multiple replication forks and must be segregated while this complex pattern of replication is still ongoing. Here, we show that replication and segregation continue in step, starting at the origin and progressing to the replication terminus. Thus, early-replicated markers on the multiple-branched chromosomes continue to separate soon after replication to form separate protonucleoids, even though they are not segregated into different daughter cells until later generations. The segregation pattern follows the pattern of chromosome replication and does not follow the cell division cycle. No extensive cohesion of sister DNA regions was seen at any growth rate. We conclude that segregation is driven by the progression of the replication forks.

  4. Malignant pigmented villonodular synovitis in the knee - report of a case with rapid clinical progression.

    Science.gov (United States)

    Imakiire, Naoaki; Fujino, Takashi; Morii, Takeshi; Honya, Keita; Mochizuki, Kazuo; Satomi, Kazuhiko; Fujioka, Yasunori

    2011-01-07

    Malignant pigmented villonodular synovitis (PVNS) (or malignant giant cell tumor of tendon sheath (GCTTS) is an extremely rare condition defined as a malignant lesion occurring with concomitant or previously documented PVNS at the same site. To date, only less than 20 cases have been reported in English literatures. We report a case of malignant PVNS in the knee in a 56-year-old woman with unpredictable rapid progression. This case raised a caution that when atypical components in specimens of recurrent benign PVNS are detected, even if low-grade or tiny, both pathologists and surgeons should consider the risk of malignant PVNS, which could display aggressive clinical progression.

  5. Association between several clinical and radiological determinants with long-term clinical progression and good prognosis of lower limb osteoarthritis.

    Directory of Open Access Journals (Sweden)

    Erlangga Yusuf

    Full Text Available OBJECTIVE: To investigate the factors associated with clinical progression and good prognosis in patients with lower limb osteoarthritis (OA. METHODS: Cohort study of 145 patients with OA in either knee, hip or both. Progression was defined as 1 new joint prosthesis or 2 increase in WOMAC pain or function score during 6-years follow-up above pre-defined thresholds. Patients without progression with decrease in WOMAC pain or function score lower than pre-defined thresholds were categorized as good prognosis. Relative risks (RRs for progression and good prognosis with 95% confidence interval (95% CI were calculated by comparing the highest tertile or category to the lowest tertile, for baseline determinants (age, sex, BMI, WOMAC pain and function scores, pain on physical examination, total range of motion (tROM, osteophytes and joint space narrowing (JSN scores, and for worsening in WOMAC pain and function score in 1-year. Adjustments were performed for age, sex, and BMI. RESULTS: Follow-up was completed by 117 patients (81%, median age 60 years, 84% female; 62 (53% and 31 patients (26% showed progression and good prognosis, respectively. These following determinants were associated with progression: pain on physical examination (RR 1.2 (1.0 to 1.5; tROM (1.4 (1.1 to 1.6; worsening in WOMAC pain (1.9 (1.2 to 2.3; worsening in WOMAC function (2.4 (1.7 to 2.6; osteophytes 1.5 (1.0 to 1.8; and JSN scores (2.3 (1.5 to 2.7. Worsening in WOMAC pain (0.1 (0.1 to 0.8 and function score (0.1 (0.1 to 0.7, were negatively associated with good prognosis. CONCLUSION: Worsening of self-reported pain and function in one year, limited tROM and higher osteophytes and JSN scores were associated with clinical progression. Worsening in WOMAC pain and function score in 1- year were associated with lower risk to have good prognosis. These findings help to inform patients with regard to their OA prognosis.

  6. Rapid clinical progression to diagnosis among African-American men with systemic lupus erythematosus.

    Science.gov (United States)

    Arbuckle, M R; James, J A; Dennis, G J; Rubertone, M V; McClain, M T; Kim, X R; Harley, J B

    2003-01-01

    The initial clinical course of systemic lupus erythematosus (SLE) is variable, ranging from relatively minor manifestations progressing over years to rapid onset of fulminate disease. We sought to identify factors associated with the rapid manifestation of SLE. Chart review of military medical records was used to identify 130 patients who met the American College of Rheumatology classification criteria for SLE. Demographics, clinical criteria date of occurrence, and the date of SLE classification (at least four clinical criteria) met were documented. Prospectively stored serum samples prior to the diagnosis were evaluated for SLE autoantibodies. Median time from the first recorded criteria to diagnosis was significantly shorter in African-American (AA) males compared with AA females and European American (EA) females and males combined. AA males were more likely to have nephritis as their first clinical symptom. Also, less time transpired between the first clinical criterion and SLE diagnosis in AA males with nephritis than in other groups presenting with nephritis. Even when cases presenting with nephritis were excluded, a diagnosis of SLE was made more rapidly in AA males. African-American men progress from initial clinical manifestations to SLE diagnosis more rapidly than other ethnic or gender groups.

  7. Assessing progression of clinical reasoning through virtual patients: An exploratory study.

    Science.gov (United States)

    Forsberg, Elenita; Ziegert, Kristina; Hult, Håkan; Fors, Uno

    2016-01-01

    To avoid test-driven learning, there have been discussions regarding the use of more formative assessments in health care education to promote students' deep learning. Feedback is important in formative assessment, but many students ignore it; therefore, interventions should be introduced which stimulate them to reflect on the new knowledge. The aim for this study was to explore if Virtual Patient (VP)-based formative assessments, in connection with self-evaluations, had an impact on postgraduate pediatric nursing students' development of clinical reasoning abilities. Students' self-evaluations served as the basis for measuring progress. Data was analysed using deductive content analysis. The findings showed a clear progression of the clinical reasoning ability of the students. After the first assessment, the students described feelings of uncertainty and that their knowledge gaps were exposed. At the mid-course assessment the awareness of improved clinical reasoning was obvious and the students were more certain of knowing how to solve the VP cases. In the final assessment, self-efficacy was expressed. VP-based assessments, in connection with self-evaluations, early in the education resulted in a gain of students' own identification of the concept of clinical reasoning, awareness of what to focus on during clinical practice and visualised expected clinical competence.

  8. Subjective cognitive concerns and neuropsychiatric predictors of progression to the early clinical stages of Alzheimer disease.

    Science.gov (United States)

    Donovan, Nancy J; Amariglio, Rebecca E; Zoller, Amy S; Rudel, Rebecca K; Gomez-Isla, Teresa; Blacker, Deborah; Hyman, Bradley T; Locascio, Joseph J; Johnson, Keith A; Sperling, Reisa A; Marshall, Gad A; Rentz, Dorene M

    2014-12-01

    To examine neuropsychiatric and neuropsychological predictors of progression from normal to early clinical stages of Alzheimer disease (AD). From a total sample of 559 older adults from the Massachusetts Alzheimer's Disease Research Center longitudinal cohort, 454 were included in the primary analysis: 283 with clinically normal cognition (CN), 115 with mild cognitive impairment (MCI), and 56 with subjective cognitive concerns (SCC) but no objective impairment, a proposed transitional group between CN and MCI. Two latent cognitive factors (memory-semantic, attention-executive) and two neuropsychiatric factors (affective, psychotic) were derived from the Alzheimer's Disease Centers' Uniform Data Set neuropsychological battery and Neuropsychiatric Inventory brief questionnaire. Factors were analyzed as predictors of time to progression to a worse diagnosis using a Cox proportional hazards regression model with backward elimination. Covariates included baseline diagnosis, gender, age, education, prior depression, antidepressant medication, symptom duration, and interaction terms. Higher/better memory-semantic factor score predicted lower hazard of progression (hazard ratio [HR] = 0.4 for 1 standard deviation [SD] increase, p <0.0001), and higher/worse affective factor score predicted higher hazard (HR = 1.3 for one SD increase, p = 0.01). No other predictors were significant in adjusted analyses. Using diagnosis as a sole predictor of transition to MCI, the SCC diagnosis carried a fourfold risk of progression compared with CN (HR = 4.1, p <0.0001). These results identify affective and memory-semantic factors as significant predictors of more rapid progression from normal to early stages of cognitive decline and highlight the subgroup of cognitively normal elderly with SCC as those with elevated risk of progression to MCI. Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

  9. A clinical index to predict progression from mild cognitive impairment to dementia due to Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Sei J Lee

    Full Text Available BACKGROUND: Mild cognitive impairment is often a precursor to dementia due to Alzheimer's disease, but many patients with mild cognitive impairment never develop dementia. New diagnostic criteria may lead to more patients receiving a diagnosis of mild cognitive impairment. OBJECTIVE: To develop a prediction index for the 3-year risk of progression from mild cognitive impairment to dementia relying only on information that can be readily obtained in most clinical settings. DESIGN AND PARTICIPANTS: 382 participants diagnosed with amnestic mild cognitive impairment enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI, a multi-site, longitudinal, observational study. MAIN PREDICTORS MEASURES: Demographics, comorbid conditions, caregiver report of participant symptoms and function, and participant performance on individual items from basic neuropsychological scales. MAIN OUTCOME MEASURE: Progression to probable Alzheimer's disease. KEY RESULTS: Subjects had a mean (SD age of 75 (7 years and 43% progressed to probable Alzheimer's disease within 3 years. Important independent predictors of progression included being female, resisting help, becoming upset when separated from caregiver, difficulty shopping alone, forgetting appointments, number of words recalled from a 10-word list, orientation and difficulty drawing a clock. The final point score could range from 0 to 16 (mean [SD]: 4.2 [2.9]. The optimism-corrected Harrell's c-statistic was 0.71(95% CI: 0.68-0.75. Fourteen percent of subjects with low risk scores (0-2 points, n = 124 converted to probable Alzheimer's disease over 3 years, compared to 51% of those with moderate risk scores (3-8 points, n = 223 and 91% of those with high risk scores (9-16 points, n = 35. CONCLUSIONS: An index using factors that can be obtained in most clinical settings can predict progression from amnestic mild cognitive impairment to probable Alzheimer's disease and may help clinicians

  10. Histologically benign, clinically aggressive: Progressive non-optic pathway pilocytic astrocytomas in adults with NF1.

    Science.gov (United States)

    Strowd, Roy E; Rodriguez, Fausto J; McLendon, Roger E; Vredenburgh, James J; Chance, Aaron B; Jallo, George; Olivi, Alessandro; Ahn, Edward S; Blakeley, Jaishri O

    2016-06-01

    Although optic pathway gliomas are the most common brain tumors associated with neurofibromatosis type 1 (NF1), extra-optic gliomas occur and may behave more aggressively with outcomes that differ by age. A retrospective case-control study was designed to describe the clinical course of adult NF1 patients with progressive extra-optic pilocytic astrocytomas (PAs) and compare to a pediatric cohort. Data for patients treated at the Johns Hopkins Comprehensive Neurofibromatosis Center from 2003 to 2013 were reviewed to identify cases (adults, age >18) and controls (pediatric, age NF1 cases and four pediatric NF1 controls were identified. Mean age was 32.3 ± 9.5 years, 66% male (cases); 12.8 ± 4.2 years, 100% male (controls). Symptomatic progression occurred in two-of-three adults (67%) while the majority of pediatric patients presented with isolated radiographic progression (n = 3, 75%). Onset tended to be more rapid in adults (4 ± 1 vs. 14 ± 8.3 months, P = 0.10). Subtotal resection was the treatment for all pediatric patients. Radiotherapy (n = 2), chemotherapy (n = 2), and targeted, biologic agents (n = 2) were administered in adults. Although all pediatric patients are living, outcomes were universally poor in adults with progression to death in all (median survival 17.1 months, range 6.6-30.3). In conclusion, despite grade I histology, all three adult NF1 patients with progressive extra-optic PAs suffered an aggressive clinical course which was not seen in pediatric patients. Clinicians should be aware of this clinico-histologic discrepancy when counseling and managing adult NF1 patients with progressive extra-optic PAs. © 2016 Wiley Periodicals, Inc.

  11. Intravascular large B-cell lymphoma presenting clinically as rapidly progressive dementia.

    Science.gov (United States)

    Brett, F M; Chen, D; Loftus, T; Langan, Y; Looby, S; Hutchinson, S

    2017-07-19

    In patients presenting with rapidly progressive dementia, prion disease may enter the differential diagnosis. The commonest malignancies masquerading as prion disease are primary CNS lymphoma and intravascular large B-cell lymphoma, both rare and difficult to diagnose without brain biopsy. This 82-year-old lady with a past history of hypertension, presented with rapidly progressive cognitive impairment and ataxia. The possibility of sCJD was raised. Brain biopsy was carried out. Western blot for prion protein was negative. Brain biopsy showed intravascular large B-cell lymphoma. She died shortly afterwards. The clinical presentation of intravascular large B-cell lymphoma is diverse. Patients may present as in this case with dementia, seizures, and myoclonus leading to a clinical diagnosis of sCJD. The diagnosis here was made at biopsy but is made at autopsy in over 50% of cases.

  12. Clinical factors associated with the diagnosis and progression of diabetic nephropathy.

    Science.gov (United States)

    Liang, Shuang; Li, Qian; Zhu, Han-Yu; Zhou, Jian-Hui; Ding, Rui; Chen, Xiang-Mei; Cai, Guang-Yan

    2014-09-01

    As an important complication of diabetic mellitus, diabetic nephropathy (DN) has been the main cause of end-stage renal disease. It is of great importance to diagnose DN early, and to identify the risk factors of disease progression in order to carry out in-time and effective therapies. Previous literatures have reported the role of several clinical factors in the diagnosis and progression of DN, including age, longer diabetes duration, diabetic retinopathy, higher level of hypertension and HbA1c, and so on. However, the significance of these clinical factors is still controversial and limited. This review aimed to evaluate the values and limitations of these factors in diagnosing and predicting the renal outcome of DN.

  13. Clinical Cancer Advances 2017: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology.

    Science.gov (United States)

    Burstein, Harold J; Krilov, Lada; Aragon-Ching, Jeanny B; Baxter, Nancy N; Chiorean, E Gabriela; Chow, Warren Allen; De Groot, John Frederick; Devine, Steven Michael; DuBois, Steven G; El-Deiry, Wafik S; Epstein, Andrew S; Heymach, John; Jones, Joshua Adam; Mayer, Deborah K; Miksad, Rebecca A; Pennell, Nathan A; Sabel, Michael S; Schilsky, Richard L; Schuchter, Lynn Mara; Tung, Nadine; Winkfield, Karen Marie; Wirth, Lori J; Dizon, Don S

    2017-02-01

    A MESSAGE FROM ASCO'S PRESIDENT I am pleased to present Clinical Cancer Advances 2017, which highlights the most promising advances in patient-oriented cancer research over the past year. The report gives us an opportunity to reflect on what an exciting time it is for cancer research and how swiftly our understanding of cancer has improved. One year ago, the White House announced the national Cancer Moonshot program to accelerate progress against cancer. This shared vision of progress has reinvigorated the research community, identified new areas of scientific collaboration, and raised our ambitions regarding what may be possible beyond the progress we have already made. When I entered the field 35 years ago, I could not have imagined where we would be today. We can now detect cancer earlier, target treatments more effectively, and manage adverse effects more effectively to enable patients to live better, more fulfilling lives. Today, two of three people with cancer live at least 5 years after diagnosis, up from roughly one of two in the 1970s. This progress has resulted from decades of incremental advances that have collectively expanded our understanding of the molecular underpinnings of cancer. There is no better current example of this than ASCO's 2017 Advance of the Year: Immunotherapy 2.0. Over the last year, there has been a wave of new successes with immunotherapy. Research has proven this approach can be effective against a wide range of hard-to-treat advanced cancers previously considered intractable. Researchers are now working to identify biologic markers that can help increase the effectiveness of treatment and determine who is most likely to benefit from immunotherapy. This knowledge will enable oncologists to make evidence-based decisions so as many patients as possible might benefit from this new type of treatment. Each successive advance builds on the previous hard work of generations of basic, translational, and clinical cancer researchers

  14. Poor R wave progression in the precordial leads: clinical implications for the diagnosis of myocardial infarction.

    Science.gov (United States)

    DePace, N L; Colby, J; Hakki, A H; Manno, B; Horowitz, L N; Iskandrian, A S

    1983-12-01

    A definite diagnosis of anterior myocardial infarction is often difficult to make in patients when a pattern of poor R wave progression in the precordial leads is present on the electrocardiogram. The purpose of this study was to determine whether a mathematical model could be devised to identify patients with anterior infarction among 102 consecutive patients with poor R wave progression. Each patient underwent exercise testing with thallium scanning. The diagnosis of anterior infarction was established in 20 (20%) of the 102 patients by the presence of fixed thallium-201 perfusion defects in the anterior wall or septum, or both. With the use of a multivariate stepwise discriminant analysis of clinical and electrocardiographic variables, five variables (sex, ST-T changes, S wave amplitude in leads V2 and V3 and the sum of the R wave amplitude in leads V3 and V4) that were statistically significant by univariate analysis were selected by the model to identify patients with anterior infarction (sensitivity 85%, specificity 71%). The discriminant model was subsequently applied prospectively to an additional 21 patients with poor R wave progression and provided a sensitivity of 85% and a specificity of 88%. Thus, anterior infarction (fixed thallium-201 defects in the anteroseptal segments) was present in 20% of patients with poor R wave progression in the precordial leads; and a mathematical model can be used to identify a subset of patients with anterior infarction in a group of patients with poor R wave progression.

  15. The association between anti-carbamylated protein (anti-CarP) antibodies and radiographic progression in early rheumatoid arthritis: a study exploring replication and the added value to ACPA and rheumatoid factor.

    Science.gov (United States)

    Ajeganova, S; van Steenbergen, H W; Verheul, M K; Forslind, K; Hafström, I; Toes, R E M; Huizinga, T W J; Svensson, B; Trouw, L A; van der Helm-van Mil, A H M

    2017-01-01

    Anti-carbamylated protein (anti-CarP) antibodies are reported to associate with more radiographic progression within the total rheumatoid arthritis (RA) population and anti-citrullinated peptide antibody (ACPA)-negative subgroup. We explored the association of anti-CarP with radiographic progression in RA and aimed to replicate the association and evaluate the added value of anti-CarP antibodies in relation to ACPA and rheumatoid factor (RF). 576 Swedish and 628 Dutch patients with RA (2394 and 3247 sets of radiographs, respectively) were longitudinally studied. Replication was restricted to the Swedish patients. In both cohorts, the association of anti-CarP with radiographic progression was determined in strata of patients with similar ACPA and RF status; results of both cohorts were combined in fixed-effect meta-analyses. The net percentage of patients for whom the radiographic progression in 5 years was additionally correctly classified when adding anti-CarP to a model including ACPA and RF was evaluated. Anti-CarP associated with radiographic progression in the total Swedish RA population (beta=1.11 per year, p=8.75×10(-13)) and in the ACPA-negative subgroup (beta=1.14 per year, p=0.034). Anti-CarP associated with more radiographic progression in the strata of ACPA-positive/RF-negative, ACPA-negative/RF-positive and ACPA-positive/RF-positive patients with RA (respective p values 0.014, 0.019 and 0.0056). A model including ACPA and RF correctly classified 54% and 57% of the patients; adding anti-CarP to this model did not increase these percentages (54% and 56% were correctly classified). Anti-CarP antibodies associated with more severe radiographic progression in the total and ACPA-negative RA population. Anti-CarP-positivity had a statistically significant additive value to ACPA and RF, but did not improve correct classification of patients. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence

  16. Host and viral genetic correlates of clinical definitions of HIV-1 disease progression.

    Directory of Open Access Journals (Sweden)

    Concepción Casado

    Full Text Available BACKGROUND: Various patterns of HIV-1 disease progression are described in clinical practice and in research. There is a need to assess the specificity of commonly used definitions of long term non-progressor (LTNP elite controllers (LTNP-EC, viremic controllers (LTNP-VC, and viremic non controllers (LTNP-NC, as well as of chronic progressors (P and rapid progressors (RP. METHODOLOGY AND PRINCIPAL FINDINGS: We re-evaluated the HIV-1 clinical definitions, summarized in Table 1, using the information provided by a selected number of host genetic markers and viral factors. There is a continuous decrease of protective factors and an accumulation of risk factors from LTNP-EC to RP. Statistical differences in frequency of protective HLA-B alleles (p-0.01, HLA-C rs9264942 (p-0.06, and protective CCR5/CCR2 haplotypes (p-0.02 across groups, and the presence of viruses with an ancestral genotype in the "viral dating" (i.e., nucleotide sequences with low viral divergence from the most recent common ancestor support the differences among principal clinical groups of HIV-1 infected individuals. CONCLUSIONS: A combination of host genetic and viral factors supports current clinical definitions that discriminate among patterns of HIV-1 progression. The study also emphasizes the need to apply a standardized and accepted set of clinical definitions for the purpose of disease stratification and research.

  17. Progress and prospects of gene therapy clinical trials for the muscular dystrophies.

    Science.gov (United States)

    Bengtsson, Niclas E; Seto, Jane T; Hall, John K; Chamberlain, Jeffrey S; Odom, Guy L

    2016-04-15

    Clinical trials represent a critical avenue for new treatment development, where early phases (I, I/II) are designed to test safety and effectiveness of new therapeutics or diagnostic indicators. A number of recent advances have spurred renewed optimism toward initiating clinical trials and developing refined therapies for the muscular dystrophies (MD's) and other myogenic disorders. MD's encompass a heterogeneous group of degenerative disorders often characterized by progressive muscle weakness and fragility. Many of these diseases result from mutations in genes encoding proteins of the dystrophin-glycoprotein complex (DGC). The most common and severe form among children is Duchenne muscular dystrophy, caused by mutations in the dystrophin gene, with an average life expectancy around 25 years of age. Another group of MD's referred to as the limb-girdle muscular dystrophies (LGMDs) can affect boys or girls, with different types caused by mutations in different genes. Mutation of the α-sarcoglycan gene, also a DGC component, causes LGMD2D and represents the most common form of LGMD. Early preclinical and clinical trial findings support the feasibility of gene therapy via recombinant adeno-associated viral vectors as a viable treatment approach for many MDs. In this mini-review, we present an overview of recent progress in clinical gene therapy trials of the MD's and touch upon promising preclinical advances.

  18. Clinical cancer advances 2011: Annual Report on Progress Against Cancer from the American Society of Clinical Oncology.

    Science.gov (United States)

    Vogelzang, Nicholas J; Benowitz, Steven I; Adams, Sylvia; Aghajanian, Carol; Chang, Susan Marina; Dreyer, Zoann Eckert; Janne, Pasi A; Ko, Andrew H; Masters, Greg A; Odenike, Olatoyosi; Patel, Jyoti D; Roth, Bruce J; Samlowski, Wolfram E; Seidman, Andrew D; Tap, William D; Temel, Jennifer S; Von Roenn, Jamie H; Kris, Mark G

    2012-01-01

    A message from ASCO'S President. It has been forty years since President Richard Nixon signed the National Cancer Act of 1971, which many view as the nation's declaration of the "War on Cancer." The bill has led to major investments in cancer research and significant increases in cancer survival. Today, two-thirds of patients survive at least five years after being diagnosed with cancer compared with just half of all diagnosed patients surviving five years after diagnosis in 1975. The research advances detailed in this year's Clinical Cancer Advances demonstrate that improvements in cancer screening, treatment, and prevention save and improve lives. But although much progress has been made, cancer remains one of the world's most serious health problems. In the United States, the disease is expected to become the nation's leading cause of death in the years ahead as our population ages. I believe we can accelerate the pace of progress, provided that everyone involved in cancer care works together to achieve this goal. It is this viewpoint that has shaped the theme for my presidential term: Collaborating to Conquer Cancer. In practice, this means that physicians and researchers must learn from every patient's experience, ensure greater collaboration between members of a patient's medical team, and involve more patients in the search for cures through clinical trials. Cancer advocates, insurers, and government agencies also have important roles to play. Today, we have an incredible opportunity to improve the quality of cancer care by drawing lessons from the real-world experiences of patients. The American Society of Clinical Oncology (ASCO) is taking the lead in this area, in part through innovative use of health information technology. In addition to our existing quality initiatives, ASCO is working with partners to develop a comprehensive rapid-learning system for cancer care. When complete, this system will provide physicians with personalized, real

  19. An ADAM33 Polymorphism Associates with Progression of Preschool Wheeze into Childhood Asthma : A Prospective Case-Control Study with Replication in a Birth Cohort Study

    NARCIS (Netherlands)

    Klaassen, Ester M. M.; Penders, John; Jobsis, Quirijn; van de Kant, Kim D. G.; Thijs, Carel; Mommers, Monique; van Schayck, Constant P.; van Eys, Guillaume; Koppelman, Gerard H.; Dompeling, Edward

    2015-01-01

    Background The influence of asthma candidate genes on the development from wheeze to asthma in young children still needs to be defined. Objective To link genetic variants in asthma candidate genes to progression of wheeze to persistent wheeze into childhood asthma. Materials and Methods In a

  20. Prognostic role of genetic biomarkers in clinical progression of prostate cancer.

    Science.gov (United States)

    Alvarez-Cubero, Maria Jesus; Martinez-Gonzalez, Luis Javier; Saiz, Maria; Carmona-Saez, Pedro; Alvarez, Juan Carlos; Pascual-Geler, Manrique; Lorente, Jose Antonio; Cozar, Jose Manuel

    2015-08-07

    The aim of this study was to analyze the use of 12 single-nucleotide polymorphisms in genes ELAC2, RNASEL and MSR1 as biomarkers for prostate cancer (PCa) detection and progression, as well as perform a genetic classification of high-risk patients. A cohort of 451 men (235 patients and 216 controls) was studied. We calculated means of regression analysis using clinical values (stage, prostate-specific antigen, Gleason score and progression) in patients and controls at the basal stage and after a follow-up of 72 months. Significantly different allele frequencies between patients and controls were observed for rs1904577 and rs918 (MSR1 gene) and for rs17552022 and rs5030739 (ELAC2). We found evidence of increased risk for PCa in rs486907 and rs2127565 in variants AA and CC, respectively. In addition, rs627928 (TT-GT), rs486907 (AG) and rs3747531 (CG-CC) were associated with low tumor aggressiveness. Some had a weak linkage, such as rs1904577 and rs2127565, rs4792311 and rs17552022, and rs1904577 and rs918. Our study provides the proof-of-principle that some of the genetic variants (such as rs486907, rs627928 and rs2127565) in genes RNASEL, MSR1 and ELAC2 can be used as predictors of aggressiveness and progression of PCa. In the future, clinical use of these biomarkers, in combination with current ones, could potentially reduce the rate of unnecessary biopsies and specific treatments.

  1. Clinical and MRI models predicting amyloid deposition in progressive aphasia and apraxia of speech.

    Science.gov (United States)

    Whitwell, Jennifer L; Weigand, Stephen D; Duffy, Joseph R; Strand, Edythe A; Machulda, Mary M; Senjem, Matthew L; Gunter, Jeffrey L; Lowe, Val J; Jack, Clifford R; Josephs, Keith A

    2016-01-01

    Beta-amyloid (Aβ) deposition can be observed in primary progressive aphasia (PPA) and progressive apraxia of speech (PAOS). While it is typically associated with logopenic PPA, there are exceptions that make predicting Aβ status challenging based on clinical diagnosis alone. We aimed to determine whether MRI regional volumes or clinical data could help predict Aβ deposition. One hundred and thirty-nine PPA (n = 97; 15 agrammatic, 53 logopenic, 13 semantic and 16 unclassified) and PAOS (n = 42) subjects were prospectively recruited into a cross-sectional study and underwent speech/language assessments, 3.0 T MRI and C11-Pittsburgh Compound B PET. The presence of Aβ was determined using a 1.5 SUVR cut-point. Atlas-based parcellation was used to calculate gray matter volumes of 42 regions-of-interest across the brain. Penalized binary logistic regression was utilized to determine what combination of MRI regions, and what combination of speech and language tests, best predicts Aβ (+) status. The optimal MRI model and optimal clinical model both performed comparably in their ability to accurately classify subjects according to Aβ status. MRI accurately classified 81% of subjects using 14 regions. Small left superior temporal and inferior parietal volumes and large left Broca's area volumes were particularly predictive of Aβ (+) status. Clinical scores accurately classified 83% of subjects using 12 tests. Phonological errors and repetition deficits, and absence of agrammatism and motor speech deficits were particularly predictive of Aβ (+) status. In comparison, clinical diagnosis was able to accurately classify 89% of subjects. However, the MRI model performed well in predicting Aβ deposition in unclassified PPA. Clinical diagnosis provides optimum prediction of Aβ status at the group level, although regional MRI measurements and speech and language testing also performed well and could have advantages in predicting Aβ status in unclassified PPA subjects.

  2. Clinical and MRI models predicting amyloid deposition in progressive aphasia and apraxia of speech

    Directory of Open Access Journals (Sweden)

    Jennifer L. Whitwell

    2016-01-01

    Full Text Available Beta-amyloid (Aβ deposition can be observed in primary progressive aphasia (PPA and progressive apraxia of speech (PAOS. While it is typically associated with logopenic PPA, there are exceptions that make predicting Aβ status challenging based on clinical diagnosis alone. We aimed to determine whether MRI regional volumes or clinical data could help predict Aβ deposition. One hundred and thirty-nine PPA (n = 97; 15 agrammatic, 53 logopenic, 13 semantic and 16 unclassified and PAOS (n = 42 subjects were prospectively recruited into a cross-sectional study and underwent speech/language assessments, 3.0 T MRI and C11-Pittsburgh Compound B PET. The presence of Aβ was determined using a 1.5 SUVR cut-point. Atlas-based parcellation was used to calculate gray matter volumes of 42 regions-of-interest across the brain. Penalized binary logistic regression was utilized to determine what combination of MRI regions, and what combination of speech and language tests, best predicts Aβ (+ status. The optimal MRI model and optimal clinical model both performed comparably in their ability to accurately classify subjects according to Aβ status. MRI accurately classified 81% of subjects using 14 regions. Small left superior temporal and inferior parietal volumes and large left Broca's area volumes were particularly predictive of Aβ (+ status. Clinical scores accurately classified 83% of subjects using 12 tests. Phonological errors and repetition deficits, and absence of agrammatism and motor speech deficits were particularly predictive of Aβ (+ status. In comparison, clinical diagnosis was able to accurately classify 89% of subjects. However, the MRI model performed well in predicting Aβ deposition in unclassified PPA. Clinical diagnosis provides optimum prediction of Aβ status at the group level, although regional MRI measurements and speech and language testing also performed well and could have advantages in predicting Aβ status in unclassified

  3. Research progress of motor function assessments and their clinical applications in Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Wei SHI

    2015-07-01

    Full Text Available Duchenne muscular dystrophy (DMD, clinically featured as progressive skeletal muscle atrophy with gradual loss of muscle strength and activity abilities, is the most common genetic muscular disease in children throughout the world. The core and continuous characteristic of DMD is motor dysfunction. Motor function assessments of DMD are now focusing on muscle strength, walking ability, range of motion and ability of activities, still without unified standards. Confirming the comprehensive, scientific, reasonable and accurate evaluation tools for DMD assessment is the premise of research in motor developmental rules of DMD, which will help to better understand the motor progress of DMD and to supply evidences for choosing treatment methods, confirming timing of intervention, assessing effect of treatments and designing rehabilitation plans. DOI: 10.3969/j.issn.1672-6731.2015.06.002

  4. Current progress of siRNA/shRNA therapeutics in clinical trials.

    Science.gov (United States)

    Burnett, John C; Rossi, John J; Tiemann, Katrin

    2011-09-01

    Through a mechanism known as RNA interference (RNAi), small interfering RNA (siRNA) molecules can target complementary mRNA strands for degradation, thus specifically inhibiting gene expression. The ability of siRNAs to inhibit gene expression offers a mechanism that can be exploited for novel therapeutics. Indeed, over the past decade, at least 21 siRNA therapeutics have been developed for more than a dozen diseases, including various cancers, viruses, and genetic disorders. Like other biological drugs, RNAi-based therapeutics often require a delivery vehicle to transport them to the targeted cells. Thus, the clinical advancement of numerous siRNA drugs has relied on the development of siRNA carriers, including biodegradable nanoparticles, lipids, bacteria, and attenuated viruses. Most therapies permit systemic delivery of the siRNA drug, while others use ex vivo delivery by autologous cell therapy. Advancements in bioengineering and nanotechnology have led to improved control of delivery and release of some siRNA therapeutics. Likewise, progress in molecular biology has allowed for improved design of the siRNA molecules. Here, we provide an overview of siRNA therapeutics in clinical trials, including their clinical progress, the challenges they have encountered, and the future they hold in the treatment of human diseases.

  5. Cellular apoptosis induced by replication of hepatitis B virus: possible link between viral genotype and clinical outcome

    Directory of Open Access Journals (Sweden)

    Zhang Jianhua

    2007-10-01

    Full Text Available Abstract HBV remains one of the major pathogens of liver diseases but the outcomes as inflammation, cirrhosis and cancer of the liver are greatly related to different viral genotypes. The aim of this study was to assess the pro-apoptotic effect of HBSP from three HBV genotypes on liver derived cells. HepG2 cells were applied in our system and transfected by HBV genotype A, B, and C. Cells were observed under phase contrast microscope, stained by apoptosis marker and analyzed by flow cytometre. HBSP expression was detected by western blot assay. BH3 sequences were aligned and analyzed by Vector NTI. HBV genotypes A, B, and C transfected cells displayed evidence of cell death which was further proved as apoptosis. Natural expression of a pro-apoptotic protein HBSP was detected during genomes transfection. The different apoptotic effects were correlated to the HBSP expression from each genome. Alignment and analysis of the BH3 domains from the three genomes revealed slight variance which might also contribute to the result. Our results suggested that variant HBSP expression and BH3 sequence of HBV genotypes may be involved in differential apoptotic effect in transfected cells. Detailed analysis of the role of HBV genotypes in cellular apoptotic process should provide molecular information on the reported clinical outcome of infection by different HBV genotypes.

  6. DNA replication and the repair of DNA strand breaks in nuclei of Physarum polycephalum. Progress report, September 1, 1977--July 31, 1978. [Monel

    Energy Technology Data Exchange (ETDEWEB)

    Brewer, E.N.; Nygaard, O.F.; Kuncio, G.

    1978-08-01

    Isolated nuclei and intact plasmodia of Physarum contain a heat-stable stimulator of nuclear DNA replication. This substance has been purified extensively and found to contain both protein and carbohydrate. The molecular weight, estimated by gel filtration, is ca. 30,000 d. The purified material does not exhibit DNA polymerase or DNase activity, and does not stimulate DNA polymerase activity per se. In the presence of the stimulatory factor, DNA chain elongation occurs at an elevated rate, and continues for a longer time than in its absence, but G/sub 2/ nuclei are not stimulated to initiate DNA synthesis. Double-strand breaks in nuclear DNA of irradiated plasmodia are repaired in vitro to a greater extent following nuclear isolation during G/sub 2/, and the DNA of unirradiated plasmodia is less susceptible to double-strand breakage during cell-free nuclear incubation, than is the DNA of S-phase nuclei. This correlation suggests a common basis for both observations, for example an increase in deoxyribonuclease activity or a decrease in DNA ligase activity during the S period. This, in turn, may account for the cell cycle-dependent sensitivity of this organism, in terms of mitotic delay, to ionizing radiation.

  7. A computational platform for robotized fluorescence microscopy (II): DNA damage, replication, checkpoint activation, and cell cycle progression by high-content high-resolution multiparameter image-cytometry.

    Science.gov (United States)

    Furia, Laura; Pelicci, Pier Giuseppe; Faretta, Mario

    2013-04-01

    Dissection of complex molecular-networks in rare cell populations is limited by current technologies that do not allow simultaneous quantification, high-resolution localization, and statistically robust analysis of multiple parameters. We have developed a novel computational platform (Automated Microscopy for Image CytOmetry, A.M.I.CO) for quantitative image-analysis of data from confocal or widefield robotized microscopes. We have applied this image-cytometry technology to the study of checkpoint activation in response to spontaneous DNA damage in nontransformed mammary cells. Cell-cycle profile and active DNA-replication were correlated to (i) Ki67, to monitor proliferation; (ii) phosphorylated histone H2AX (γH2AX) and 53BP1, as markers of DNA-damage response (DDR); and (iii) p53 and p21, as checkpoint-activation markers. Our data suggest the existence of cell-cycle modulated mechanisms involving different functions of γH2AX and 53BP1 in DDR, and of p53 and p21 in checkpoint activation and quiescence regulation during the cell-cycle. Quantitative analysis, event selection, and physical relocalization have been then employed to correlate protein expression at the population level with interactions between molecules, measured with Proximity Ligation Analysis, with unprecedented statistical relevance. Copyright © 2013 International Society for Advancement of Cytometry.

  8. [Main progress on studies of pharmacological activities and clinical applications of Guizhi Fuling capsule].

    Science.gov (United States)

    Su, Zhen-zhen; Li, Na; Cao, Liang; Wang, Tuan-jie; Zhang, Chen-feng; Ding, Gang; Wang, Zhen-zhong; Xiao, Wei

    2015-03-01

    Guizhi Fuling capsule is a traditional Chinese medicine composed of five kinds of medicinal plants, Cinnamomi Ramulus, Poria, Moutan Cortex, Persicae Semen, and Paeoniae Radix Alba. Pharmacology studies have shown that Guizhi Fuling capsule has many activities: anti-inflammatory, analgesic, anti-tumor, regulating smooth muscle, endocrine regulation and enhancing immunity. It achieved obvious effects in the treatment of uterine fibroids, pelvic inflammatory disease, dysmenorrheal, endometriosis, ovarian cysts, breast hyperplasia and other gynecological diseases. This paper reviewed the main progress on studies of pharmacological activities and clinical applications of Guizhi Fuling capsule in recent years.

  9. Insulin-like growth factor-I extends in vitro replicative life span of skeletal muscle satellite cells by enhancing G1/S cell cycle progression via the activation of phosphatidylinositol 3'-kinase/Akt signaling pathway

    Science.gov (United States)

    Chakravarthy, M. V.; Abraha, T. W.; Schwartz, R. J.; Fiorotto, M. L.; Booth, F. W.

    2000-01-01

    Interest is growing in methods to extend replicative life span of non-immortalized stem cells. Using the insulin-like growth factor I (IGF-I) transgenic mouse in which the IGF-I transgene is expressed during skeletal muscle development and maturation prior to isolation and during culture of satellite cells (the myogenic stem cells of mature skeletal muscle fibers) as a model system, we elucidated the underlying molecular mechanisms of IGF-I-mediated enhancement of proliferative potential of these cells. Satellite cells from IGF-I transgenic muscles achieved at least five additional population doublings above the maximum that was attained by wild type satellite cells. This IGF-I-induced increase in proliferative potential was mediated via activation of the phosphatidylinositol 3'-kinase/Akt pathway, independent of mitogen-activated protein kinase activity, facilitating G(1)/S cell cycle progression via a down-regulation of p27(Kip1). Adenovirally mediated ectopic overexpression of p27(Kip1) in exponentially growing IGF-I transgenic satellite cells reversed the increase in cyclin E-cdk2 kinase activity, pRb phosphorylation, and cyclin A protein abundance, thereby implicating an important role for p27(Kip1) in promoting satellite cell senescence. These observations provide a more complete dissection of molecular events by which increased local expression of a growth factor in mature skeletal muscle fibers extends replicative life span of primary stem cells than previously known.

  10. Insulin-like growth factor-I extends in vitro replicative life span of skeletal muscle satellite cells by enhancing G1/S cell cycle progression via the activation of phosphatidylinositol 3'-kinase/Akt signaling pathway

    Science.gov (United States)

    Chakravarthy, M. V.; Abraha, T. W.; Schwartz, R. J.; Fiorotto, M. L.; Booth, F. W.

    2000-01-01

    Interest is growing in methods to extend replicative life span of non-immortalized stem cells. Using the insulin-like growth factor I (IGF-I) transgenic mouse in which the IGF-I transgene is expressed during skeletal muscle development and maturation prior to isolation and during culture of satellite cells (the myogenic stem cells of mature skeletal muscle fibers) as a model system, we elucidated the underlying molecular mechanisms of IGF-I-mediated enhancement of proliferative potential of these cells. Satellite cells from IGF-I transgenic muscles achieved at least five additional population doublings above the maximum that was attained by wild type satellite cells. This IGF-I-induced increase in proliferative potential was mediated via activation of the phosphatidylinositol 3'-kinase/Akt pathway, independent of mitogen-activated protein kinase activity, facilitating G(1)/S cell cycle progression via a down-regulation of p27(Kip1). Adenovirally mediated ectopic overexpression of p27(Kip1) in exponentially growing IGF-I transgenic satellite cells reversed the increase in cyclin E-cdk2 kinase activity, pRb phosphorylation, and cyclin A protein abundance, thereby implicating an important role for p27(Kip1) in promoting satellite cell senescence. These observations provide a more complete dissection of molecular events by which increased local expression of a growth factor in mature skeletal muscle fibers extends replicative life span of primary stem cells than previously known.

  11. Clinical experience in using lenvatinib in patients with progressive, radioactive iodine-refractory differentiated thyroid cancer

    Directory of Open Access Journals (Sweden)

    P. A. Isaev

    2016-01-01

    Full Text Available None of the variants of therapy currently available for patients with differentiated thyroid cancer (DTС refracted to therapy with radioactive iodine 131I (RAI is not radical and does not allow to obtain full complete recovery including this is related to traditional chemotherapy regimens increasing toxicity of treatment contribute to improvement of the clinical effect. With the introduction of multicinase inhibitors into clinical practice made it possible to increase improve therapeutic outcomes. In December of 2015 in the Russian Federation was registered lenvantinib for therapy of patients with progressing DTC resistant to RAI therapy, which according to opinion may substantially improve the results of treatment of such patients and has a potential to change current clinical practice. The article deals with description of 5 clinical cases of inoperable patients with DTС refractory to RAI therapy receiving treatment with lenvatinib in the frameworks of the international randomized clinical trial phase III SELECT. The range of therapeutic effects varied from complete regression of the tumour to stabilization.

  12. Impact of tumour necrosis factor inhibitor treatment on radiographic progression in rheumatoid arthritis patients in clinical practice

    DEFF Research Database (Denmark)

    Ornbjerg, Lykke Midtbøll; Østergaard, Mikkel; Bøyesen, Pernille;

    2013-01-01

    To compare radiographic progression during treatment with disease-modifying antirheumatic drugs (DMARD) and subsequent treatment with tumour necrosis factor α inhibitors (TNF-I) in rheumatoid arthritis (RA) patients in clinical practice.......To compare radiographic progression during treatment with disease-modifying antirheumatic drugs (DMARD) and subsequent treatment with tumour necrosis factor α inhibitors (TNF-I) in rheumatoid arthritis (RA) patients in clinical practice....

  13. DNA replication stress: causes, resolution and disease.

    Science.gov (United States)

    Mazouzi, Abdelghani; Velimezi, Georgia; Loizou, Joanna I

    2014-11-15

    DNA replication is a fundamental process of the cell that ensures accurate duplication of the genetic information and subsequent transfer to daughter cells. Various pertubations, originating from endogenous or exogenous sources, can interfere with proper progression and completion of the replication process, thus threatening genome integrity. Coordinated regulation of replication and the DNA damage response is therefore fundamental to counteract these challenges and ensure accurate synthesis of the genetic material under conditions of replication stress. In this review, we summarize the main sources of replication stress and the DNA damage signaling pathways that are activated in order to preserve genome integrity during DNA replication. We also discuss the association of replication stress and DNA damage in human disease and future perspectives in the field. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  14. Replication Stress: A Lifetime of Epigenetic Change

    Directory of Open Access Journals (Sweden)

    Simran Khurana

    2015-09-01

    Full Text Available DNA replication is essential for cell division. Challenges to the progression of DNA polymerase can result in replication stress, promoting the stalling and ultimately collapse of replication forks. The latter involves the formation of DNA double-strand breaks (DSBs and has been linked to both genome instability and irreversible cell cycle arrest (senescence. Recent technological advances have elucidated many of the factors that contribute to the sensing and repair of stalled or broken replication forks. In addition to bona fide repair factors, these efforts highlight a range of chromatin-associated changes at and near sites of replication stress, suggesting defects in epigenome maintenance as a potential outcome of aberrant DNA replication. Here, we will summarize recent insight into replication stress-induced chromatin-reorganization and will speculate on possible adverse effects for gene expression, nuclear integrity and, ultimately, cell function.

  15. Axonal loss and neurofilament phosphorylation changes accompany lesion development and clinical progression in multiple sclerosis.

    Science.gov (United States)

    Schirmer, Lucas; Antel, Jack P; Brück, Wolfgang; Stadelmann, Christine

    2011-07-01

    Neuroaxonal damage and loss are increasingly recognized as disability determining features in multiple sclerosis (MS) pathology. However, little is known about the long-term sequelae of inflammatory demyelination on neurons and axons. Spinal cord tissue of 31 MS patients was compared to three amyotrophic lateral sclerosis (ALS) and 10 control subjects. MS lesions were staged according to the density of KiM-1P positive macrophages and microglia and the presence of myelin basic protein (MBP) positive phagocytes. T cells were quantified in the parenchyma and meninges. Neuroaxonal changes were studied by immunoreactivity (IR) for amyloid precursor protein (APP) and variably phosphorylated neurofilaments (SMI312, SMI31, SMI32). Little T cell infiltration was still evident in chronic inactive lesions. The loss of SMI32 IR in ventral horn neurons correlated with MS lesion development and disease progression. Similarly, axonal loss in white matter (WM) lesions correlated with disease duration. A selective reduction of axonal phosphorylated neurofilaments (SMI31) was observed in WM lesions. In ALS, the loss of neuronal SMI32 IR was even more pronounced, whereas the relative axonal reduction resembled that found in MS. Progressive neuroaxonal neurofilament alterations in the context of chronic inflammatory demyelination may reflect changes in neuroaxonal metabolism and result in chronic neuroaxonal dysfunction as a putative substrate of clinical progression.

  16. Clinical Significance of Optic Disc Progression by Topographic Change Analysis Maps in Glaucoma: An 8-Year Follow-Up Study

    Directory of Open Access Journals (Sweden)

    D. Kourkoutas

    2014-01-01

    Full Text Available Aim. To investigate the ability of Heidelberg Retina Tomograph (HRT3 Topographic Change Analysis (TCA map to predict the subsequent development of clinical change, in patients with glaucoma. Materials. 61 eyes of 61 patients, which, from a retrospective review were defined as stable on optic nerve head (ONH stereophotographs and visual field (VF, were enrolled in a prospective study. Eyes were classified as TCA-stable or TCA-progressed based on the TCA map. All patients underwent HRT3, VF, and ONH stereophotography at 9–12 months intervals. Clinical glaucoma progression was determined by masked assessment of ONH stereophotographs and VF Guided Progression Analysis. Results. The median (IQR total HRT follow-up period was 8.1 (7.3, 9.1 years, which included a median retrospective and prospective follow-up time of 3.9 (3.1, 5.0 and 4.0 (3.5, 4.7 years, respectively. In the TCA-stable eyes, VF and/or photographic progression occurred in 5/13 (38.4% eyes compared to 11/48 (22.9% of the TCA-progressed eyes. There was no statistically significant association between TCA progression and clinically relevant (photographic and/or VF progression (hazard ratio, 1.18; P=0.762. The observed median time to clinical progression from enrollment was significantly shorter in the TCA-progressed group compared to the TCA-stable group (P=0.04. Conclusion. Our results indicate that the commercially available TCA progression criteria do not adequately predict subsequent photographic and/or VF progression.

  17. Subchondral insufficiency fractures of the femoral head: associated imaging findings and predictors of clinical progression

    Energy Technology Data Exchange (ETDEWEB)

    Hackney, Lauren A.; Joseph, Gabby B.; Link, Thomas M. [University of California, San Francisco, Department of Radiology and Biomedical Imaging, San Francisco, CA (United States); Lee, Min Hee [University of California, San Francisco, Department of Radiology and Biomedical Imaging, San Francisco, CA (United States); University of Ulsan College of Medicine, Department of Radiology and Research Institute of Radiology, Asan Medical Center, Seoul (Korea, Republic of); Vail, Thomas P. [University of California, Department of Orthopaedic Surgery, San Francisco, CA (United States)

    2016-06-15

    To characterize the morphology and imaging findings of femoral head subchondral insufficiency fractures (SIF), and to investigate clinical outcomes in relation to imaging findings. Fifty-one patients with hip/pelvis magnetic resonance (MR) images and typical SIF characteristics were identified and reviewed by two radiologists. Thirty-five patients had follow-up documentation allowing assessment of clinical outcome. Subgroup comparisons were performed using regression models adjusted for age and body mass index. SIF were frequently associated with cartilage loss (35/47, 74.5 %), effusion (33/42, 78.6 %), synovitis (29/44, 66 %), and bone marrow oedema pattern (BMEP) (average cross-sectional area 885.7 ± 730.2 mm{sup 2}). Total hip arthroplasty (THA) was required in 16/35 patients, at an average of 6 months post-MRI. Compared to the THA cohort, the non-THA group had significantly (p < 0.05) smaller overlying cartilage defect size (10 mm vs. 29 mm), smaller band length ratio and fracture diameters, and greater incidence of parallel fracture morphology (p < 0.05). Male gender and increased age were significantly associated with progression, p < 0.05. SIF were associated with synovitis, cartilage loss, effusion, and BMEP. Male gender and increased age had a significant association with progression to THA, as did band length ratio, fracture diameter, cartilage defect size, and fracture deformity/morphology. (orig.)

  18. Optimising translational oncology in clinical practice: strategies to accelerate progress in drug development.

    Science.gov (United States)

    Stahel, R; Bogaerts, J; Ciardiello, F; de Ruysscher, D; Dubsky, P; Ducreux, M; Finn, S; Laurent-Puig, P; Peters, S; Piccart, M; Smit, E; Sotiriou, C; Tejpar, S; Van Cutsem, E; Tabernero, J

    2015-02-01

    Despite intense efforts, the socioeconomic burden of cancer remains unacceptably high and treatment advances for many common cancers have been limited, suggesting a need for a new approach to drug development. One issue central to this lack of progress is the heterogeneity and genetic complexity of many tumours. This results in considerable variability in therapeutic response and requires knowledge of the molecular profile of the tumour to guide appropriate treatment selection for individual patients. While recent advances in the molecular characterisation of different cancer types have the potential to transform cancer treatment through precision medicine, such an approach presents a major economic challenge for drug development, since novel targeted agents may only be suitable for a small cohort of patients. Identifying the patients who would benefit from individual therapies and recruiting sufficient numbers of patients with particular cancer subtypes into clinical trials is challenging, and will require collaborative efforts from research groups and industry in order to accelerate progress. A number of molecular screening platforms have already been initiated across Europe, and it is hoped that these networks, along with future collaborations, will benefit not only patients but also society through cost reductions as a result of more efficient use of resources. This review discusses how current developments in translational oncology may be applied in clinical practice in the future, assesses current programmes for the molecular characterisation of cancer and describes possible collaborative approaches designed to maximise the benefits of translational science for patients with cancer.

  19. Monitoring progression in Friedreich ataxia (FRDA): the use of clinical scales.

    Science.gov (United States)

    Bürk, Katrin; Schulz, Stefanie R; Schulz, Jörg B

    2013-08-01

    Friedreich ataxia (FRDA) is a progressive neurodegenerative disorder associated with ataxia, dysarthria, pyramidal tract signs, sensory loss, cardiomyopathy and diabetes. There is no cure for FRDA so far. Studies of the natural history of the disease and future therapeutic trials require development of appropriate outcome markers. Since any therapeutic benefit is expected to modulate deterioration over time rather than to reverse disability, potential outcome measures must be sensitive instruments carefully analysed for their significance. Clinical scales may represent an appropriate measuring tool. Over the last few years the construction, evaluation and validation of sensitive clinical scales for the assessment of disease severity and progression in ataxia have had considerable impact on our understanding of the disease. Currently, there are three different scales that are most frequently applied: The International Cooperative Ataxia Rating Scale (ICARS), the Friedreich Ataxia Rating Scale (FARS) and the Scale for the Assessment and Rating of Ataxia (SARA). All scales have been validated and compared with regard to their testing properties.

  20. Progress with palbociclib in breast cancer: latest evidence and clinical considerations.

    Science.gov (United States)

    Rocca, Andrea; Schirone, Alessio; Maltoni, Roberta; Bravaccini, Sara; Cecconetto, Lorenzo; Farolfi, Alberto; Bronte, Giuseppe; Andreis, Daniele

    2017-02-01

    Deregulation of the cell cycle is a hallmark of cancer, and research on cell cycle control has allowed identification of potential targets for anticancer treatment. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved, with their coregulatory partners cyclin D, in the G1-S transition. Inhibition of this step halts cell cycle progression in cells in which the involved pathway, including the retinoblastoma protein (Rb) and the E2F family of transcription factors, is functioning, although having been deregulated. Among breast cancers, those with functioning cyclin D-CDK4/6-Rb-E2F are mainly hormone-receptor (HR) positive, with some HER2-positive and rare triple-negative cases. Deregulation results from genetic or otherwise occurring hyperactivation of molecules subtending cell cycle progression, or inactivation of cell cycle inhibitors. Based on results of randomized clinical trials, palbociclib was granted accelerated approval by the US Food and Drug Administration (FDA) for use in combination with letrozole as initial endocrine-based therapy for metastatic disease in postmenopausal women with HR-positive, HER2-negative breast cancer, and was approved for use in combination with fulvestrant in women with HR-positive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. This review provides an update of the available knowledge on the cell cycle and its regulation, on the alterations in cyclin D-CDK4/6-Rb-E2F axis in breast cancer and their roles in endocrine resistance, on the preclinical activity of CDK4/6 inhibitors in breast cancer, both as monotherapy and as partners of combinatorial synergic treatments, and on the clinical development of palbociclib in breast cancer.

  1. Levels of uninvolved immunoglobulins predict clinical status and progression-free survival for multiple myeloma patients.

    Science.gov (United States)

    Harutyunyan, Nika M; Vardanyan, Suzie; Ghermezi, Michael; Gottlieb, Jillian; Berenson, Ariana; Andreu-Vieyra, Claudia; Berenson, James R

    2016-07-01

    Multiple myeloma (MM) is characterized by the enhanced production of the same monoclonal immunoglobulin (M-Ig or M protein). Techniques such as serum protein electrophoresis and nephelometry are routinely used to quantify levels of this protein in the serum of MM patients. However, these methods are not without their shortcomings and problems accurately quantifying M proteins remain. Precise quantification of the types and levels of M-Ig present is critical to monitoring patient response to therapy. In this study, we investigated the ability of the HevyLite (HLC) immunoassay to correlate with clinical status based on levels of involved and uninvolved antibodies. In our cohort of MM patients, we observed that significantly higher ratios and greater differences of involved HLC levels compared to uninvolved HLC levels correlated with a worse clinical status. Similarly, higher absolute levels of involved HLC antibodies and lower levels of uninvolved HLC antibodies also correlated with a worse clinical status and a shorter progression-free survival. These findings suggest that the HLC assay is a useful and a promising tool for determining the clinical status and survival time for patients with multiple myeloma.

  2. Archaeal DNA replication.

    Science.gov (United States)

    Kelman, Lori M; Kelman, Zvi

    2014-01-01

    DNA replication is essential for all life forms. Although the process is fundamentally conserved in the three domains of life, bioinformatic, biochemical, structural, and genetic studies have demonstrated that the process and the proteins involved in archaeal DNA replication are more similar to those in eukaryal DNA replication than in bacterial DNA replication, but have some archaeal-specific features. The archaeal replication system, however, is not monolithic, and there are some differences in the replication process between different species. In this review, the current knowledge of the mechanisms governing DNA replication in Archaea is summarized. The general features of the replication process as well as some of the differences are discussed.

  3. Clinical and magnetic resonance imaging predictors of disease progression in multiple sclerosis: a nine-year follow-up study.

    Science.gov (United States)

    Lavorgna, L; Bonavita, S; Ippolito, D; Lanzillo, R; Salemi, G; Patti, F; Valentino, P; Coniglio, G; Buccafusca, M; Paolicelli, D; d'Ambrosio, A; Bresciamorra, V; Savettieri, G; Zappia, M; Alfano, B; Gallo, A; Simone, Il; Tedeschi, G

    2014-02-01

    The objective of this paper is to identify clinical or magnetic resonance imaging (MRI) predictors of long-term clinical progression in a large cohort of multiple sclerosis (MS) patients. A total of 241 relapsing-remitting (RR) MS patients were included in a nine-year follow-up (FU) study. The reference MRIs were acquired at baseline (BL) as part of a multicenter, cross-sectional, clinical-MRI study. Volumetric MRI metrics were measured by a fully automated, operator-independent, multi-parametric segmentation method. Clinical progression was evaluated as defined by: conversion from RR to secondary progressive (SP) disease course; progression of Expanded Disability Status Scale (EDSS); achievement and time to reach EDSS 4. We concluded that conversion from RR to SP (OR 0.79; CI 0.7-0.9), progression of EDSS (OR 0.85; CI 0.77-0.93), achievement of EDSS 4 (OR 0.8; CI 0.7-0.9), and time to reach EDSS 4 (HR 0.88; CI 0.82-0.94) were all predicted by BL gray matter (GM) volume and, except for progression of EDSS, by BL EDSS (respectively: (OR 2.88; CI 1.9-4.36), (OR 2.7; CI 1.7-4.2), (HR 3.86; CI 1.94-7.70)). BL GM volume and EDSS are the best long-term predictors of disease progression in RRMS patients with a relatively long and mild disease.

  4. T cell vaccination benefits relapsing progressive multiple sclerosis patients: a randomized, double-blind clinical trial.

    Directory of Open Access Journals (Sweden)

    Dimitrios Karussis

    Full Text Available BACKGROUND: T-cell vaccination (TCV for multiple sclerosis (MS refers to treatment with autologous anti-myelin T-cells, attenuated by irradiation. Previously published clinical trials have been all open-labeled. AIM: To evaluate the safety and efficacy of TCV in progressive MS, in a double-blind, controlled clinical trial. METHODOLOGY: Twenty-six patients with relapsing-progressive MS were enrolled in the study (mean age: 39±9.8 years; mean EDSS: 4.4±1.7. T-cell lines reactive to 9 different peptides of the myelin antigens, MBP, MOG and PLP were raised from the patients' peripheral blood. The patients were randomized into two groups: 19 were treated with TCV (four subcutaneous injections of 10-30×10(6 T-cells, attenuated by irradiation, on days 1, 30, 90 and 180 and 7 patients were treated with sham injections. Twenty-four patients (17 in the TCV group and 7 in the placebo were eligible for per-protocol analysis. RESULTS: At one year following the inclusion, an increase in the EDSS (+0.50 and an increase in 10-meter walking time (+0.18 sec, were observed in the placebo group; in the TCV group there was a decrease in the EDSS (-0.44; p<0.01 and in the 10-meter walking time (0.84 sec; p<0.005. Sixteen of the 17 patients (94.1% in the TCV group remained relapse-free during the year of the study, as compared to 42.9% in the placebo group (p = 0.01 and p = 0.03 with adjustment. The proportion of patients with any relapse during the year of the study in the TCV-group, was reduced by 89.6%., as compared to the placebo-treated group. MRI parameters did not change significantly. CONCLUSIONS: This is the first controlled, double-blind trial with TCV in progressive MS. The results demonstrate the feasibility and safety of the procedure, and provide significant indications of clinical efficacy. Further studies with larger groups of subjects are warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01448252.

  5. Word-finding difficulty: a clinical analysis of the progressive aphasias.

    Science.gov (United States)

    Rohrer, Jonathan D; Knight, William D; Warren, Jane E; Fox, Nick C; Rossor, Martin N; Warren, Jason D

    2008-01-01

    The patient with word-finding difficulty presents a common and challenging clinical problem. The complaint of 'word-finding difficulty' covers a wide range of clinical phenomena and may signify any of a number of distinct pathophysiological processes. Although it occurs in a variety of clinical contexts, word-finding difficulty generally presents a diagnostic conundrum when it occurs as a leading or apparently isolated symptom, most often as the harbinger of degenerative disease: the progressive aphasias. Recent advances in the neurobiology of the focal, language-based dementias have transformed our understanding of these processes and the ways in which they breakdown in different diseases, but translation of this knowledge to the bedside is far from straightforward. Speech and language disturbances in the dementias present unique diagnostic and conceptual problems that are not fully captured by classical models derived from the study of vascular and other acute focal brain lesions. This has led to a reformulation of our understanding of how language is organized in the brain. In this review we seek to provide the clinical neurologist with a practical and theoretical bridge between the patient presenting with word-finding difficulty in the clinic and the evidence of the brain sciences. We delineate key illustrative speech and language syndromes in the degenerative dementias, compare these syndromes with the syndromes of acute brain damage, and indicate how the clinical syndromes relate to emerging neurolinguistic, neuroanatomical and neurobiological insights. We propose a conceptual framework for the analysis of word-finding difficulty, in order both better to define the patient's complaint and its differential diagnosis for the clinician and to identify unresolved issues as a stimulus to future work.

  6. Leukocyte scintigraphy: correlation of serial scintigraphic findings and clinical progression of inflammatory bowel disease

    Energy Technology Data Exchange (ETDEWEB)

    Ho, Y.; Kelly, M.J.; Kaliff, V. [Alfred Hospital, Prahan, VIC (Australia). Department of Nuclear Medicine

    1997-12-01

    Full text: This study was performed (a) to determine whether the clinical progress of individual patients with inflammatory bowel disease mirrored changes in leukocyte scans, and (b) to assess the reasons for significant discrepancies. Two nuclear medicine physicians reviewed 44 white cell scans in 20 consecutive patients (4 males, 18 females) who were referred for two or more leukocyte scans (using either the {sup 111}In Oxine or {sup 99m}Tc HMPAO labelling methods) by three gastroenterologists between 1 January 1992 and 1 June 1996. The sequential scanpairs (range 2-18 months apart) were classified by consensus reading as showing no change, more severe or less severe disease. Questionnaires were sent to the referring gastroenterologists to determine whether the overall clinical status of each patient was unchanged, better or worse in the interval between the two scans. There was complete agreement between clinical and scintigraphic assessment in 45% (10/22) of the study pairs. Review of responses of the three individual gastroenterologists showed a wide range of agreement (4/4, 4/5, 2/13). Review of data showed that most disagreement was based on subjective clinical assessment, and hence of uncertain significance. In two patients, however, potentially preventable false negative leukocyte scans occurred in patients with active proctitis. This may be overcome by rigorous attention to ensure complete emptying of radioactivity from the bladder when {sup 99m}Tc HMPAO is used. It was concluded that serial leukocyte scans add to clinical assessment but careful technique is needed to avoid false negative scans in the rectum

  7. Recent publications from the Alzheimer's Disease Neuroimaging Initiative: Reviewing progress toward improved AD clinical trials.

    Science.gov (United States)

    Weiner, Michael W; Veitch, Dallas P; Aisen, Paul S; Beckett, Laurel A; Cairns, Nigel J; Green, Robert C; Harvey, Danielle; Jack, Clifford R; Jagust, William; Morris, John C; Petersen, Ronald C; Saykin, Andrew J; Shaw, Leslie M; Toga, Arthur W; Trojanowski, John Q

    2017-04-01

    The Alzheimer's Disease Neuroimaging Initiative (ADNI) has continued development and standardization of methodologies for biomarkers and has provided an increased depth and breadth of data available to qualified researchers. This review summarizes the over 400 publications using ADNI data during 2014 and 2015. We used standard searches to find publications using ADNI data. (1) Structural and functional changes, including subtle changes to hippocampal shape and texture, atrophy in areas outside of hippocampus, and disruption to functional networks, are detectable in presymptomatic subjects before hippocampal atrophy; (2) In subjects with abnormal β-amyloid deposition (Aβ+), biomarkers become abnormal in the order predicted by the amyloid cascade hypothesis; (3) Cognitive decline is more closely linked to tau than Aβ deposition; (4) Cerebrovascular risk factors may interact with Aβ to increase white-matter (WM) abnormalities which may accelerate Alzheimer's disease (AD) progression in conjunction with tau abnormalities; (5) Different patterns of atrophy are associated with impairment of memory and executive function and may underlie psychiatric symptoms; (6) Structural, functional, and metabolic network connectivities are disrupted as AD progresses. Models of prion-like spreading of Aβ pathology along WM tracts predict known patterns of cortical Aβ deposition and declines in glucose metabolism; (7) New AD risk and protective gene loci have been identified using biologically informed approaches; (8) Cognitively normal and mild cognitive impairment (MCI) subjects are heterogeneous and include groups typified not only by "classic" AD pathology but also by normal biomarkers, accelerated decline, and suspected non-Alzheimer's pathology; (9) Selection of subjects at risk of imminent decline on the basis of one or more pathologies improves the power of clinical trials; (10) Sensitivity of cognitive outcome measures to early changes in cognition has been improved and

  8. Predictive factors of rapidly progressive-interstitial lung disease in patients with clinically amyopathic dermatomyositis.

    Science.gov (United States)

    Xu, Y; Yang, C S; Li, Y J; Liu, X D; Wang, J N; Zhao, Q; Xiao, W G; Yang, P T

    2016-01-01

    Clinically amyopathic dermatomyositis (CADM) is a unique subset of dermatomyositis, showing a high incidence of lung involvements. The aim of this study is to identify risk factors, other than melanoma differentiation-associated protein (MDA)-5, for developing rapidly progressive-interstitial lung disease (RP-ILD) in patients with CADM. Forty CADM patients, in whom 11 patients developed RP-ILD, were enrolled. Clinical features and laboratory findings were compared between the patients with and without RP-ILD. We found that skin ulceration, CRP, serum ferritin, anti-MDA5 Ab, and lymphocytopenia were significantly associated with ILD. Multivariate logistic regression analysis indicated that anti-MDA5 Ab(+), elevated CRP, and decreased counts of lymphocyte were independent risk factors for RP-ILD, which can provide a precise predict for RP-ILD in CADM patients. When anti-MDA5 Ab(+) was removed from the multivariate regression model, using skin ulcerations, elevated serum ferritin and decreased counts of lymphocyte can also precisely predict RP-ILD. Except for MDA-5, more commonly available clinical characteristics, such as skin ulcerations, serum ferritin, and count of lymphocyte may also help to predict prognosis in CADM.

  9. The clinical and laboratory characteristics of acute spontaneous urticaria and its progression to chronic spontaneous urticaria.

    Science.gov (United States)

    Magen, Eli; Zueva, Ekaterina; Mishal, Joseph; Schlesinger, Menachem

    2016-09-01

    The natural history of the progression from acute spontaneous urticaria (ASU) to chronic spontaneous urticaria (CSU), CSU remains poorly understood. To identify clinical and laboratory patient attributes that may be predictive of ASU progression to CSU. We prospectively studied consecutive adult patients (age ≥ 18 years) with a diagnosis of urticaria of urticaria activity score assessment were performed in all the patients at baseline and then at weeks 7, 12, 24, and 48. Of 114 patients with acute urticaria and without identifiable causes, 73 patients (64%) were included in the ASU group, 41 patients in the CSU group (36%), and 44 healthy subjects in the control group. At baseline, 26 patients in the CSU group (63.4%) had a positive ASST result, whereas only 17 patients with a positive ASST result (23.3%) were revealed in the ASU group (p < 0.001). Patients with baseline ASST positive results were characterized by more profound basopenia (mean [standard deviation], 0.05 ± 0.08 cell/mm(3)) and more anti-thyroid peroxidase antibodies (18 [41.8%]) than those with the negative baseline ASST result (mean [standard deviation], 0.13 ± 0.09 cell/mm(3), p < 0.001 more profound basopenia; and 13 (18.1%), p = 0.009 more thyroid peroxidase antibodies). We observed the disappearance of ASST positive result in some patients with CSU with baseline positive ASST results, whereas, in some subjects with CSU, baseline negative ASST results came to be positive results throughout the study period. A baseline positive ASST result of patients with ASU was a significant determinant (odds ratio 5.91 [95% confidence interval, 2.57-13.62]; p < 0.001) for a CSU diagnosis at week 7. The patients with ASU who progressed toward CSU were characterized by a positive ASST result, thyroid autoimmunity, and profound basopenia at baseline.

  10. Defects of mitochondrial DNA replication.

    Science.gov (United States)

    Copeland, William C

    2014-09-01

    Mitochondrial DNA is replicated by DNA polymerase γ in concert with accessory proteins such as the mitochondrial DNA helicase, single-stranded DNA binding protein, topoisomerase, and initiating factors. Defects in mitochondrial DNA replication or nucleotide metabolism can cause mitochondrial genetic diseases due to mitochondrial DNA deletions, point mutations, or depletion, which ultimately cause loss of oxidative phosphorylation. These genetic diseases include mitochondrial DNA depletion syndromes such as Alpers or early infantile hepatocerebral syndromes, and mitochondrial DNA deletion disorders, such as progressive external ophthalmoplegia, ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy. This review focuses on our current knowledge of genetic defects of mitochondrial DNA replication (POLG, POLG2, C10orf2, and MGME1) that cause instability of mitochondrial DNA and mitochondrial disease.

  11. Regulation of beta cell replication

    DEFF Research Database (Denmark)

    Lee, Ying C; Nielsen, Jens Høiriis

    2008-01-01

    Beta cell mass, at any given time, is governed by cell differentiation, neogenesis, increased or decreased cell size (cell hypertrophy or atrophy), cell death (apoptosis), and beta cell proliferation. Nutrients, hormones and growth factors coupled with their signalling intermediates have been...... suggested to play a role in beta cell mass regulation. In addition, genetic mouse model studies have indicated that cyclins and cyclin-dependent kinases that determine cell cycle progression are involved in beta cell replication, and more recently, menin in association with cyclin-dependent kinase...... inhibitors has been demonstrated to be important in beta cell growth. In this review, we consider and highlight some aspects of cell cycle regulation in relation to beta cell replication. The role of cell cycle regulation in beta cell replication is mostly from studies in rodent models, but whether...

  12. [Chronic progressive external ophthalmoplegia with mitochondrial anomalies. Clinical, histological, biochemical and genetic analysis (9 cases)].

    Science.gov (United States)

    Drouet, A

    1996-01-01

    We report the clinical signs and histological findings in nine patients with mitochondrial ocular myopathies. There were four males and five females. Of age ranging from 47 to 82 years. A more often asymetrical ptosis was in all cases of chronic progressive external ophtalmoplegia (CPEO), but muscle weakness in limbs was not usual. The prognosis in this group was good, but ubidecarenone (150 mg/d) used for two cases, did not improve ophtalmoplegia. The serum creatine kinase was normal in eight of nine cases and electromyography showed myopathic changes in three cases. Histoenzymatic analysis of the muscle biopsy and biochemical studies of mitochondria isolated from the muscle sample demonstrated mitochondrial myopathy associated with partial deficiency of complexes I and/or IV of the electron transfer chain. One of seven patients studied had single deletion by Southern blot analysis, in a heteroplasmic state and another an A-->G transition at position 3243 within the mitochondrial tRNA leu (UUR) gene. Chronic progressive external ophtalmoplegia, without large deletion, may have abnormality in other coding regions of mt DNA such as tRNA, rRNA or protein genes.

  13. Slowly progressive fluent aphasia; Clinical features and an imaging study including MRI, SPECT and PET

    Energy Technology Data Exchange (ETDEWEB)

    Sakurai, Yasuhisa; Momose, Toshimitsu; Watanabe, Toshiaki; Ishikawa, Takashi; Iwata, Makoto (Tokyo Univ. (Japan). Faculty of Medicine); Bando, Mitsuaki

    1991-05-01

    Three patients with slowly progressive fluent aphasia are reported. One of the patients presented with memory disturbance. They were characterized clinically by having selective deficits in vocabulary, which resulted in impairment of confrontation naming, and auditory comprehension. MRI showed an atrophy not only in the left temporal lobe (including the superior, middle and inferior temporal gyri), hippocampus, parahippocampual gyrus, and fusiform gyrus, but also in the left parietal lobe. I-123 IMP SPECT and F-18 FDG PET were used to determine regional cerebral blood flow and regional cerebral metabolic rate, respectively. In addition to the decreased tracer uptake in the left temporal and/or parietal lobe, a decreased uptake was seen in the bilateral basal ganglia, the inner side of the temporal lobe (including the bilateral hippocampus), the right anterior temporal lobe, and the left thalamus. These findings may deny the previous thought that lesions are localized in slowly progressive fluent aphasia. Furthermore, noticeable difficulty in naming, i.e., patients unable to recognize the right answer, are considered attributable to widespread lesions from the whole left temporal lobe, including the hippocampus, to the right temporal lobe. (N.K.).

  14. The differential diagnosis of multiple sclerosis: classification and clinical features of relapsing and progressive neurological syndromes.

    Science.gov (United States)

    Trojano, M; Paolicelli, D

    2001-11-01

    In the absence of pathognomonic clinical features or a definitive laboratory test, multiple sclerosis (MS) remains ultimately a diagnosis of exclusion. Accurate diagnosis is increasingly important with available disease modifying therapy. Unfortunately the rate of misdiagnosis remains around 5%-10%, indicating that 1 in 20 patients thought to have MS has, instead, a condition resembling MS. In this review we describe conditions that may be confused with MS because they can present as lesions disseminated in time, space, or both. Conditions often confused with MS may be inflammatory (systemic lupus erythematosus, Sjögren's syndrome, vasculitis, sarcoidosis, Behçet's disease), infectious (Lyme disease, syphilis, progressive multifocal leukoencephalopathy, HTLV-1 infection, herpes zoster), genetic (lysosomal disorders, adrenoleukodystrophy, mitochondrial disorders, CADASIL), metabolic (vitamin B12 deficiency), neoplastic (CNS lymphoma) and spinal (degenerative and vascular malformations) diseases. The key to the accurate diagnosis of MS is vigilance for atypical features, suggesting the possibility of an alternative diagnosis.

  15. Clinical Significance of HER-2 Splice Variants in Breast Cancer Progression and Drug Resistance

    Directory of Open Access Journals (Sweden)

    Claire Jackson

    2013-01-01

    Full Text Available Overexpression of human epidermal growth factor receptor (HER-2 occurs in 20–30% of breast cancers and confers survival and proliferative advantages on the tumour cells making HER-2 an ideal therapeutic target for drugs like Herceptin. Continued delineation of tumour biology has identified splice variants of HER-2, with contrasting roles in tumour cell biology. For example, the splice variant 16HER-2 (results from exon 16 skipping increases transformation of cancer cells and is associated with treatment resistance; conversely, Herstatin (results from intron 8 retention and p100 (results from intron 15 retention inhibit tumour cell proliferation. This review focuses on the potential clinical implications of the expression and coexistence of HER-2 splice variants in cancer cells in relation to breast cancer progression and drug resistance. “Individualised” strategies currently guide breast cancer management; in accordance, HER-2 splice variants may prove valuable as future prognostic and predictive factors, as well as potential therapeutic targets.

  16. Progress in Early Childhood Caries and Opportunities in Research, Policy, and Clinical Management

    DEFF Research Database (Denmark)

    Garcia, Raul; Borrelli, Belinda; Dhar, Vineet;

    2015-01-01

    The 2014 Early Childhood Caries Conference encompassed evidence-based reviews on the state of the science regarding early childhood carries (ECC) epidemiology, etiology, prevention, and disease management. The purpose of this paper was to discuss the work presented at the conference and identify...... opportunities in research, policy, and clinical management that may improve early childhood caries outcomes and lower costs of care. While great progress has been made since the 1997 ECC Conference, there remains a paucity of high-quality evidence from randomized controlled trials on what are the most effective...... to identify preschool children at risk for caries. Fluoridated toothpaste and fluoride varnish currently are the most effective chemotherapeutic strategies to prevent ECC. Motivational interviewing, a form of patient-centered counseling, is effective for motivating oral health behaviors and shows promise...

  17. Replication forks reverse at high frequency upon replication stress in Physarum polycephalum.

    Science.gov (United States)

    Maric, Chrystelle; Bénard, Marianne

    2014-12-01

    The addition of hydroxyurea after the onset of S phase allows replication to start and permits the successive detecting of replication-dependent joint DNA molecules and chicken foot structures in the synchronous nuclei of Physarum polycephalum. We find evidence for a very high frequency of reversed replication forks upon replication stress. The formation of these reversed forks is dependent on the presence of joint DNA molecules, the impediment of the replication fork progression by hydroxyurea, and likely on the propensity of some replication origins to reinitiate replication to counteract the action of this compound. As hydroxyurea treatment enables us to successively detect the appearance of joint DNA molecules and then of reversed replication forks, we propose that chicken foot structures are formed both from the regression of hydroxyurea-frozen joint DNA molecules and from hydroxyurea-stalled replication forks. These experiments underscore the transient nature of replication fork regression, which becomes detectable due to the hydroxyurea-induced slowing down of replication fork progression.

  18. Nodal colloid goiter: clinical and morphological criteria of thyroid autonomy and progressive growth

    Directory of Open Access Journals (Sweden)

    S S Antonova

    2006-03-01

    Full Text Available Goal. To work up clinical and morphological criteria of thyroid authonomy and progressive growth in nodal colloid goiter (NCG. Methods. A group of patients with nodal euthyroid goiter (NEG (40 patients and a group of patients with nodular toxic goiter (NTG (40 patients were formed to compare clinical and morphological criteria of NCG growth to/with development of functional autonomy (FA. All patients were conducted research including physical examination, thyroid palpation, ultrasound, blood level of TSH and T4, scintigraphy, aspiration (needle biopsy, immunocytological and immunohistological reactions and statistics. In the study the method of indirect immunoperoxidase reaction with monoclonal rat/mouse antigens to Ki-67, TSH, galectin-3, Apo-test (“Dako Corporation”, “Novocastra Laboratories Ltd.” was used. Results. 1. In NEG expression of cell proliferation marker Ki-67 for certain rises pro rata to increase of proliferation degree, and in NTG grows according to FA development. 2. Apoptosis expression in NEG decreases according to degree of thyrocytes in a nodule, but in NTG falls pro rata to accumulation of thyroid FA. 3. Positive reaction for TSH in NEG tissue was found in 100%, whereas negative reaction for this receptor in NTG tissue was observed in 81% of all cases. 4. Galectin-3 was expressed in focuses of severe dysplasia of thyroid nodes tissue comparable to galectin-3 expression in the tissue of high-grade differentiated adenocarcinomas. Summary/conclusion. 1. Severe and moderate expression of Ki-67 and mild or negative immunomorphological reaction for Apo-test allows to refer such kinds of nodules to fast-growing/rapid-growing ones. 2. Reliable negative expression TSH receptor in the tissue of NCG is evidence of FA development and is an indication for a treatment of radioactive iodine or for an operation. 3. Galectin-3 probably is an early marker of malignant transformation in thyroid tissue. 4. Having conducted complex

  19. The semantic variant of primary progressive aphasia: clinical and neuroimaging evidence in single subjects.

    Directory of Open Access Journals (Sweden)

    Leonardo Iaccarino

    Full Text Available We present a clinical-neuroimaging study in a series of patients with a clinical diagnosis of semantic variant of primary progressive aphasia (svPPA, with the aim to provide clinical-functional correlations of the cognitive and behavioral manifestations at the single-subject level.We performed neuropsychological investigations, 18F-FDG-PET single-subject and group analysis, with an optimized SPM voxel-based approach, and correlation analyses. A measurement of white matter integrity by means of diffusion tensor imaging (DTI was also available for a subgroup of patients.Cognitive assessment confirmed the presence of typical semantic memory deficits in all patients, with a relative sparing of executive, attentional, visuo-constructional, and episodic memory domains. 18F-FDG-PET showed a consistent pattern of cerebral hypometabolism across all patients, which correlated with performance in semantic memory tasks. In addition, a majority of patients also presented with behavioral disturbances associated with metabolic dysfunction in limbic structures. In a subgroup of cases the DTI analysis showed FA abnormalities in the inferior longitudinal and uncinate fasciculi.Each svPPA individual had functional derangement involving an extended, connected system within the left temporal lobe, a crucial part of the verbal semantic network, as well as an involvement of limbic structures. The latter was associated with behavioral manifestations and extended beyond the area of atrophy shown by CT scan.Single-subject 18F-FDG-PET analysis can account for both cognitive and behavioral alterations in svPPA. This provides useful support to the clinical diagnosis.

  20. Regulation of Unperturbed DNA Replication by Ubiquitylation

    Directory of Open Access Journals (Sweden)

    Sara Priego Moreno

    2015-06-01

    Full Text Available Posttranslational modification of proteins by means of attachment of a small globular protein ubiquitin (i.e., ubiquitylation represents one of the most abundant and versatile mechanisms of protein regulation employed by eukaryotic cells. Ubiquitylation influences almost every cellular process and its key role in coordination of the DNA damage response is well established. In this review we focus, however, on the ways ubiquitylation controls the process of unperturbed DNA replication. We summarise the accumulated knowledge showing the leading role of ubiquitin driven protein degradation in setting up conditions favourable for replication origin licensing and S-phase entry. Importantly, we also present the emerging major role of ubiquitylation in coordination of the active DNA replication process: preventing re-replication, regulating the progression of DNA replication forks, chromatin re-establishment and disassembly of the replisome at the termination of replication forks.

  1. Analysis of midwifery students' written reflections to evaluate progression in learning during clinical practice at birthing units.

    OpenAIRE

    Persson, Eva-Kristina; Kvist, LInda; Ekelin, Maria

    2015-01-01

    Written daily reflections during clinical practice on birthing units have been used during several years in midwifery education at Lund University, Sweden. However, the usefulness of these reflections for evaluation of progression in learning and professional development of students has to date not been evaluated. In order to analyse written reflections, two taxonomies developed by Bloom and Pettersen have been applied to the texts. Progression in the professional development of midwifery stu...

  2. Assembly of Slx4 signaling complexes behind DNA replication forks.

    Science.gov (United States)

    Balint, Attila; Kim, TaeHyung; Gallo, David; Cussiol, Jose Renato; Bastos de Oliveira, Francisco M; Yimit, Askar; Ou, Jiongwen; Nakato, Ryuichiro; Gurevich, Alexey; Shirahige, Katsuhiko; Smolka, Marcus B; Zhang, Zhaolei; Brown, Grant W

    2015-08-13

    Obstructions to replication fork progression, referred to collectively as DNA replication stress, challenge genome stability. In Saccharomyces cerevisiae, cells lacking RTT107 or SLX4 show genome instability and sensitivity to DNA replication stress and are defective in the completion of DNA replication during recovery from replication stress. We demonstrate that Slx4 is recruited to chromatin behind stressed replication forks, in a region that is spatially distinct from that occupied by the replication machinery. Slx4 complex formation is nucleated by Mec1 phosphorylation of histone H2A, which is recognized by the constitutive Slx4 binding partner Rtt107. Slx4 is essential for recruiting the Mec1 activator Dpb11 behind stressed replication forks, and Slx4 complexes are important for full activity of Mec1. We propose that Slx4 complexes promote robust checkpoint signaling by Mec1 by stably recruiting Dpb11 within a discrete domain behind the replication fork, during DNA replication stress.

  3. 1!Serum urate as a predictor of clinical and radiographic progression in Parkinson’s disease

    Science.gov (United States)

    Schwarzschild, Michael A.; Schwid, Steven R.; Marek, Kenneth; Watts, Arthur; Lang, Anthony E.; Oakes, David; Shoulson, Ira; Ascherio, Alberto

    2008-01-01

    Context Prospective epidemiological studies consistently indicate that Parkinson’s disease (PD) risk declines with increasing serum urate. Objective To determine whether serum urate, a purine metabolite and potent antioxidant, predicts prognosis in PD. Design, Setting, and Participants Prospective study among 804 subjects with early PD enrolled in the PRECEPT study, a clinical trial of the neuroprotectant potential of CEP-1347, conducted between April 2002 and August 2005 (average follow-up time 21.4 months). Main Outcome Measures The primary study endpoint was progression to clinical disability sufficient to warrant dopaminergic therapy. Cox proportional hazards models were used to estimate the hazard ratio (HR) of reaching endpoint according to quintiles of baseline serum urate, adjusting for gender, age and other potential covariates. Change in striatal uptake of [123I]β-CIT, a marker for the presynaptic dopamine transporter, was assessed with linear regression for a subset of 399 subjects. Results The adjusted HR of reaching endpoint declined with increasing baseline concentrations of urate; subjects in the top quintile reached the endpoint at only half the rate of subjects in the bottom quintile (HR=0.51; 95% CI: 0.37 to 0.72; p=0.0002). This association was markedly stronger in men (HR=0.39; 95% CI: 0.26 to 0.60; pdisease modifying therapy in PD. PMID:18413464

  4. 466 Bee venom Immunotherapy with Standardized Extract, Two Case Comunication and Clinical Progress

    Science.gov (United States)

    Cardona, Aristoteles Alvarez; Nieto, Leticia Hernandez; Melendez, Alvaro Pedroza

    2012-01-01

    Background Bee venom immunotherapy is a safe and effective treatment, indicated in patients with previous history of severe systemic reactions to bee venom, demonstrating succesful desensitization in more than 90% of cases with standardized extract. Currently in Mexico there is no standardized extract commercially available for treatment, despite of having high activity of beekeeping and occupational exposure with at least 17,478 registered stings per year and an annually honey production of nearly 70 tons. Methods We present the clinical progress of 2 patients with history of severe systemic reactions to bee venom and occupational exposure, both with demonstrated sensitization by specific IgE and who underwent specific immunotherapy with standardized extract (Alk-US) reaching a maintenance weekly dose of 100 mcg (PLA2) for the last 4 years. Results Both patients sufered of accidental stings after reached the maintenance dose presenting mild local reactions to stings. Both patients had very different clinical course presenting a wide variety of adverse reactions during desensitization protocol; from mild local to generalized reactions all generally well tolerated allowed to reach the maintenance dose with succesful desensitization proved by accidental exposure without severe systemic reactions. Conclusions Bee venom specific immunotherapy with standardized extract is a well tolerated and efective treatment preventing the development of life threathening reactions in sensitized patients. It is important to promote the use and availability of standardized extract in developing countries with poor safety measures and high occupational exposure.

  5. Bio-electrospraying and cell electrospinning: progress and opportunities for basic biology and clinical sciences.

    Science.gov (United States)

    Poncelet, Denis; de Vos, Paul; Suter, Nicolai; Jayasinghe, Suwan N

    2012-01-11

    Engineering of functional tissues is a fascinating and fertile arena of research and development. This flourishing enterprise weaves together many areas of research to tackle the most complex question faced to date, namely how to design and reconstruct a synthetic three-dimensional fully functional tissue on demand. At present our healthcare is under threat by several social and economical issues together with those of a more scientific and clinical nature. One such issue arises from our increasing life expectancy, resulting in an ageing society. This steeply growing ageing society requires functional organotypic tissues on demand for repair, replacement, and rejuvenation (R(3) ). Several approaches are pioneered and developed to assist conventional tissue/organ transplantation. In this Progress Report, "non-contact jet-based" approaches for engineering functional tissues are introduced and bio-electrosprays and cell electrospinning, i.e., biotechniques that have demonstrated as being benign for directly handling living cells and whole organisms, are highlighted. These biotechniques possess the ability to directly handle heterogeneous cell populations as suspensions with a biopolymer and/or other micro/nanomaterials for directly forming three-dimensional functional living reconstructs. These discoveries and developments have provided a promising biotechnology platform with far-reaching ramifications for a wide range of applications in basic biological laboratories to their utility in the clinic.

  6. Mitigating preventable chronic disease: Progress report of the Cleveland Clinic's Lifestyle 180 program

    Directory of Open Access Journals (Sweden)

    Ricanati Elizabeth HW

    2011-11-01

    Full Text Available Abstract Background Poor lifestyle choices are key in development and progression of preventable chronic diseases. The purpose of the study was to design and test a program to mitigate the physical and fiscal consequences of chronic diseases. Methods Here we report the outcomes for 429 participants with one or more chronic conditions, including obesity, hypertension, hyperlipidemia and diabetes mellitus, many of whom had failed traditional disease management programs, who enrolled into a comprehensive lifestyle intervention. The Lifestyle 180 program integrates nutrition, physical activity and stress management interventions and was conducted at the Wellness Institute of the Cleveland Clinic, United States. An intensive 6 week immersion course, with 8 hours of group instruction per week, was followed by 3 follow-up, 4 hour-long sessions over the course of 6 months. Results Changes in biometric (weight, height, waist circumference, resting heart rate and blood pressure and laboratory variables (fasting lipid panel, blood glucose, insulin, hemoglobin A1c, ultra sensitive C-reactive protein at 6 months were compared with baseline (pre-post analysis. At week 30, biometric and laboratory data were available for 244 (57% and 299 (70% participants, respectively. These had a mean ± SD reduction in weight (6.8 ± 6.9 kg, P Conclusion Implementation of a comprehensive lifestyle modification program among adults with common chronic conditions results in significant and clinically meaningful improvements in biometric and laboratory outcomes after 6 months.

  7. The hypocretin/orexin system in sleep disorders: preclinical insights and clinical progress

    Directory of Open Access Journals (Sweden)

    Chow M

    2016-03-01

    Full Text Available Matthew Chow, Michelle CaoDepartment of Psychiatry and Behavioral Sciences, Division of Sleep Medicine, Stanford University School of Medicine, Stanford, CA, USAAbstract: Much of the understanding of the hypocretin/orexin (HCRT/OX system in sleep–wake regulation came from narcolepsy–cataplexy research. The neuropeptides hypocretin-1 and -2/orexin-A and -B (HCRT-1 and -2/OX-A and -B, respectively, as we know, are intimately involved in the regulation wakefulness. The HCRT/OX system regulates sleep–wake control through complex interactions between monoaminergic/cholinergic (wake-promoting and gamma-aminobutyric acid-ergic (sleep-promoting neuronal systems. Deficiency of HCRT/OX results in loss of sleep–wake control or stability with consequent unstable transitions between wakefulness to nonrapid eye movement and rapid eye movement sleep. This manifests clinically as abnormal daytime sleepiness with sleep attacks and cataplexy. Research on the development of HCRT/OX agonists and antagonists for the treatment of sleep disorders has dramatically increased with the US Food and Drug Administration approval of the first-in-class dual HCRT/OX receptor antagonist for the treatment of insomnia. This review focuses on the origin, mechanisms of HCRT/OX receptors, clinical progress, and applications for the treatment of sleep disorders.Keywords: hypocretin, orexin, narcolepsy, insomnia, orexin antagonist, orexin agonist

  8. Therapeutic targeting of replicative immortality

    OpenAIRE

    Yaswen, Paul; MacKenzie, Karen L.; Keith, W. Nicol; Hentosh, Patricia; Rodier, Francis; Zhu, Jiyue; Firestone, Gary L.; Matheu, Ander; Carnero, Amancio; Bilsland, Alan; Sundin, Tabetha; Honoki, Kanya; Fujii, Hiromasa; Georgakilas, Alexandros G.; Amedei, Amedeo

    2015-01-01

    One of the hallmarks of malignant cell populations is the ability to undergo continuous proliferation. This property allows clonal lineages to acquire sequential aberrations that can fuel increasingly autonomous growth, invasiveness, and therapeutic resistance. Innate cellular mechanisms have evolved to regulate replicative potential as a hedge against malignant progression. When activated in the absence of normal terminal differentiation cues, these mechanisms can result in a state of persis...

  9. 异种移植的研究进展%Research progress of clinical xenotransplantation

    Institute of Scientific and Technical Information of China (English)

    张锦鑫; 李霄; 李俊杰

    2012-01-01

    供体器官和细胞的匮乏限制了临床同种移植的发展.开展以猪为供体的异种移植研究是缓解供体短缺的重要方法.目前,猪的胰岛细胞、神经元细胞、肝细胞和角膜移植已初步应用于临床,但实体器官移植,如心脏、肝脏、肾脏等仍存在较大的免疫障碍和生理屏障,距离临床应用尚有不小的差距.随着表达一种或多种人的免疫和凝血调节基因猪的出现,异种移植研究取得显著进展,受体和移植器官的存活时间明显延长,而种间交叉感染的风险也较低,但免疫排斥和生理屏障仍是阻碍异种移植进入临床应用的最大障碍.本文就当前异种移植临床前研究的最新进展作一综述,希望能为相关研究者提供一些参考.%The shortage of organs and cells from the donors continues to restrict allotransplantation.To carry out the xenotransplantation of pig as the donor is a very important method to alleviate the problem.At present,the organs of pigs (such as islet cells,neurons,liver ceils and cornea) have been initially used in clinical practice.However,significant barriers to be overcome before pig organ xenotransplantation can become a clinical therapy because of the immune and physiological disorders.With pigs that express one or more human thromboregulatory or anti-inflammatory genes being developed,the research of the xenotransplantation has made significant progress,the survival time is logner,at the same time,risk of cross-infection between species is smaller.However,immune rejection and physiological obstacles still prevent organ xenotransplantation from clinical application.This review will draw attention to the latest progress of the xenotransplantation,and provide some references for researchers.

  10. Clinical speech impairment in Parkinson′s disease, progressive supranuclear palsy, and multiple system atrophy

    Directory of Open Access Journals (Sweden)

    Sachin S

    2008-01-01

    Full Text Available Context: Speech abnormalities are common to the three Parkinsonian syndromes, namely Parkinson′s disease (PD, progressive supranuclear palsy (PSP and multiple system atrophy (MSA, the nature and severity of which is of clinical interest and diagnostic value. Aim: To evaluate the clinical pattern of speech impairment in patients with PD, PSP and MSA and to identify significant differences on quantitative speech parameters when compared to controls. Design and Setting: Cross-sectional study conducted in a tertiary medical teaching institute. Materials and Methods: Twenty-two patients with PD, 18 patients with PSP and 20 patients with MSA and 10 age-matched healthy controls were recruited over a period of 1.5 years. The patients were clinically evaluated for the presence and characteristics of dysarthria. This was followed by quantitative assessment of three parameters: maximum phonation time (MPT, semantic fluency and reading speed. The outcome measures were compared between the patient groups and with controls. Results: Patients with PD had hypophonic monotonous speech with occasional rushes of speech while patients with MSA and PSP had mixed dysarthria with ataxic and spastic elements respectively. All quantitative parameters were affected when compared to controls ( P values < 0.001, 0.012 and 0.008 respectively. Maximum phonation time was significantly less in PSP when compared to MSA and PD ( P =0.015. Reading speed also showed a similar trend which was not statistically significant. Semantic fluency was comparable in all three groups. Conclusion: Dysarthria in PD, PSP and MSA have many overlapping but certain distinctive features as well which could serve as a diagnostic clue. Patients with PSP had profound speech impairment probably indicative of the more severe frontostriatial pathology.

  11. Transepithelial corneal collagen crosslinking for progressive keratoconus: 24-month clinical results.

    Science.gov (United States)

    Caporossi, Aldo; Mazzotta, Cosimo; Paradiso, Anna Lucia; Baiocchi, Stefano; Marigliani, Davide; Caporossi, Tomaso

    2013-08-01

    To assess the clinical results of transepithelial collagen crosslinking (CXL) in patients 26 years and younger with progressive keratoconus suitable for epithelium-off (epi-off) CXL. Department of Ophthalmology, Siena University Hospital, Siena, Italy. Prospective case series. The study included 26 eyes (26 patients) treated by transepithelial (epithelium-on) CXL. The mean age was 22 years (range 11 to 26 years) (10 younger than 18 years; 16 between 19 years and 26 years). Preoperative and postoperative examinations included uncorrected (UDVA) and corrected (CDVA) distance visual acuities, simulated maximum keratometry (K), coma and spherical aberration, and corneal optical coherence tomography optical pachymetry. The solution for transepithelial CXL (Ricrolin TE) comprised riboflavin 0.1%, dextran 15.0%, trometamol (Tris), and ethylenediaminetetraacetic acid. Ultraviolet-A treatment was performed with the Caporossi Baiocchi Mazzotta X Linker Vega at 3 mW/cm(2). After relative improvement in the first 3 to 6 months, the UDVA and CDVA gradually returned to baseline preoperative values. After 12 months of stability, the simulated maximum K value worsened at 24 months. Coma aberration showed no statistically significant change. Spherical aberration increased at 24 months. Pachymetry showed a progressive, statistically significant decrease at 24 months. Fifty percent of pediatric patients were retreated with epi-off CXL due to significant deterioration of all parameters after 12 months of follow-up. Functional results after transepithelial CXL showed keratoconus instability, in particular in pediatric patients 18 years old and younger; there was also functional regression in patients between 19 years and 26 years old after 24 months of follow-up. mentioned. Copyright © 2013 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.

  12. Weight change, obesity and risk of prostate cancer progression among men with clinically localized prostate cancer.

    Science.gov (United States)

    Dickerman, Barbra A; Ahearn, Thomas U; Giovannucci, Edward; Stampfer, Meir J; Nguyen, Paul L; Mucci, Lorelei A; Wilson, Kathryn M

    2017-09-01

    Obesity is associated with an increased risk of fatal prostate cancer. We aimed to elucidate the importance and relevant timing of obesity and weight change for prostate cancer progression. We identified 5,158 men diagnosed with localized prostate cancer (clinical stage T1/T2) from 1986 to 2012 in the Health Professionals Follow-up Study. Men were followed for biochemical recurrence and lethal prostate cancer (development of distant metastasis or prostate cancer-specific mortality) until 2012. Cox regression estimated hazard ratios (HRs) for body mass index (BMI) at age 21, BMI at diagnosis, "long-term" weight change from age 21 to diagnosis and "short-term" weight change over spans of 4 and 8 years preceding diagnosis. Because weight, weight change and mortality are strongly associated with smoking, we repeated analyses among never smokers only (N = 2,559). Among all patients, neither weight change nor BMI (at age 21 or at diagnosis) was associated with lethal prostate cancer. Among never smokers, long-term weight gain was associated with an increased risk of lethal disease (HR for gaining >30 pounds vs. stable weight [±10 pounds] 1.59, 95% CI, 1.01-2.50, p-trend = 0.06). Associations between weight change, BMI and lethal prostate cancer were stronger for men with BMI ≥ 25 at age 21 compared to those with BMI obesity were not associated with an increased risk of biochemical recurrence. Our findings among never smoker men diagnosed with localized prostate cancer suggest a positive association between long-term weight gain and risk of lethal prostate cancer. Metabolic changes associated with weight gain may promote prostate cancer progression. © 2017 UICC.

  13. Non-HDL Cholesterol and Triglycerides: Implications for Coronary Atheroma Progression and Clinical Events.

    Science.gov (United States)

    Puri, Rishi; Nissen, Steven E; Shao, Mingyuan; Elshazly, Mohamed B; Kataoka, Yu; Kapadia, Samir R; Tuzcu, E Murat; Nicholls, Stephen J

    2016-11-01

    Non-high-density lipoprotein cholesterol (non-HDLC) levels reflect the full burden of cholesterol transported in atherogenic lipoproteins. Genetic studies suggest a causal association between elevated triglycerides (TGs)-rich lipoproteins and atherosclerosis. We evaluated associations between achieved non-HDLC and TG levels on changes in coronary atheroma volume. Data were analyzed from 9 clinical trials involving 4957 patients with coronary disease undergoing serial intravascular ultrasonography to assess changes in percent atheroma volume (ΔPAV) and were evaluated against on-treatment non-HDLC and TG levels. The effects of lower (cholesterol (LDLC) 0) was associated with achieved TG levels >200 mg/dL, respectively. Lower on-treatment non-HDLC and TG levels associated with significant PAV regression compared with higher non-HDLC and TG levels across all levels of LDLC and C-reactive protein and irrespective of diabetic status (P<0.001 across all comparisons). ΔPAV were more strongly influenced by changes in non-HDLC (β=0.62; P<0.001) compared with changes in LDLC (β=0.51; P<0.001). Kaplan-Meier sensitivity analyses demonstrated significantly greater major adverse cardiovascular event rates in those with higher versus lower non-HDLC and TG levels, with an earlier separation of the non-HDLC compared with the LDLC curve. Achieved non-HDLC levels seem more closely associated with coronary atheroma progression than LDLC. Plaque progression associates with achieved TGs, but only above levels of 200 mg/dL. These observations support a more prominent role for non-HDLC (and possibly TG) lowering in combating residual cardiovascular risk. © 2016 American Heart Association, Inc.

  14. Plasma HIV-1 tropism and risk of short-term clinical progression to AIDS or death

    Directory of Open Access Journals (Sweden)

    Maria Casadellà Fontdevila

    2014-11-01

    Full Text Available Introduction: It is uncertain if plasma HIV-1 tropism is an independent predictor of short-term risk of clinical progression / death, in addition to the CD4 count and HIV RNA level. We conducted a nested case-control study within EuroSIDA to assess this question amongst people with current HIV RNA level >1000 copies/mL, including both people on ART and those ART naïve. Methods: People with an AIDS diagnosis or who died from any causes for whom there was a stored plasma sample with HIV-1 RNA (VL≥1,000 copies/mL available in the time window of 3–12 months prior to the event were identified. At least one control was selected for each case matched for age, VL and HCV status at the time of sampling. Controls were event-free after a matched duration of time from the date of sampling. Plasma HIV tropism was estimated using 454 and population sequencing (PS. Non-R5 HIV was defined as: (a ≥2% of sequences with a Geno2Pheno (G2P FPR≤3.75% by 454, and (b a G2P FPR≤10% by PS. We also compared CD4 slopes over the 12 months following the date of sampling using a linear mixed model with random intercept according to HIV tropism and ART status. Results: The study included 266 subjects, 100 cases and 166 controls, with sample taken on average in 2006; 23% and 24% had non-R5 HIV by 454 and PS respectively. There were 19% women, 25% MSM, 92% Caucasians, 22% HCV+. At the time of sampling, 26% were ART-naïve, 25% had started but were off ART and 49% were receiving ART. The median age, CD4 and viral load was 41 years, 350 cells/mm3 and 4.81 log c/mL, respectively. Baseline characteristics were well balanced by tropism. Factors independently associated with clinical progression or death were female gender (OR=2.12; 95% CI=1.04, 4.36; p=0.038, CD4+ count (OR=0.90 per 100 cells/mm3 higher; 95% CI 0.80, 1.00; p=0.058, being on ART (OR=2.72; 95% CI 1.15, 6.41; p=0.022 and calendar year of sample (OR=0.84 per more recent year; 95% CI=0.77, 0.91; p<0

  15. Replication Restart in Bacteria.

    Science.gov (United States)

    Michel, Bénédicte; Sandler, Steven J

    2017-07-01

    In bacteria, replication forks assembled at a replication origin travel to the terminus, often a few megabases away. They may encounter obstacles that trigger replisome disassembly, rendering replication restart from abandoned forks crucial for cell viability. During the past 25 years, the genes that encode replication restart proteins have been identified and genetically characterized. In parallel, the enzymes were purified and analyzed in vitro, where they can catalyze replication initiation in a sequence-independent manner from fork-like DNA structures. This work also revealed a close link between replication and homologous recombination, as replication restart from recombination intermediates is an essential step of DNA double-strand break repair in bacteria and, conversely, arrested replication forks can be acted upon by recombination proteins and converted into various recombination substrates. In this review, we summarize this intense period of research that led to the characterization of the ubiquitous replication restart protein PriA and its partners, to the definition of several replication restart pathways in vivo, and to the description of tight links between replication and homologous recombination, responsible for the importance of replication restart in the maintenance of genome stability. Copyright © 2017 American Society for Microbiology.

  16. Regulation of chromosomal replication in Caulobacter crescentus.

    Science.gov (United States)

    Collier, Justine

    2012-03-01

    The alpha-proteobacterium Caulobacter crescentus is characterized by its asymmetric cell division, which gives rise to a replicating stalked cell and a non-replicating swarmer cell. Thus, the initiation of chromosomal replication is tightly regulated, temporally and spatially, to ensure that it is coordinated with cell differentiation and cell cycle progression. Waves of DnaA and CtrA activities control when and where the initiation of DNA replication will take place in C. crescentus cells. The conserved DnaA protein initiates chromosomal replication by directly binding to sites within the chromosomal origin (Cori), ensuring that DNA replication starts once and only once per cell cycle. The CtrA response regulator represses the initiation of DNA replication in swarmer cells and in the swarmer compartment of pre-divisional cells, probably by competing with DnaA for binding to Cori. CtrA and DnaA are controlled by multiple redundant regulatory pathways that include DNA methylation-dependent transcriptional regulation, temporally regulated proteolysis and the targeting of regulators to specific locations within the cell. Besides being critical regulators of chromosomal replication, CtrA and DnaA are also master transcriptional regulators that control the expression of many genes, thus connecting DNA replication with other events of the C. crescentus cell cycle. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. Pirfenidone in patients with rapidly progressive interstitial lung disease associated with clinically amyopathic dermatomyositis

    Science.gov (United States)

    Li, Ting; Guo, Li; Chen, Zhiwei; Gu, Liyang; Sun, Fangfang; Tan, Xiaoming; Chen, Sheng; Wang, Xiaodong; Ye, Shuang

    2016-09-01

    To evaluate the efficacy of pirfenidone in patients with rapidly progressive interstitial lung disease (RPILD) related to clinically amyopathic dermatomyositis (CADM), we conducted an open-label, prospective study with matched retrospective controls. Thirty patients diagnosed with CADM-RPILD with a disease duration pirfenidone at a target dose of 1800 mg/d in addition to conventional treatment, such as a glucocorticoid and/or other immunosuppressants. Matched patients without pirfenidone treatment (n = 27) were retrospectively selected as controls between October 2012 and September 2015. We found that the pirfenidone add-on group displayed a trend of lower mortality compared with the control group (36.7% vs 51.9%, p = 0.2226). Furthermore, the subgroup analysis indicated that the pirfenidone add-on had no impact on the survival of acute ILD patients (disease duration pirfenidone add-on (n = 10) had a significantly higher survival rate compared with the control subgroup (n = 9) (90% vs 44.4%, p = 0.0450). Our data indicated that the pirfenidone add-on may improve the prognosis of patients with subacute ILD related to CADM.

  18. Plasma HIV-1 tropism and risk of short-term clinical progression to AIDS or death

    DEFF Research Database (Denmark)

    Fontdevila, Maria Casadellà; Cozzi-Lepri, Alessandro; Phillips, Andrew;

    2014-01-01

    INTRODUCTION: It is uncertain if plasma HIV-1 tropism is an independent predictor of short-term risk of clinical progression / death, in addition to the CD4 count and HIV RNA level. We conducted a nested case-control study within EuroSIDA to assess this question amongst people with current HIV RNA...... level >1000 copies/mL, including both people on ART and those ART naïve. METHODS: People with an AIDS diagnosis or who died from any causes for whom there was a stored plasma sample with HIV-1 RNA (VL)≥1,000 copies/mL available in the time window of 3-12 months prior to the event were identified....... At least one control was selected for each case matched for age, VL and HCV status at the time of sampling. Controls were event-free after a matched duration of time from the date of sampling. Plasma HIV tropism was estimated using 454 and population sequencing (PS). Non-R5 HIV was defined as: (a) ≥2...

  19. Endothelial haemostatic factors are associated with progression of urinary albumin excretion in clinically healthy subjects

    DEFF Research Database (Denmark)

    Clausen, P; Feldt-Rasmussen, B; Jensen, G;

    1999-01-01

    ), whereas no changes in UAER were seen in subjects with vWF and tPA below the medians. Subjects with high tPA were also characterized by an excess of other cardiovascular risk factors at baseline. No significant differences in these risk factors were present between subjects with high or low vWF. High...... of endothelial dysfunction, predicts a subsequent increase of UAER in patients with diabetes. The aim of this study is to test the hypothesis that high concentrations of vWF as well as other haemostatic factors predict progression of UAER in clinically healthy subjects. UAER was measured together with selected...... markers of haemostatic function-vWF, tissue plasminogen activator (tPA), plasminogen activator inhibitor, factor VII and fibrinogen-in healthy volunteers aged 40-65 years. After a mean follow-up of 4.1 years, 64 of 74 agreed to a re-examination including re-measurement of UAER. Baseline vWF and tPA were...

  20. Role of Chronic Inflammation in Myopia Progression: Clinical Evidence and Experimental Validation

    Directory of Open Access Journals (Sweden)

    Hui-Ju Lin

    2016-08-01

    Full Text Available Prevention and treatment of myopia is an important public problem worldwide. We found a higher incidence of myopia among patients with inflammatory diseases such as type 1 diabetes mellitus (7.9%, uveitis (3.7%, or systemic lupus erythematosus (3.5% compared to those without inflammatory diseases (p < 0.001 using data from children (<18 years old in the National Health Insurance Research database. We then examined the inhibition of myopia by atropine in Syrian hamsters with monocular form deprivation (MFD, an experimental myopia model. We found atropine downregulated inflammation in MFD eyes. The expression levels of c-Fos, nuclear factor κB (NFκB, interleukin (IL-6, and tumor necrosis factor (TNF-α were upregulated in myopic eyes and downregulated upon treatment with atropine. The relationship between the inflammatory response and myopia was investigated by treating MFD hamsters with the immunosuppressive agent cyclosporine A (CSA or the inflammatory stimulators lipopolysaccharide (LPS or peptidoglycan (PGN. Myopia progression was slowed by CSA application but was enhanced by LPS and PGN administration. The levels of c-Fos, NF-κB, IL-6, and TNF-α were upregulated in LPS- and PGN-treated eyes and downregulated by CSA treatment. These findings provide clinical and experimental evidence that inflammation plays a crucial role in the development of myopia.

  1. Clinical value of MRI and acute madopar responsiveness test in diagnosing progressive supranuclear palsy

    Directory of Open Access Journals (Sweden)

    LI Xiao-hong

    2013-07-01

    Full Text Available Objective To investigate the MRI abnormalities and acute madopar responsiveness test in diagnosing progressive supranuclear palsy (PSP and Parkinson's disease (PD. Methods Seventeen patients with PSP and 17 gender and age matched patients with PD were studied with cranial MRI examinations and results of acute madopar responsiveness test, and the clinical manifestations of PSP were summarized. Results The atrophy of the midbrain tegmentum and hummingbird sign was demonstrated in all of the PSP patients in our study, but was not observed in the PD patients. The areas of the midbrain on mid-sagittal MRI in PSP patients [(77.35 ± 15.30 mm2] were significantly smaller than that in those with PD [(142.35 ± 31.49 mm2]. The average ratio of the area of the midbrain to the area of pons in the patients with PSP [(14.31 ± 2.47%] was significantly smaller than that in those with PD [(24.08 ± 4.73%; P = 0.000, for all]. According to the result of acute madopar responsiveness test, the maximum Unified Parkinson's Disease Rating Scale (UPDRS Ⅲ improvement rate of 2 patients with PSP and 16 patients with PD was more than 30% (χ2 = 23.142, P = 0.000. Conclusion The assessment of the mid-sagittal MRI and acute madopar responsiveness test may be a useful method to differentiate PSP from PD.

  2. A Novel Rrm3 Function in Restricting DNA Replication via an Orc5-Binding Domain Is Genetically Separable from Rrm3 Function as an ATPase/Helicase in Facilitating Fork Progression

    DEFF Research Database (Denmark)

    Syed, Salahuddin; Madsen, Claus Desler; Rasmussen, Lene J.;

    2016-01-01

    In response to replication stress cells activate the intra-S checkpoint, induce DNA repair pathways, increase nucleotide levels, and inhibit origin firing. Here, we report that Rrm3 associates with a subset of replication origins and controls DNA synthesis during replication stress. The N......-terminal domain required for control of DNA synthesis maps to residues 186–212 that are also critical for binding Orc5 of the origin recognition complex. Deletion of this domain is lethal to cells lacking the replication checkpoint mediator Mrc1 and leads to mutations upon exposure to the replication stressor......-dependent error-free DNA damage bypass act as independent mechanisms on DNA lesions that arise when Rrm3 catalytic activity is disrupted whereas these mechanisms are dispensable for DNA damage tolerance when the replication function is disrupted, indicating that the DNA lesions generated by the loss of each...

  3. Rapid progression of intracranial melanoma metastases controlled with combined BRAF/MEK inhibition after discontinuation of therapy: a clinical challenge.

    Science.gov (United States)

    N Cagney, Daniel; Alexander, Brian M; Hodi, F Stephen; Buchbinder, Elizabeth I; Ott, Patrick A; Aizer, Ayal A

    2016-09-01

    Novel systemic therapies with anti-tumor activity in the brain including small molecules targeting BRAF and MEK, and immune checkpoint inhibition, offer the possibility of improved control of intracranial disease. A number of prospective trials support the judicious use of modern systemic therapies in patients with melanoma and limited brain metastases .The intracranial clinical course of patients who progress extracranially on BRAF/MEK inhibition remains poorly described in the literature. In this report, we highlight a series of clinical cases, with rapid progression of intracranial disease following discontinuation of dabrafenib/trametinib for extracranial disease progression or toxicity, a previously unreported finding in the medical literature with significant implications for patient care.

  4. Clinical features and predictors for disease natural progression in adults with Pompe disease : a nationwide prospective observational study

    NARCIS (Netherlands)

    van der Beek, Nadine A. M. E.; de Vries, Juna M.; Hagemans, Marloes L. C.; Hop, Wim C. J.; Kroos, Marian A.; Wokke, John H. J.; de Visser, Marianne; van Engelen, Baziel G. M.; Kuks, Jan B. M.; van der Kooi, Anneke J.; Notermans, Nicolette C.; Faber, Karin G.; Verschuuren, Jan J. G. M.; Reuser, Arnold J. J.; van der Ploeg, Ans T.; van Doorn, Pieter A.

    2012-01-01

    Background: Due partly to physicians' unawareness, many adults with Pompe disease are diagnosed with great delay. Besides, it is not well known which factors influence the rate of disease progression, and thus disease outcome. We delineated the specific clinical features of Pompe disease in adults,

  5. Predicting Progression from Mild Cognitive Impairment to Alzheimer's Dementia Using Clinical, MRI, and Plasma Biomarkers via Probabilistic Pattern Classification.

    Directory of Open Access Journals (Sweden)

    Igor O Korolev

    Full Text Available Individuals with mild cognitive impairment (MCI have a substantially increased risk of developing dementia due to Alzheimer's disease (AD. In this study, we developed a multivariate prognostic model for predicting MCI-to-dementia progression at the individual patient level.Using baseline data from 259 MCI patients and a probabilistic, kernel-based pattern classification approach, we trained a classifier to distinguish between patients who progressed to AD-type dementia (n = 139 and those who did not (n = 120 during a three-year follow-up period. More than 750 variables across four data sources were considered as potential predictors of progression. These data sources included risk factors, cognitive and functional assessments, structural magnetic resonance imaging (MRI data, and plasma proteomic data. Predictive utility was assessed using a rigorous cross-validation framework.Cognitive and functional markers were most predictive of progression, while plasma proteomic markers had limited predictive utility. The best performing model incorporated a combination of cognitive/functional markers and morphometric MRI measures and predicted progression with 80% accuracy (83% sensitivity, 76% specificity, AUC = 0.87. Predictors of progression included scores on the Alzheimer's Disease Assessment Scale, Rey Auditory Verbal Learning Test, and Functional Activities Questionnaire, as well as volume/cortical thickness of three brain regions (left hippocampus, middle temporal gyrus, and inferior parietal cortex. Calibration analysis revealed that the model is capable of generating probabilistic predictions that reliably reflect the actual risk of progression. Finally, we found that the predictive accuracy of the model varied with patient demographic, genetic, and clinical characteristics and could be further improved by taking into account the confidence of the predictions.We developed an accurate prognostic model for predicting MCI-to-dementia progression

  6. Rescue from replication stress during mitosis.

    Science.gov (United States)

    Fragkos, Michalis; Naim, Valeria

    2017-04-03

    Genomic instability is a hallmark of cancer and a common feature of human disorders, characterized by growth defects, neurodegeneration, cancer predisposition, and aging. Recent evidence has shown that DNA replication stress is a major driver of genomic instability and tumorigenesis. Cells can undergo mitosis with under-replicated DNA or unresolved DNA structures, and specific pathways are dedicated to resolving these structures during mitosis, suggesting that mitotic rescue from replication stress (MRRS) is a key process influencing genome stability and cellular homeostasis. Deregulation of MRRS following oncogene activation or loss-of-function of caretaker genes may be the cause of chromosomal aberrations that promote cancer initiation and progression. In this review, we discuss the causes and consequences of replication stress, focusing on its persistence in mitosis as well as the mechanisms and factors involved in its resolution, and the potential impact of incomplete replication or aberrant MRRS on tumorigenesis, aging and disease.

  7. Tumor-selective replication herpes simplex virus-based technology significantly improves clinical detection and prognostication of viable circulating tumor cells

    DEFF Research Database (Denmark)

    Zhang, Wen; Bao, Li; Yang, Shaoxing

    2016-01-01

    Detection of circulating tumor cells remains a significant challenge due to their vast physical and biological heterogeneity. We developed a cell-surface-marker-independent technology based on telomerase-specific, replication-selective oncolytic herpes-simplex-virus-1 that targets telomerase...

  8. Monitoring progression of clinical reasoning skills during health sciences education using the case method - a qualitative observational study.

    Science.gov (United States)

    Orban, Kristina; Ekelin, Maria; Edgren, Gudrun; Sandgren, Olof; Hovbrandt, Pia; Persson, Eva K

    2017-09-11

    Outcome- or competency-based education is well established in medical and health sciences education. Curricula are based on courses where students develop their competences and assessment is also usually course-based. Clinical reasoning is an important competence, and the aim of this study was to monitor and describe students' progression in professional clinical reasoning skills during health sciences education using observations of group discussions following the case method. In this qualitative study students from three different health education programmes were observed while discussing clinical cases in a modified Harvard case method session. A rubric with four dimensions - problem-solving process, disciplinary knowledge, character of discussion and communication - was used as an observational tool to identify clinical reasoning. A deductive content analysis was performed. The results revealed the students' transition over time from reasoning based strictly on theoretical knowledge to reasoning ability characterized by clinical considerations and experiences. Students who were approaching the end of their education immediately identified the most important problem and then focused on this in their discussion. Practice knowledge increased over time, which was seen as progression in the use of professional language, concepts, terms and the use of prior clinical experience. The character of the discussion evolved from theoretical considerations early in the education to clinical reasoning in later years. Communication within the groups was supportive and conducted with a professional tone. Our observations revealed progression in several aspects of students' clinical reasoning skills on a group level in their discussions of clinical cases. We suggest that the case method can be a useful tool in assessing quality in health sciences education.

  9. Evaluation of Study and Patient Characteristics of Clinical Studies in Primary Progressive Multiple Sclerosis: A Systematic Review.

    Directory of Open Access Journals (Sweden)

    T Ziemssen

    Full Text Available So far, clinical studies in primary progressive MS (PPMS have failed to meet their primary efficacy endpoints. To some extent this might be attributable to the choice of assessments or to the selection of the study population.The aim of this study was to identify outcome influencing factors by analyzing the design and methods of previous randomized studies in PPMS patients without restriction to intervention or comparator.A systematic literature search was conducted in MEDLINE, EMBASE, BIOSIS and the COCHRANE Central Register of Controlled Trials (inception to February 2015. Keywords included PPMS, primary progressive multiple sclerosis and chronic progressive multiple sclerosis. Randomized, controlled trials of at least one year's duration were selected if they included only patients with PPMS or if they reported sufficient PPMS subgroup data. No restrictions with respect to intervention or comparator were applied. Study quality was assessed by a biometrics expert. Relevant baseline characteristics and outcomes were extracted and compared.Of 52 PPMS studies identified, four were selected. Inclusion criteria were notably different among studies with respect to both the definition of PPMS and the requirements for the presence of disability progression at enrolment. Differences between the study populations included the baseline lesion load, pretreatment status and disease duration. The rate of disease progression may also be an important factor, as all but one of the studies included a large proportion of patients with a low progression rate. In addition, the endpoints specified could not detect progression adequately.Optimal PPMS study methods involve appropriate patient selection, especially regarding the PPMS phenotype and progression rate. Functional composite endpoints might be more sensitive than single endpoints in capturing progression.

  10. Evaluation of Study and Patient Characteristics of Clinical Studies in Primary Progressive Multiple Sclerosis: A Systematic Review

    Science.gov (United States)

    Ziemssen, T.; Rauer, S.; Stadelmann, C.; Henze, T.; Koehler, J.; Penner, I.-K.; Lang, M.; Poehlau, D.; Baier-Ebert, M.; Schieb, H.; Meuth, S.

    2015-01-01

    Background So far, clinical studies in primary progressive MS (PPMS) have failed to meet their primary efficacy endpoints. To some extent this might be attributable to the choice of assessments or to the selection of the study population. Objective The aim of this study was to identify outcome influencing factors by analyzing the design and methods of previous randomized studies in PPMS patients without restriction to intervention or comparator. Methods A systematic literature search was conducted in MEDLINE, EMBASE, BIOSIS and the COCHRANE Central Register of Controlled Trials (inception to February 2015). Keywords included PPMS, primary progressive multiple sclerosis and chronic progressive multiple sclerosis. Randomized, controlled trials of at least one year’s duration were selected if they included only patients with PPMS or if they reported sufficient PPMS subgroup data. No restrictions with respect to intervention or comparator were applied. Study quality was assessed by a biometrics expert. Relevant baseline characteristics and outcomes were extracted and compared. Results Of 52 PPMS studies identified, four were selected. Inclusion criteria were notably different among studies with respect to both the definition of PPMS and the requirements for the presence of disability progression at enrolment. Differences between the study populations included the baseline lesion load, pretreatment status and disease duration. The rate of disease progression may also be an important factor, as all but one of the studies included a large proportion of patients with a low progression rate. In addition, the endpoints specified could not detect progression adequately. Conclusion Optimal PPMS study methods involve appropriate patient selection, especially regarding the PPMS phenotype and progression rate. Functional composite endpoints might be more sensitive than single endpoints in capturing progression. PMID:26393519

  11. Clinical value of nutritional status in neurodegenerative diseases: What is its impact and how it affects disease progression and management?

    Science.gov (United States)

    Tsagalioti, Eftyhia; Trifonos, Christina; Morari, Aggeliki; Vadikolias, Konstantinos; Giaginis, Constantinos

    2016-11-30

    Neurodegenerative diseases constitute a major problem of public health that is associated with an increased risk of mortality and poor quality of life. Malnutrition is considered as a major problem that worsens the prognosis of patients suffering from neurodegenerative diseases. In this aspect, the present review is aimed to critically collect and summarize all the available existing clinical data regarding the clinical impact of nutritional assessment in neurodegenerative diseases, highlighting on the crucial role of nutritional status in disease progression and management. According to the currently available clinical data, the nutritional status of patients seems to play a very important role in the development and progression of neurodegenerative diseases. A correct nutritional evaluation of neurodegenerative disease patients and a right nutrition intervention is essential in monitoring their disease.

  12. DNA replication and cancer

    DEFF Research Database (Denmark)

    Boyer, Anne-Sophie; Walter, David; Sørensen, Claus Storgaard

    2016-01-01

    A dividing cell has to duplicate its DNA precisely once during the cell cycle to preserve genome integrity avoiding the accumulation of genetic aberrations that promote diseases such as cancer. A large number of endogenous impacts can challenge DNA replication and cells harbor a battery of pathways...... causing DNA replication stress and genome instability. Further, we describe cellular and systemic responses to these insults with a focus on DNA replication restart pathways. Finally, we discuss the therapeutic potential of exploiting intrinsic replicative stress in cancer cells for targeted therapy....

  13. Subjective cognitive concerns and neuropsychiatric predictors of progression to the early clinical stages of Alzheimer’s disease

    Science.gov (United States)

    Donovan, Nancy J.; Amariglio, Rebecca E.; Zoller, Amy S.; Rudel, Rebecca K.; Gomez-Isla, Teresa; Blacker, Deborah; Hyman, Bradley T.; Locascio, Joseph J.; Johnson, Keith A.; Sperling, Reisa A.; Marshall, Gad A.; Rentz, Dorene M.

    2014-01-01

    Objectives To examine neuropsychiatric and neuropsychological predictors of progression from normal to early clinical stages of Alzheimer’s disease (AD). Design Longitudinal study Setting Massachusetts Alzheimer’s Disease Research Center longitudinal cohort Participants From a total sample of 559 older adults, 454 were included in the primary analysis: 283 with clinically normal cognition (CN), 115 with mild cognitive impairment (MCI) and 56 with subjective cognitive concerns (SCC) but no objective impairment, a proposed transitional group between CN and MCI. Measurements Two latent cognitive factors (Memory-Semantic, Attention-Executive) and two neuropsychiatric factors (Affective, Psychotic) were derived from the Alzheimer’s Disease Centers’ Uniform Data Set neuropsychological battery and Neuropsychiatric Inventory brief questionnaire. Factors were analyzed as predictors of time to progression to a worse diagnosis using a Cox proportional-hazards regression model with backward elimination. Covariates included baseline diagnosis, gender, age, education, prior depression, antidepressant medication, symptom duration, and interaction terms. Results Higher/better Memory-Semantic factor score predicted lower hazard of progression (HR=0.4 for one SD increase, p<0.0001), and higher/worse Affective factor score predicted higher hazard (HR=1.3 for one SD increase, p=0.01). No other predictors were significant in adjusted analyses. Using diagnosis as a sole predictor of transition to MCI, the SCC diagnosis carried a 4-fold risk of progression compared to CN (HR=4.1, p<0.0001). Conclusions These results identify affective and memory-semantic factors as significant predictors of more rapid progression from normal to early stages of cognitive decline and highlight the subgroup of cognitively normal elderly with SCC as those with elevated risk of progression to MCI. PMID:24698445

  14. A study of familial MELAS: Evaluation of A3243G mutation, clinical phenotype, and magnetic resonance spectroscopy-monitored progression

    Directory of Open Access Journals (Sweden)

    Chunnuan Chen

    2012-01-01

    Full Text Available The clinical manifestations of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS syndrome are nonspecific and can easily be misdiagnosed. Magnetic resonance spectroscopy (MRS-based detection of lactate in the brain has been found to be of diagnostic help in MELAS syndrome, however, the issue of whether MRS features vary by stage remains unresolved. We assessed the causative mutation and radiological features of a family of MELAS. Four of the family members harbored the A3243G mutation, probably of maternal inheritance. However, the clinical phenotypic expression was different in these patients. MRS showed a lactate peak, decreased N-acetylaspartate, choline, and creatine, which became more pronounced with progression of the disease, demonstrating that brain-MRS-based detection of lactate may be a suitable way to monitor the progression and treatment of MELAS.

  15. Relevance of Retinal Thickness Changes in the OCT Inner and Outer Rings to Predict Progression to Clinical Macular Edema

    DEFF Research Database (Denmark)

    Vujosevic, Stela; Varano, Monica; Egan, Catherine

    2015-01-01

    PURPOSE: To characterize the relevance of macular thickness changes in the inner and outer rings in the progression of macular edema in eyes/patients with diabetes type 2. METHODS: A total of 374 type 2 diabetic patients with mild nonproliferative diabetic retinopathy (ETDRS levels 20-35) were...... included in a 12-month prospective observational study to identify retinopathy progression. Retinal thickness analyses were performed in 194 eyes/patients using Cirrus SD- OCT and 166 eyes/patients using Spectralis SD-OCT. The DRCR.net classification of subclinical and clinical macular edema was used....... A composite grading of macular edema is proposed in this study. RESULTS: A total of 317 eyes/patients completed the study. SD-OCT identified clinical macular edema in 24 eyes/patients (6.7%) and subclinical macular edema in 104 eyes/patients (28.9%) at baseline. Increased thickness of the central subfield...

  16. An evaluation of molecular and clinical remission in rheumatoid arthritis by assessing radiographic progression

    OpenAIRE

    2013-01-01

    Objectives. To determine whether molecular remission defined by a multi-biomarker disease activity (MBDA) score predicts a reduced risk of joint damage progression, and whether the MBDA score can augment existing classifications of remission. Methods. The study examined 271 visits for 163 RA patients in the Leiden Early Arthritis Cohort. The MBDA score and other variables from each visit were evaluated for prediction of progression [change in Sharp–van der Heijde Score (ΔSHS) >3] over the ens...

  17. Myelopathy in systemic lupus erythematosus: clinical, laboratory, radiological and progression findings in a cohort of 1,193 patients

    OpenAIRE

    Beatriz Lavras Costallat; Daniel Miranda Ferreira; Lilian Tereza Lavras Costallat; Simone Appenzeller

    2016-01-01

    Abstract Objective To describe clinical, laboratory, radiological and progression characteristics of myelopathy in systemic lupus erythematosus (SLE). Patients and methods A retrospective analysis was performed on a cohort of 1193 patients with SLE (ACR criteria) in order to identify patients with myelopathy (neuropsychiatric ACR). Disease activity was assessed by the SLE activity index (SLEDAI) on the date of the event and functional capacity was assessed by the Expanded Disability Status ...

  18. Progress in Researches on the Pharmaceutical Mechanism and Clinical Application of Ginkgo Biloba Extract on Various Kinds of Diseases

    Institute of Scientific and Technical Information of China (English)

    WANG Guo-xia; CAO Fu-liang; CHEN Jun

    2006-01-01

    Progress made over the pharmaceutical mechanism and clinical application of Ginkgo BiIoba extract (GBE) on various kinds of diseases were reviewed in this paper. The effective elements contained in GBE are mainly kinds of Ginkgo flavonoid and Ginkgolide, which have marked protective effects on cardio-cerebral vascular and central nerve systems. In clinical practice, it is applied mostly in treatment of cardio-cerebral vascular diseases. Also it shows apparent effects in the treatment processes of some other diseases as an adjuvant, and therefore, has been gradually accepted by the medical circle in the world, proving to be a medicine of wide prospect in development and application.

  19. FTLD-TDP and progressive supranuclear palsy in comorbidity-a report of two cases with different clinical presentations.

    Science.gov (United States)

    Storey, Kateřina; Johanidesová, Silvie; Matěj, Radoslav; Keller, Jiří; Rohan, Zdeněk; Rusina, Robert

    2016-12-03

    Frontotemporal lobar degeneration with transactive response DNA-binding protein 43 (FTLD-TDP) and progressive supranuclear palsy (PSP) are distinct neurodegenerations with different clinical presentations. We report two cases with FTLD-TDP and PSP in comorbidity: a patient with amnestic dementia developing frontal lobe dementia, Parkinsonism and supranuclear gaze palsy and a patient with cerebellar ataxia and nystagmus developing akinesia, rigidity, and subcortical dementia. Neuropathological examination revealed neuronal and glial tau pathology together with ubiquitin, and phospho-TDP-43-immunoreactivities in the hippocampus, striatum, mesencephalon, and frontal and temporal cortices. Clinical and neuropathological correlations in atypical neurodegenerations are crucial to describe new entities of overlapping syndromes.

  20. [Research progress in mechanisms and clinical application for blonanserin and lurasidone in improving cognitive function of schizophrenia].

    Science.gov (United States)

    Zheng, Qi; Liu, Bangshan; Xu, Shuyin; Liao, Mei; Zhang, Yan; Li, Lingjiang

    2017-04-28

    Cognition deficit is one of the most common symptoms of schizophrenia, including abstract thinking and memory, and attention deficits. Previous studies have suggested that the improvement of cognition is very important for the recovery of disease and social function for the patients. Recent studies indicated that two new atypical antipsychotics, blonanserin and lurasidone, are expected to improve the cognitive impairment in patients with schizophrenia. This review introduces pathogenesis of cognitive impairment in schizophrenia, mechanisms of blonanserin and lurasidone in the improvement of cognitive impairment and progress in their clinical application for schizophrenia. We hope that this review could guide clinical use of antipsychotics and provide new directions for future studies.

  1. Amyloid-β deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression

    Science.gov (United States)

    Mormino, Elizabeth C.; Schultz, Aaron P.; Wigman, Sarah; Ward, Andrew M.; Larvie, Mykol; Amariglio, Rebecca E.; Marshall, Gad A.; Rentz, Dorene M.; Johnson, Keith A.; Sperling, Reisa A.

    2015-01-01

    Cross-sectional functional magnetic resonance imaging studies using a memory task in patients with mild cognitive impairment have produced discordant results, with some studies reporting increased hippocampal activity—consistent with findings in genetic at-risk populations—and other studies reporting decreased hippocampal activity, relative to normal controls. However, previous studies in mild cognitive impairment have not included markers of amyloid-β, which may be particularly important in prediction of progression along the Alzheimer’s disease continuum. Here, we examine the contribution of amyloid-β deposition to cross-sectional and longitudinal measures of hippocampal functional magnetic resonance imaging activity, hippocampal volume, global cognition and clinical progression over 36 months in 33 patients with mild cognitive impairment. Amyloid-β status was examined with positron emission tomography imaging using Pittsburg compound-B, hippocampal functional magnetic resonance imaging activity was assessed using an associative face-name memory encoding task, and hippocampal volume was quantified with structural magnetic resonance imaging. Finally global cognition was assessed using the Mini-Mental State Examination and clinical progression was assessed using the Clinical Dementia Rating (Sum of Boxes). At baseline, amyloid-β positive patients with mild cognitive impairment showed increased hippocampal activation, smaller hippocampal volumes, and a trend towards lower Mini-Mental State Examination scores and higher Clinical Dementia Ratings compared to amyloid-β negative patients with mild cognitive impairment. Longitudinally, amyloid-β positive patients with mild cognitive impairment continued to show high levels of hippocampal activity, despite increasing rates of hippocampal atrophy, decline on the Mini-Mental State Examination and faster progression on the Clinical Dementia Ratings. When entered simultaneously into the same linear mixed model

  2. Amyloid-β deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression.

    Science.gov (United States)

    Huijbers, Willem; Mormino, Elizabeth C; Schultz, Aaron P; Wigman, Sarah; Ward, Andrew M; Larvie, Mykol; Amariglio, Rebecca E; Marshall, Gad A; Rentz, Dorene M; Johnson, Keith A; Sperling, Reisa A

    2015-04-01

    Cross-sectional functional magnetic resonance imaging studies using a memory task in patients with mild cognitive impairment have produced discordant results, with some studies reporting increased hippocampal activity--consistent with findings in genetic at-risk populations--and other studies reporting decreased hippocampal activity, relative to normal controls. However, previous studies in mild cognitive impairment have not included markers of amyloid-β, which may be particularly important in prediction of progression along the Alzheimer's disease continuum. Here, we examine the contribution of amyloid-β deposition to cross-sectional and longitudinal measures of hippocampal functional magnetic resonance imaging activity, hippocampal volume, global cognition and clinical progression over 36 months in 33 patients with mild cognitive impairment. Amyloid-β status was examined with positron emission tomography imaging using Pittsburg compound-B, hippocampal functional magnetic resonance imaging activity was assessed using an associative face-name memory encoding task, and hippocampal volume was quantified with structural magnetic resonance imaging. Finally global cognition was assessed using the Mini-Mental State Examination and clinical progression was assessed using the Clinical Dementia Rating (Sum of Boxes). At baseline, amyloid-β positive patients with mild cognitive impairment showed increased hippocampal activation, smaller hippocampal volumes, and a trend towards lower Mini-Mental State Examination scores and higher Clinical Dementia Ratings compared to amyloid-β negative patients with mild cognitive impairment. Longitudinally, amyloid-β positive patients with mild cognitive impairment continued to show high levels of hippocampal activity, despite increasing rates of hippocampal atrophy, decline on the Mini-Mental State Examination and faster progression on the Clinical Dementia Ratings. When entered simultaneously into the same linear mixed model

  3. Analysis of midwifery students' written reflections to evaluate progression in learning during clinical practice at birthing units.

    Science.gov (United States)

    Persson, Eva K; Kvist, Linda J; Ekelin, Maria

    2015-03-01

    Written daily reflections during clinical practice on birthing units have been used during several years in midwifery education at Lund University, Sweden. However, the usefulness of these reflections for evaluation of progression in learning and professional development of students has to date not been evaluated. In order to analyse written reflections, two taxonomies developed by Bloom and Pettersen have been applied to the texts. Progression in the professional development of midwifery students can be seen through levels of complexity in cognitive and psycho-motor learning areas and also in the description of learning situations. Progression can be seen from a basic description of facts in simple situations at the beginning of the students' practice to a complex description of complicated situations towards the end of the practice. Written daily reflections appear to be a suitable method to help students to reflect in a structured way, thereby helping their professional development. Reflections can help clinical supervisors to understand the needs of the individual student and to support their knowledge accruement. Daily written reflections on clinical practice can be of use in other health education programs.

  4. Long-term outcome in BRAFV600E melanoma patients treated with vemurafenib: Patterns of disease progression and clinical management of limited progression

    Science.gov (United States)

    Puzanov, Igor; Amaravadi, Ravi K.; McArthur, Grant A.; Flaherty, Keith T.; Chapman, Paul B.; Sosman, Jeffrey A.; Ribas, Antoni; Shackleton, Mark; Hwu, Patrick; Chmielowski, Bartosz; Nolop, Keith B.; Lin, Paul S.; Kim, Kevin B.

    2016-01-01

    Introduction Vemurafenib induces tumour regression in most patients with BRAFV600E-mutant melanoma; eventually, most experience progressive disease (PD). Long-term follow-up of patients with BRAFV600E melanoma treated in the phase 1 vemurafenib trial is reported. Methods Patients received vemurafenib 240–1120 mg (dose escalation cohort) or 960 mg (extension cohort) orally twice daily. Clinical response was evaluated every 8 weeks by RECIST. Patients with PD amenable to local therapy (surgery or radiotherapy) were allowed to continue vemurafenib after progression. Overall survival (OS) from time of treatment initiation and from PD was estimated. Sites of PD were recorded. Results Forty-eight patients (escalation cohort, n = 16; extension cohort, n = 32) received therapeutic doses of vemurafenib (≥240 mg twice daily). Forty-three patients had PD by the time of this analysis, and 5 remained progression free (follow-up time, 1.2–56.1 months). Median OS was 14 months (range, 1.2–56.1); 3- and 4-year melanoma-specific survival rate in the extension cohort was 26% and 19%, respectively. Median OS was 26.0 months (range, 7.7–56.1) among 20 patients who continued vemurafenib after local therapy. Median treatment duration beyond initial PD was 3.8 months (range, 1.1–26.6). In the extension cohort, 6 and 5 patients were alive after 3 and 4 years, respectively, on vemurafenib monotherapy. Conclusions Some patients with melanoma achieved long-term survival with vemurafenib monotherapy. Continuation of vemurafenib after PD might be beneficial in some patients because remaining disease might continue to respond to BRAF inhibition. PMID:25980594

  5. Prevalence of Prostate Cancer Clinical States and Mortality in the United States: Estimates Using a Dynamic Progression Model.

    Directory of Open Access Journals (Sweden)

    Howard I Scher

    Full Text Available To identify patient populations most in need of treatment across the prostate cancer disease continuum, we developed a novel dynamic transition model based on risk of disease progression and mortality.We modeled the flow of patient populations through eight prostate cancer clinical states (PCCS that are characterized by the status of the primary tumor, presence of metastases, prior and current treatment, and testosterone levels. Simulations used published US incidence rates for each year from 1990. Progression and mortality rates were derived from published clinical trials, meta-analyses, and observational studies. Model outputs included the incidence, prevalence, and mortality for each PCCS. The impact of novel treatments was modeled in three distinct scenarios: metastatic castration-resistant prostate cancer (mCRPC, non-metastatic CRPC (nmCRPC, or both.The model estimated the prevalence of prostate cancer as 2,219,280 in the US in 2009 and 3,072,480 in 2020, and incidence of mCRPC as 36,100 and 42,970, respectively. All-cause mortality in prostate cancer was estimated at 168,290 in 2009 and 219,360 in 2020, with 20.5% and 19.5% of these deaths, respectively, occurring in men with mCRPC. The majority (86% of incidence flow into mCRPC states was from the nmCRPC clinical state. In the scenario with novel interventions for nmCRPC states, the progression to mCRPC is reduced, thus decreasing mCRPC incidence by 12% in 2020, with a sustained decline in mCRPC mortality. A limitation of the model is that it does not estimate prostate cancer-specific mortality.The model informs clinical trial design for prostate cancer by quantifying outcomes in PCCS, and demonstrates the impact of an effective therapy applied in an earlier clinical state of nmCRPC on the incidence of mCRPC morbidity and subsequent mortality.

  6. Achieving progress through clinical governance? A national study of health care managers' perceptions in the NHS in England

    Science.gov (United States)

    Freeman, T; Walshe, K

    2004-01-01

    Background: A national cross sectional study was undertaken to explore the perceptions concerning the importance of, and progress in, aspects of clinical governance among board level and directorate managers in English acute, ambulance, and mental health/learning disabilities (MH/LD) trusts. Participants: A stratified sample of acute, ambulance, and mental health/learning disabilities trusts in England (n = 100), from each of which up to 10 board level and 10 directorate level managers were randomly sampled. Methods: Fieldwork was undertaken between April and July 2002 using the Organisational Progress in Clinical Governance (OPCG) schedule to explore managers' perceptions of the importance of, and organisational achievement in, 54 clinical governance competency items in five aggregated domains: improving quality; managing risks; improving staff performance; corporate accountability; and leadership and collaboration. The difference between ratings of importance and achievement was termed a shortfall. Results: Of 1916 individuals surveyed, 1177 (61.4%) responded. The competency items considered most important and recording highest perceived achievement related to corporate accountability structures and clinical risks. The highest shortfalls between perceived importance and perceived achievement were reported in joint working across local health communities, feedback of performance data, and user involvement. When aggregated into domains, greatest achievement was perceived in the assurance related areas of corporate accountability and risk management, with considerably less perceived achievement and consequently higher shortfalls in quality improvement and leadership and collaboration. Directorate level managers' perceptions of achievement were found to be significantly lower than those of their board level colleagues on all domains other than improving performance. No differences were found in perceptions of achievement between different types of trusts, or between

  7. Control of chromosome replication in caulobacter crescentus.

    Science.gov (United States)

    Marczynski, Gregory T; Shapiro, Lucy

    2002-01-01

    Caulobacter crescentus permits detailed analysis of chromosome replication control during a developmental cell cycle. Its chromosome replication origin (Cori) may be prototypical of the large and diverse class of alpha-proteobacteria. Cori has features that both affiliate and distinguish it from the Escherichia coli chromosome replication origin. For example, requirements for DnaA protein and RNA transcription affiliate both origins. However, Cori is distinguished by several features, and especially by five binding sites for the CtrA response regulator protein. To selectively repress and limit chromosome replication, CtrA receives both protein degradation and protein phosphorylation signals. The signal mediators, proteases, response regulators, and kinases, as well as Cori DNA and the replisome, all show distinct patterns of temporal and spatial organization during cell cycle progression. Future studies should integrate our knowledge of biochemical activities at Cori with our emerging understanding of cytological dynamics in C. crescentus and other bacteria.

  8. Normal and mutant HTT interact to affect clinical severity and progression in Huntington disease

    DEFF Research Database (Denmark)

    Aziz, N A; Jurgens, C K; Landwehrmeyer, G B;

    2009-01-01

    OBJECTIVE: Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the HD gene (HTT). We aimed to assess whether interaction between CAG repeat sizes in the mutant and normal allele could affect disease severity and progression. METHODS: Using...... with less severe symptoms and pathology. CONCLUSIONS: Increasing CAG repeat size in normal HTT diminishes the association between mutant CAG repeat size and disease severity and progression in Huntington disease. The underlying mechanism may involve interaction of the polyglutamine domains of normal...

  9. Anatomic, Clinical, and Neuropsychological Correlates of Spelling Errors in Primary Progressive Aphasia

    Science.gov (United States)

    Shim, HyungSub; Hurley, Robert S.; Rogalski, Emily; Mesulam, M.-Marsel

    2012-01-01

    This study evaluates spelling errors in the three subtypes of primary progressive aphasia (PPA): agrammatic (PPA-G), logopenic (PPA-L), and semantic (PPA-S). Forty-one PPA patients and 36 age-matched healthy controls were administered a test of spelling. The total number of errors and types of errors in spelling to dictation of regular words,…

  10. Ramsay Hunt Syndrome : Clinical Characterization of Progressive Myoclonus Ataxia Caused by GOSR2 Mutation

    NARCIS (Netherlands)

    van Egmond, Martje E.; Verschuuren - Bemelmans, Cornelia; Nibbeling, Esther A.; Elting, Jan Willem J.; Sival, Deborah A.; Brouwer, Oebele F.; de Vries, Jeroen J.; Kremer, Hubertus P.; Sinke, Richard J.; Tijssen, Marina A.; de Koning, Tom J.

    2014-01-01

    BACKGROUND: Ramsay Hunt syndrome (progressive myoclonus ataxia) is a descriptive diagnosis characterized by myoclonus, ataxia, and infrequent seizures. Often the etiology cannot be determined. Recently, a mutation in the GOSR2 gene (c.430G>T, p.Gly144Trp) was reported in 6 patients with childhood-on

  11. Clinical evaluation of techniques used in the surgical treatment of progressive hemifacial atrophy

    NARCIS (Netherlands)

    R. Roddi (Roberto); E. Riggio (Egidio); P.M. Gilbert (Philip); S.E.R. Hovius (Steven); J. Michiel Vaandrager (J.); J.C.H.M. van der Meulen (Jacques)

    1994-01-01

    textabstractWe critically review 13 patients with progressive hemifacial atrophy treated with three basic surgical procedures (free flap transplantation, alloplastic implants, micro-fat injections ‘lipofilling’) and further ancillary techniques. In spite of the satisfactory results achieved with the

  12. Clinical marker for Alzheimer disease pathology in logopenic primary progressive aphasia

    NARCIS (Netherlands)

    Giannini, Lucia A. A.; Irwin, David J.; McMillan, Corey T.; Ash, Sharon; Rascovsky, Katya; Wolk, David A.; Van Deerlin, Vivianna M.; Lee, Edward B.; Trojanowski, John Q.; Grossman, Murray

    2017-01-01

    Objective: To determine whether logopenic features of phonologic loop dysfunction reflect Alzheimer disease (AD) neuropathology in primary progressive aphasia (PPA). Methods: We performed a retrospective case-control study of 34 patients with PPA with available autopsy tissue. We compared baseline a

  13. Anatomic, Clinical, and Neuropsychological Correlates of Spelling Errors in Primary Progressive Aphasia

    Science.gov (United States)

    Shim, HyungSub; Hurley, Robert S.; Rogalski, Emily; Mesulam, M.-Marsel

    2012-01-01

    This study evaluates spelling errors in the three subtypes of primary progressive aphasia (PPA): agrammatic (PPA-G), logopenic (PPA-L), and semantic (PPA-S). Forty-one PPA patients and 36 age-matched healthy controls were administered a test of spelling. The total number of errors and types of errors in spelling to dictation of regular words,…

  14. Clinical research progress of hemifacial spasm%面肌痉挛的临床研究进展

    Institute of Scientific and Technical Information of China (English)

    王芳; 马停停; 韩慧敏

    2016-01-01

    面肌痉挛又称面肌抽搐,是因一侧面神经异常兴奋弓起同侧面部肌肉出现阵发非自主无痛性,反复发作的强直或抽搐,该病发病机制尚无定论,其病程进展缓慢,呈渐进性发展。随着微血管减压术的推广及广泛应用,人们对面肌痉挛的发病机制有了更深的认识。本文针对面肌痉挛的临床诊断及内外科治疗的进展进行综述,有助于临床对面肌痉挛的规范诊疗。%Hemifacial Spasm,also called facial tic is one side facial muscular paroxysm non-spontaneous and non-pain recurrent rigidity or tic caused by abnormal excitement of the same side facial nerves.The pathogenesisof the disease is still unclear with slow symptoms progression and progressive development.With the widespread application of microvas-cular decompression,the pathogenesis of hemifacial spasm is more profoundly understood.In this article,a review is made about clinical diagnose and progress of medical and surgical treatment to improve the standardized clinical treatment of facial spasm.

  15. The analysis of the clinical and tool parameters characterizing a cardiomyopathyat various forms of the progressing muscular dystrophies

    Directory of Open Access Journals (Sweden)

    Poverennova I.E.

    2017-03-01

    Full Text Available Purpose: studying of clinical and tool characteristics of cardiomyopathies at various forms of the progressing muscular dystrophies. Material and methods. There had been 103 patients with hereditary forms of the progressing muscular dystrophies examined, among which 35 persons were with Duchenne muscular dystrophy, 28 with an atrophic myo-tonia, and 40 with a limb girdle dystrophy is conducted. Assessment of clinical and tool features of cardiomyopathies at these types of the hereditary progressing muscular dystrophies had been carried out. Results. In the group of patients with diffusion damage of a myocardium in the form of dystrophic violations had been revealed. Existence of a negative tooth of T in some assignments and lengthenings of an interval of QT is noted. With a dystrophic myotonia violation of a warm rhythm occurred at patients by 87 times more often than in the group of comparison. Violation of a rhythm of heart in group of patients with a limb girdle dystrophy came to light 91 times more often in reference to the group of comparison. Conclusion. Violations in a cardiovascular system at Duchenne muscular dystrophy are preferentially diffusion changes in a myocardium. At a dystrophic myotonia and a limb girdle dystrophy cardial violations concern mainly excitability and the conductivity of heart which are the main reason of developing of this disease at these patients.

  16. HBV replication is significantly reduced by IL-6

    Directory of Open Access Journals (Sweden)

    Jeng King-Song

    2009-04-01

    Full Text Available Abstract Interleukin-6 (IL-6 is a pleiotropic cytokine with pivotal functions in the regulation of the biological responses of several target cells including hepatocytes. The level of serum IL-6 has been reported to be elevated in patients with chronic hepatitis B, cirrhosis and hepatocellular carcinoma and represents the best marker of HBV-related clinical progression as compared with several other cytokines. In this study, we found that IL-6 was able to effectively suppress hepatitis B virus (HBV replication and prevent the accumulation of HBV covalently closed circular DNA (cccDNA in a human hepatoma cell line. We also demonstrated that the suppression of HBV replication by IL-6 requires concurrently a moderate reduction of viral transcripts/core proteins and a marked decrease in viral genome-containing nucleocapsids. Studies on the stability of existing viral capsids suggest that the IL-6 effect on the reduction of genome-containing nucleocapsids is mediated through the prevention of the formation of genome-containing nucleocapsids, which is similar to the effect of interferons. However, IFN-α/β and IFN-γ did not participate in the IL-6-induced suppression of HBV replication. Taken together, our results will provide important information to better understand the role of IL-6 in the course of HBV infection.

  17. Progress of clinical research on therapeutic hepatitis B vaccines%治疗性乙型肝炎疫苗临床研究进展

    Institute of Scientific and Technical Information of China (English)

    叶琳

    2014-01-01

    Chronic hepatitis B caused by hepatitis B virus (HBV) infection is a severe global public health problem.Current anti-viral drugs are effective in suppressing HBV replication but fail to clear the virus in most cases.How to effectively and comprehensively stimulate patients' immune system and reconstruct immunity against HBV may be the key to eliminate chronic infection.Therapeutic HBV vaccine is promising to become a new strategy.A variety of therapeutic HBV vaccines are being developed,including protein,peptide,DNA,and autologous dendritic cell vaccines.The progress of clinical research on the vaccines and their combined application with anti-viral drugs is summarized in this review.%乙型肝炎病毒感染所致的慢性肝炎是严重的全球性公共卫生问题,目前使用的药物仅能抑制病毒复制,不能彻底清除病毒.如何有效、全面地激发患者的免疫系统,重建对乙型肝炎病毒的免疫力,可能是消除慢性感染的关键.治疗性乙型肝炎疫苗有望成为新的治疗策略.目前,国内外研究的治疗性乙型肝炎疫苗主要包括蛋白疫苗、多肽疫苗、DNA疫苗和自体树突状细胞疫苗,此文对疫苗的临床试验进展及其与抗病毒药物联合应用研究进行综述.

  18. The Replication Recipe: What makes for a convincing replication?

    NARCIS (Netherlands)

    Brandt, M.J.; IJzerman, H.; Dijksterhuis, A.J.; Farach, F.J.; Geller, J.; Giner-Sorolla, R.; Grange, J.A.; Perugini, M.; Spies, J.R.; Veer, A. van 't

    2014-01-01

    Psychological scientists have recently started to reconsider the importance of close replications in building a cumulative knowledge base; however, there is no consensus about what constitutes a convincing close replication study. To facilitate convincing close replication attempts we have developed

  19. Dopamine Transporter Neuroimaging as an Enrichment Biomarker in Early Parkinson's Disease Clinical Trials: A Disease Progression Modeling Analysis.

    Science.gov (United States)

    Conrado, Daniela J; Nicholas, Timothy; Tsai, Kuenhi; Macha, Sreeraj; Sinha, Vikram; Stone, Julie; Corrigan, Brian; Bani, Massimo; Muglia, Pierandrea; Watson, Ian A; Kern, Volker D; Sheveleva, Elena; Marek, Kenneth; Stephenson, Diane T; Romero, Klaus

    2017-07-27

    Given the recognition that disease-modifying therapies should focus on earlier Parkinson's disease stages, trial enrollment based purely on clinical criteria poses significant challenges. The goal herein was to determine the utility of dopamine transporter neuroimaging as an enrichment biomarker in early motor Parkinson's disease clinical trials. Patient-level longitudinal data of 672 subjects with early-stage Parkinson's disease in the Parkinson's Progression Markers Initiative (PPMI) observational study and the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) clinical trial were utilized in a linear mixed-effects model analysis. The rate of worsening in the motor scores between subjects with or without a scan without evidence of dopamine transporter deficit was different both statistically and clinically. The average difference in the change from baseline of motor scores at 24 months between biomarker statuses was -3.16 (90% confidence interval [CI] = -0.96 to -5.42) points. Dopamine transporter imaging could identify subjects with a steeper worsening of the motor scores, allowing trial enrichment and 24% reduction of sample size. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  20. Modeling DNA Replication.

    Science.gov (United States)

    Bennett, Joan

    1998-01-01

    Recommends the use of a model of DNA made out of Velcro to help students visualize the steps of DNA replication. Includes a materials list, construction directions, and details of the demonstration using the model parts. (DDR)

  1. Eukaryotic DNA Replication Fork.

    Science.gov (United States)

    Burgers, Peter M J; Kunkel, Thomas A

    2017-06-20

    This review focuses on the biogenesis and composition of the eukaryotic DNA replication fork, with an emphasis on the enzymes that synthesize DNA and repair discontinuities on the lagging strand of the replication fork. Physical and genetic methodologies aimed at understanding these processes are discussed. The preponderance of evidence supports a model in which DNA polymerase ε (Pol ε) carries out the bulk of leading strand DNA synthesis at an undisturbed replication fork. DNA polymerases α and δ carry out the initiation of Okazaki fragment synthesis and its elongation and maturation, respectively. This review also discusses alternative proposals, including cellular processes during which alternative forks may be utilized, and new biochemical studies with purified proteins that are aimed at reconstituting leading and lagging strand DNA synthesis separately and as an integrated replication fork.

  2. Progressive skin extension: clinical and histological evaluation of a modified procedure using Kirschner wires.

    Science.gov (United States)

    Molea, G; Schonauer, F; Blasi, F

    1999-04-01

    We describe a modification of a skin traction system for progressive skin extension before excision of skin lesions. The traction device consists of Kirschner wires and plastic straps. It results in more homogeneous traction and greater sparing of healthy skin as compared with the earlier silicone bar method. Moreover, the procedure results in lower rates of infection, skin necrosis and breakage of the cutaneous bridges. Histological changes to the treated skin area are similar to those obtained with skin expansion procedures.

  3. Abiotic self-replication.

    Science.gov (United States)

    Meyer, Adam J; Ellefson, Jared W; Ellington, Andrew D

    2012-12-18

    The key to the origins of life is the replication of information. Linear polymers such as nucleic acids that both carry information and can be replicated are currently what we consider to be the basis of living systems. However, these two properties are not necessarily coupled. The ability to mutate in a discrete or quantized way, without frequent reversion, may be an additional requirement for Darwinian evolution, in which case the notion that Darwinian evolution defines life may be less of a tautology than previously thought. In this Account, we examine a variety of in vitro systems of increasing complexity, from simple chemical replicators up to complex systems based on in vitro transcription and translation. Comparing and contrasting these systems provides an interesting window onto the molecular origins of life. For nucleic acids, the story likely begins with simple chemical replication, perhaps of the form A + B → T, in which T serves as a template for the joining of A and B. Molecular variants capable of faster replication would come to dominate a population, and the development of cycles in which templates could foster one another's replication would have led to increasingly complex replicators and from thence to the initial genomes. The initial genomes may have been propagated by RNA replicases, ribozymes capable of joining oligonucleotides and eventually polymerizing mononucleotide substrates. As ribozymes were added to the genome to fill gaps in the chemistry necessary for replication, the backbone of a putative RNA world would have emerged. It is likely that such replicators would have been plagued by molecular parasites, which would have been passively replicated by the RNA world machinery without contributing to it. These molecular parasites would have been a major driver for the development of compartmentalization/cellularization, as more robust compartments could have outcompeted parasite-ridden compartments. The eventual outsourcing of metabolic

  4. Diet-induced mouse model of fatty liver disease and nonalcoholic steatohepatitis reflecting clinical disease progression and methods of assessment.

    Science.gov (United States)

    Clapper, Jason R; Hendricks, Michelle D; Gu, Guibao; Wittmer, Carrie; Dolman, Carrie S; Herich, John; Athanacio, Jennifer; Villescaz, Christiane; Ghosh, Soumitra S; Heilig, Joseph S; Lowe, Carolyn; Roth, Jonathan D

    2013-10-01

    Shortcomings of previously reported preclinical models of nonalcoholic steatohepatitis (NASH) include inadequate methods used to induce disease and assess liver pathology. We have developed a dietary model of NASH displaying features observed clinically and methods for objectively assessing disease progression. Mice fed a diet containing 40% fat (of which ∼18% was trans fat), 22% fructose, and 2% cholesterol developed three stages of nonalcoholic fatty liver disease (steatosis, steatohepatitis with fibrosis, and cirrhosis) as assessed by histological and biochemical methods. Using digital pathology to reconstruct the left lateral and right medial lobes of the liver, we made comparisons between and within lobes to determine the uniformity of collagen deposition, which in turn informed experimental sampling methods for histological, biochemical, and gene expression analyses. Gene expression analyses conducted with animals stratified by disease severity led to the identification of several genes for which expression highly correlated with the histological assessment of fibrosis. Importantly, we have established a biopsy method allowing assessment of disease progression. Mice subjected to liver biopsy recovered well from the procedure compared with sham-operated controls with no apparent effect on liver function. Tissue obtained by biopsy was sufficient for gene and protein expression analyses, providing the opportunity to establish an objective method of assessing liver pathology before subjecting animals to treatment. The improved assessment techniques and the observation that mice fed the high-fat diet exhibit many clinically relevant characteristics of NASH establish a preclinical model for identifying pharmacological interventions with greater likelihood of translating to the clinic.

  5. Effect of Four Approaches to Oral Feeding Progression on Clinical Outcomes in Preterm Infants

    Directory of Open Access Journals (Sweden)

    Rita H. Pickler

    2015-01-01

    Full Text Available Background. The purpose of this study of preterm infants was to test the effect of four approaches to the time of transition from gavage to full oral feedings, time to discharge, and weight gain during the transition. Methods. A randomized experimental design was used with four intervention groups: early start (32 weeks’ postmenstrual age/slow progressing experience (gradually increasing oral feedings offered per day; early start/maximum experience (oral feedings offered at every feeding opportunity; late start (34 weeks’ postmenstrual age/slow progressing experience; and late start/maximum experience. Results. The analysis included 86 preterm infants. Once oral feedings were initiated, infants in the late start/maximum experience group achieved full oral feeding and were discharged to home significantly sooner than infants in either early start group. Although not significantly different, these infants also achieved these outcomes sooner than infants in the late start/slow progressing experience group. There were no differences in weight gain across groups. Conclusions. Results suggest starting oral feedings later in preterm infants may result in more rapid transition to full oral feedings and discharge although not at early postnatal ages. Provision of a more consistent approach to oral feeding may support infant neurodevelopment and reduce length of hospitalization.

  6. Adenovirus DNA Replication

    OpenAIRE

    Hoeben, Rob C.; Uil, Taco G.

    2013-01-01

    Adenoviruses have attracted much attention as probes to study biological processes such as DNA replication, transcription, splicing, and cellular transformation. More recently these viruses have been used as gene-transfer vectors and oncolytic agents. On the other hand, adenoviruses are notorious pathogens in people with compromised immune functions. This article will briefly summarize the basic replication strategy of adenoviruses and the key proteins involved and will deal with the new deve...

  7. Correlation between molecular biomarkers and risk factors for the clinical progression of benign prostatic hyperplasia using tissue microarray immunostaining

    Institute of Scientific and Technical Information of China (English)

    Ma Ding; Yang Bing; Zhou Zhe; Pan Dongliang; Zhang Xianghua

    2014-01-01

    Background The pathogenesis of benign prostatic hyperplasia (BPH) has been widely studied,and several biomarkers are known to play roles in its development.This study aimed to investigate the possible role of cysteine-rich protein 61 (CYR61),vascular endothelial growth factor (VEGF),androgen receptor (AR),interleukin-6 (IL-6),cytochrome c,caspase-3,and proliferating cell nuclear antigen (PCNA) in the clinical progression of BPH.Methods Tissue specimens from 96 BPH cases who underwent transurethral resection of the prostate were processed and transferred to tissue microarrays.Patient age,prostate volume,serum prostate-specific antigen (PSA) level,and International Prostate Symptom Score (IPSS) of all BPH cases were collected before surgery.The expression of CYR61,VEGF,AR,IL-6,cytochrome c,caspase-3,and PCNA was examined by immunostaining in the BPH specimens,and any possible correlation between the different biomarkers and risk factors for BPH clinical progression was analyzed.Results The expression of CYR61,VEGF,AR,IL-6,cytochrome c,caspase-3,and PCNA in the BPH cases was 68.8% (66/96),77.1% (74/96),43.8% (42/96),31.3% (30/96),35.4% (34/96),56.3% (54/96),and 29.2% (28/96),respectively.The expression of both CYR61 and VEGF was positively correlated with patient age,prostate volume,and serum PSA level (P <0.05).Furthermore,cytochrome c and caspase-3 expression were inversely related to prostate volume (P <0.05),and AR expression was positively related to serum PSA level (P <0.05).Conclusion CYR61 and VEGF expression might serve as biomarkers for predicting the clinical progression of BPH due to effects on stromal cell proliferation and angiogenesis.

  8. Evidence for sequential and increasing activation of replication origins along replication timing gradients in the human genome.

    Science.gov (United States)

    Guilbaud, Guillaume; Rappailles, Aurélien; Baker, Antoine; Chen, Chun-Long; Arneodo, Alain; Goldar, Arach; d'Aubenton-Carafa, Yves; Thermes, Claude; Audit, Benjamin; Hyrien, Olivier

    2011-12-01

    Genome-wide replication timing studies have suggested that mammalian chromosomes consist of megabase-scale domains of coordinated origin firing separated by large originless transition regions. Here, we report a quantitative genome-wide analysis of DNA replication kinetics in several human cell types that contradicts this view. DNA combing in HeLa cells sorted into four temporal compartments of S phase shows that replication origins are spaced at 40 kb intervals and fire as small clusters whose synchrony increases during S phase and that replication fork velocity (mean 0.7 kb/min, maximum 2.0 kb/min) remains constant and narrowly distributed through S phase. However, multi-scale analysis of a genome-wide replication timing profile shows a broad distribution of replication timing gradients with practically no regions larger than 100 kb replicating at less than 2 kb/min. Therefore, HeLa cells lack large regions of unidirectional fork progression. Temporal transition regions are replicated by sequential activation of origins at a rate that increases during S phase and replication timing gradients are set by the delay and the spacing between successive origin firings rather than by the velocity of single forks. Activation of internal origins in a specific temporal transition region is directly demonstrated by DNA combing of the IGH locus in HeLa cells. Analysis of published origin maps in HeLa cells and published replication timing and DNA combing data in several other cell types corroborate these findings, with the interesting exception of embryonic stem cells where regions of unidirectional fork progression seem more abundant. These results can be explained if origins fire independently of each other but under the control of long-range chromatin structure, or if replication forks progressing from early origins stimulate initiation in nearby unreplicated DNA. These findings shed a new light on the replication timing program of mammalian genomes and provide a general

  9. Plasma HIV-1 Tropism and the Risk of Short-Term Clinical Progression to AIDS or Death

    DEFF Research Database (Denmark)

    Casadellà, Maria; Cozzi-Lepri, Alessandro; Phillips, Andrew

    2017-01-01

    -naïve. Baseline factors independently associated with clinical progression or death were female gender (OR = 2.13 vs. male, 95CI = 1.04, 4.36), p = 0.038), CD4+T-cell count (OR = 0.90 (95CI = 0.80, 1.00) per 100 cells/mm3 higher, p = 0.058), being on ART (OR = 2.72 vs. being off-ART (95CI = 1.15, 6.41), p = 0...

  10. Rationale and Design of the DIPAK 1 Study : A Randomized Controlled Clinical Trial Assessing the Efficacy of Lanreotide to Halt Disease Progression in Autosomal Dominant Polycystic Kidney Disease

    NARCIS (Netherlands)

    Meijer, Esther; Drenth, Joost P. H.; d'Agnolo, Hedwig; Casteleijn, Niek F.; de Fijter, Johan W.; Gevers, Tom J.; Kappert, Peter; Peters, Dorien J. M.; Salih, Mahdi; Soonawala, Darius; Spithoven, Edwin M.; Torres, Vicente E.; Visser, Folkert W.; Wetzels, Jack F. M.; Zietse, Robert; Gansevoort, Ron T.

    Background: There are limited therapeutic options to slow the progression of autosomal dominant polycystic kidney disease (ADPKD). Recent clinical studies indicate that somatostatin analogues are promising for treating polycystic liver disease and potentially also for the kidney phenotype. We report

  11. Rationale and Design of the DIPAK 1 Study: A Randomized Controlled Clinical Trial Assessing the Efficacy of Lanreotide to Halt Disease Progression in Autosomal Dominant Polycystic Kidney Disease

    NARCIS (Netherlands)

    Meijer, E.; Drenth, J.P.H.; d'Agnolo, H.; Casteleijn, N.F.; Fijter, J.W. de; Gevers, T.J.G.; Kappert, P.; Peters, D.J.; Salih, M.; Soonawala, D.; Spithoven, E.M.; Torres, V.E.; Visser, F.W.; Wetzels, J.F.M.; Zietse, R.; Gansevoort, R.T.

    2014-01-01

    BACKGROUND: There are limited therapeutic options to slow the progression of autosomal dominant polycystic kidney disease (ADPKD). Recent clinical studies indicate that somatostatin analogues are promising for treating polycystic liver disease and potentially also for the kidney phenotype. We report

  12. Rationale and design of the DIPAK 1 study: A randomized controlled clinical trial assessing the efficacy of lanreotide to halt disease progression in autosomal dominant polycystic kidney disease

    NARCIS (Netherlands)

    E. Meijer (Esther); J.P.H. Drenth (Joost); H. D'Agnolo (Hedwig); E. Casteleijn (Eric); J.W. de Fijter (Johan); T.J.G. Gevers (Tom); P. Kappert (Peter); D. Peters (Dorien); M. Salih (Mahdi); D. Soonawala (Darius); E.M. Spithoven (Edwin); V.E. Torres (Vicente); F.W. Visser (Folkert); J.F.M. Wetzels (Jack); R. Zietse (Bob); R.T. Gansevoort (Ron)

    2014-01-01

    textabstractBackground There are limited therapeutic options to slow the progression of autosomal dominant polycystic kidney disease (ADPKD). Recent clinical studies indicate that somatostatin analogues are promising for treating polycystic liver disease and potentially also for the kidney

  13. Minichromosome replication in vitro: inhibition of re-replication by replicatively assembled nucleosomes.

    Science.gov (United States)

    Krude, T; Knippers, R

    1994-08-19

    Single-stranded circular DNA, containing the SV40 origin sequence, was used as a template for complementary DNA strand synthesis in cytosolic extracts from HeLa cells. In the presence of the replication-dependent chromatin assembly factor CAF-1, defined numbers of nucleosomes were assembled during complementary DNA strand synthesis. These minichromosomes were then induced to semiconservatively replicate by the addition of the SV40 initiator protein T antigen (re-replication). The results indicate that re-replication of minichromosomes appears to be inhibited by two independent mechanisms. One acts at the initiation of minichromosome re-replication, and the other affects replicative chain elongation. To directly demonstrate the inhibitory effect of replicatively assembled nucleosomes, two types of minichromosomes were prepared: (i) post-replicative minichromosomes were assembled in a reaction coupled to replication as above; (ii) pre-replicative minichromosomes were assembled independently of replication on double-stranded DNA. Both types of minichromosomes were used as templates for DNA replication under identical conditions. Replicative fork movement was found to be impeded only on post-replicative minichromosome templates. In contrast, pre-replicative minichromosomes allowed one unconstrained replication cycle, but re-replication was inhibited due to a block in fork movement. Thus, replicatively assembled chromatin may have a profound influence on the re-replication of DNA.

  14. Targeting DNA Replication Stress for Cancer Therapy

    Science.gov (United States)

    Zhang, Jun; Dai, Qun; Park, Dongkyoo; Deng, Xingming

    2016-01-01

    The human cellular genome is under constant stress from extrinsic and intrinsic factors, which can lead to DNA damage and defective replication. In normal cells, DNA damage response (DDR) mediated by various checkpoints will either activate the DNA repair system or induce cellular apoptosis/senescence, therefore maintaining overall genomic integrity. Cancer cells, however, due to constitutive growth signaling and defective DDR, may exhibit “replication stress” —a phenomenon unique to cancer cells that is described as the perturbation of error-free DNA replication and slow-down of DNA synthesis. Although replication stress has been proven to induce genomic instability and tumorigenesis, recent studies have counterintuitively shown that enhancing replicative stress through further loosening of the remaining checkpoints in cancer cells to induce their catastrophic failure of proliferation may provide an alternative therapeutic approach. In this review, we discuss the rationale to enhance replicative stress in cancer cells, past approaches using traditional radiation and chemotherapy, and emerging approaches targeting the signaling cascades induced by DNA damage. We also summarize current clinical trials exploring these strategies and propose future research directions including the use of combination therapies, and the identification of potential new targets and biomarkers to track and predict treatment responses to targeting DNA replication stress. PMID:27548226

  15. Targeting DNA Replication Stress for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Jun Zhang

    2016-08-01

    Full Text Available The human cellular genome is under constant stress from extrinsic and intrinsic factors, which can lead to DNA damage and defective replication. In normal cells, DNA damage response (DDR mediated by various checkpoints will either activate the DNA repair system or induce cellular apoptosis/senescence, therefore maintaining overall genomic integrity. Cancer cells, however, due to constitutive growth signaling and defective DDR, may exhibit “replication stress” —a phenomenon unique to cancer cells that is described as the perturbation of error-free DNA replication and slow-down of DNA synthesis. Although replication stress has been proven to induce genomic instability and tumorigenesis, recent studies have counterintuitively shown that enhancing replicative stress through further loosening of the remaining checkpoints in cancer cells to induce their catastrophic failure of proliferation may provide an alternative therapeutic approach. In this review, we discuss the rationale to enhance replicative stress in cancer cells, past approaches using traditional radiation and chemotherapy, and emerging approaches targeting the signaling cascades induced by DNA damage. We also summarize current clinical trials exploring these strategies and propose future research directions including the use of combination therapies, and the identification of potential new targets and biomarkers to track and predict treatment responses to targeting DNA replication stress.

  16. 体感诱发电位临床新进展%Progress in clinical application of somatosensory evoked potential

    Institute of Scientific and Technical Information of China (English)

    彭超; 汤颖

    2013-01-01

    体感诱发电位广泛应用于临床,它在一定程度上反映了特异性躯体感觉传入通路、脑干网状结构及大脑皮层的机能状态,对于中枢系统诊断有不可替代的作用,总结了近几年诱发电位的新进展,进一步为临床服务。%Somatosensory evoked potentials are widely clinical application. It is to some extent reflects the specificity of somatosensory transmission pathways, brainstem reticular formation and of the cerebral cortex functional status. For the diagnosis of central nervous system have an irreplaceable role. Summed up in recent years, evoked potential new progress more clinical services.

  17. Weight as predictors of clinical progression and treatment failure: results from the TREAT Asia Pediatric HIV Observational Database.

    Science.gov (United States)

    Kariminia, Azar; Durier, Nicolas; Jourdain, Gonzague; Saghayam, Suneeta; Do, Chau V; Nguyen, Lam Van; Hansudewechakul, Rawiwan; Lumbiganon, Pagakrong; Chokephaibulkit, Kulkanya; Truong, Khanh Huu; Sirisanthana, Virat; Ung, Vibol; Vonthanak, Saphonn; Ananworanich, Jintanat; Nik Yusoff, Nik Khairulddin; Kurniati, Nia; Azahar Razali, Kamarul; Fong, Moy Siew; Nallusamy, Revathy; Wati, Dewi Kumara

    2014-09-01

    To evaluate the value of time-updated weight and height in predicting clinical progression, and immunological and virological failure in children receiving combination antiretroviral therapy (cART). We used Cox regression to analyze data of a cohort of Asian children. A total of 2608 children were included; median age at cART was 5.7 years. Time-updated weight for age z score < -3 was associated with mortality (P < 0.001) independent of CD4% and < -2 was associated with immunological failure (P ≤ 0.03) independent of age at cART. Weight monitoring provides useful data to inform clinical management of children on cART in resource-limited settings.

  18. Progressive Neuronal Degeneration of Childhood with Liver's Disease (Alpers' Disease) Clinical Features and Neuropathological Studies of 4 Sibling

    Institute of Scientific and Technical Information of China (English)

    Yupu Guo; Zhong Guo; Haowen Liu; Mingwe Wang; Hongwei Duan; Shufang Gao; Haitao Ren

    2000-01-01

    We report four siblings of a family with Alpers' disease. Three of four siblings occurred diarrhea and myoclonus at the ages of 7 to 8 years old. During the disease evolution, symptoms of subacute encephalopathy such as headache, visual disturbance, cortical blindness, progressive seizures and mental retardation were presented at the ages of 15 to 20 years old. Downhill progression led them to death in multiple organ failure within six to eight months of onset. CT showed hypodensity lesions in the bilateral oc cipital and temporal lobes. Spongiform changes, which characterized by diffuse neuronal degeneration or loss and astrocytosis, were most severe in the gray matter. White matter was slightly involved, while basal ganglia, pons, brain stem and cerebellum were not involved. Physical examination of the only live brother of the four siblings showed short status (165 cm), arched feet and improper nose-pointed test of the left side. Muscle biopsy of him showed a large amount of Red-Ragged (RR) fibers and abnormal mitochondria. Clinical features and pathological findings of autopsy in all the four siblings were consistent with progressive neuronal degeneration of childhood with liver disease (PNDC) - Alpers' disease. The muscle biopsy showed the characteristic findings of mitochondrial myopathy. Our report confirmed the classification of late onset Alpers' disease as a mitochondrial disorders.

  19. Recent progress in clinical application of vitamin D in renal transplantation

    Directory of Open Access Journals (Sweden)

    Shuai YUAN

    2014-03-01

    Full Text Available As an important steroid, vitamin D is synthesized mainly from 7-dehydrocholesterol in the skin. When it is carried to the liver and kidney sequentially, it is transformed to 1,25-dihydroxyvitamin D3[1,25-(OH2D3], which is the most active form of vitamin D. Kidney transplant recipients usually have low vitamin D levels, especially in the early post-transplantation period, possibly due to decreased sunlight exposure and intake of immunosuppressant. Traditionally, the recipients will receive vitamin D supplements to treat the osteoporosis or to maintain calcium and phosphorus homeostasis for a long time in the post-transplantation period. Along with the progress in the study of vitamin D receptors (VDR, extraskeletal effects of vitamin D have received more and more attention. VDR exists in many types of cells including activated T cells and tissues, and it is considered as a base of above-mentioned physiological effect of vitamin D. It also possesses potential effects in immune-modulation and anti-infection as well as regulation of bone metabolism. This paper reviews the recent research progress focusing on the effects of vitamin D in immunomodulatory and non-immunomodulatory aspects in order to provide reference for rational administration of vitamin D. DOI: 10.11855/j.issn.0577-7402.2014.03.17

  20. Association between clinical parameters and the presence of Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis in patients with progressive periodontal lesions

    Directory of Open Access Journals (Sweden)

    Rakić Mia

    2010-01-01

    Full Text Available Background/Aim. Periodontitis is a chronic inflammatory disease of periodontal tissues with consequential is bone loss as a result of host immunological reactions caused by periopathogens. The aim of the study was to investigate if there is a correlation between clinical parameters and the presence of two most aggressive periopathogens (Aggregatibacter actinomycetemcomitans - Aa and Porphyromonas gingivalis - Pg in patients with progressive periodontal lesions. Methods. A total of 34 systemic healthy people, 23 to 70 years old, were included in the study. The patients were clinically and radiologically examined, and after that, the representative pocket with greatest pocket depth was chosen and the sample was collected from that place. The measured clinic parameters were: gingival index, index of gingival bleeding, pocket depth and plaque indices. The multiplex Polymerase Chain Reaction (PCR method was used for detection of periopathogens. After obtaining results, appropriate statistical tests were used to correlate the clinical and microbiological results. Results. Aa and Pg were detected in the same percentage of samples. Aa and Pg were detected in 35.29% samples alone, and in 29.41% both were detected. The values of measured clinical parameters did not show a statistical significance between the groups. In analysis of correlations among clinical parameters inside the groups, a statistical significance was found only between gingival and plaque index in the group with Aa. Conclusion. Clinical course of periodontitis in the developed stage does not differ in relation to the presence of different periopathogens as the major inductors of immunologically guided destructive processes.

  1. Three-tiered risk stratification model to predict progression in Barrett's esophagus using epigenetic and clinical features.

    Directory of Open Access Journals (Sweden)

    Fumiaki Sato

    Full Text Available Barrett's esophagus predisposes to esophageal adenocarcinoma. However, the value of endoscopic surveillance in Barrett's esophagus has been debated because of the low incidence of esophageal adenocarcinoma in Barrett's esophagus. Moreover, high inter-observer and sampling-dependent variation in the histologic staging of dysplasia make clinical risk assessment problematic. In this study, we developed a 3-tiered risk stratification strategy, based on systematically selected epigenetic and clinical parameters, to improve Barrett's esophagus surveillance efficiency.We defined high-grade dysplasia as endpoint of progression, and Barrett's esophagus progressor patients as Barrett's esophagus patients with either no dysplasia or low-grade dysplasia who later developed high-grade dysplasia or esophageal adenocarcinoma. We analyzed 4 epigenetic and 3 clinical parameters in 118 Barrett's esophagus tissues obtained from 35 progressor and 27 non-progressor Barrett's esophagus patients from Baltimore Veterans Affairs Maryland Health Care Systems and Mayo Clinic. Based on 2-year and 4-year prediction models using linear discriminant analysis (area under the receiver-operator characteristic (ROC curve: 0.8386 and 0.7910, respectively, Barrett's esophagus specimens were stratified into high-risk (HR, intermediate-risk (IR, or low-risk (LR groups. This 3-tiered stratification method retained both the high specificity of the 2-year model and the high sensitivity of the 4-year model. Progression-free survivals differed significantly among the 3 risk groups, with p = 0.0022 (HR vs. IR and p<0.0001 (HR or IR vs. LR. Incremental value analyses demonstrated that the number of methylated genes contributed most influentially to prediction accuracy.This 3-tiered risk stratification strategy has the potential to exert a profound impact on Barrett's esophagus surveillance accuracy and efficiency.

  2. Blood and Marrow Transplant Clinical Trials Network: progress since the State of the Science Symposium 2007.

    Science.gov (United States)

    Ferrara, James L M

    2014-02-01

    Outcomes of hematopoietic cell transplantation continue to improve. New techniques have reduced transplant toxicities, and there are new sources of hematopoietic stem cells from related and unrelated donors. In June 2007, the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) convened a State of the Science Symposium (SOSS) in Ann Arbor and identified 11 high priority clinical trials for the network to pursue. This article reviews both the status of those trials and the record of achievement of the BMT CTN as it convenes another SOSS in Grapevine, Texas in February 2014.

  3. Progress on Clinical Study of Acupuncture Treatment for Chronic Pelvic Inflammation

    Institute of Scientific and Technical Information of China (English)

    ZHAO Wen-jie; HUANG Guo-qi

    2008-01-01

    @@ Chronic pelvic inflammation is mostly caused byincomplete treatment of acute pelvic inflammation orby transference from pathologic condition due to poorbody constitution, including chronic endometritis,chronic salpingo-oophoritis and chronic inflammationof connective tissue, and is a commonly andfrequently encountered disease in the gynecologydepartment. Due to long duration, intractablecondition and high recurrent rate, it is also acommonly encountered reason to induce heterotopicpregnancy, sterility, pelvic pain and pelvic adhesivediseases. In the investigative study on the domesticliterature about acupuncture treatment of chronicpelvic inflammation in the recent five years, theauthor hopes to summarize the information forreference in the clinical treatment and to point outsome issues existing in the current clinical study.

  4. Investigating variation in replicability: A "Many Labs" replication project

    NARCIS (Netherlands)

    Klein, R.A.; Ratliff, K.A.; Vianello, M.; Adams, R.B.; Bahnik, S.; Bernstein, M.J.; Bocian, K.; Brandt, M.J.; Brooks, B.; Brumbaugh, C.C.; Cemalcilar, Z.; Chandler, J.; Cheong, W.; Davis, W.E.; Devos, T.; Eisner, M.; Frankowska, N.; Furrow, D.; Galliani, E.M.; Hasselman, F.W.; Hicks, J.A.; Hovermale, J.F.; Hunt, S.J.; Huntsinger, J.R.; IJzerman, H.; John, M.S.; Joy-Gaba, J.A.; Kappes, H.B.; Krueger, L.E.; Kurtz, J.; Levitan, C.A.; Mallett, R.K.; Morris, W.L.; Nelson, A.J.; Nier, J.A.; Packard, G.; Pilati, R.; Rutchick, A.M.; Schmidt, K.; Skorinko, J.L.M.; Smith, R.; Steiner, T.G.; Storbeck, J.; Van Swol, L.M.; Thompson, D.; Veer, A.E. van 't; Vaughn, L.A.; Vranka, M.; Wichman, A.L.; Woodzicka, J.A.; Nosek, B.A.

    2014-01-01

    Although replication is a central tenet of science, direct replications are rare in psychology. This research tested variation in the replicability of 13 classic and contemporary effects across 36 independent samples totaling 6,344 participants. In the aggregate, 10 effects replicated consistently.

  5. Hepatitis B virus replication

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Hepadnaviruses, including human hepatitis B virus (HBV), replicate through reverse transcription of an RNA intermediate, the pregenomic RNA (pgRNA). Despite this kinship to retroviruses, there are fundamental differences beyond the fact that hepadnavirions contain DNA instead of RNA. Most peculiar is the initiation of reverse transcription: it occurs by protein-priming, is strictly committed to using an RNA hairpin on the pgRNA,ε, as template, and depends on cellular chaperones;moreover, proper replication can apparently occur only in the specialized environment of intact nucleocapsids.This complexity has hampered an in-depth mechanistic understanding. The recent successful reconstitution in the test tube of active replication initiation complexes from purified components, for duck HBV (DHBV),now allows for the analysis of the biochemistry of hepadnaviral replication at the molecular level. Here we review the current state of knowledge at all steps of the hepadnaviral genome replication cycle, with emphasis on new insights that turned up by the use of such cellfree systems. At this time, they can, unfortunately,not be complemented by three-dimensional structural information on the involved components. However, at least for the s RNA element such information is emerging,raising expectations that combining biophysics with biochemistry and genetics will soon provide a powerful integrated approach for solving the many outstanding questions. The ultimate, though most challenging goal,will be to visualize the hepadnaviral reverse transcriptase in the act of synthesizing DNA, which will also have strong implications for drug development.

  6. Annual Research Review: Progress in Using Brain Morphometry as a Clinical Tool for Diagnosing Psychiatric Disorders

    Science.gov (United States)

    Haubold, Alexander; Peterson, Bradley S.; Bansal, Ravi

    2012-01-01

    Brain morphometry in recent decades has increased our understanding of the neural bases of psychiatric disorders by localizing anatomical disturbances to specific nuclei and subnuclei of the brain. At least some of these disturbances precede the overt expression of clinical symptoms and possibly are endophenotypes that could be used to diagnose an…

  7. Clinical factors, anticitrullinated peptide antibodies and MRI-detected subclinical inflammation in relation to progression from clinically suspect arthralgia to arthritis.

    Science.gov (United States)

    van Steenbergen, Hanna W; Mangnus, Lukas; Reijnierse, Monique; Huizinga, Tom W J; van der Helm-van Mil, Annette H M

    2016-10-01

    Patients with clinically suspect arthralgia (CSA) have, according to their rheumatologists, an increased risk of rheumatoid arthritis (RA), but their actual outcome is unexplored. This longitudinal study investigated (1) progression from CSA to clinically detectable arthritis and (2) associations of clinical factors, serological factors (among which are anticitrullinated peptide antibodies (ACPAs)) and MRI-detected subclinical inflammation with arthritis development. 150 patients with CSA were followed for ≥6 months. At baseline, clinical and serological data were collected and unilateral 1.5 T-MRI of metacarpophalangeal (MCP), wrist and metatarsophalangeal (MTP) joints was made. MRI scoring was done according to the RA MRI scoring system. Subclinical MRI inflammation was defined based on MRI results of 193 symptom-free persons. During follow-up (median=75 weeks, IQR=41-106 weeks), 30 patients developed clinical arthritis; 87% did so <20 weeks after inclusion. In multivariable analyses, age, localisation of initial symptoms in small and large joints (compared with small joints only), C-reactive protein level, ACPA-positivity and subclinical MRI inflammation significantly associated with arthritis development; ACPA and MRI inflammation were most strongly associated (HR (95% CI) respectively, 6.43 (2.57 to 16.05) and 5.07 (1.77 to 14.50)). After 1-year follow-up, 31% of the patients with MRI inflammation and 71% of the ACPA-positive patients with MRI inflammation had progressed to arthritis. Forty-three per cent of the patients that developed arthritis within 1 year were ACPA-negative; 78% of them had subclinical MRI inflammation at baseline. When MRI inflammation was absent arthritis development was infrequent (6% in all patients with CSA and 3% in ACPA-negative patients with CSA). Subclinical MRI inflammation precedes clinical arthritis with a few months. Subclinical MRI inflammation is, independent of other factors such as ACPA, associated with

  8. Breastfeeding progression in preterm infants is influenced by factors in infants, mothers and clinical practice

    DEFF Research Database (Denmark)

    Maastrup, Ragnhild; Hansen, Bo Moelholm; Kronborg, Hanne;

    2014-01-01

    BACKGROUND AND AIM: Many preterm infants are not capable of exclusive breastfeeding from birth. To guide mothers in breastfeeding, it is important to know when preterm infants can initiate breastfeeding and progress. The aim was to analyse postmenstrual age (PMA) at breastfeeding milestones...... in different preterm gestational age (GA) groups, to describe rates of breastfeeding duration at pre-defined times, as well as analyse factors associated with PMA at the establishment of exclusive breastfeeding. METHODS: The study was part of a prospective survey of a national Danish cohort of preterm infants...... based on questionnaires and structured telephone interviews, including 1,221 mothers and their 1,488 preterm infants with GA of 24-36 weeks. RESULTS: Of the preterm infants, 99% initiated breastfeeding and 68% were discharged exclusively breastfed. Breastfeeding milestones were generally reached...

  9. Overview of gene therapy clinical progress including cancer treatment with gene-modified T cells.

    Science.gov (United States)

    Brenner, Malcolm K; Okur, Fatma V

    2009-01-01

    It is now twenty years since the first legal gene transfer studies were approved, and there has been considerable disappointment in the slow rate of progress that followed the initial studies. Gradually, however, as the limitations of available vectors are acknowledged and overcome, and with advances in our understanding of the molecular and cell biology of genetic diseases and of cancer, unequivocal successes are now being reported. In this paper we describe the remaining major roadblocks to successful gene therapy and outline approaches to overcome them. We also illustrate how genetically modified immune system cells are already being used for the effective treatment of hematological and other malignancies, and how these approaches are being modified so that they can be effective in treating a broader range of malignancies.

  10. Progress in the clinical development and utilization of vision prostheses: an update

    Directory of Open Access Journals (Sweden)

    Brandli A

    2016-05-01

    Full Text Available Alice Brandli, Chi D Luu, Robyn H Guymer, Lauren N Ayton Centre for Eye Research Australia, Department of Surgery (Ophthalmology, The University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, VIC, Australia Abstract: Vision prostheses, or “bionic eyes”, are implantable medical bionic devices with the potential to restore rudimentary sight to people with profound vision loss or blindness. In the past two decades, this field has rapidly progressed, and there are now two commercially available retinal prostheses in the US and Europe, and a number of next-generation devices in development. This review provides an update on the development of these devices and a discussion on the future directions for the field. Keywords: vision prostheses, bionic eye, vision restoration, blindness, medical bionics, retinitis pigmentosa

  11. A Randomized Clinical Trial of Cogmed Working Memory Training in School-Age Children with ADHD: A Replication in a Diverse Sample Using a Control Condition

    Science.gov (United States)

    Chacko, A.; Bedard, A. C.; Marks, D. J.; Feirsen, N.; Uderman, J. Z.; Chimiklis, A.; Rajwan, E.; Cornwell, M.; Anderson, L.; Zwilling, A.; Ramon, M.

    2014-01-01

    Background: Cogmed Working Memory Training (CWMT) has received considerable attention as a promising intervention for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children. At the same time, methodological weaknesses in previous clinical trials call into question reported efficacy of CWMT. In particular, lack of equivalence…

  12. Acute gouty arthritis and rapidly progressive renal failure as manifestation of multiple myeloma: clinical case description

    Directory of Open Access Journals (Sweden)

    O.V. Gudym

    2017-09-01

    Full Text Available The article describes a clinical case of multiple myeloma in 78-year-old man, its clinical onset was as an acute attack of gout. The patient was admitted to hospital due to the development of the first acute attack of gout. The attack was characterized by polyarthricular joint lesion of the upper and lower extremities, pronounced inflammatory reaction, insufficient response to the use of non-steroidal anti-inflammatory drugs, and a high level of hyperuricemia. The serum uric acid concentration ranged from 636 to 712 μmol/l. The study of the synovial fluid of the inflamed knee joint made it possible to reveal uric acid crystals and to confirm the diagnosis of acute gouty arthritis. Simultaneously, the patient had significant renal impairment: creatinine was 574 μmol/l, urea — 39.9 mmol/l, glomerular filtration rate according to CKD-EPI — 8 ml/min. The daily proteinuria was 1.8 g. A retrospective assessment of laboratory parameters allowed to reveal completely normal indicators of renal function 6 months ago. Considering the development of acute gouty arthritis, its polyarticular nature, persistent course, rapid involvement of new joints, high uric acid levels during an acute attack exceeding 600 μmol/l (10 mg/dL, rapid development of renal failure within 6 months until the terminal stage, it was suggested the secondary nature of gout on the background of kidney damage by another pathological process. Further clinical, laboratory and instrumental studies allowed verifying multiple myeloma with renal damage. Bence Jones protein in the urine was not detected, there was also no evidence of hyperproteinemia. However, pain in the spine, ribs and chest was the basis for carrying out an X-ray study of the bones of the skeleton. Changes in the skeleton typical for multiple myeloma have been identified. Myelogram showed a high content of plasma cells (21.1 %, electrophoresis of blood proteins showed a high M-gradient (30.42 %, and a cytochemical

  13. Department of Clinical Investigation Annual Research Progress Report, Fiscal Year 1984. Volume 1,

    Science.gov (United States)

    1984-10-01

    the Efficacy of Electroacutherapy in the 254 Treatment of Temporormandibular Joint Pain. (C) 9 C-49-83 The Effect of the Periodontal Ligament on...of Periodic Review Results Objective(s): To determine pathologic and clinical-pathologic criteria for the diagnosis of IGA nephropathy, the prognosis ...significance of hematuria, microscopic or macroscopic, as well as prognosis in patients who have neither personal or family history of renal disease, nor

  14. Department of Clinical Investigation, Annual Research Progress Report, Fiscal Year 2007 (Madigan Army Medical Center)

    Science.gov (United States)

    2007-09-30

    researchers. Lab modules revolve around the processing and analysis of a clinical blood sample and include the genotyping of student DNA isolated...Meatoplasty in the Management of Urethral Stricture Disease Due to Lichen Sclerosus Vascular Surgery, Department of Surgery Andersen CA #202086 O...pleomorphisms found in the populations will be determined for their association to periodontitis using genomic DNA isolated from cheek swab samples

  15. Refinement of variant selection for the LDL-C genetic risk score in the diagnosis of the polygenic form of clinical Familial Hypercholesterolemia and replication in samples from six countries

    Science.gov (United States)

    Futema, Marta; Shah, Sonia; Cooper, Jackie A; Li, KaWah; Whittall, Ros A; Sharifi, Mahtab; Goldberg, Olivia; Drogari, Euridiki; Mollaki, Vasiliki; Wiegman, Albert; Defesche, Joep; D’Agostino, Maria N; D’Angelo, Antonietta; Rubba, Paolo; Fortunato, Giuliana; Walus-Miarka, Małgorzata; Hegele, Robert A; Bamimore, Mary Aderayo; Durst, Ronen; Leitersdorf, Eran; Mulder, Monique T; Roeters van Lennep, Janine E; Sijbrands, Eric J G; Whittaker, John C; Talmud, Philippa J; Humphries, Steve E

    2016-01-01

    Background Familial Hypercholesterolemia (FH) is an autosomal-dominant disorder caused by mutations in one of three genes. In the 60% of patients who are mutation-negative we have recently shown that the clinical phenotype can be associated with an accumulation of common small-effect LDL-C-raising alleles using a 12-SNP score. The aims of the study were to improve the selection of SNPs, and to replicate the results in additional samples. Methods Receiver-operating characteristic curves were used to determine the optimum number of LDL-C SNPs. For replication analysis, we genotyped patients with a clinical diagnosis of FH from six countries for six LDL-C-associated alleles. We compared the weighted SNP score among patients with no confirmed mutation (FH/M-), those with a mutation (FH/M+), and controls from an UK population sample (WHII). Results Increasing the number of SNPs to 33 did not improve the ability of the score to discriminate between FH/M- and controls, while sequential removal of SNPs with smaller effects/lower frequency showed a weighted score of six SNPs performed as well as the 12-SNP score. Meta-analysis of the weighted 6-SNP score, based on polymorphisms in CELSR2, APOB, ABCG5/8, LDLR and APOE loci, in the independent FH/M- cohorts showed a consistently higher score in comparison to the WHII population (P95% likelihood of a polygenic explanation of their increased LDL-C. Conclusion A 6-SNP LDL-C score consistently distinguishes FH/M- patients from healthy subjects. The hypercholesterolemia in 88% of mutation-negative patients is likely to have a polygenic basis. PMID:25414277

  16. The Long-term Clinical Outcome after Corneal Collagen Cross-linking in Korean Patients with Progressive Keratoconus.

    Science.gov (United States)

    Kim, Tae Gi; Kim, Ki Young; Han, Jung Bin; Jin, Kyung Hyun

    2016-10-01

    To evaluate the long-term clinical effectiveness and safety of corneal collagen cross-linking (CXL) in progressive keratoconus compared with untreated contralateral eyes. In this retrospective study, nine eyes of nine patients with progressive keratoconus who received CXL (treatment group) and nine untreated contralateral eyes with keratoconus (control group) were included. All patients were followed for at least 5 years and assessed with best-corrected visual acuity, maximum keratometry, mean keratometry, corneal astigmatism, and corneal thickness. Clinical data were collected preoperatively and at 1, 3, 6, 12, 24, 36, 48, and 60 months, postoperatively. Mean best-corrected visual acuity improved significantly from 0.58 ± 0.37 logarithm of minimum angle of resolution preoperatively to 0.39 ± 0.29 logarithm of minimum angle of resolution at 5 years after corneal CXL (p = 0.012). There was significant flattening of the maximum keratometry and mean keratometry from preoperative values of 63.39 ± 10.89 and 50.87 ± 6.27 diopter (D) to postoperative values of 60.89 ± 11.29 and 49.54 ± 7.23 D, respectively (p = 0.038, 0.021). Corneal astigmatism decreased significantly from 7.20 ± 1.83 D preoperatively to 5.41 ± 1.79 D postoperatively (p = 0.021). The thinnest corneal thickness decreased from 434.00 ± 54.13 to 365.78 ± 71.58 µm during 1 month after treatment, then increased to 402.67 ± 52.55 µm at 5 years, which showed a statistically significant decrease compared to the baseline (p = 0.020). In the untreated contralateral eyes, mean keratometry increased significantly at 2 years compared with the baseline (p = 0.043). CXL seems to be an effective and safe treatment for halting the progression of keratoconus over a long-term follow-up period of up to 5 years in progressive keratoconus.

  17. The Economic and Clinical Impact of Sustained Use of a Progressive Mobility Program in a Neuro-ICU.

    Science.gov (United States)

    Hester, Jeannette M; Guin, Peggy R; Danek, Gale D; Thomas, Jaime R; Titsworth, William L; Reed, Richard K; Vasilopoulos, Terrie; Fahy, Brenda G

    2017-06-01

    To investigate a progressive mobility program in a neurocritical care population with the hypothesis that the benefits and outcomes of the program (e.g., decreased length of stay) would have a significant positive economic impact. Retrospective analysis of economic and clinical outcome data before, immediately following, and 2 years after implementation of the Progressive Upright Mobility Protocol Plus program (UF Health Shands Hospital, Gainesville, FL) involving a series of planned movements in a sequential manner with an additional six levels of rehabilitation in the neuro-ICU at UF Health Shands Hospital. Thirty-bed neuro-ICU in an academic medical center. Adult neurologic and neurosurgical patients: 1,118 patients in the pre period, 731 patients in the post period, and 796 patients in the sustained period. Implementation of Progressive Upright Mobility Protocol Plus. ICU length of stay decreased from 6.5 to 5.8 days in the immediate post period and 5.9 days in the sustained period (F(2,2641) = 3.1; p = 0.045). Hospital length of stay was reduced from 11.3 ± 14.1 days to 8.6 ± 8.8 post days and 8.8 ± 9.3 days sustained (F(2,2641) = 13.0; p ICU length of stay (p = 0.031) and hospital length of stay (p < 0.001) remained after adjustment for age, sex, diagnoses, sedation, and ventilation. Hospital-acquired infections were reduced by 50%. Average total cost per patient after adjusting for inflation was significantly reduced by 16% (post period) and 11% (sustained period) when compared with preintervention (F(2,2641) = 3.1; p = 0.045). Overall, these differences translated to an approximately $12.0 million reduction in direct costs from February 2011 through the end of 2013. An ongoing progressive mobility program in the neurocritical care population has clinical and financial benefits associated with its implementation and should be considered.

  18. Current experimental perspectives on the clinical progression of alcoholic liver disease.

    Science.gov (United States)

    Breitkopf, Katja; Nagy, Laura E; Beier, Juliane I; Mueller, Sebastian; Weng, Honglei; Dooley, Steven

    2009-10-01

    Chronic alcohol abuse is an important cause of morbidity and mortality throughout the world. Liver damage due to chronic alcohol intoxication initially leads to accumulation of lipids within the liver and with ongoing exposure this condition of steatosis may first progress to an inflammatory stage which leads the way for fibrogenesis and finally cirrhosis of the liver. While the earlier stages of the disease are considered reversible, cirrhotic destruction of the liver architecture beyond certain limits causes irreversible damage of the organ and often represents the basis for cancer development. This review will summarize current knowledge about the molecular mechanisms underlying the different stages of alcoholic liver disease (ALD). Recent observations have led to the identification of new molecular mechanisms and mediators of ALD. For example, plasminogen activator inhibitor 1 was shown to play a central role for steatosis, the anti-inflammatory adipokine, adiponectin profoundly regulates liver macrophage function and excessive hepatic deposition of iron is caused by chronic ethanol intoxication and increases the risk of hepatocellular carcinoma development.

  19. DNA replication origins in archaea

    OpenAIRE

    Zhenfang eWu; Jingfang eLiu; Haibo eYang; Hua eXiang

    2014-01-01

    DNA replication initiation, which starts at specific chromosomal site (known as replication origins), is the key regulatory stage of chromosome replication. Archaea, the third domain of life, use a single or multiple origin(s) to initiate replication of their circular chromosomes. The basic structure of replication origins is conserved among archaea, typically including an AT-rich unwinding region flanked by several conserved repeats (origin recognition box, ORB) that are located adjacent to ...

  20. ANATOMICAL PROGRESSION OF CORONARY-ARTERY DISEASE IN HUMANS AS SEEN BY PROSPECTIVE, REPEATED, QUANTITATED CORONARY ANGIOGRAPHY - RELATION TO CLINICAL EVENTS AND RISK-FACTORS

    NARCIS (Netherlands)

    LICHTLEN, PR; NIKUTTA, P; JOST, S; DECKERS, J; WIESE, B; RAFFLENBEUL, W; NELLESSEN, U; AMENDE, [No Value; HAMM, C; KALTENBACH, M; KLEPZIG, H; KOBER, G; BACHMANN, K; HAETINGER, S; WERNER, H; SCHMUTZLER, H; BIAS, H; SERRUYS, P; REIBER, H; BONNIER, H; MICHELS, R; TROQUAY, R; LIE, K; DEMUINCK, ED; SCHNEIDER, B; HECKER, H

    1992-01-01

    Background. At present, there is extensive knowledge on the clinical course of coronary artery disease (CAD), whereas data on the underlying anatomical changes and their relation to clinical events are still limited. Methods and Results. We investigated progression and regression of CAD prospectivel

  1. 早产的临床研究进展%Clinical Research Progress of Premature Birth

    Institute of Scientific and Technical Information of China (English)

    文思敏

    2012-01-01

    早产是导致围生儿发病和死亡的重要原因,因此研究早产预测及防治方法具有重要的临床意义.目前国内外对早产的预测研究较多,多项预测指标联合应用对早产预测临床意义较大.早产的治疗方法也越来越多,但药物治疗的效果存在争议.由于医学干预早产儿的死亡仍较难避免,因此国内外学者把目光投向早期早产预测,现就对早产有一定临床指导意义的预测指标以及治疗予以综述.%Preterm birth is a major cause of perinatal morbidity and mortality, therefore it is of great clinical significance in researching the forecast and prevention methods of preterm birth. At present,a lot of researches on preterm birth prediction are going on in China and abroad, and combined application of multiple prediction indexes has great clinical significance. Treatments of preterm birth are becoming more and more,but the medication treatment effect is still controversial. Premature death due to medical intervention is still difficult to avoid, therefore scholars in China and abroad are turning their attention to early prediction of preterm labor. Here is to make a review on the prediction indexes and treatments of a certain clinical significance.

  2. Joint modelling of longitudinal and multi-state processes: application to clinical progressions in prostate cancer.

    Science.gov (United States)

    Ferrer, Loïc; Rondeau, Virginie; Dignam, James; Pickles, Tom; Jacqmin-Gadda, Hélène; Proust-Lima, Cécile

    2016-09-30

    Joint modelling of longitudinal and survival data is increasingly used in clinical trials on cancer. In prostate cancer for example, these models permit to account for the link between longitudinal measures of prostate-specific antigen (PSA) and time of clinical recurrence when studying the risk of relapse. In practice, multiple types of relapse may occur successively. Distinguishing these transitions between health states would allow to evaluate, for example, how PSA trajectory and classical covariates impact the risk of dying after a distant recurrence post-radiotherapy, or to predict the risk of one specific type of clinical recurrence post-radiotherapy, from the PSA history. In this context, we present a joint model for a longitudinal process and a multi-state process, which is divided into two sub-models: a linear mixed sub-model for longitudinal data and a multi-state sub-model with proportional hazards for transition times, both linked by a function of shared random effects. Parameters of this joint multi-state model are estimated within the maximum likelihood framework using an EM algorithm coupled with a quasi-Newton algorithm in case of slow convergence. It is implemented under R, by combining and extending mstate and JM packages. The estimation program is validated by simulations and applied on pooled data from two cohorts of men with localized prostate cancer. Thanks to the classical covariates available at baseline and the repeated PSA measurements, we are able to assess the biomarker's trajectory, define the risks of transitions between health states and quantify the impact of the PSA dynamics on each transition intensity. Copyright © 2016 John Wiley & Sons, Ltd.

  3. Standards for scalable clinical decision support: need, current and emerging standards, gaps, and proposal for progress.

    Science.gov (United States)

    Kawamoto, Kensaku; Del Fiol, Guilherme; Lobach, David F; Jenders, Robert A

    2010-01-01

    Despite their potential to significantly improve health care, advanced clinical decision support (CDS) capabilities are not widely available in the clinical setting. An important reason for this limited availability of CDS capabilities is the application-specific and institution-specific nature of most current CDS implementations. Thus, a critical need for enabling CDS capabilities on a much larger scale is the development and adoption of standards that enable current and emerging CDS resources to be more effectively leveraged across multiple applications and care settings. Standards required for such effective scaling of CDS include (i) standard terminologies and information models to represent and communicate about health care data; (ii) standard approaches to representing clinical knowledge in both human-readable and machine-executable formats; and (iii) standard approaches for leveraging these knowledge resources to provide CDS capabilities across various applications and care settings. A number of standards do exist or are under development to meet these needs. However, many gaps and challenges remain, including the excessive complexity of many standards; the limited availability of easily accessible knowledge resources implemented using standard approaches; and the lack of tooling and other practical resources to enable the efficient adoption of existing standards. Thus, the future development and widespread adoption of current CDS standards will depend critically on the availability of tooling, knowledge bases, and other resources that make the adoption of CDS standards not only the right approach to take, but the cost-effective path to follow given the alternative of using a traditional, ad hoc approach to implementing CDS.

  4. Considering Cost-Effectiveness in Cardiology Clinical Guidelines: Progress and Prospects.

    Science.gov (United States)

    Hlatky, Mark A

    2016-01-01

    Since the 1980s, when the American College of Cardiology (ACC) and the American Heart Association (AHA) established a joint task force to examine the use of cardiovascular procedures and therapies, cardiologists have been leaders in the development of clinical practice guidelines. The ACC/AHA guidelines development process has evolved considerably over the last 30 or more years. Guidelines now focus on clinical conditions, such as angina, instead of procedures, such as bypass surgery. There is a formal organizational structure, with dedicated staff, a standing committee on practice guidelines, and specific panels of volunteer experts on each topic. This process tightly manages conflicts of interest and strives for evidence-based, as opposed to opinion-based, guidelines, with a clear citation of the supporting evidence. Traditional clinical guidelines consider only what is best for the individual patient, and have explicitly not considered the cost to society. Nevertheless, in many guidelines development meetings, high cost was implicitly considered: if a procedure was extremely costly, the evidence needed to be very strong. The Guidelines Committee recognized that cost considerations ought to be made more transparent, and that the evidence on economic value should be explicitly cited when available. These considerations were formalized by a recent white paper on incorporating economic considerations into ACC/AHA guidelines. In considering value, it is necessary to assess the quality of the evidence as well as to define levels of value. The next ACC/AHA guideline will incorporate value as a part of its recommendations. This will be an evidence-based process in which published economic assessments relating to key questions will be reviewed.

  5. Department of Clinical Investigation Annual Research Progress Report, Fiscal Year 1993. Volume 1

    Science.gov (United States)

    1993-10-01

    Steroid In Reducing Post- Tonsillectomy Morbidity. 309 o0) C-89-91 Compassionate Use Protocol for Centoxin (HA-lA). (C) 310 C-90-91 Phase I Protocol...treated with Nd:YAG Laser to Patients Not Treated with Laser : Survival and Clinical data. Chest 1993; 10:44S. Atkins, J; Johnson, JE; Blanton, HM. The...Medical Center. 308 Detail Summary Sheet Date: 15 Dec 93 Protocol Number: C-76-91 Status: Ongoing Title: Efficacy of Steroid in Reducing Post- Tonsillectomy

  6. Progress in the research of genetics and clinical manifestation of paroxysmal kinesigenic dyskinesia

    Directory of Open Access Journals (Sweden)

    HUANG Xiao-jun

    2013-05-01

    Full Text Available Paroxysmal kinesigenic dyskinesia (PKD is a disorder characterized by recurrent and brief attacks that are induced by sudden voluntary movement with highly clinical and genetic heterogeneity. Familial PKD are mostly autosomal dominant inherited and proline-rich transmembrare protein 2 (PRRT2 gene has been identified as the causative gene for PKD. So far 56 mutations have been documented and most of them are nonsense ones. No obvious genotype-phenotype correlation has been observed and the function of PRRT2 is still unclear, but the interaction between PRRT2 and synaptosomal-associated protein 25 (SNAP25 will shed the light on the research of PKD mechanism.

  7. Replication studies in longevity

    DEFF Research Database (Denmark)

    Varcasia, O; Garasto, S; Rizza, T

    2001-01-01

    In Danes we replicated the 3'APOB-VNTR gene/longevity association study previously carried out in Italians, by which the Small alleles (less than 35 repeats) had been identified as frailty alleles for longevity. In Danes, neither genotype nor allele frequencies differed between centenarians and 20...

  8. Replication-Fork Dynamics

    NARCIS (Netherlands)

    Duderstadt, Karl E.; Reyes-Lamothe, Rodrigo; van Oijen, Antoine M.; Sherratt, David J.

    2014-01-01

    The proliferation of all organisms depends on the coordination of enzymatic events within large multiprotein replisomes that duplicate chromosomes. Whereas the structure and function of many core replisome components have been clarified, the timing and order of molecular events during replication re

  9. Coronavirus Attachment and Replication

    Science.gov (United States)

    1988-03-28

    synthesis during RNA replication of vesicular stomatitis virus. J. Virol. 49:303-309. Pedersen, N.C. 1976a. Feline infectious peritonitis: Something old...receptors on intestinal brush border membranes from normal host species were developed for canine (CCV), feline (FIPV), porcine (TGEV), human (HCV...gastroenteritis receptor on pig BBMs ...... ................. ... 114 Feline infectious peritonitis virus receptor on cat BBMs ... .............. 117 Human

  10. What features improve the accuracy of the clinical diagnosis of progressive supranuclear palsy-parkinsonism (PSP-P)?

    Science.gov (United States)

    Williams, David R; Lees, Andrew J

    2010-02-15

    Progressive supranuclear palsy-parkinsonism (PSP-P) is a primary tauopathy characterised by neurofibrillary degeneration, which is frequently mistaken for Parkinson's disease (PD), multiple system atrophy (MSA), and vascular parkinsonism (VP) at presentation. The aim of this study was to identify particular clinical features (green flags) that may be helpful in differentiating PSP-P from these other disorders. We identified 37 patients with PSP-P from 726 patients archived at the Queen Square Brain Bank. Using a retrospective case notes review the clinical features were compared between the PSP-P group and Lewy body associated parkinsonism (PD, n = 444 and dementia with Lewy bodies (DLB), n = 46), MSA (n = 90), and VP (n = 19), using the chi(2)-test for proportions for a two-by-two contingency table. The sensitivity, specificity, and positive predictive values (PPV) and negative predictive values (NPV) were calculated for individual clinical features. A specificity of >0.85 or a PPV of >0.85 were considered reliable discriminators. No clinical features were predictive of PSP-P, but late drug induced dyskinesias (specificity 0.92, PPV 0.99), late autonomic dysfunction (specificity 0.94, PPV 0.99) and any visual hallucinations (specificity 0.94, PPV 0.99) were better in distinguishing PD and PSP-P than predicted using operational diagnostic criteria for PD. PSP-P shares many clinical features with PD and DLB, MSA and VP, but visual hallucinations, drug induced dyskinesias and autonomic dysfunction are very uncommon and may be helpful exclusion criteria.

  11. Clinical and immunological markers of dengue progression in a study cohort from a hyperendemic area in Malaysia.

    Science.gov (United States)

    Rathakrishnan, Anusyah; Klekamp, Benjamin; Wang, Seok Mui; Komarasamy, Thamil Vaani; Natkunam, Santha Kumari; Sathar, Jameela; Azizan, Azliyati; Sanchez-Anguiano, Aurora; Manikam, Rishya; Sekaran, Shamala Devi

    2014-01-01

    With its elusive pathogenesis, dengue imposes serious healthcare, economic and social burden on endemic countries. This study describes the clinical and immunological parameters of a dengue cohort in a Malaysian city, the first according to the WHO 2009 dengue classification. This longitudinal descriptive study was conducted in two Malaysian hospitals where patients aged 14 and above with clinical symptoms suggestive of dengue were recruited with informed consent. Among the 504 participants, 9.3% were classified as non-dengue, 12.7% without warning signs, 77.0% with warning signs and 1.0% with severe dengue based on clinical diagnosis. Of these, 37% were misdiagnosed as non-dengue, highlighting the importance of both clinical diagnosis and laboratory findings. Thrombocytopenia, prolonged clotting time, liver enzymes, ALT and AST served as good markers for dengue progression but could not distinguish between patients with and without warning signs. HLA-A*24 and -B*57 were positively associated with Chinese and Indians patients with warning signs, respectively, whereas A*03 may be protective in the Malays. HLA-A*33 was also positively associated in patients with warning signs when compared to those without. Dengue NS1, NS2A, NS4A and NS4B were found to be important T cell epitopes; however with no apparent difference between with and without warning signs patients. Distinction between the 2 groups of patients was also not observed in any of the cytokines analyzed; nevertheless, 12 were significantly differentially expressed at the different phases of illness. The new dengue classification system has allowed more specific detection of dengue patients, however, none of the clinical parameters allowed distinction of patients with and without warning signs. While the HLA-A*33 may be predictive marker for development of warning signs; larger studies will be needed to support this findings.

  12. Clinical and immunological markers of dengue progression in a study cohort from a hyperendemic area in Malaysia.

    Directory of Open Access Journals (Sweden)

    Anusyah Rathakrishnan

    Full Text Available With its elusive pathogenesis, dengue imposes serious healthcare, economic and social burden on endemic countries. This study describes the clinical and immunological parameters of a dengue cohort in a Malaysian city, the first according to the WHO 2009 dengue classification.This longitudinal descriptive study was conducted in two Malaysian hospitals where patients aged 14 and above with clinical symptoms suggestive of dengue were recruited with informed consent. Among the 504 participants, 9.3% were classified as non-dengue, 12.7% without warning signs, 77.0% with warning signs and 1.0% with severe dengue based on clinical diagnosis. Of these, 37% were misdiagnosed as non-dengue, highlighting the importance of both clinical diagnosis and laboratory findings. Thrombocytopenia, prolonged clotting time, liver enzymes, ALT and AST served as good markers for dengue progression but could not distinguish between patients with and without warning signs. HLA-A*24 and -B*57 were positively associated with Chinese and Indians patients with warning signs, respectively, whereas A*03 may be protective in the Malays. HLA-A*33 was also positively associated in patients with warning signs when compared to those without. Dengue NS1, NS2A, NS4A and NS4B were found to be important T cell epitopes; however with no apparent difference between with and without warning signs patients. Distinction between the 2 groups of patients was also not observed in any of the cytokines analyzed; nevertheless, 12 were significantly differentially expressed at the different phases of illness.The new dengue classification system has allowed more specific detection of dengue patients, however, none of the clinical parameters allowed distinction of patients with and without warning signs. While the HLA-A*33 may be predictive marker for development of warning signs; larger studies will be needed to support this findings.

  13. Progress of clinical practice on the management of burn-associated pain: Lessons from animal models.

    Science.gov (United States)

    McIntyre, Matthew K; Clifford, John L; Maani, Christopher V; Burmeister, David M

    2016-09-01

    Opioid-based analgesics provide the mainstay for attenuating burn pain, but they have a myriad of side effects including respiratory depression, nausea, impaired gastrointestinal motility, sedation, dependence, physiologic tolerance, and opioid-induced hyperalgesia. To test and develop novel analgesics, validated burn-relevant animal models of pain are indispensable. Herein we review such animal models, which are mostly limited to rodent models of burn-induced, inflammatory, and neuropathic pain. The latter two are pain syndromes that provide insight into the pain caused by systemic pro-inflammatory cytokines and direct injury to nerves (e.g., after severe burn), respectively. To date, no single animal model optimally mimics the complex pathophysiology and pain that a human burn patient experiences. No currently available burn-pain model examines effects of pharmacological intervention on wound healing. As cornerstones of pain and wound healing, pro-inflammatory mediators may be utilized for insight into both processes. Moreover, common clinical concerns such as systemic inflammatory response syndrome and multiple organ dysfunction remain unaddressed. For development of analgesics, these aberrations can significantly alter the potential efficacy and/or adverse effects of a prescribed analgesic following burn trauma. We therefore suggest that a multi-model strategy would be the most clinically relevant when evaluating novel analgesics for use in burn patients.

  14. Progress in the Discovery of Treatments for C. difficile Infection: A Clinical and Medicinal Chemistry Review

    Science.gov (United States)

    Tsutsumi, Lissa S.; Owusu, Yaw B.; Hurdle, Julian G.; Sun, Dianqing

    2014-01-01

    Clostridium difficile is an anaerobic, Gram-positive pathogen that causes C. difficile infection, which results in significant morbidity and mortality. The incidence of C. difficile infection in developed countries has become increasingly high due to the emergence of newer epidemic strains, a growing elderly population, extensive use of broad spectrum antibiotics, and limited therapies for this diarrheal disease. Because treatment options currently available for C. difficile infection have some drawbacks, including cost, promotion of resistance, and selectivity problems, new agents are urgently needed to address these challenges. This review article focuses on two parts: the first part summarizes current clinical treatment strategies and agents under clinical development for C. difficile infection; the second part reviews newly reported anti-difficile agents that have been evaluated or reevaluated in the last five years and are in the early stages of drug discovery and development. Antibiotics are divided into natural product inspired and synthetic small molecule compounds that may have the potential to be more efficacious than currently approved treatments. This includes potency, selectivity, reduced cytotoxicity, and novel modes of action to prevent resistance. PMID:24236721

  15. Progress and problems for randomized clinical trials: from streptomycin to the era of megatrials.

    Science.gov (United States)

    Hilbrich, Lutz; Sleight, Peter

    2006-09-01

    Randomized clinical trials (RCTs) are the definitive contributors to evidence-based medicine. RCTs assessing serious outcomes in cardiovascular disease have grown, with 'megatrials' becoming more common with the realization that wrong conclusions resulted from random error in inadequately sized trials. Simple design and a heterogeneous patient population were early features, but multinational trials have increased in scientific, logistical, bureaucratic, regulatory, and legal complexity. These studies now exceed the financial means of academia or medical charities. Governments have left the bill with the pharmaceutical industry, encouraging a symbiosis with academics, who contribute medical and scientific expertise, and access to patients. Industry provides pharmacological, pharmaceutical, technical and regulatory know-how, good clinical practice expertise, and legal assistance during the trial. Study supervision is then in the hands of an independent steering committee and associated subcommittees, until appropriate dissemination of results. Prospectively defined interaction with the sponsor facilitates unbiased design and conduct, but arrangements need careful implementation to avoid conflicts of interest. The patient is protected by a strong data safety monitoring board that is wholly independent. Megatrials are under threat from over-regulation, increasing costs, and difficulties in execution. These issues merit urgent public and political education and debate.

  16. Progressive outer retinal necrosis syndrome: a comprehensive review of its clinical presentation, relationship to immune system status, and management.

    Science.gov (United States)

    Austin

    2000-12-01

    Progressive outer retinal necrosis (PORN) syndrome is a form of the Varicella zoster virus (VZV) chorioretinitis found almost exclusively in people with the acquired immunodeficiency syndrome (AIDS). This destructive infection has an extremely rapid course that may lead to no light perception in affected eyes within days or weeks. Attempts at its treatment have had limited success. Rhegmatogenous retinal detachments often occur after the development of atrophic retinal holes, and silicone oil temponade has been found to be the most successful reattachment procedure. Unfortunately, cataract formation is common after such surgery. PORN needs to be differentiated from acute retinal necrosis (ARN) syndrome, a necrotizing retinitis that can also be caused by VZV. PORN and ARN are found at opposite ends of the spectrum of necrotizing herpetic retinopathies (NHR), where its clinical presentation depends upon immune system status. After a brief case presentation, the distinguishing clinical characteristics of PORN, its differentiation from ARN, attempts at its treatment, the role of the immune system status on its clinical appearance and treatment, and management of complications such as retinal detachment and subsequent cataracts are discussed.

  17. Current perspectives of mi-RNA in oesophageal adenocarcinoma: Roles in predicting carcinogenesis, progression and values in clinical management.

    Science.gov (United States)

    Amin, Moein; Lam, Alfred King-yin

    2015-06-01

    Aberrant expressions of micro-ribonucleic acids (miRs) are closely associated with the pathogenesis in many human cancers. In oesophageal adenocarcinomas, altered expressions of different sets of miRs are noted to be associated with the development of adenocarcinoma from Barrett's oesophagus. In different studies, miRs such as miR-192, miR-196 and miR-21 were frequently noted to up-regulated whereas miR-203, miR-205 and miR-let-7 were commonly down-regulated during the development of Barrett's oesophagus to oesophageal adenocarcinoma. In addition, changes in the expression of miRs are associated with the predication of metastasis, prognosis and response to chemo-radiation in the patients with oesophageal adenocarcinoma. Experimental studies in manipulating the miRs in cancer cell lines could provide hints for therapeutics for the cancer. However, the number of studies reported on these aspects of oesophageal adenocarcinoma was limited and the miRs noted needed to be confirmed by additional studies. Overall, the mechanisms of involvements of miRs in pathogenesis and progression of oesophageal adenocarcinoma are complex. Although miRs have the potential to act as prognostic and clinical biomarkers for cancer therapy in oesophageal adenocarcinoma, more works in larger populations and clinical trials are needed to validate these clinical implications.

  18. Hepatitis E Virus Superinfection and Clinical Progression in Hepatitis B Patients

    Directory of Open Access Journals (Sweden)

    Nghiem Xuan Hoan

    2015-12-01

    Full Text Available Hepatitis E virus (HEV infection may cause acute hepatitis and lead to hepatic failure in developing and developed countries. We studied HEV seroprevalences in patients with hepatitis B virus (HBV infection to understand the consequences of HEV superinfection in a Vietnamese population. This cross-sectional study was conducted from 2012 to 2013 and included 1318 Vietnamese patients with HBV-related liver diseases and 340 healthy controls. The case group included patients with acute (n = 26 and chronic hepatitis B (n = 744, liver cirrhosis (n = 160, hepatocellular carcinoma (n = 166 and patients with both liver cirrhosis and hepatocellular carcinoma (n = 222. Anti-HEV IgG and IgM antibodies were assessed in patients and controls by ELISA. HEV-RNA was identified by PCR assays and sequencing. Seroprevalences of anti-HEV IgG among hepatitis B patients and controls were 45% and 31%, respectively (adjusted P = 0.034. Anti-HEV IgM seroprevalences were 11.6% and 4.7% in patients and controls, respectively (adjusted P = 0.005. Seroprevalences were higher among the elder individuals. When stratifying for patient groups, those with liver cirrhosis had the highest anti-HEV IgG (52% and anti-HEV IgM (19% seroprevalences. Hepatitis B patients with current HEV infection had abnormal liver function tests compared to patients with past or without HEV infection. One HEV isolate was retrieved from a patient with both liver cirrhosis and hepatocellular carcinoma and identified as HEV genotype 3. This study indicates high prevalences of HEV infection in Vietnamese HBV patients and among healthy individuals and shows that HEV superinfection may influence the outcome and progression of HBV-related liver disease.

  19. The Clinical Significance of Uric Acid and Complement Activation in the Progression of IgA Nephropathy

    Directory of Open Access Journals (Sweden)

    Yasar Caliskan

    2016-02-01

    Full Text Available Background/Aims: The aim of this study is to investigate the utility of clinical [age, gender, mean arterial pressure (MAP] and laboratory parameters [eGFR, hemoglobin (Hgb, serum levels of creatinine, uric acid, albumin, proteinuria, hematuria] and also histopathological lesions (Oxford classification parameters, crescents, intensity and pattern of staining for C3, C1Q, IgA, IgG, IgM as progression markers in patients with IgA Nephropathy (IgAN. Methods: A total of 111 IgAN patients with a follow-up period >1 year or who reached kidney failure [GFR category G5 chronic kidney disease (CKD] Results: Mean follow-up period was 33±29 months. Thirty-seven (33.3% patients progressed to kidney failure and 4 (3.6% patients developed eGFR decline ≥50% from the baseline after a median of 23 and 65 months, respectively. In multivariate Cox regression analysis, baseline levels of Hgb (HR:0.782, 95% CI 0.559-0.973, p=0.037, serum uric acid (HR:1.293, 95% CI 1.023-1.621, p=0.046, eGFR (HR:0.966, 95% CI 0.947-0.984, p=0.004 and intensity of C3 staining (HR:1.550, 95% CI 1.198-1.976, p=0.049 predicted primary endpoint. Serum uric acid level was associated independently with T score (β=0.303, p=0.005 in patients with eGFR>30 ml/min/m2. Conclusions: Hyperuricemia and the deposition of C3 are independent risk factors for IgAN progression.

  20. Everyday Cognition scale items that best discriminate between and predict progression from clinically normal to mild cognitive impairment

    Science.gov (United States)

    Marshall, Gad A.; Zoller, Amy S.; Kelly, Kathleen E.; Amariglio, Rebecca E.; Locascio, Joseph J.; Johnson, Keith A.; Sperling, Reisa A.; Rentz, Dorene M.

    2014-01-01

    Background Impairment in instrumental activities of daily living (IADL) starts as individuals with amnestic mild cognitive impairment (MCI) transition to Alzheimer’s disease (AD) dementia. However, most IADL scales have not shown IADL alterations in clinically normal (CN) elderly. The objective of this study was to determine which of the IADL-related Everyday Cognition (ECog) scale items are most sensitive for detection of early functional changes. Methods We assessed 290 CN and 495 MCI participants from the Alzheimer’s Disease Neuroimaging Initiative. We performed logistic regression analyses predicting the probability of CN vs. MCI diagnosis using only the 17 participant-based and 17 informant-based ECog items related to IADL. We then performed Cox regression analyses to predict progression from CN to MCI. All analyses were adjusted for demographic characteristics. Results We found that worse performance on “remembering a few shopping items” (participant and informant-based p<0.0001), “remembering appointments” (participant and informant-based p<0.0001), “developing a schedule in advance of anticipated events” (participant-based p=0.007), “balancing checkbook” (participant-based p=0.02), and “keeping mail and papers organized” (informant-based p=0.002) best discriminated MCI from CN. We found that worse performance on “keeping mail and papers organized” (participant-based Hazard Ratio (HR)=2.27, p=0.07) marginally predicted greater hazard of progressing from CN to MCI. Conclusions Our results indicate that a few simple questions targeting early functional changes, addressed either to the individual or informant, can effectively distinguish between CN elderly and individuals with MCI. Additionally, one of the above questions related to organization suggested which CN individuals are likely to progress to MCI. PMID:25274110

  1. Clinical features and predictors for disease natural progression in adults with Pompe disease: a nationwide prospective observational study

    Directory of Open Access Journals (Sweden)

    van der Beek Nadine AME

    2012-11-01

    Full Text Available Abstract Background Due partly to physicians’ unawareness, many adults with Pompe disease are diagnosed with great delay. Besides, it is not well known which factors influence the rate of disease progression, and thus disease outcome. We delineated the specific clinical features of Pompe disease in adults, and mapped out the distribution and severity of muscle weakness, and the sequence of involvement of the individual muscle groups. Furthermore, we defined the natural disease course and identified prognostic factors for disease progression. Methods We conducted a single-center, prospective, observational study. Muscle strength (manual muscle testing, and hand-held dynamometry, muscle function (quick motor function test, and pulmonary function (forced vital capacity in sitting and supine positions were assessed every 3–6 months and analyzed using repeated-measures ANOVA. Results Between October 2004 and August 2009, 94 patients aged between 25 and 75 years were included in the study. Although skeletal muscle weakness was typically distributed in a limb-girdle pattern, many patients had unfamiliar features such as ptosis (23%, bulbar weakness (28%, and scapular winging (33%. During follow-up (average 1.6 years, range 0.5-4.2 years, skeletal muscle strength deteriorated significantly (mean declines of −1.3% point/year for manual muscle testing and of −2.6% points/year for hand-held dynamometry; both p15 years and pulmonary involvement (forced vital capacity in sitting position Conclusions Recognizing patterns of common and less familiar characteristics in adults with Pompe disease facilitates timely diagnosis. Longer disease duration and reduced pulmonary function stand out as predictors of rapid disease progression, and aid in deciding whether to initiate enzyme replacement therapy, or when.

  2. A novel approach to evaluating the reproducibility of a replication technique for the manufacture of electroconductive replicas for use in quantitative clinical dental wear studies.

    Science.gov (United States)

    Chadwick, R G; Mitchell, H L; Ward, S

    2004-04-01

    The assessment of the progression of tooth surface loss has until recently been limited to either the application of subjective ranking scales or visual comparison of sequential study casts. The development of quantitative measuring techniques offers the potential of greater accuracy and sensitivity. As direct intra-oral measurement is problematical such approaches often utilize impressions of the teeth, recorded at different epochs, to construct replicas for mapping and comparison. This in vitro investigation sought to determine the reproducibility of such an approach taking into account the total process chain. Two inlay cavities (one large, one small) were prepared in the palatal aspect of a plastic maxillary central incisor and restored with two flush fitting inlays. A series of impressions of this tooth were recorded, using a special tray and an addition cured light bodied silicone impression material (President, Coltene, Switzerland), with (a) both inlays in (b) both inlays out (c) large inlay out and small inlay in (d) large inlay in and small inlay out - a total of 16 impressions. Electroconductive replicas were fabricated from these and mapped using a computer controlled probe. Each series simulated wear of the tooth. A surface matching and difference detection algorithm was then used to compare each series of replicas and calculate the proportion of the surface undergoing simulated wear by a direct comparison of (a) matched to (b) or, indirectly as the summation of the results of matches of (a) with (c) and (a) with (d). The mean proportion of the surface with wear calculated directly was 26.6% (s.d.=0.6) and indirectly 26.1% (s.d. = 0.5). A one-way anova revealed no significant difference (P > 0.05). It is concluded that determining wear by this method is highly reproducible.

  3. Functional Activities Questionnaire items that best discriminate and predict progression from clinically normal to mild cognitive impairment

    Science.gov (United States)

    Marshall, Gad A.; Zoller, Amy S.; Lorius, Natacha; Amariglio, Rebecca E.; Locascio, Joseph J.; Johnson, Keith A.; Sperling, Reisa A.; Rentz, Dorene M.

    2015-01-01

    Background Impairment in instrumental activities of daily living (IADL) emerges in the transition from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) dementia. Some IADL scales are sensitive to early deficits in MCI, but none have been validated for detecting subtle functional changes in clinically normal (CN) elderly at risk for AD. Methods Data from 624 subjects participating in the Alzheimer’s Disease Neuroimaging Initiative and 524 subjects participating in the Massachusetts Alzheimer’s Disease Research Center, which are two large cohorts including CN elderly and MCI subjects, were used to determine which Functional Activities Questionnaire items best discriminate between and predict progression from CN to MCI. Results We found that “Remembering appointments” and “assembling tax records” best discriminated between CN and MCI subjects, while worse performance on “paying attention and understanding a TV program”, “paying bills/balancing checkbook”, and “heating water and turning off the stove” predicted greater hazard of progressing from a diagnosis of CN to MCI. Conclusions These results demonstrate that certain questions are especially sensitive in detecting the earliest functional changes in CN elderly at risk for AD. As the field moves toward earlier intervention in preclinical AD, it is important to determine which IADL changes can be detected at that stage and track decline over time. PMID:26017560

  4. Towards optimal clinical and epidemiological registration of haematological malignancies: Guidelines for recording progressions, transformations and multiple diagnoses.

    Science.gov (United States)

    Gavin, Anna; Rous, Brian; Marcos-Gragera, Rafael; Middleton, Richard; Steliarova-Foucher, Eva; Maynadie, Marc; Zanetti, Roberto; Visser, Otto

    2015-06-01

    Haematological malignancies (HM) represent over 6% of the total cancer incidence in Europe and affect all ages, ranging between 45% of all cancers in children and 7% in the elderly. Thirty per cent of childhood cancer deaths are due to HM, 8% in the elderly. Their registration presents specific challenges, mainly because HM may transform or progress in the course of the disease into other types of HM. In the context of cancer registration decisions have to be made about classifying subsequent notifications on the same patient as the same tumour (progression), a transformation or a new tumour registration. Allocation of incidence date and method of diagnosis must also be standardised. We developed European Network of Cancer Registries (ENCR) recommendations providing specific advice for cancer registries to use haematology and molecular laboratories as data sources, conserve the original date of incidence in case of change of diagnosis, make provision for recording both the original as well as transformed tumour and to apply precise rules for recording and counting multiple diagnoses. A reference table advising on codes which reflect a potential transformation or a new tumour is included. This work will help to improve comparability of data produced by population-based cancer registries, which are indispensable for aetiological research, health care planning and clinical research, an increasing important area with the application of targeted therapies.

  5. Direct Visualization of DNA Replication Dynamics in Zebrafish Cells.

    Science.gov (United States)

    Kuriya, Kenji; Higashiyama, Eriko; Avşar-Ban, Eriko; Tamaru, Yutaka; Ogata, Shin; Takebayashi, Shin-ichiro; Ogata, Masato; Okumura, Katsuzumi

    2015-12-01

    Spatiotemporal regulation of DNA replication in the S-phase nucleus has been extensively studied in mammalian cells because it is tightly coupled with the regulation of other nuclear processes such as transcription. However, little is known about the replication dynamics in nonmammalian cells. Here, we analyzed the DNA replication processes of zebrafish (Danio rerio) cells through the direct visualization of replicating DNA in the nucleus and on DNA fiber molecules isolated from the nucleus. We found that zebrafish chromosomal DNA at the nuclear interior was replicated first, followed by replication of DNA at the nuclear periphery, which is reminiscent of the spatiotemporal regulation of mammalian DNA replication. However, the relative duration of interior DNA replication in zebrafish cells was longer compared to mammalian cells, possibly reflecting zebrafish-specific genomic organization. The rate of replication fork progression and ori-to-ori distance measured by the DNA combing technique were ∼ 1.4 kb/min and 100 kb, respectively, which are comparable to those in mammalian cells. To our knowledge, this is a first report that measures replication dynamics in zebrafish cells.

  6. Application of MultiStem(®) Allogeneic Cells for Immunomodulatory Therapy: Clinical Progress and Pre-Clinical Challenges in Prophylaxis for Graft Versus Host Disease.

    Science.gov (United States)

    Vaes, Bart; Van't Hof, Wouter; Deans, Robert; Pinxteren, Jef

    2012-01-01

    The last decade has seen much progress in adjunctive cell therapy for immune disorders. Both corporate and institutional Phase III studies have been run using mesenchymal stromal cells (MSC) for treatment of Graft versus Host Disease (GvHD), and product approval has been achieved for treatment of pediatric GvHD in Canada and New Zealand (Prochymal(®); Osiris Therapeutics). This effectiveness has prompted the prophylactic use of adherent stem cells at the time of allogeneic hematopoietic stem cell transplantation (HSCT) to prevent occurrence of GvHD and possibly provide stromal support for hematopoietic recovery. The MultiStem(®) product is an adult adherent stem cell product derived from bone marrow which has significant clinical exposure. MultiStem cells are currently in phase II clinical studies for treatment of ischemic stroke and ulcerative colitis, with Phase I studies completed in acute myocardial infarction and for GvHD prophylaxis in allogeneic HSCT, demonstrating that MultiStem administration was well tolerated while the incidence and severity of GvHD was reduced. In advancing this clinical approach, it is important to recognize that alternate models exist based on clinical manufacturing strategies. Corporate sponsors exploit the universal donor properties of adherent stem cells and manufacture at large scale, with many products obtained from one or limited donors and used across many patients. In Europe, institutional sponsors often produce allogeneic product in a patient designated context. For this approach, disposable bioreactors producing <10 products/donor in a closed system manner are very well suited. In this review, the use of adherent stem cells for GvHD prophylaxis is summarized and the suitability of disposable bioreactors for MultiStem production is presented, with an emphasis on quality control parameters, which are critical with a multiple donor approach for manufacturing.

  7. Application of MultiStem® allogeneic cells for immunomodulatory therapy: clinical progress and pre-clinical challenges in prophylaxis for graft vs host disease

    Directory of Open Access Journals (Sweden)

    Bart eVaes

    2012-11-01

    Full Text Available The last decade has seen much progress in adjunctive cell therapy for immune disorders. Both corporate and institutional Phase III studies have been run using mesenchymal stromal cells (MSC for treatment of Graft vs Host Disease (GvHD, and product approval has been achieved for treatment of pediatric GvHD in Canada and New Zealand (Prochymal®; Osiris Therapeutics. This effectiveness has prompted the prophylactic use of adherent stem cells at the time of allogeneic hematopoietic stem cell transplantation (HSCT to prevent occurrence of GvHD and possibly provide stromal support for hematopoietic recovery. The MultiStem® product is an adult adherent stem cell product derived from bone marrow which has significant clinical exposure. MultiStem cells are currently in phase II clinical studies for treatment of ischemic stroke and ulcerative colitis, with Phase I studies completed in acute myocardial infarction and for GvHD prophylaxis in allogeneic HSCT, demonstrating that MultiStem administration was well tolerated while the incidence and severity of GvHD was reduced. In advancing this clinical approach, it is important to recognize that alternate models exist based on clinical manufacturing strategies. Corporate sponsors exploit the universal donor properties of adherent stem cells and manufacture at large scale, with many products obtained from one or limited donors and used across many patients. In Europe, institutional sponsors often produce allogeneic product in a patient designated context. For this approach, disposable bioreactors producing <10 products per donor in a closed system manner are very well suited. In this review, the use of adherent stem cells for GvHD prophylaxis is summarized and the suitability of disposable bioreactors for MultiStem production is presented, with an emphasis on quality control parameters, which are critical with a multiple donor approach for manufacturing.

  8. Assessing the HIV Care Continuum in Latin America: progress in clinical retention, cART use and viral suppression

    Directory of Open Access Journals (Sweden)

    Peter F Rebeiro

    2016-04-01

    Full Text Available Introduction: We assessed trends in HIV Care Continuum outcomes associated with delayed disease progression and reduced transmission within a large Latin American cohort over a decade: clinical retention, combination antiretroviral therapy (cART use and viral suppression (VS. Methods: Adults from Caribbean, Central and South America network for HIV epidemiology clinical cohorts in seven countries contributed data between 2003 and 2012. Retention was defined as two or more HIV care visits annually, >90 days apart. cART was defined as prescription of three or more antiretroviral agents annually. VS was defined as HIV-1 RNA <200 copies/mL at last measurement annually. cART and VS denominators were subjects with at least one visit annually. Multivariable modified Poisson regression was used to assess temporal trends and examine associations between age, sex, HIV transmission mode, cohort, calendar year and time in care. Results: Among 18,799 individuals in retention analyses, 14,380 in cART analyses and 13,330 in VS analyses, differences existed between those meeting indicator definitions versus those not by most characteristics. Retention, cART and VS significantly improved from 2003 to 2012 (63 to 77%, 74 to 91% and 53 to 82%, respectively; p<0.05, each. Female sex (risk ratio (RR=0.97 vs. males and injection drug use as HIV transmission mode (RR=0.83 vs. male sexual contact with males (MSM were significantly associated with lower retention, but unrelated with cART or VS. MSM (RR=0.96 significantly decreased the probability of cART compared with heterosexual transmission. Conclusions: HIV Care Continuum outcomes improved over time in Latin America, though disparities for vulnerable groups remain. Efforts must be made to increase retention, cART and VS, while engaging in additional research to sustain progress in these settings.

  9. Assessing the HIV Care Continuum in Latin America: progress in clinical retention, cART use and viral suppression

    Science.gov (United States)

    Rebeiro, Peter F; Cesar, Carina; Shepherd, Bryan E; De Boni, Raquel B; Cortés, Claudia P; Rodriguez, Fernanda; Belaunzarán-Zamudio, Pablo; Pape, Jean W; Padgett, Denis; Hoces, Daniel; McGowan, Catherine C; Cahn, Pedro

    2016-01-01

    Introduction We assessed trends in HIV Care Continuum outcomes associated with delayed disease progression and reduced transmission within a large Latin American cohort over a decade: clinical retention, combination antiretroviral therapy (cART) use and viral suppression (VS). Methods Adults from Caribbean, Central and South America network for HIV epidemiology clinical cohorts in seven countries contributed data between 2003 and 2012. Retention was defined as two or more HIV care visits annually, >90 days apart. cART was defined as prescription of three or more antiretroviral agents annually. VS was defined as HIV-1 RNA <200 copies/mL at last measurement annually. cART and VS denominators were subjects with at least one visit annually. Multivariable modified Poisson regression was used to assess temporal trends and examine associations between age, sex, HIV transmission mode, cohort, calendar year and time in care. Results Among 18,799 individuals in retention analyses, 14,380 in cART analyses and 13,330 in VS analyses, differences existed between those meeting indicator definitions versus those not by most characteristics. Retention, cART and VS significantly improved from 2003 to 2012 (63 to 77%, 74 to 91% and 53 to 82%, respectively; p<0.05, each). Female sex (risk ratio (RR)=0.97 vs. males) and injection drug use as HIV transmission mode (RR=0.83 vs. male sexual contact with males (MSM)) were significantly associated with lower retention, but unrelated with cART or VS. MSM (RR=0.96) significantly decreased the probability of cART compared with heterosexual transmission. Conclusions HIV Care Continuum outcomes improved over time in Latin America, though disparities for vulnerable groups remain. Efforts must be made to increase retention, cART and VS, while engaging in additional research to sustain progress in these settings. PMID:27065108

  10. The performance of matrices in daily clinical practice to predict rapid radiologic progression in patients with early RA.

    Science.gov (United States)

    De Cock, D; Vanderschueren, G; Meyfroidt, S; Joly, J; Van der Elst, K; Westhovens, R; Verschueren, P

    2014-04-01

    To compare in daily clinical practice the reliability of matrices that forecast rapid radiologic progression (RRP) at year one, at year two, and over 2 years in patients with early rheumatoid arthritis (RA). Overall, 74 early RA patients with X-rays of hands and feet at baseline, year one, and year two were included. Initial DMARD combination therapy with steroids (ICTS) or DMARD monotherapy (IMT) was initiated according to patients' RA severity, based on rheumatologist opinion. The images were scored via the modified Sharp/van der Heijde (SvH) method. A total Sharp score progression of equal or higher than five per year was considered RRP. Six matrices were tested: ASPIRE CRP/ESR matrices, the BEST matrix, two SWEFOT matrices, and the ESPOIR matrix. Patients were placed in each of them yielding a RRP probability. The performance was tested by Area Under the Curve analysis reflecting the predictive value. Four patients developed RRP in year one, five in year two, and four over 2 years. With regard to face validity, the predicted probability did not correspond to the risk in reality: the one ICTS patient who developed RRP over 2 years was always found in the lowest RRP categories of all matrices. The ASPIRE CRP matrix yielded at least a moderate predicting value for the three time points. The other matrices showed moderate to no predicting value. The performance of all matrices was disappointing and it is impossible to fully rely on the existing matrices in daily clinical practice. © 2013 Published by Elsevier Inc.

  11. Evidence, research, and clinical practice: a patient-centered framework for progress in wound care.

    Science.gov (United States)

    van Rijswijk, Lia; Gray, Mikel

    2012-01-01

    Traditional criteria used in selecting wound care interventions are being slowly replaced with an evidence-based practice approach. The value of such an approach for providing optimal care has been established, but the definition of evidence-based care and the process used to generate evidence continue to evolve. For example, the role of studies developed to demonstrate efficacy, randomized controlled trials, the value of effectiveness studies designed to evaluate outcomes in real world practice, and the use of disease-oriented (interim) study outcomes for wound care research, such as reduces wound fluid or improves granulation tissue formation, have been topics of international conversations and consensus documents. In addition, the use in some clinical studies and most systematic study reviews of ingredient or characteristic-based categories to group products that may not share a common operational definition of how they function has led to a high variability in outcomes, resulting in inconclusive or low-level evidence. These concerns and debates, along with their influence on practice, may cast doubt on the value of evidence-based practice guidelines for some clinicians, slowing their rate of implementation, and extending the discussion about definitions of evidence-based care and the relative merits of various research designs. At the same time, amid growing concerns about medical device safety, clinicians must answer 3 questions about an intervention and its related products or devices in order to provide safe and effective care: (1) Can it work? (2) Does it work? (3) Is it worth it? Reviewing current knowledge about wound care, wound treatment modalities, and the basic principles of research within the existing framework of questions to be answered suggests a clear path toward obtaining much-needed evidence. In wound care, using clearly defined processes to study patient-centered outcomes (eg, quality of life, complete healing) and only product groupings that

  12. Effects of acupressure on progress of labor and cesarean section rate: randomized clinical trial.

    Science.gov (United States)

    Mafetoni, Reginaldo Roque; Shimo, Antonieta Keiko Kakuda

    2015-01-01

    OBJECTIVE To analyze the effects of acupressure at the SP6 point on labor duration and cesarean section rates in parturients served in a public maternity hospital. METHODS This controlled, randomized, double-blind, pragmatic clinical trial involved 156 participants with gestational age ≥ 37 weeks, cervical dilation ≥ 4 cm, and ≥ 2 contractions in 10 min. The women were randomly divided into an acupressure, placebo, or control group at a university hospital in an inland city in the state of Sao Paulo, Brazil, in 2013. Acupressure was applied to the SP6 point during contractions for 20 min. RESULTS The average labor duration was significantly different between the SP6 acupressure group [221.5 min (SD = 162.4)] versus placebo [397.9 min (SD = 265.6)] and versus control [381.9 min (SD = 358.3)] (p = 0.0047); however, the groups were similar regarding the cesarean section rates (p = 0.2526) and Apgar scores in the first minute (p = 0.9542) and the fifth minute (p = 0.7218) of life of the neonate. CONCLUSIONS The SP6 acupressure point proved to be a complementary measure to induce labor and may shorten the labor duration without causing adverse effects to the mother or the newborn. However, it did not affect the cesarean section rate.

  13. Emdogain does not prevent progressive root resorption after replantation of avulsed teeth: a clinical study.

    Science.gov (United States)

    Schjøtt, M; Andreasen, J O

    2005-02-01

    Emdogain has been shown in clinical and experimental studies to promote regeneration of all periodontal tissues: cementum with anchoring fibres, a functional, periodontal ligament and alveolar bone in connection with treatment of marginal periodontitis. The intention of this study was to analyse whether this regenerative capacity upon the periodontal ligament also worked in a trauma situation where a significant number of PDL cells have been eliminated because of unphysiologic storage or actual damage during avulsion or replantation. Furthermore if ankylosis sites already established because of earlier replantation after avulsion could be surgical removed and application of Emdogain could revert the ankylosis stage to a normal PDL situation. The first treatment situation was tested in seven patients with a total of 16 avulsed teeth with varying time of extra oral storage. The teeth were extra-orally endodontically treated and the root and socket covered with Emdogain before replantation. All teeth demonstrated subsequent ankylosis, primarily diagnosed by a percussion test. The second treatment situation where an ankylosis was already established constituted of seven patients with a total of 11 teeth because of previous replantation after avulsion. These teeth were all extracted, the ankylosis sites removed and the root and socket treated with Emdogain. After 6 months all teeth showed recurrence of ankylosis. It is concluded that Emdogain was not able to prevent or cure ankylosis.

  14. [A progress in the standardization in clinical enzymology using calibrators adapted to several techniques].

    Science.gov (United States)

    Dourson, J L; Lessinger, J M; Férard, G

    1997-01-01

    Results in enzymology obtained in routine conditions, differ considerably according to the measurement procedures, and the use of conversion factors is not an advisable solution. Some studies show that between-laboratory agreement of results can be improved by using validated enzyme calibrators. The conditions, which are required to define a strategy for the development of such calibrators, are described in a first part. The example of lipase activity, which is measured in routine conditions with important between-method discrepancy, is studied in a second part. This example emphasised the need of an a priori control of the validity of the calibrators. Under these conditions, between-method agreement is in fact considerably improved. With the collaboration of manufacturers for the development of validated enzyme multicalibrators, it will be possible to improve the efficiency of the information transmitted by clinical chemists to clinicians. Thus, enzyme activities measurements could benefit from the same improvement as immunoassay of proteins with the use of CRM 470 by manufacturers to calibrate their standards.

  15. Reversible Switching of Cooperating Replicators

    Science.gov (United States)

    Urtel, Georg C.; Rind, Thomas; Braun, Dieter

    2017-02-01

    How can molecules with short lifetimes preserve their information over millions of years? For evolution to occur, information-carrying molecules have to replicate before they degrade. Our experiments reveal a robust, reversible cooperation mechanism in oligonucleotide replication. Two inherently slow replicating hairpin molecules can transfer their information to fast crossbreed replicators that outgrow the hairpins. The reverse is also possible. When one replication initiation site is missing, single hairpins reemerge from the crossbreed. With this mechanism, interacting replicators can switch between the hairpin and crossbreed mode, revealing a flexible adaptation to different boundary conditions.

  16. CASE OF DIAGNOSIS OF APICAL FORM OF HYPERTROPHIC CARDIOMYOPATHY WITH A PATIENT WITH PROGRESSIVE ANGINA CLINIC

    Directory of Open Access Journals (Sweden)

    N. S. Krylova

    2015-01-01

    Full Text Available Objective of work: to describe the apical form of hypertrophic cardiomyopathy (AFHC developing under the "mask" of the ischemic heart disease not diagnosed for a long period.Materials and methods. Patient B., 73 y.o., female, was brought to the cardiology department with complains of severe pressing pain behind the breastbone caused with no apparent reason and lasting for over 4 hours. The following examination of the patient was performed: electrocardiography (ECG, echocardiography (EchoCG, Holter ECG monitoring, coronary angiography (CAG, ventriculography.Results. The final diagnosis for the patient was set on the basis of the following readings: ECG data (basic rhythm – atrial fibrillation, left ventricle (LV hypertrophy, negative T-waves in leads V1–6, ST segment depression up to 1–2 mm in leads V4–6, EchoCG (hypertrophy of apical segments of the LV with decreasing of its cavity, moderate dilatation of the left atrium, intraventricular obstruction in the apical third of the LV with the maximum pressure gradient of up to 48 mm Hg., CAG (stenotic lesions of coronary arteries were found, ventriculography (LV volume is not increased, no violations of local contractility, narrowing of the LV cavity in the lower third is observed with thinning in the apex, which indicatesexpressed apical hypertrophy of the LV myocard. AFHC, apical form with moderate obstruction in the lower third of the left ventricle. Stress angina syndrome. CAG and ventriculography were main diagnostic methods that allowed setting the final diagnosis.Conclusion. The clinical case sets forth the peculiarities of diagnostics, therapy, and post-therapy management of patients with this form of AFHC.

  17. Clinical features of isolated gestational proteinuria progressing to pre-eclampsia: retrospective observational study

    Science.gov (United States)

    Akaishi, Rina; Yamada, Takahiro; Morikawa, Mamoru; Nishida, Ryutaro; Minakami, Hisanori

    2014-01-01

    Objectives Some women with isolated gestational proteinuria (IGP) later develop hypertension and are diagnosed with pre-eclampsia (PE). This study was performed to determine whether clinical features of such proteinuria preceding PE (P-PE) differ from those of other PE (O-PE). Design Retrospective observational study after approval of the institutional review board of ethics. Setting A single university hospital. Proteinuria was defined as a protein-to-creatinine ratio (mg/mg; P/Cr) of ≥0.27 in the spot urine specimen. IGP was defined as proteinuria in the absence of hypertension. P-PE was defined as PE in which proteinuria preceded hypertension by more than 2 days. Participants All of 10 and 18 consecutive women with P-PE and O-PE, respectively, who gave birth between January 2008 and August 2013. Results Proteinuria appeared earlier (at 30.2±3.0 vs 35.3±4.3 weeks, p=0.001), the P/Cr level was greater at birth (7.28±2.14 vs 3.19±2.49, pIGP was 10.0±5.9 days (range 3–20), and the time interval until delivery after diagnosis of PE was 6.1±8.2 days (range 0–23) in 10 women with P-PE. The P/Cr levels at birth were significantly inversely correlated with the antenatal lowest antithrombin activity and fibrinogen levels among the 28 women with PE. Conclusions Women with P-PE were likely to exhibit greater proteinuria in the urine, greater water retention in the interstitial space and more enhanced coagulation–fibrinolysis, thus suggesting that they may constitute a more severe form of PE than women with O-PE do. PMID:24747797

  18. The nature of replication of tick-borne encephalitis virus strains isolated from residents of the Russian Far East with inapparent and clinical forms of infection.

    Science.gov (United States)

    Leonova, Galina N; Maystrovskaya, Olga S; Kondratov, Ilya G; Takashima, Ikuo; Belikov, Sergei I

    2014-08-30

    We describe the biological properties and molecular characteristics of complete genomes of 33 tick-borne encephalitis virus (TBEV) strains that induced different forms of infection, from inapparent to severe focal ones resulting in fatal outcome. Hemagglutinating activity of Oshima-like strains was higher at pH 5.8, while activity of Sofjin- and Senhzang-like strains were higher at pH 6.2 and 6.8, respectively. We determined susceptibility of porcine kidney (PK) cell cultures to these TBEV strains by cytopathic effect (CPE), plaque formation, and size of plaques. The clinical TBEV strains had higher virus titers both in tissue culture infectious dose 50(TCID50) and in plaque-forming unit (PFU) titers and larger plaques than the inapparent strains. A comparison of virus multiplication kinetics by PFU in culture fluid with kinetics of ELISA antigen and hemagglutinin accumulation suggested a different mechanism of interaction between these virus strains and PK cells at the initial stage of cell infection.

  19. Association between Single Nucleotide Polymorphism of Vitamin D Receptor Gene FokI Polymorphism and Clinical Progress of Benign Prostatic Hyperplasia

    Directory of Open Access Journals (Sweden)

    Li Ruan

    2015-01-01

    Full Text Available Background. The aim of the study was to investigate the association between single nucleotide polymorphism (SNP of vitamin D receptor (VDR gene and clinical progress of benign prostatic hyperplasia (BPH in Chinese men. Methods. The DNA was extracted from blood of 200 BPH patients with operation (progression group and 200 patients without operation (control group, respectively. The genotypes of VDR gene FokI SNP represented by “F/f” were identified by PCR-restriction fragment length polymorphism. The odds ratio (OR of having progression of BPH for having the genotype were calculated. Results. Our date indicated that the f alleles of the VDR gene FokI SNP associated with the progression of BPH (P=0.009. Conclusion. For the first time, our study demonstrated that VDR gene FokI SNP may be associated with the risk of BPH progress.

  20. A warning to the Brazilian Speech-Language Pathology and Audiology community about the importance of scientific and clinical activities in primary progressive aphasia.

    Science.gov (United States)

    Beber, Bárbara Costa; Brandão, Lenisa; Chaves, Márcia Lorena Fagundes

    2015-01-01

    This article aims to warn the Brazilian Speech-Language Pathology and Audiology scientific community about the importance and necessity of scientific and clinical activities regarding Primary Progressive Aphasia. This warning is based on a systematic literature review of the scientific production on Primary Progressive Aphasia, from which nine Brazilian articles were selected. It was observed that there is an obvious lack of studies on the subject, as all the retrieved articles were published in medical journals and much of it consisted of small samples; only two articles described the effectiveness of speech-language therapy in patients with Primary Progressive Aphasia. A perspective for the future in the area and characteristics of Speech-Language Therapy for Primary Progressive Aphasia are discussed. As a conclusion, it is evident the need for greater action by Speech-Language Pathology and Audiology on Primary Progressive Aphasia.

  1. CLINICAL-SIGNIFICANCE OF INTERLEUKIN-6 MEASUREMENT IN EARLY RHEUMATOID-ARTHRITIS - RELATION WITH LABORATORY AND CLINICAL-VARIABLES AND RADIOLOGICAL PROGRESSION IN A 3 YEAR PROSPECTIVE-STUDY

    NARCIS (Netherlands)

    VANLEEUWEN, MA; WESTRA, J; LIMBURG, PC; VANRIEL, PLCM; VANRIJSWIJK, MH

    1995-01-01

    Objective-To evaluate the clinical significance of interleukin-6 (IL-6) measurements in relation to laboratory and clinical measures of disease activity and radiological progression in early rheumatoid arthritis (RA). Methods-A Irrespective study was performed in 51 patients with early RA during the

  2. Expression of FGFR3 and FGFR4 and clinical risk factors associated with progression-free survival in synovial sarcoma.

    Science.gov (United States)

    Charbonneau, Bridget; Vogel, Rachel Isaksson; Manivel, J Carlos; Rizzardi, Anthony; Schmechel, Stephen C; Ognjanovic, Simona; Subramanian, Subbaya; Largaespada, David; Weigel, Brenda

    2013-09-01

    Although rare, synovial sarcoma (SS) is one of the most common soft tissue sarcomas affecting young adults. To investigate potential tumor markers related to synovial sarcoma prognosis, we carried out a single-institution retrospective analysis of 103 patients diagnosed with SS between 1980 and 2009. Clinical outcome data were obtained from medical records, and archived tissue samples were used to evaluate the relationship between progression-free survival (PFS) and several prognostic factors, including tumor expression of FGFR3 and FGFR4. No associations were found between PFS and gender, body mass index, tumor site, SS18-SSX translocation, or FGFR4 expression. As seen in previous studies, age at diagnosis (5 cm, 22% 10-year PFS; P < .0001) were associated with PFS in SS patients. In addition, in a subset of patients with available archived tumor samples taken prior to chemotherapy or radiation (n = 34), higher FGFR3 expression was associated with improved PFS (P = .030). To the best of our knowledge, this is the largest study of SS to date to suggest a potential clinical role for FGFR3. While small numbers make this investigation somewhat exploratory, the findings merit future investigation on a larger scale.

  3. Uncertainty of measurement and clinical value of semen analysis: has standardisation through professional guidelines helped or hindered progress?

    Science.gov (United States)

    Tomlinson, M J

    2016-09-01

    This article suggests that diagnostic semen analysis has no more clinical value today than it had 25-30 years ago, and both the confusion surrounding its evidence base (in terms of relationship with conception) and the low level of confidence in the clinical setting is attributable to an associated high level of 'uncertainty'. Consideration of the concept of measurement uncertainty is mandatory for medical laboratories applying for the ISO15189 standard. It is evident that the entire semen analysis process is prone to error every step from specimen collection to the reporting of results and serves to compound uncertainty associated with diagnosis or prognosis. Perceived adherence to published guidelines for the assessment of sperm concentration, motility and morphology does not guarantee a reliable and reproducible test result. Moreover, the high level of uncertainty associated with manual sperm motility and morphology can be attributed to subjectivity and lack a traceable standard. This article describes where and why uncertainty exists and suggests that semen analysis will continue to be of limited value until it is more adequately considered and addressed. Although professional guidelines for good practice have provided the foundations for testing procedures for many years, the risk in following rather prescriptive guidance to the letter is that unless they are based on an overwhelmingly firm evidence base, the quality of semen analysis will remain poor and the progress towards the development of more innovative methods for investigating male infertility will be slow.

  4. Plant-Derived Anti-Inflammatory Compounds: Hopes and Disappointments regarding the Translation of Preclinical Knowledge into Clinical Progress

    Directory of Open Access Journals (Sweden)

    Robert Fürst

    2014-01-01

    Full Text Available Many diseases have been described to be associated with inflammatory processes. The currently available anti-inflammatory drug therapy is often not successful or causes intolerable side effects. Thus, new anti-inflammatory substances are still urgently needed. Plants were the first source of remedies in the history of mankind. Since their chemical characterization in the 19th century, herbal bioactive compounds have fueled drug development. Also, nowadays, new plant-derived agents continuously enrich our drug arsenal (e.g., vincristine, galantamine, and artemisinin. The number of new, pharmacologically active herbal ingredients, in particular that of anti-inflammatory compounds, rises continuously. The major obstacle in this field is the translation of preclinical knowledge into evidence-based clinical progress. Human trials of good quality are often missing or, when available, are frequently not suitable to really prove a therapeutical value. This minireview will summarize the current situation of 6 very prominent plant-derived anti-inflammatory compounds: curcumin, colchicine, resveratrol, capsaicin, epigallocatechin-3-gallate (EGCG, and quercetin. We will highlight their clinical potential and/or pinpoint an overestimation. Moreover, we will sum up the planned trials in order to provide insights into the inflammatory disorders that are hypothesized to be beneficially influenced by the compound.

  5. Progress on clinical study of peri-implantitis%种植体周围炎临床研究进展

    Institute of Scientific and Technical Information of China (English)

    杨光艳

    2012-01-01

    Peri-implantitis is defined as an inflammatory process that: (1) affects the tissues around an osseointegrated implant in function, (2) results in loss of supporting bone and failure of osseointegration, (3) even leads to loss of the implant. Peri-implantitis is one of the frequent complications related to dental implant treatment. This review indicate the progresses of clinical research on peri-implantitis, in three aspects: risk factors, clinical diagnosis and treatment.%种植体周围炎是指发生在已形成骨结合并行使功能的种植体周围组织的炎症性过程,可使支持骨丧失、骨性结合失败,甚至导致种植体脱落.种植体周围炎是牙种植术后常见的并发症之一.本文就危险因素、临床诊断和治疗三方面综述种植体周围炎的临床研究进展.

  6. Defining natural history: assessment of the ability of college students to aid in characterizing clinical progression of Niemann-Pick disease, type C.

    Directory of Open Access Journals (Sweden)

    Jenny Shin

    Full Text Available Niemann-Pick Disease, type C (NPC is a fatal, neurodegenerative, lysosomal storage disorder. It is a rare disease with broad phenotypic spectrum and variable age of onset. These issues make it difficult to develop a universally accepted clinical outcome measure to assess urgently needed therapies. To this end, clinical investigators have defined emerging, disease severity scales. The average time from initial symptom to diagnosis is approximately 4 years. Further, some patients may not travel to specialized clinical centers even after diagnosis. We were therefore interested in investigating whether appropriately trained, community-based assessment of patient records could assist in defining disease progression using clinical severity scores. In this study we evolved a secure, step wise process to show that pre-existing medical records may be correctly assessed by non-clinical practitioners trained to quantify disease progression. Sixty-four undergraduate students at the University of Notre Dame were expertly trained in clinical disease assessment and recognition of major and minor symptoms of NPC. Seven clinical records, randomly selected from a total of thirty seven used to establish a leading clinical severity scale, were correctly assessed to show expected characteristics of linear disease progression. Student assessment of two new records donated by NPC families to our study also revealed linear progression of disease, but both showed accelerated disease progression, relative to the current severity scale, especially at the later stages. Together, these data suggest that college students may be trained in assessment of patient records, and thus provide insight into the natural history of a disease.

  7. Therapeutic targeting of replicative immortality.

    Science.gov (United States)

    Yaswen, Paul; MacKenzie, Karen L; Keith, W Nicol; Hentosh, Patricia; Rodier, Francis; Zhu, Jiyue; Firestone, Gary L; Matheu, Ander; Carnero, Amancio; Bilsland, Alan; Sundin, Tabetha; Honoki, Kanya; Fujii, Hiromasa; Georgakilas, Alexandros G; Amedei, Amedeo; Amin, Amr; Helferich, Bill; Boosani, Chandra S; Guha, Gunjan; Ciriolo, Maria Rosa; Chen, Sophie; Mohammed, Sulma I; Azmi, Asfar S; Bhakta, Dipita; Halicka, Dorota; Niccolai, Elena; Aquilano, Katia; Ashraf, S Salman; Nowsheen, Somaira; Yang, Xujuan

    2015-12-01

    One of the hallmarks of malignant cell populations is the ability to undergo continuous proliferation. This property allows clonal lineages to acquire sequential aberrations that can fuel increasingly autonomous growth, invasiveness, and therapeutic resistance. Innate cellular mechanisms have evolved to regulate replicative potential as a hedge against malignant progression. When activated in the absence of normal terminal differentiation cues, these mechanisms can result in a state of persistent cytostasis. This state, termed "senescence," can be triggered by intrinsic cellular processes such as telomere dysfunction and oncogene expression, and by exogenous factors such as DNA damaging agents or oxidative environments. Despite differences in upstream signaling, senescence often involves convergent interdependent activation of tumor suppressors p53 and p16/pRB, but can be induced, albeit with reduced sensitivity, when these suppressors are compromised. Doses of conventional genotoxic drugs required to achieve cancer cell senescence are often much lower than doses required to achieve outright cell death. Additional therapies, such as those targeting cyclin dependent kinases or components of the PI3K signaling pathway, may induce senescence specifically in cancer cells by circumventing defects in tumor suppressor pathways or exploiting cancer cells' heightened requirements for telomerase. Such treatments sufficient to induce cancer cell senescence could provide increased patient survival with fewer and less severe side effects than conventional cytotoxic regimens. This positive aspect is countered by important caveats regarding senescence reversibility, genomic instability, and paracrine effects that may increase heterogeneity and adaptive resistance of surviving cancer cells. Nevertheless, agents that effectively disrupt replicative immortality will likely be valuable components of new combinatorial approaches to cancer therapy. Copyright © 2015 The Authors

  8. Chromatin replication and epigenome maintenance

    DEFF Research Database (Denmark)

    Alabert, Constance; Groth, Anja

    2012-01-01

    initiates, whereas the replication process itself disrupts chromatin and challenges established patterns of genome regulation. Specialized replication-coupled mechanisms assemble new DNA into chromatin, but epigenome maintenance is a continuous process taking place throughout the cell cycle. If DNA...

  9. Chromatin replication and epigenome maintenance

    DEFF Research Database (Denmark)

    Alabert, Constance; Groth, Anja

    2012-01-01

    initiates, whereas the replication process itself disrupts chromatin and challenges established patterns of genome regulation. Specialized replication-coupled mechanisms assemble new DNA into chromatin, but epigenome maintenance is a continuous process taking place throughout the cell cycle. If DNA...

  10. Coordination between chromosome replication, segregation, and cell division in Caulobacter crescentus

    DEFF Research Database (Denmark)

    Jensen, Rasmus Bugge

    2006-01-01

    Progression through the Caulobacter crescentus cell cycle is coupled to a cellular differentiation program. The swarmer cell is replicationally quiescent, and DNA replication initiates at the swarmer-to-stalked cell transition. There is a very short delay between initiation of DNA replication......, and the completely replicated terminus regions stay associated with each other after chromosome replication is completed, disassociating very late in the cell cycle shortly before the final cell division event. Invagination of the cytoplasmic membrane occurs earlier than separation of the replicated terminus regions...

  11. A randomized clinical trial of Acceptance and Commitment Therapy vs. Progressive Relaxation Training for obsessive compulsive disorder

    Science.gov (United States)

    Twohig, Michael P.; Hayes, Steven C.; Plumb, Jennifer C.; Pruitt, Larry D.; Collins, Angela B.; Hazlett-Stevens, Holly; Woidneck, Michelle R.

    2010-01-01

    Objective Effective treatments for adult OCD exist, but refusal and drop-out rates are high and treatments are not effective for all individuals who complete them. Thus, additional treatment options are needed. This study investigated the effectiveness of eight sessions of Acceptance and Commitment Therapy (ACT) for adult obsessive compulsive disorder (OCD) compared to Progressive Relaxation Training (PRT). Method 79 adults (66% Female) diagnosed with OCD (M age=37, 89% Caucasian) participated in a randomized clinical trial of 8 sessions of ACT or PRT with no in-session exposure. The following assessments were completed at pretreatment, posttreatment, and three month follow-up by an assessor who was unaware of treatment conditions: Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Beck Depression Inventory-II, Quality of Life Scale, Acceptance and Action Questionnaire, Thought Action Fusion Scale, and Thought Control Questionnaire. The Treatment Evaluation Inventory-Short Form was completed at posttreatment. Results ACT produced greater changes at posttreatment and follow-up over PRT on OCD severity (Y-BOCS: ACT pre=24.22, post=12.76, follow-up=11.79; PRT pre=25.4, post=18.67, follow-up=16.23), and produced greater change on depression among those reporting at least mild depression before treatment. Clinically significant change in OCD severity occurred more in the ACT condition than PRT using multiple criteria (clinical response rates: ACT post=46-56%, follow-up 46-66%; PRT post=13%-18%, follow-up 16-18%). Quality of life improved in both conditions but was marginally in favor of ACT at post. Finally, treatment refusal (2.4% ACT, 7.8% PRT) and drop-out (9.8% ACT, 13.2% PRT) were low in both conditions. Conclusions ACT is worth exploring further as a treatment for OCD. PMID:20873905

  12. Cytolytic replication of echoviruses in colon cancer cell lines

    Directory of Open Access Journals (Sweden)

    Gullberg Maria

    2011-10-01

    Full Text Available Abstract Background Colorectal cancer is one of the most common cancers in the world, killing nearly 50% of patients afflicted. Though progress is being made within surgery and other complementary treatments, there is still need for new and more effective treatments. Oncolytic virotherapy, meaning that a cancer is cured by viral infection, is a promising field for finding new and improved treatments. We have investigated the oncolytic potential of several low-pathogenic echoviruses with rare clinical occurrence. Echoviruses are members of the enterovirus genus within the family Picornaviridae. Methods Six colon cancer cell lines (CaCo-2, HT29, LoVo, SW480, SW620 and T84 were infected by the human enterovirus B species echovirus 12, 15, 17, 26 and 29, and cytopathic effects as well as viral replication efficacy were investigated. Infectivity was also tested in spheroids grown from HT29 cells. Results Echovirus 12, 17, 26 and 29 replicated efficiently in almost all cell lines and were considered highly cytolytic. The infectivity of these four viruses was further evaluated in artificial tumors (spheroids, where it was found that echovirus 12, 17 and 26 easily infected the spheroids. Conclusions We have found that echovirus 12, 17 and 26 have potential as oncolytic agents against colon cancer, by comparing the cytolytic capacity of five low-pathogenic echoviruses in six colon cancer cell lines and in artificial tumors.

  13. Initiation of adenovirus DNA replication.

    OpenAIRE

    Reiter, T; Fütterer, J; Weingärtner, B; Winnacker, E L

    1980-01-01

    In an attempt to study the mechanism of initiation of adenovirus DNA replication, an assay was developed to investigate the pattern of DNA synthesis in early replicative intermediates of adenovirus DNA. By using wild-type virus-infected cells, it was possible to place the origin of adenovirus type 2 DNA replication within the terminal 350 to 500 base pairs from either of the two molecular termini. In addition, a variety of parameters characteristic of adenovirus DNA replication were compared ...

  14. Chromatin replication and epigenome maintenance

    DEFF Research Database (Denmark)

    Alabert, Constance; Groth, Anja

    2012-01-01

    Stability and function of eukaryotic genomes are closely linked to chromatin structure and organization. During cell division the entire genome must be accurately replicated and the chromatin landscape reproduced on new DNA. Chromatin and nuclear structure influence where and when DNA replication...... initiates, whereas the replication process itself disrupts chromatin and challenges established patterns of genome regulation. Specialized replication-coupled mechanisms assemble new DNA into chromatin, but epigenome maintenance is a continuous process taking place throughout the cell cycle. If DNA...

  15. Replication Research and Special Education

    Science.gov (United States)

    Travers, Jason C.; Cook, Bryan G.; Therrien, William J.; Coyne, Michael D.

    2016-01-01

    Replicating previously reported empirical research is a necessary aspect of an evidence-based field of special education, but little formal investigation into the prevalence of replication research in the special education research literature has been conducted. Various factors may explain the lack of attention to replication of special education…

  16. Replication Research and Special Education

    Science.gov (United States)

    Travers, Jason C.; Cook, Bryan G.; Therrien, William J.; Coyne, Michael D.

    2016-01-01

    Replicating previously reported empirical research is a necessary aspect of an evidence-based field of special education, but little formal investigation into the prevalence of replication research in the special education research literature has been conducted. Various factors may explain the lack of attention to replication of special education…

  17. New therapeutic approaches targeted at the late stages of the HIV-1 replication cycle.

    Science.gov (United States)

    Jiang, Yan; Liu, Xinyong; De Clercq, Erik

    2011-01-01

    Owing to the serious clinical consequences associated with acquisition of resistance to current antiretroviral drugs, discovery of new drug targets and development of novel anti-HIV-1 therapeutic agents have become a high research priority. The late stages of HIV-1 replication involve the processes of assembly, budding and maturation, and comprise several new potential therapeutic targets which have not (yet) been targeted by any of the antiretroviral drugs approved at present. The structural protein Gag plays a central role in these stages through its different regions and mature Gag proteins working in concert. In this article, we highlight a number of steps in the late stages of HIV-1 replication that represent promising targets for drug discovery. Recent progress in development of related inhibitors targeting at CA, zinc fingers of NC, p6-Tsg101 interaction, lipid rafts of plasma membrane, proteolytic cleavage sites in Gag and gp160 processing is also reviewed.

  18. Replication data collection highlights value in diversity of replication attempts

    Science.gov (United States)

    DeSoto, K. Andrew; Schweinsberg, Martin

    2017-01-01

    Researchers agree that replicability and reproducibility are key aspects of science. A collection of Data Descriptors published in Scientific Data presents data obtained in the process of attempting to replicate previously published research. These new replication data describe published and unpublished projects. The different papers in this collection highlight the many ways that scientific replications can be conducted, and they reveal the benefits and challenges of crucial replication research. The organizers of this collection encourage scientists to reuse the data contained in the collection for their own work, and also believe that these replication examples can serve as educational resources for students, early-career researchers, and experienced scientists alike who are interested in learning more about the process of replication. PMID:28291224

  19. The DNA damage checkpoint response to replication stress: A Game of Forks.

    Directory of Open Access Journals (Sweden)

    Rachel eJossen

    2013-03-01

    Full Text Available Conditions challenging replication fork progression, collectively referred to as replication stress, represent a major source of genomic instability and are associated to cancer onset. The replication checkpoint, a specialized branch of the DNA damage checkpoint, monitors fork problems and triggers a cellular response aimed at preserving genome integrity. Here, we review the mechanisms by which the replication checkpoint monitors and responds to replication stress, focusing on the checkpoint-mediated pathways contributing to protect replication fork integrity. We discuss how cells achieve checkpoint signaling inactivation once replication stress is overcome and how a failure to timely revert checkpoint-mediated changes in cellular physiology might impact on replication dynamics and genome integrity. We also highlight the checkpoint function as an anti-cancer barrier preventing cells malignant transformation following oncogene-induced replication stress.

  20. Clinical research progress of vitamin D%维生素D的临床研究进展

    Institute of Scientific and Technical Information of China (English)

    袁辉辉; 楼慧玲

    2013-01-01

    近年来的研究发现维生素D不仅在骨骼疾病中发挥重要作用,在非骨骼疾病中也起到十分重要的作用.基础研究证实维生素D受体广泛分布于体内各种组织细胞中,越来越多的临床研究发现补充维生素D在预防和治疗骨质疏松症、心脑血管病、肺部疾病、慢性代谢性及肿瘤性疾病中有重要作用.本文就维生素D与上述疾病关系的研究进展进行综述,主要着眼于当前的临床热点研究方面.结果显示观察性研究证据支持维生素D与上述非骨骼系统疾病有很强的相关性,但是尚缺乏大规模和长期的随机临床试验证据,因此,需要更多的研究来探讨补充维生素D在预防和治疗非骨骼疾病中的作用.%Researches in recent years have found that vitamin D plays an important role not only in skeletal diseases, but also in non-skeletal diseases. Basic researches have confirmed that vitamin D receptors are widely distributed in all kinds of cells in vivo. More and more clinical studies have found that vitamin D plays an important role in the prevention and treatment of osteoporosis, cardiovascular and cerebrovascular diseases, lung diseases, and chronic metabolic and neoplastic diseases. In this paper, we review the research progress of the relationship among vitamin D and the diseases mentioned above, and mainly focus on the clinical aspects of current hot research. The results show that the observational studies support strongly correlation among vitamin D and the non -skeletal diseases mentioned above. But there still remains a paucity of large-scale and long-term randomized clinical trials. Therefore, more clinical studies are needed to clarify the effect of vitamin D supplementation on preventing and treating non -skeletal diseases.

  1. The sub-cellular localization of Sulfolobus DNA replication.

    Science.gov (United States)

    Gristwood, Tamzin; Duggin, Iain G; Wagner, Michaela; Albers, Sonja V; Bell, Stephen D

    2012-07-01

    Analyses of the DNA replication-associated proteins of hyperthermophilic archaea have yielded considerable insight into the structure and biochemical function of these evolutionarily conserved factors. However, little is known about the regulation and progression of DNA replication in the context of archaeal cells. In the current work, we describe the generation of strains of Sulfolobus solfataricus and Sulfolobus acidocaldarius that allow the incorporation of nucleoside analogues during DNA replication. We employ this technology, in conjunction with immunolocalization analyses of replisomes, to investigate the sub-cellular localization of nascent DNA and replisomes. Our data reveal a peripheral localization of replisomes in the cell. Furthermore, while the two replication forks emerging from any one of the three replication origins in the Sulfolobus chromosome remain in close proximity, the three origin loci are separated.

  2. Anatomy of Mammalian Replication Domains

    Science.gov (United States)

    Takebayashi, Shin-ichiro; Ogata, Masato; Okumura, Katsuzumi

    2017-01-01

    Genetic information is faithfully copied by DNA replication through many rounds of cell division. In mammals, DNA is replicated in Mb-sized chromosomal units called “replication domains.” While genome-wide maps in multiple cell types and disease states have uncovered both dynamic and static properties of replication domains, we are still in the process of understanding the mechanisms that give rise to these properties. A better understanding of the molecular basis of replication domain regulation will bring new insights into chromosome structure and function. PMID:28350365

  3. Changes in muscle activity determine progression of clinical symptoms in patients with chronic spine-related muscle pain. A complex clinical and neurophysiological approach.

    Science.gov (United States)

    Wytrazek, Marcin; Huber, Juliusz; Lisinski, Przemyslaw

    2011-01-01

    Spine-related muscle pain can affect muscle strength and motor unit activity. This study was undertaken to investigate whether surface electromyographic (sEMG) recordings performed during relaxation and maximal contraction reveal differences in the activity of muscles with or without trigger points (TRPs). We also analyzed the possible coexistence of characteristic spontaneous activity in needle electromyographic (eEMG) recordings with the presence of TRPs. Thirty patients with non-specific cervical and back pain were evaluated using clinical, neuroimaging and electroneurographic examinations. Muscle pain was measured using a visual analog scale (VAS), and strength using Lovett's scale; trigger points were detected by palpation. EMG was used to examine motor unit activity. Trigger points were found mainly in the trapezius muscles in thirteen patients. Their presence was accompanied by increased pain intensity, decreased muscle strength, increased resting sEMG amplitude, and decreased sEMG amplitude during muscle contraction. eEMG revealed characteristic asynchronous discharges in TRPs. The results of EMG examinations point to a complexity of muscle pain that depends on progression of the myofascial syndrome.

  4. 新型非浸润模板法制备抗癌载药微粒的研究进展%Research progress of novel particle replication for anti-cancer biomaterials

    Institute of Scientific and Technical Information of China (English)

    罗琳; 王运灿; 王天强; 郝建原; 刘钰

    2013-01-01

    In recent years,a method to produce shape-specific nanoparticles which can load any cargo has become a hot and difficult area of research. This review starts with a brief introduction of the advanced nanoparticles,which can load any cargo. A novel method called PRINT (particle replication in non-wetting templates) can be used to design and prepare the templates through the low surface energy perfluoropolyether network. By the confined space of template,shape-controlled particles are fabricated. The method of nanofabrication and application in loading anti-cancer drug is summarized. The anti-cancer drug particles with different haspect ratios contributes to different drug release rates. This breakthrough in nanotechnology will have tremendous potential for applications in nanomedicine and diagnostics.%  近年来,能够精确控制尺寸、形态、组成的纳米微粒制备方法的研究成为科学研究的难点与热点。本文简述了一项新型的纳米微粒制备技术:非浸润模板微印制技术(PRINT,particle replication in non-wetting templates),该技术是将微细加工技术应用到材料合成领域,以不亲水不亲油的含氟材料为模板,预先根据所需微结构的尺寸、形态设计制作模板,利用模板的空间局限作用,压印制备特定尺寸、形态、取向、排布的单分散载药微粒。重点阐述了PRINT技术微粒制备的方法以及在抗癌载药微粒的制备与应用,最后总结指出由PRINT技术制备的多种不同高宽比的形态抗癌载药微粒在病体细胞中具有不同的释药效果,该项技术在纳米微粒制备领域的突破有望推动纳米医药与生物诊断研究领域的巨大发展。

  5. Clinical progression of autoimmune thyroiditis in children and adolescents treated at the Instituto Nacional de Salud del Niño

    OpenAIRE

    Núñez Almache, Oswaldo; Facultad de Medicina, Universidad Nacional Federico Villarreal, Lima, Perú; Servicio de Endocrinología, Instituto Nacional de Salud del Niño, Lima, Perú; Del Aguila Villar, Carlos; Facultad de Medicina, Universidad Nacional Federico Villarreal, Lima, Perú; Servicio de Endocrinología, Instituto Nacional de Salud del Niño, Lima, Perú; Chavez Tejada, Eliana; Servicio de Endocrinología, Instituto Nacional de Salud del Niño (INSN), Lima; Espinoza Robles, Oscar; Servicio de Endocrinología, Instituto Nacional de Salud del Niño, Lima, Perú; Pinto Ibárcena, Paola; Servicio de Endocrinología, Instituto Nacional de Salud del Niño (INSN), Lima; Calagua Quispe, Martha; Servicio de Endocrinología, Instituto Nacional de Salud del Niño, Lima, Perú; De los Santos La Torre, Miguel; Servicio de Endocrinología, Instituto Nacional de Salud del Niño (INSN), Lima

    2016-01-01

    Introduction. Autoimmune thyroiditis is the most common cause of hypothyroidism in children. Clinical diagnosis depends on biochemical condition and monitoring is essential to adopt therapeutic measures and ensure proper growth and development. Objective. To describe the clinical progression of autoimmune thyroiditis in children and adolescents. Design. Retrospective, longitudinal series of cases study. Setting. Department of Endocrinology, Instituto Nacional de Salud del Niño, Lima, Peru (a ...

  6. 楔状缺损临床研究进展%Clinical research progress of wedge shaped defects

    Institute of Scientific and Technical Information of China (English)

    韦界飞

    2012-01-01

    Wedge shaped defects is common non-caries dental disease, which caused by chronic consumption of hard tissue close to lips, huccal and neck. The defects formed by the intersection of two planes, with neatly edge, hard and smooth surface; the defects general had the same color of dental hard tissue, but sometimes could also be with other different colors; the defects were commonly found in the premolars, especially in the first premolar; wedge-shaped defect increase with age growth. In recent years, there were more and more studies focusing on the etiology and clinical progress. Here, we summarized the risk factors, prevalence and clinical treatment for wedge shaped defects.%楔状缺损是非龋性疾病中的常见病,是牙齿唇、颊面牙颈部硬组织发生慢性消耗所致的缺损.其缺损由两个平面相交而成,边缘整齐,表面坚硬光滑,一般均为牙体硬组织本色,有时可有不同程度的着色,好发生于前磨牙,尤其是第一前磨牙,随着年龄增长,楔状缺损有增加的趋势,年龄愈大,楔状缺损愈严重.近年来国内外学者对于楔状缺损的病因学研究更加深入、临床治疗进展的报道也越来越多,本文对楔状缺损的病因、流行情况及治疗进展进行综述.

  7. Progression and survival in prostatic adenocarcinoma: a comparison of clinical stage, Gleason grade, S-phase fraction and DNA ploidy.

    Science.gov (United States)

    Vesalainen, S; Nordling, S; Lipponen, P; Talja, M; Syrjänen, K

    1994-08-01

    Clinical data were reviewed in 325 patients with prostatic adenocarcinoma followed up for a mean of 13 years. Paraffin-embedded tumour biopsy specimens from the primary tumours were available for flow cytometry (FCM) in 273 cases. Intra-tumour heterogeneity in DNA index (DI) was found in 4% of the tumours (54 cases were analysed). S-phase fraction (SPF) and DNA ploidy were significantly interrelated. Aneuploidy and high SPF were significantly related to both a high T category and high Gleason score. The progression in T1-2M0 tumours was related to Gleason score (P = 0.009), DNA ploidy (P = 0.006) and SPF (P = 0.007), while the Gleason score (P = 0.0013), DNA ploidy (P = 0.002) and SPF (P DNA ploidy (P system in which the DNA ploidy or SPF and the Gleason score were combined was found to be of significant prognostic value in all M0 tumours (P < 0.001). The results suggest that FCM can be used as an adjunct to conventional histological assessments for determination of the correct prognostic category in prostatic adenocarcinoma.

  8. The Viral Polymerase Inhibitor 7-Deaza-2'-C-Methyladenosine Is a Potent Inhibitor of In Vitro Zika Virus Replication and Delays Disease Progression in a Robust Mouse Infection Model.

    Directory of Open Access Journals (Sweden)

    Joanna Zmurko

    2016-05-01

    Full Text Available Zika virus (ZIKV is an emerging flavivirus typically causing a dengue-like febrile illness, but neurological complications, such as microcephaly in newborns, have potentially been linked to this viral infection. We established a panel of in vitro assays to allow the identification of ZIKV inhibitors and demonstrate that the viral polymerase inhibitor 7-deaza-2'-C-methyladenosine (7DMA efficiently inhibits replication. Infection of AG129 (IFN-α/β and IFN-γ receptor knock-out mice with ZIKV resulted in acute neutrophilic encephalitis with viral antigens accumulating in neurons of the brain and spinal cord. Additionally, high levels of viral RNA were detected in the spleen, liver and kidney, and levels of IFN-γ and IL-18 were systematically increased in serum of ZIKV-infected mice. Interestingly, the virus was also detected in testicles of infected mice. In line with its in vitro anti-ZIKV activity, 7DMA reduced viremia and delayed virus-induced morbidity and mortality in infected mice, which also validates this small animal model to assess the in vivo efficacy of novel ZIKV inhibitors. Since AG129 mice can generate an antibody response, and have been used in dengue vaccine studies, the model can also be used to assess the efficacy of ZIKV vaccines.  .

  9. Time to biochemical recurrence after radical prostatectomy is an important predictor of clinical progression, distant metastases and cancer-specific death

    Directory of Open Access Journals (Sweden)

    E. I. Veliev

    2014-01-01

    Full Text Available Prostate-specific antigen is a sensitive marker for recurrent prostate cancer (PC after radical prostatectomy (RPE, which can predict thedevelopment of clinical progression and distant metastases well long before they occur. The objective of the investigation was to analyze the relationship of the time to biochemical recurrence (BCR after RPE to the development of clinical progression, distant metastases, and PC death. The vast majority (80.5 % of BCRs was common within the first 2 years after RPE and the recurrence was attended by the highest rate of clinical progression, metastases, and PC death during the first year. Correlation analysis shows that there is a statistically significant inverse correlation between the time to BCR following RPE with the development of clinical progression (rs = -0.43; p < 0.001, metastases (rs = -0.46; p < 0.001, and PC death (rs = -0.41; p < 0.001. Regardless of the time to recurrence, none of 27 patients with favorable histological characteristics (a total of post-RPE Gleason scores of ≤ 6, organ-confined disease, and a negative surgical margin developed distant metastases; only one case had a local tumor recurrence.

  10. The Clinical Presentation of Mitochondrial Diseases in Children with Progressive Intellectual and Neurological Deterioration: A National, Prospective, Population-Based Study

    Science.gov (United States)

    Verity, Christopher M.; Winstone, Anne Marie; Stellitano, Lesley; Krishnakumar, Deepa; Will, Robert; McFarland, Robert

    2010-01-01

    Aim: Our aim was to study the clinical presentation, mode of diagnosis, and epidemiology of mitochondrial disorders in children from the UK who have progressive intellectual and neurological deterioration (PIND). Method: Since April 1997, we have identified patients aged 16 years or younger with suspected PIND through the monthly notification card…

  11. Xiaoxuming decoction’s clinical study progress%小续命汤临床研究进展

    Institute of Scientific and Technical Information of China (English)

    刘燕凤; 孙燕; 王骏; 俞晓飞; 潘卫东

    2016-01-01

    目的:总结小续命汤在临床及实验方面的研究成果,为中医进一步研究小续命汤的作用机制提供有益的借鉴。方法通过以“小续命汤”为关键词,对中国知网、万方数据知识服务平台、维普数据库进行检索,收集、整理了1984年以来中医研究小续命汤的相关期刊及学术论文,总结小续命汤的临床应用和药理实验两方面的研究现状。结果小续命汤已不局限于中风的治疗,还可用于周围神经病、类风湿性关节炎、颈椎病、鼻炎等其他疾病的治疗,众多药理实验表明,小续命汤具有神经保护、改善认知、调脂、抗凋亡等作用。结论小续命汤临床治疗应用广泛,可能与抗线粒体氧化,减少细胞凋亡等有关。%Objective Overview the research progress of Xiaoxuming decoction’s clinical and experimental stud-y,and to provide a useful reference for further research on its mechanism. Methods Conducted through CNKI,Wan-fang Data,VIP Data by using keywords“Xiaoxuming decoction”,we collect and sort out relevant journals and papers of TCM on Xiaoxuming decoction’s research since 1984. We summarized the present situation from its clinical appli-cation and pharmacological studies. Results Xiaoxuming decoction is not limited to the treatment of stroke only,but also for peripheral neuropathy,rheumatoid,cervical spondylosis,rhinitis and other disease. Many Pharmacological ex-periments show that Xiaoxuming decoction has neuroprotective,improve cognition,lower lipids and anti-apoptotic effects. Conclusion Xiaoxuming decoction has a broader clinical application,it may be related to anti mitochondrial oxidation and decrease of apoptosis.

  12. Virology, Immunology, and Clinical Course of HIV Infection.

    Science.gov (United States)

    McCutchan, J. Allen

    1990-01-01

    Presents overview of medical aspects of human immunodeficiency virus Type 1 (HIV-1) disease. Addresses structure and replication of virus, current methods for detecting HIV-1 in infected persons, effects of the virus on immune system, and clinical course of HIV-1 disease. Emphasizes variable causes of progression through HIV-1 infection stages;…

  13. Virology, Immunology, and Clinical Course of HIV Infection.

    Science.gov (United States)

    McCutchan, J. Allen

    1990-01-01

    Presents overview of medical aspects of human immunodeficiency virus Type 1 (HIV-1) disease. Addresses structure and replication of virus, current methods for detecting HIV-1 in infected persons, effects of the virus on immune system, and clinical course of HIV-1 disease. Emphasizes variable causes of progression through HIV-1 infection stages;…

  14. Replicated Spectrographs in Astronomy

    CERN Document Server

    Hill, Gary J

    2014-01-01

    As telescope apertures increase, the challenge of scaling spectrographic astronomical instruments becomes acute. The next generation of extremely large telescopes (ELTs) strain the availability of glass blanks for optics and engineering to provide sufficient mechanical stability. While breaking the relationship between telescope diameter and instrument pupil size by adaptive optics is a clear path for small fields of view, survey instruments exploiting multiplex advantages will be pressed to find cost-effective solutions. In this review we argue that exploiting the full potential of ELTs will require the barrier of the cost and engineering difficulty of monolithic instruments to be broken by the use of large-scale replication of spectrographs. The first steps in this direction have already been taken with the soon to be commissioned MUSE and VIRUS instruments for the Very Large Telescope and the Hobby-Eberly Telescope, respectively. MUSE employs 24 spectrograph channels, while VIRUS has 150 channels. We compa...

  15. SUMO and KSHV Replication

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Pei-Ching [Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 112, Taiwan (China); Kung, Hsing-Jien, E-mail: hkung@nhri.org.tw [Institute for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan (China); Department of Biochemistry and Molecular Medicine, University of California, Davis, CA 95616 (United States); UC Davis Cancer Center, University of California, Davis, CA 95616 (United States); Division of Molecular and Genomic Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan (China)

    2014-09-29

    Small Ubiquitin-related MOdifier (SUMO) modification was initially identified as a reversible post-translational modification that affects the regulation of diverse cellular processes, including signal transduction, protein trafficking, chromosome segregation, and DNA repair. Increasing evidence suggests that the SUMO system also plays an important role in regulating chromatin organization and transcription. It is thus not surprising that double-stranded DNA viruses, such as Kaposi’s sarcoma-associated herpesvirus (KSHV), have exploited SUMO modification as a means of modulating viral chromatin remodeling during the latent-lytic switch. In addition, SUMO regulation allows the disassembly and assembly of promyelocytic leukemia protein-nuclear bodies (PML-NBs), an intrinsic antiviral host defense, during the viral replication cycle. Overcoming PML-NB-mediated cellular intrinsic immunity is essential to allow the initial transcription and replication of the herpesvirus genome after de novo infection. As a consequence, KSHV has evolved a way as to produce multiple SUMO regulatory viral proteins to modulate the cellular SUMO environment in a dynamic way during its life cycle. Remarkably, KSHV encodes one gene product (K-bZIP) with SUMO-ligase activities and one gene product (K-Rta) that exhibits SUMO-targeting ubiquitin ligase (STUbL) activity. In addition, at least two viral products are sumoylated that have functional importance. Furthermore, sumoylation can be modulated by other viral gene products, such as the viral protein kinase Orf36. Interference with the sumoylation of specific viral targets represents a potential therapeutic strategy when treating KSHV, as well as other oncogenic herpesviruses. Here, we summarize the different ways KSHV exploits and manipulates the cellular SUMO system and explore the multi-faceted functions of SUMO during KSHV’s life cycle and pathogenesis.

  16. Universal Temporal Profile of Replication Origin Activation in Eukaryotes

    Science.gov (United States)

    Goldar, Arach

    2011-03-01

    The complete and faithful transmission of eukaryotic genome to daughter cells involves the timely duplication of mother cell's DNA. DNA replication starts at multiple chromosomal positions called replication origin. From each activated replication origin two replication forks progress in opposite direction and duplicate the mother cell's DNA. While it is widely accepted that in eukaryotic organisms replication origins are activated in a stochastic manner, little is known on the sources of the observed stochasticity. It is often associated to the population variability to enter S phase. We extract from a growing Saccharomyces cerevisiae population the average rate of origin activation in a single cell by combining single molecule measurements and a numerical deconvolution technique. We show that the temporal profile of the rate of origin activation in a single cell is similar to the one extracted from a replicating cell population. Taking into account this observation we exclude the population variability as the origin of observed stochasticity in origin activation. We confirm that the rate of origin activation increases in the early stage of S phase and decreases at the latter stage. The population average activation rate extracted from single molecule analysis is in prefect accordance with the activation rate extracted from published micro-array data, confirming therefore the homogeneity and genome scale invariance of dynamic of replication process. All these observations point toward a possible role of replication fork to control the rate of origin activation.

  17. The Cell Cycle Timing of Human Papillomavirus DNA Replication.

    Science.gov (United States)

    Reinson, Tormi; Henno, Liisi; Toots, Mart; Ustav, Mart; Ustav, Mart

    2015-01-01

    Viruses manipulate the cell cycle of the host cell to optimize conditions for more efficient viral genome replication. One strategy utilized by DNA viruses is to replicate their genomes non-concurrently with the host genome; in this case, the viral genome is amplified outside S phase. This phenomenon has also been described for human papillomavirus (HPV) vegetative genome replication, which occurs in G2-arrested cells; however, the precise timing of viral DNA replication during initial and stable replication phases has not been studied. We developed a new method to quantitate newly synthesized DNA levels and used this method in combination with cell cycle synchronization to show that viral DNA replication is initiated during S phase and is extended to G2 during initial amplification but follows the replication pattern of cellular DNA during S phase in the stable maintenance phase. E1 and E2 protein overexpression changes the replication time from S only to both the S and G2 phases in cells that stably maintain viral episomes. These data demonstrate that the active synthesis and replication of the HPV genome are extended into the G2 phase to amplify its copy number and the duration of HPV genome replication is controlled by the level of the viral replication proteins E1 and E2. Using the G2 phase for genome amplification may be an important adaptation that allows exploitation of changing cellular conditions during cell cycle progression. We also describe a new method to quantify newly synthesized viral DNA levels and discuss its benefits for HPV research.

  18. Effect of antiretroviral therapy on clinical and immunologic disease progression in HIV positive children: One-year follow-up study

    Directory of Open Access Journals (Sweden)

    Ankur Patel

    2012-01-01

    Full Text Available Objective: To study the effect of antiretroviral therapy (ART on clinical, immunologic, and nutritional progression of disease in human immunodeficiency virus (HIV-infected children for 1 year. Materials and Methods: The study included 54 children aged 1.5-15 years who registered at the ART center, Surat, from August 2007 to August 2009. During the study period, the children were followed-up at 6 monthly intervals up to 1 year after starting ART. World Health Organization (WHO clinical staging and CD4 cell count as per national guidelines, and nutritional status were used to measure clinical and immunologic progression of disease up to 1 year. Results: Out of 54 children, mother-to-child transmission was reported in 96.2% children; for 74% of the children, both parents were HIV positive. All the children were classified according to WHO clinical staging into 4 stages and as per CD4 cell count (%, followed up at 6 and 12 months and the benefits with ART reported. At 12 months follow-up, 15% of the study group children had died. Both mean CD4 count and a relative percentage showed significant increase (P < 0.01 in the study group 1 year after ART. Conclusion: The present study reports benefits of ART in terms of clinical and immunologic progression of disease, nutritional status of HIV-infected children after 1 year of ART.

  19. Myelopathy in systemic lupus erythematosus: clinical, laboratory, radiological and progression findings in a cohort of 1,193 patients

    Directory of Open Access Journals (Sweden)

    Beatriz Lavras Costallat

    2016-06-01

    Full Text Available Abstract Objective To describe clinical, laboratory, radiological and progression characteristics of myelopathy in systemic lupus erythematosus (SLE. Patients and methods A retrospective analysis was performed on a cohort of 1193 patients with SLE (ACR criteria in order to identify patients with myelopathy (neuropsychiatric ACR. Disease activity was assessed by the SLE activity index (SLEDAI on the date of the event and functional capacity was assessed by the Expanded Disability Status Scale (EDSS at the last visit. Results We identified 14 (1.2% patients with myelopathy. All were women with a mean age of 30 ± 11.5 years. Myelopathy occurred at the diagnosis of SLE in four (28% patients; and nine (64% patients had another type of neuropsychiatric manifestation associated. Neurological recurrence was observed in one (7% patient. Disease activity was observed in 2 (14% patients. Cerebrospinal fluid presented pleocytosis on 7 (53% patients; antiphospholipid antibodies were positive in 5 (45%. Magnetic resonance imaging (MRI showed T2 hyperintensity with a predominance of longitudinal involvement in 6 (86% patients. Most were treated with intravenous corticosteroids and cyclophosphamide. No patient had full recovery and four (36% had high EDSS scores. Three (21% patients died from sepsis early in the course of their myelopathy, during or after immunosuppressive therapy. Conclusions Myelopathy occurred in 14 (1.2% of the patients in our cohort and this may be the first manifestation of the disease occurring independently of systemic disease activity. Although rare, myelopathy shows great morbidity and mortality, can be recurrent and MRI is critical for diagnosis.

  20. Basosquamous Carcinoma of the Head and Neck: Clinical and Histologic Characteristics and Their Impact on Disease Progression

    Directory of Open Access Journals (Sweden)

    Kai Wermker

    2015-03-01

    Full Text Available OBJECTIVES: Basosquamous carcinoma (BSC is a rare tumor entity, and the most common onset is in the head and neck region (BSC-HN. The data on diagnosis, treatment, and especially risk assessment concerning disease course and outcome are deficient or inconsistent. This study aimed to evaluate risk factors for local relapse (LR and lymph node metastasis (LNM and their impact on progression-free survival (PFS. MATERIALS AND METHODS: In a retrospective monocentric study, patients with BSC-HN treated between 1999 and 2011 were analyzed regarding clinical and histologic characteristics. Prognostic parameters for LR, LNM, and PFS were evaluated. In total, 89 patients (55 male, 34 female, mean age of 71.8 years with a mean follow-up time of 47.7 months (range 12-112 were included. RESULTS: LR occurred in four patients (4.5%, LNM occurred in five patients (5.6%. Patients with LNM had a significantly shorter PFS time (16.1 months compared with patients without LNM (154.2 months; P < .001. Tumor depth and size (T classification, incomplete resection, localization at the ear, deep maximal vertical infiltration, muscle and vessel invasion all showed significant (P < .05 associations with LR, LNM, and shorter PFS time. BSC showed more histologic features of basal cell carcinoma (BCC, especially with regard to BerEP4 expression. CONCLUSION: While histology shows some typical characteristics of BCC, the biologic behavior and aggressiveness of BSC are similar to those of cutaneous squamous cell carcinoma. This is the first study to show that LR and, especially, LNM indicate a higher risk of an unfavorable outcome.

  1. Efficient usage of Adabas replication

    CERN Document Server

    Storr, Dieter W

    2011-01-01

    In today's IT organization replication becomes more and more an essential technology. This makes Software AG's Event Replicator for Adabas an important part of your data processing. Setting the right parameters and establishing the best network communication, as well as selecting efficient target components, is essential for successfully implementing replication. This book provides comprehensive information and unique best-practice experience in the field of Event Replicator for Adabas. It also includes sample codes and configurations making your start very easy. It describes all components ne

  2. MCM5: a new actor in the link between DNA replication and Meier-Gorlin syndrome.

    Science.gov (United States)

    Vetro, Annalisa; Savasta, Salvatore; Russo Raucci, Annalisa; Cerqua, Cristina; Sartori, Geppo; Limongelli, Ivan; Forlino, Antonella; Maruelli, Silvia; Perucca, Paola; Vergani, Debora; Mazzini, Giuliano; Mattevi, Andrea; Stivala, Lucia Anna; Salviati, Leonardo; Zuffardi, Orsetta

    2017-02-15

    Meier-Gorlin syndrome (MGORS) is a rare disorder characterized by primordial dwarfism, microtia, and patellar aplasia/hypoplasia. Recessive mutations in ORC1, ORC4, ORC6, CDT1, CDC6, and CDC45, encoding members of the pre-replication (pre-RC) and pre-initiation (pre-IC) complexes, and heterozygous mutations in GMNN, a regulator of cell-cycle progression and DNA replication, have already been associated with this condition. We performed whole-exome sequencing (WES) in a patient with a clinical diagnosis of MGORS and identified biallelic variants in MCM5. This gene encodes a subunit of the replicative helicase complex, which represents a component of the pre-RC. Both variants, a missense substitution within a conserved domain critical for the helicase activity, and a single base deletion causing a frameshift and a premature stop codon, were predicted to be detrimental for the MCM5 function. Although variants of MCM5 have never been reported in specific human diseases, defect of this gene in zebrafish causes a phenotype of growth restriction overlapping the one associated with orc1 depletion. Complementation experiments in yeast showed that the plasmid carrying the missense variant was unable to rescue the lethal phenotype caused by mcm5 deletion. Moreover cell-cycle progression was delayed in patient's cells, as already shown for mutations in the ORC1 gene. Altogether our findings support the role of MCM5 as a novel gene involved in MGORS, further emphasizing that this condition is caused by impaired DNA replication.European Journal of Human Genetics advance online publication, 15 February 2017; doi:10.1038/ejhg.2017.5.

  3. Antiviral effects of artesunate on JC polyomavirus replication in COS-7 cells.

    Science.gov (United States)

    Sharma, Biswa Nath; Marschall, Manfred; Rinaldo, Christine Hanssen

    2014-11-01

    The human JC polyomavirus (JCPyV) causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). A growing number of patients with induced or acquired immunosuppression are at risk for infection, and no effective antiviral therapy is presently available. The widely used antimalarial drug artesunate has shown broad antiviral activity in vitro but limited clinical success. The aim of this study was to investigate the effect of artesunate on JCPyV replication in vitro. The permissivity for JCPyV MAD-4 was first compared in four cell lines, and the monkey kidney cell line COS-7 was selected. Artesunate caused a concentration-dependent decrease in the extracellular JCPyV DNA load 96 h postinfection, with a 50% effective concentration (EC50) of 2.9 μM. This effect correlated with a decreased expression of capsid protein VP1 and a reduced release of infectious viral progeny. For concentrations of <20 μM, transient reductions in cellular DNA replication and proliferation were seen, while for higher concentrations, some cytotoxicity was detected. A selective index of 16.6 was found when cytotoxicity was calculated based on cellular DNA replication in the mock-infected cells, but interestingly, cellular DNA replication in the JCPyV-infected cells was more strongly affected. In conclusion, artesunate is efficacious in inhibiting JCPyV replication at micromolar concentrations, which are achievable in plasma. The inhibition at EC50 probably reflects an effect on cellular proteins and involves transient cytostatic effects. Our results, together with the favorable distribution of the active metabolite dihydroartemisinin to the central nervous system, suggest a potential use for artesunate in patients with PML.

  4. Pre-cART Elevation of CRP and CD4+ T-cell Immune Activation Associated with HIV Clinical Progression in a Multinational Case-Cohort Study

    Science.gov (United States)

    Balagopal, Ashwin; Asmuth, David M.; Yang, Wei-Teng; Campbell, Thomas B.; Gupte, Nikhil; Smeaton, Laura; Kanyama, Cecilia; Grinsztejn, Beatriz; Santos, Breno; Supparatpinyo, Khuanchai; Badal-Faesen, Sharlaa; Lama, Javier R.; Lalloo, Umesh G.; Zulu, Fatima; Pawar, Jyoti S; Riviere, Cynthia; Kumarasamy, Nagalingeswaran; Hakim, James; Li, Xiao-Dong; Pollard, Richard B.; Semba, Richard D.; Thomas, David L.; Bollinger, Robert C.; Gupta, Amita

    2015-01-01

    Background Despite the success of combination antiretroviral therapy (cART), a subset of HIV-infected patients who initiate cART develop early clinical progression to AIDS; therefore some cART initiators are not fully benefitted by cART. Immune activation pre-cART may predict clinical progression in cART initiators. Methods A case-cohort study (n=470) within the multinational Prospective Evaluation of Antiretrovirals in Resource-Limited Settings (PEARLS) clinical trial (1571 HIV treatment-naïve adults who initiated cART; CD4+ T cell count <300 cells/mm3; nine countries) was conducted. A subcohort of 30 participants/country was randomly selected; additional cases were added from the main cohort. Cases (n=236 [random subcohort–36; main cohort–200]) had clinical progression (incident WHO Stage 3/4 event or death) within 96 weeks following cART initiation. Immune activation biomarkers were quantified pre-cART. Associations between biomarkers and clinical progression were examined using weighted multivariable Cox-proportional hazards models. Results Median age was 35 years, 45% were women, 49% black, 31% Asian, and 9% white. Median CD4+ T-cell count was 167 cells/mm3. In multivariate analysis, highest quartile CRP concentration (adjusted hazards ratio [aHR] 2.53, 95%CI 1.02-6.28) and CD4+ T-cell activation (aHR 5.18, 95CI 1.09-24.47) were associated with primary outcomes, compared to lowest quartiles. sCD14 had a trend towards association with clinical failure (aHR 2.24, 95%CI 0.96–5.21). Conclusions Measuring CRP and CD4+ T-cell activation may identify patients with CD4+ T cell counts < 300 cells/mm3 at risk for early clinical progression when initiating cART. Additional vigilance and symptom-based screening may be required in this subset of patients even after beginning cART. PMID:26017661

  5. Charter School Replication. Policy Guide

    Science.gov (United States)

    Rhim, Lauren Morando

    2009-01-01

    "Replication" is the practice of a single charter school board or management organization opening several more schools that are each based on the same school model. The most rapid strategy to increase the number of new high-quality charter schools available to children is to encourage the replication of existing quality schools. This policy guide…

  6. Early steps of retrovirus replicative cycle

    Directory of Open Access Journals (Sweden)

    Saïb Ali

    2004-05-01

    Full Text Available Abstract During the last two decades, the profusion of HIV research due to the urge to identify new therapeutic targets has led to a wealth of information on the retroviral replication cycle. However, while the late stages of the retrovirus life cycle, consisting of virus replication and egress, have been partly unraveled, the early steps remain largely enigmatic. These early steps consist of a long and perilous journey from the cell surface to the nucleus where the proviral DNA integrates into the host genome. Retroviral particles must bind specifically to their target cells, cross the plasma membrane, reverse-transcribe their RNA genome, while uncoating the cores, find their way to the nuclear membrane and penetrate into the nucleus to finally dock and integrate into the cellular genome. Along this journey, retroviruses hijack the cellular machinery, while at the same time counteracting cellular defenses. Elucidating these mechanisms and identifying which cellular factors are exploited by the retroviruses and which hinder their life cycle, will certainly lead to the discovery of new ways to inhibit viral replication and to improve retroviral vectors for gene transfer. Finally, as proven by many examples in the past, progresses in retrovirology will undoubtedly also provide some priceless insights into cell biology.

  7. LHCb experience with LFC replication

    CERN Document Server

    Bonifazi, F; Perez, E D; D'Apice, A; dell'Agnello, L; Düllmann, D; Girone, M; Re, G L; Martelli, B; Peco, G; Ricci, P P; Sapunenko, V; Vagnoni, V; Vitlacil, D

    2008-01-01

    Database replication is a key topic in the framework of the LHC Computing Grid to allow processing of data in a distributed environment. In particular, the LHCb computing model relies on the LHC File Catalog, i.e. a database which stores information about files spread across the GRID, their logical names and the physical locations of all the replicas. The LHCb computing model requires the LFC to be replicated at Tier-1s. The LCG 3D project deals with the database replication issue and provides a replication service based on Oracle Streams technology. This paper describes the deployment of the LHC File Catalog replication to the INFN National Center for Telematics and Informatics (CNAF) and to other LHCb Tier-1 sites. We performed stress tests designed to evaluate any delay in the propagation of the streams and the scalability of the system. The tests show the robustness of the replica implementation with performance going much beyond the LHCb requirements.

  8. DATABASE REPLICATION IN HETEROGENOUS PLATFORM

    Directory of Open Access Journals (Sweden)

    Hendro Nindito

    2014-01-01

    Full Text Available The application of diverse database technologies in enterprises today is increasingly a common practice. To provide high availability and survavibality of real-time information, a database replication technology that has capability to replicate databases under heterogenous platforms is required. The purpose of this research is to find the technology with such capability. In this research, the data source is stored in MSSQL database server running on Windows. The data will be replicated to MySQL running on Linux as the destination. The method applied in this research is prototyping in which the processes of development and testing can be done interactively and repeatedly. The key result of this research is that the replication technology applied, which is called Oracle GoldenGate, can successfully manage to do its task in replicating data in real-time and heterogeneous platforms.

  9. LHCb experience with LFC replication

    CERN Document Server

    Carbone, Angelo; Dafonte Perez, Eva; D'Apice, Antimo; dell'Agnello, Luca; Duellmann, Dirk; Girone, Maria; Lo Re, Giuseppe; Martelli, Barbara; Peco, Gianluca; Ricci, Pier Paolo; Sapunenko, Vladimir; Vagnoni, Vincenzo; Vitlacil, Dejan

    2007-01-01

    Database replication is a key topic in the framework of the LHC Computing Grid to allow processing of data in a distributed environment. In particular, the LHCb computing model relies on the LHC File Catalog, i.e. database which stores information about files spread across the GRID, their logical names and the physical locations of all the replicas. The LHCb computing model requires the LFC to be replicated at Tier-1s. The LCG 3D project deals with the database replication issue and provides a replication service based on Oracle Streams technology. This paper describes the deployment of the LHC File Catalog replication to the INFN National Center for Telematics and Informations (CNAF) and to other LHCb Tier-1 sites. We performed stress tests designed to evaluate any delay in the propagation of the streams and the scalability of the system. The tests show the robustness of the replica implementation with performance going much beyond the LHCb requirements.

  10. Urine biomarkers of tubular injury do not improve on the clinical model predicting chronic kidney disease progression.

    Science.gov (United States)

    Hsu, Chi-Yuan; Xie, Dawei; Waikar, Sushrut S; Bonventre, Joseph V; Zhang, Xiaoming; Sabbisetti, Venkata; Mifflin, Theodore E; Coresh, Josef; Diamantidis, Clarissa J; He, Jiang; Lora, Claudia M; Miller, Edgar R; Nelson, Robert G; Ojo, Akinlolu O; Rahman, Mahboob; Schelling, Jeffrey R; Wilson, Francis P; Kimmel, Paul L; Feldman, Harold I; Vasan, Ramachandran S; Liu, Kathleen D

    2017-01-01

    Few investigations have evaluated the incremental usefulness of tubular injury biomarkers for improved prediction of chronic kidney disease (CKD) progression. As such, we measured urinary kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, N-acetyl-ß-D-glucosaminidase and liver fatty acid binding protein under highly standardized conditions among 2466 enrollees of the prospective Chronic Renal Insufficiency Cohort Study. During 9433 person-years of follow-up, there were 581 cases of CKD progression defined as incident end-stage renal disease or halving of the estimated glomerular filtration rate. Levels of the urine injury biomarkers, normalized for urine creatinine, were strongly associated with CKD progression in unadjusted Cox proportional hazard models with hazard ratios in the range of 7 to 15 comparing the highest with the lowest quintiles. However, after controlling for the serum creatinine-based estimated glomerular filtration rate and urinary albumin/creatinine ratio, none of the normalized biomarkers was independently associated with CKD progression. None of the biomarkers improved on the high (0.89) C-statistic for the base clinical model. Thus, among patients with CKD, risk prediction with a clinical model that includes the serum creatinine-based estimated glomerular filtration rate and the urinary albumin/creatinine ratio is not improved on with the addition of renal tubular injury biomarkers. Copyright © 2016 International Society of Nephrology. All rights reserved.

  11. No erosive progression revealed by MRI in rheumatoid arthritis patients treated with etanercept, even in patients with persistent MRI and clinical signs of joint inflammation

    DEFF Research Database (Denmark)

    Døhn, Uffe Møller; Skjødt, Henrik; Hetland, Merete;

    2007-01-01

    The aim of this study is to investigate the course of magnetic resonance imaging (MRI) signs of inflammatory and destructive changes in rheumatoid arthritis (RA) wrist and metacarpophalangeal (MCP) joints during etanercept treatment. MRI of the non-dominant wrist and second to fifth MCP joints...... was performed in five clinical active RA patients before and 4 and 16 weeks after initiation of etanercept treatment. MRI was evaluated according to the EULAR-OMERACT RA MRI reference image atlas. The median 28-joint count disease activity score (DAS28; erythrocyte sedimentation rate based) was 5.6 (range 5...... patient showed erosive regression, while no patient showed erosive progression on MRI during 16 weeks of etanercept therapy; even though clinical and MRI signs of joint inflammation remained. This small study supports that erosive progression judged by MRI is minimal in RA patients treated with etanercept...

  12. The DNA Replication Stress Hypothesis of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Yuri B. Yurov

    2011-01-01

    Full Text Available A well-recognized theory of Alzheimer’s disease (AD pathogenesis suggests ectopic cell cycle events to mediate neurodegeneration. Vulnerable neurons of the AD brain exhibit biomarkers of cell cycle progression and DNA replication suggesting a reentry into the cell cycle. Chromosome reduplication without proper cell cycle completion and mitotic division probably causes neuronal cell dysfunction and death. However, this theory seems to require some inputs in accordance with the generally recognized amyloid cascade theory as well as to explain causes and consequences of genomic instability (aneuploidy in the AD brain. We propose that unscheduled and incomplete DNA replication (replication stress destabilizes (epigenomic landscape in the brain and leads to DNA replication “catastrophe” causing cell death during the S phase (replicative cell death. DNA replication stress can be a key element of the pathogenetic cascade explaining the interplay between ectopic cell cycle events and genetic instabilities in the AD brain. Abnormal cell cycle reentry and somatic genome variations can be used for updating the cell cycle theory introducing replication stress as a missing link between cell genetics and neurobiology of AD.

  13. Review of progresses on clinical applications of ion selective electrodes for electrolytic ion tests: from conventional ISEs to graphene-based ISEs

    OpenAIRE

    Rongguo Yan; Shuai Qiu; Lei Tong; Yin Qian

    2016-01-01

    There exist several positively and negatively charged electrolytes or ions in human blood, urine, and other body fluids. Tests that measure the concentration of these ions in clinics are performed using a more affordable, portable, and disposable potentiometric sensing method with few sample volumes, which requires the use of ion-selective electrodes (ISEs) and reference electrodes. This review summarily descriptively presents progressive developments and applications of ion selective electro...

  14. CLINICAL APPLICATION OF NEIGUAN (内关 PC 6) IN THE TREATMENT OF DISORDERS OF THE DIGESTIVE SYSTEM--THE RELATED RESEARCH PROGRESS

    Institute of Scientific and Technical Information of China (English)

    王淑斌; 刘俊岭

    2004-01-01

    In the present paper, the authors review recent situations of disorders of the digestive system and its related research progresses. In clinical practice, Neiguan (PC 6) is usually selected as one of the main intra-gastric examination, cesarean section, etc. Concerning experimental indicated that Neiguan (PC 6) is an important and effective acupoint for treatment of gastrointestinal disorders in clinic. Stimulation of Neiguan (PC 6) induced favorable regulation of both the peripheral nervous system and central nervous system, and changes of the gastrointestinal hormone secretion may contribute to its effects in treating various disorders.

  15. 系统性红斑狼疮临床治疗新进展%New progress of clinical treatment of systemic lupus erythematosus

    Institute of Scientific and Technical Information of China (English)

    李开平

    2015-01-01

    Systemic lupus erythematosus is a common clinical disease.It has a serious impact on the patients health and life.In this paper,the author briefly introduces the new progress of clinical treatment of systemic lupus erythematosus.%目的:系统性红斑狼疮是一种临床常见疾病,对患者的健康和生活造成严重的影响。本文简要介绍系统性红斑狼疮临床治疗新进展。

  16. NACSA Charter School Replication Guide: The Spectrum of Replication Options. Authorizing Matters. Replication Brief 1

    Science.gov (United States)

    O'Neill, Paul

    2010-01-01

    One of the most important and high-profile issues in public education reform today is the replication of successful public charter school programs. With more than 5,000 failing public schools in the United States, there is a tremendous need for strong alternatives for parents and students. Replicating successful charter school models is an…

  17. International Expansion through Flexible Replication

    DEFF Research Database (Denmark)

    Jonsson, Anna; Foss, Nicolai Juul

    2011-01-01

    to local environments and under the impact of new learning. To illuminate these issues, we draw on a longitudinal in-depth study of Swedish home furnishing giant IKEA, involving more than 70 interviews. We find that IKEA has developed organizational mechanisms that support an ongoing learning process aimed......, etc.) are replicated in a uniform manner across stores, and change only very slowly (if at all) in response to learning (“flexible replication”). We conclude by discussing the factors that influence the approach to replication adopted by an international replicator....

  18. The Psychology of Replication and Replication in Psychology.

    Science.gov (United States)

    Francis, Gregory

    2012-11-01

    Like other scientists, psychologists believe experimental replication to be the final arbiter for determining the validity of an empirical finding. Reports in psychology journals often attempt to prove the validity of a hypothesis or theory with multiple experiments that replicate a finding. Unfortunately, these efforts are sometimes misguided because in a field like experimental psychology, ever more successful replication does not necessarily ensure the validity of an empirical finding. When psychological experiments are analyzed with statistics, the rules of probability dictate that random samples should sometimes be selected that do not reject the null hypothesis, even if an effect is real. As a result, it is possible for a set of experiments to have too many successful replications. When there are too many successful replications for a given set of experiments, a skeptical scientist should be suspicious that null or negative findings have been suppressed, the experiments were run improperly, or the experiments were analyzed improperly. This article describes the implications of this observation and demonstrates how to test for too much successful replication by using a set of experiments from a recent research paper.

  19. Regulation of Replication Recovery and Genome Integrity

    DEFF Research Database (Denmark)

    Colding, Camilla Skettrup

    Preserving genome integrity is essential for cell survival. To this end, mechanisms that supervise DNA replication and respond to replication perturbations have evolved. One such mechanism is the replication checkpoint, which responds to DNA replication stress and acts to ensure replication pausing...

  20. Analysis of JC virus DNA replication using a quantitative and high-throughput assay.

    Science.gov (United States)

    Shin, Jong; Phelan, Paul J; Chhum, Panharith; Bashkenova, Nazym; Yim, Sung; Parker, Robert; Gagnon, David; Gjoerup, Ole; Archambault, Jacques; Bullock, Peter A

    2014-11-01

    Progressive Multifocal Leukoencephalopathy (PML) is caused by lytic replication of JC virus (JCV) in specific cells of the central nervous system. Like other polyomaviruses, JCV encodes a large T-antigen helicase needed for replication of the viral DNA. Here, we report the development of a luciferase-based, quantitative and high-throughput assay of JCV DNA replication in C33A cells, which, unlike the glial cell lines Hs 683 and U87, accumulate high levels of nuclear T-ag needed for robust replication. Using this assay, we investigated the requirement for different domains of T-ag, and for specific sequences within and flanking the viral origin, in JCV DNA replication. Beyond providing validation of the assay, these studies revealed an important stimulatory role of the transcription factor NF1 in JCV DNA replication. Finally, we show that the assay can be used for inhibitor testing, highlighting its value for the identification of antiviral drugs targeting JCV DNA replication.

  1. Biomarkers of replicative senescence revisited

    DEFF Research Database (Denmark)

    Nehlin, Jan

    2016-01-01

    Biomarkers of replicative senescence can be defined as those ultrastructural and physiological variations as well as molecules whose changes in expression, activity or function correlate with aging, as a result of the gradual exhaustion of replicative potential and a state of permanent cell cycle...... with their chronological age and present health status, help define their current rate of aging and contribute to establish personalized therapy plans to reduce, counteract or even avoid the appearance of aging biomarkers....

  2. Disease progression model for Clinical Dementia Rating–Sum of Boxes in mild cognitive impairment and Alzheimer’s subjects from the Alzheimer’s Disease Neuroimaging Initiative

    Directory of Open Access Journals (Sweden)

    Samtani MN

    2014-05-01

    Full Text Available Mahesh N Samtani, Nandini Raghavan, Gerald Novak, Partha Nandy, Vaibhav A Narayan On behalf of the Alzheimer’s disease Neuroimaging Initiative Janssen Research and Development, LLC, Raritan, New Jersey, USA Background: The objective of this analysis was to develop a nonlinear disease progression model, using an expanded set of covariates that captures the longitudinal Clinical Dementia Rating Scale–Sum of Boxes (CDR–SB scores. These were derived from the Alzheimer’s disease Neuroimaging Initiative ADNI-1 study, of 301 Alzheimer’s disease and mild cognitive impairment patients who were followed for 2–3 years. Methods: The model describes progression rate and baseline disease score as a function of covariates. The covariates that were tested fell into five groups: a hippocampal volume; b serum and cerebrospinal fluid (CSF biomarkers; c demographics and apolipoprotein Epsilon 4 (ApoE4 allele status; d baseline cognitive tests; and e disease state and comedications. Results: Covariates associated with baseline disease severity were disease state, hippocampal volume, and comedication use. Disease progression rate was influenced by baseline CSF biomarkers, Trail-Making Test part A score, delayed logical memory test score, and current level of impairment as measured by CDR–SB. The rate of disease progression was dependent on disease severity, with intermediate scores around the inflection point score of 10 exhibiting high disease progression rate. The CDR–SB disease progression rate in a typical patient, with late mild cognitive impairment and mild Alzheimer’s disease, was estimated to be approximately 0.5 and 1.4 points/year, respectively. Conclusions: In conclusion, this model describes disease progression in terms of CDR–SB changes in patients and its dependency on novel covariates. The CSF biomarkers included in the model discriminate mild cognitive impairment subjects as progressors and nonprogressors. Therefore, the model may

  3. A Randomized Clinical Trial of Acceptance and Commitment Therapy versus Progressive Relaxation Training for Obsessive-Compulsive Disorder

    Science.gov (United States)

    Twohig, Michael P.; Hayes, Steven C.; Plumb, Jennifer C.; Pruitt, Larry D.; Collins, Angela B.; Hazlett-Stevens, Holly; Woidneck, Michelle R.

    2010-01-01

    Objective: Effective treatments for obsessive-compulsive disorder (OCD) exist, but additional treatment options are needed. The effectiveness of 8 sessions of acceptance and commitment therapy (ACT) for adult OCD was compared with progressive relaxation training (PRT). Method: Seventy-nine adults (61% female) diagnosed with OCD (mean age = 37…

  4. A Randomized Clinical Trial of Acceptance and Commitment Therapy versus Progressive Relaxation Training for Obsessive-Compulsive Disorder

    Science.gov (United States)

    Twohig, Michael P.; Hayes, Steven C.; Plumb, Jennifer C.; Pruitt, Larry D.; Collins, Angela B.; Hazlett-Stevens, Holly; Woidneck, Michelle R.

    2010-01-01

    Objective: Effective treatments for obsessive-compulsive disorder (OCD) exist, but additional treatment options are needed. The effectiveness of 8 sessions of acceptance and commitment therapy (ACT) for adult OCD was compared with progressive relaxation training (PRT). Method: Seventy-nine adults (61% female) diagnosed with OCD (mean age = 37…

  5. Polycomb proteins control proliferation and transformation independently of cell cycle checkpoints by regulating DNA replication

    DEFF Research Database (Denmark)

    Piunti, Andrea; Rossi, Alessandra; Cerutti, Aurora;

    2014-01-01

    that PRCs regulate cellular proliferation and transformation independently of the Ink4a/Arf-pRb-p53 pathway. We provide evidence that PRCs localize at replication forks, and that loss of their function directly affects the progression and symmetry of DNA replication forks. Thus, we have identified a novel...

  6. The Werner and Bloom syndrome proteins help resolve replication blockage by converting (regressed) holliday junctions to functional replication forks.

    Science.gov (United States)

    Machwe, Amrita; Karale, Rajashree; Xu, Xioahua; Liu, Yilun; Orren, David K

    2011-08-16

    Cells cope with blockage of replication fork progression in a manner that allows DNA synthesis to be completed and genomic instability minimized. Models for resolution of blocked replication involve fork regression to form Holliday junction structures. The human RecQ helicases WRN and BLM (deficient in Werner and Bloom syndromes, respectively) are critical for maintaining genomic stability and thought to function in accurate resolution of replication blockage. Consistent with this notion, WRN and BLM localize to sites of blocked replication after certain DNA-damaging treatments and exhibit enhanced activity on replication and recombination intermediates. Here we examine the actions of WRN and BLM on a special Holliday junction substrate reflective of a regressed replication fork. Our results demonstrate that, in reactions requiring ATP hydrolysis, both WRN and BLM convert this Holliday junction substrate primarily to a four-stranded replication fork structure, suggesting they target the Holliday junction to initiate branch migration. In agreement, the Holliday junction binding protein RuvA inhibits the WRN- and BLM-mediated conversion reactions. Importantly, this conversion product is suitable for replication with its leading daughter strand readily extended by DNA polymerases. Furthermore, binding to and conversion of this Holliday junction are optimal at low MgCl(2) concentrations, suggesting that WRN and BLM preferentially act on the square planar (open) conformation of Holliday junctions. Our findings suggest that, subsequent to fork regression events, WRN and/or BLM could re-establish functional replication forks to help overcome fork blockage. Such a function is highly consistent with phenotypes associated with WRN- and BLM-deficient cells.

  7. Challenges relating to solid tumour brain metastases in clinical trials, part 1: patient population, response, and progression. A report from the RANO group.

    Science.gov (United States)

    Lin, Nancy U; Lee, Eudocia Q; Aoyama, Hidefumi; Barani, Igor J; Baumert, Brigitta G; Brown, Paul D; Camidge, D Ross; Chang, Susan M; Dancey, Janet; Gaspar, Laurie E; Harris, Gordon J; Hodi, F Stephen; Kalkanis, Steven N; Lamborn, Kathleen R; Linskey, Mark E; Macdonald, David R; Margolin, Kim; Mehta, Minesh P; Schiff, David; Soffietti, Riccardo; Suh, John H; van den Bent, Martin J; Vogelbaum, Michael A; Wefel, Jeffrey S; Wen, Patrick Y

    2013-09-01

    Therapeutic outcomes for patients with brain metastases need to improve. A critical review of trials specifically addressing brain metastases shows key issues that could prevent acceptance of results by regulatory agencies, including enrolment of heterogeneous groups of patients and varying definitions of clinical endpoints. Considerations specific to disease, modality, and treatment are not consistently addressed. Additionally, the schedule of CNS imaging and consequences of detection of new or progressive brain metastases in trials mainly exploring the extra-CNS activity of systemic drugs are highly variable. The Response Assessment in Neuro-Oncology (RANO) working group is an independent, international, collaborative effort to improve the design of trials in patients with brain tumours. In this two-part series, we review the state of clinical trials of brain metastases and suggest a consensus recommendation for the development of criteria for future clinical trials.

  8. Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG)

    DEFF Research Database (Denmark)

    Rustin, Gordon John Sampson; Vergote, Ignace; Eisenhauer, Elizabeth

    2011-01-01

    the serum marker CA 125 and has specified the situations where these criteria should be used. However, the publications did not include detailed definitions, nor were they written to accommodate the new version of Response Evaluation Criteria In Solid Tumors (RECIST) criteria (version 1.1) now available....... Thus, we recommend that the definitions described later in detail are incorporated into clinical trial protocols to maintain consistency. The criteria for defining progression are now acceptable in clinical trials of recurrent disease as they have since been validated (Pujade-Lauraine, personal...... communication, 2010). The GCIG requests that data from all clinical trials using these definitions are made available to GCIG trial centers so that continual validation and improvement can be accomplished. These definitions were developed from analyzing patients receiving cytotoxic chemotherapy and have not yet...

  9. Research progress on diabetes care clinic%糖尿病护理门诊的研究进展

    Institute of Scientific and Technical Information of China (English)

    张立颖; 彭梦苗; 李亚洁; 谢翠华; 李梅

    2013-01-01

    综述了国外、国内糖尿病医疗及护理门诊发展史,以及国外糖尿病门诊概况、国内糖尿病护理门诊概况及存在问题.%It reviewed the development history of foreign and domestic diabetic medical and nursing clinics, overview of in diabetes clinic a-broad,diabetes nursing clinic overview at home and problems in it.

  10. The lag time in initiating clinical testing of new drugs in combination with radiation therapy, a significant barrier to progress?

    OpenAIRE

    Blumenfeld, P; Pfeffer, R M; Symon, Z; Den, R B; Dicker, A.P.; Raben, D.; Lawrence, Y R

    2014-01-01

    Background: The clinical development of new drugs with radiation appears to be limited. We hypothesised that phase I clinical trials with radiation therapy (RT) are initiated too late into a new drug's lifetime, impeding the ability to complete RT–drug development programmes before patent expiration. Methods: We identified novel drug–radiation phase I combination trials performed between 1980 and 2012 within the PubMed and ClinicalTrials.gov databases. Data gathered for each drug included: da...

  11. Nucleotide Metabolism and DNA Replication.

    Science.gov (United States)

    Warner, Digby F; Evans, Joanna C; Mizrahi, Valerie

    2014-10-01

    The development and application of a highly versatile suite of tools for mycobacterial genetics, coupled with widespread use of "omics" approaches to elucidate the structure, function, and regulation of mycobacterial proteins, has led to spectacular advances in our understanding of the metabolism and physiology of mycobacteria. In this article, we provide an update on nucleotide metabolism and DNA replication in mycobacteria, highlighting key findings from the past 10 to 15 years. In the first section, we focus on nucleotide metabolism, ranging from the biosynthesis, salvage, and interconversion of purine and pyrimidine ribonucleotides to the formation of deoxyribonucleotides. The second part of the article is devoted to DNA replication, with a focus on replication initiation and elongation, as well as DNA unwinding. We provide an overview of replication fidelity and mutation rates in mycobacteria and summarize evidence suggesting that DNA replication occurs during states of low metabolic activity, and conclude by suggesting directions for future research to address key outstanding questions. Although this article focuses primarily on observations from Mycobacterium tuberculosis, it is interspersed, where appropriate, with insights from, and comparisons with, other mycobacterial species as well as better characterized bacterial models such as Escherichia coli. Finally, a common theme underlying almost all studies of mycobacterial metabolism is the potential to identify and validate functions or pathways that can be exploited for tuberculosis drug discovery. In this context, we have specifically highlighted those processes in mycobacterial DNA replication that might satisfy this critical requirement.

  12. Plasmid Rolling-Circle Replication.

    Science.gov (United States)

    Ruiz-Masó, J A; MachóN, C; Bordanaba-Ruiseco, L; Espinosa, M; Coll, M; Del Solar, G

    2015-02-01

    Plasmids are DNA entities that undergo controlled replication independent of the chromosomal DNA, a crucial step that guarantees the prevalence of the plasmid in its host. DNA replication has to cope with the incapacity of the DNA polymerases to start de novo DNA synthesis, and different replication mechanisms offer diverse solutions to this problem. Rolling-circle replication (RCR) is a mechanism adopted by certain plasmids, among other genetic elements, that represents one of the simplest initiation strategies, that is, the nicking by a replication initiator protein on one parental strand to generate the primer for leading-strand initiation and a single priming site for lagging-strand synthesis. All RCR plasmid genomes consist of a number of basic elements: leading strand initiation and control, lagging strand origin, phenotypic determinants, and mobilization, generally in that order of frequency. RCR has been mainly characterized in Gram-positive bacterial plasmids, although it has also been described in Gram-negative bacterial or archaeal plasmids. Here we aim to provide an overview of the RCR plasmids' lifestyle, with emphasis on their characteristic traits, promiscuity, stability, utility as vectors, etc. While RCR is one of the best-characterized plasmid replication mechanisms, there are still many questions left unanswered, which will be pointed out along the way in this review.

  13. Role of CDC6 in DNA replication, cell cycle checkpoints, tumorigenesis and tumor progression%周期蛋白6在DNA复制、细胞周期检测点和肿瘤发生发展中的作用

    Institute of Scientific and Technical Information of China (English)

    张佳华; 黄士昂

    2009-01-01

    Cell-division cycle 6 (CDC6) is one of the major proteins consisting pre-replicative complexes(Pre-RC). It controls cells cycle from G1 phase into S phase, and participates in the activation and maintenance of S-M phase checkpoint mechanisms of mitosis. Recent studies have unveiled its proto-oncogenic activity and overexpression in many kinds of human cancer cells, and it plays an important role in tumorigenesis and tumor progression.CDC6-driven oneogenesis may be related with INK4/ARF link and/or some alternative mechanisms.%周期蛋白6(CDC6)是组成前复制复合物(Pre-RC)的主要蛋白之一,控制细胞从G1期进入S期,同时也参与激活和维持有丝分裂S-M期检测点机制.最近的研究发现其也具有原癌基因的特性,并在人多种肿瘤细胞中存在高表达,对肿瘤发生发展起重要作用.CDC6致癌机制可能与INK4/ARF连结物信号途径和(或)某些替代机制有关.

  14. Patellofemoral Osteoarthritis Progression and Alignment Changes after Open-Wedge High Tibial Osteotomy Do Not Affect Clinical Outcomes at Mid-term Follow-up.

    Science.gov (United States)

    Goshima, Kenichi; Sawaguchi, Takeshi; Shigemoto, Kenji; Iwai, Shintaro; Nakanishi, Akira; Ueoka, Ken

    2017-10-01

    To evaluate the clinical and radiological outcomes of open-wedge high tibial osteotomy (OWHTO) with respect to the patellofemoral joint and to assess whether patellofemoral osteoarthritis (OA) progression and alignment changes after OWHTO affect clinical outcomes. Inclusion criteria were consecutive patients who underwent OWHTO from March 2005 to September 2013. Exclusion criteria were loss to follow-up within 2 years and absence of second-look arthroscopy findings at the time of plate removal. The clinical parameters, including anterior knee pain while climbing stairs, Japanese Orthopedic Association score, and Oxford Knee Score, were evaluated. Radiological outcomes, including weight-bearing line ratio, modified Blackburne-Peel ratio, posterior tibial slope, tilting angle, lateral shift ratio, and patellofemoral OA (Kellgren-Lawrence grade), were evaluated preoperatively and at the final follow-up. Cartilage status (International Cartilage Repair Society grade) was evaluated at the initial HTO and at plate removal. Fifty-three patients (60 knees) were included in this study. The mean follow-up was 58.2 ± 22.4 months. Two knees (3%) presented with mild anterior knee pain after OWHTO. The mean Japanese Orthopedic Association score (66.9 ± 11.2 to 91.2 ± 9.7) significantly improved (P < .001), and the mean Oxford Knee Score at the final follow-up was 42.0 ± 5.3. The mean modified Blackburne-Peel ratio (0.9 ± 0.1 to 0.7 ± 0.1, P < .001) and tilting angle (6.8 ± 3.7 to 5.6 ± 3.4, P = .033) significantly decreased after OWHTO, whereas no significant changes in posterior tibial slope (P = .511) and lateral shift ratio (P = .522) were observed. Radiologically, patellofemoral OA had progressed in 15 knees (27%), and arthroscopically patellofemoral cartilage degeneration had progressed in 27 knees (45%). However, there was no significant correlation between changes in patellofemoral alignment and clinical outcomes. Changes in patellofemoral alignment and

  15. [Anarthria, progressive apraxia and extrapyramidal syndrome: an uncommon clinical form of corticobasal degeneration? A case studied by HMPAO Tc99m single-photon emission tomography].

    Science.gov (United States)

    Fayet, G; Vercelletto, M; Bertout, C; De Kersaint-Gilly, A; Fève, J R

    1995-04-01

    A 48-year-old man presented with impaired joint movement and buccofacial apraxia. The disease progressed for six years associating an akineto-hypertonic syndrome, marked anarthria, saliva incontinence, bi-opercular syndrome, bucco-facial apraxia, severe global gestual apraxia and a frontal syndrom. Oculo-motricity and gait were normal. Magnetic resonance imaging of the brain demonstrated fronto-parietal atrophy and HMPAO Tc99 tomography revealed hypoperfusion of the cortex clearly predominating in the left parietal region. These particular findings with predominantly intense joint involvement is similar to the clinical picture in corticobasal degeneration--subcortical signs (progressively uncontrollable hypertonia) together with cortical signs (severe gestual apraxia). The neuroradiological imaging and functional results also suggest a degenerative process.

  16. Progressive preoperative pneumoperitoneum preparation (the Goni Moreno protocol) prior to large incisional hernia surgery: volumetric, respiratory and clinical impacts. A prospective study.

    Science.gov (United States)

    Sabbagh, C; Dumont, F; Fuks, D; Yzet, T; Verhaeghe, P; Regimbeau, J-M

    2012-02-01

    Progressive preoperative pneumoperitoneum (PPP) is used to prepare incisional hernias with loss of domain (IHLD) operations. The aim of the present study was to analyze the effect of PPP on peritoneal volume [measured using a new computed tomography (CT)-based method] and respiratory function. From July 2004 to July 2008, 19 patients were included in a prospective, observational study. The volumes of the incisional hernia (VIH), the abdominal cavity (VAC), the total peritoneal content (VP) and the VIH/VP ratio were measured before and after PPP using abdominal CT scan data. Spirometric parameters were measured before and after PPP, and postoperative clinical data were evaluated. Before and after PPP, the mean VIH was 1,420 cc and 2,110 cc (P  VIH before PPP. After PPP, the spirometric measurements revealed a restrictive syndrome. The overall postoperative morbidity rate was 37%. PPP increased the hernia and abdominal volumes. PPP induced a progressive, restrictive syndrome.

  17. Clinical features and radiological findings of adenovirus pneumonia associated with progression to acute respiratory distress syndrome: A single center study in 19 adult patients

    Energy Technology Data Exchange (ETDEWEB)

    Cha, Min Jae; Chong, Semin [Dept. of Radiology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul (Korea, Republic of); Chung, Myung Jin; Lee, Kyung Soo; KIm, Tae Jung; Kim, Tae Sung; Han, Jung Ho [Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2016-11-15

    To describe radiologic findings of adenovirus pneumonia and to understand clinico-radiological features associated with progression to acute respiratory distress syndrome (ARDS) in patients with adenovirus pneumonia. This study included 19 patients diagnosed with adenovirus pneumonia at a tertiary referral center, in the period between March 2003 and April 2015. Clinical findings were reviewed, and two radiologists assessed imaging findings by consensus. Chi-square, Fisher's exact, and Student's t tests were used for comparing patients with and without subsequent development of ARDS. Of 19 patients, nine were immunocompromised, and 10 were immunocompetent. Twelve patients (63%) progressed to ARDS, six of whom (32%) eventually died from the disease. The average time for progression to ARDS from symptom onset was 9.6 days. Initial chest radiographic findings were normal (n = 2), focal opacity (n = 9), or multifocal or diffuse opacity (n = 8). Computed tomography (CT) findings included bilateral (n = 17) or unilateral (n = 2) ground-glass opacity with consolidation (n = 14) or pleural effusion (n = 11). Patients having subsequent ARDS had a higher probability of pleural effusion and a higher total CT extent compared with the non-ARDS group (p = 0.010 and 0.007, respectively). However, there were no significant differences in clinical variables such as patient age and premorbid condition. Adenovirus pneumonia demonstrates high rates of ARDS and mortality, regardless of patient age and premorbid conditions, in the tertiary care setting. Large disease extent and presence of pleural effusion on CT are factors suggestive of progression to ARDS.

  18. Strong association between serological status and probability of progression to clinical visceral leishmaniasis in prospective cohort studies in India and Nepal.

    Directory of Open Access Journals (Sweden)

    Epco Hasker

    Full Text Available INTRODUCTION: Asymptomatic persons infected with the parasites causing visceral leishmaniasis (VL usually outnumber clinically apparent cases by a ratio of 4-10 to 1. We assessed the risk of progression from infection to disease as a function of DAT and rK39 serological titers. METHODS: We used available data on four cohorts from villages in India and Nepal that are highly endemic for Leishmania donovani. In each cohort two serosurveys had been conducted. Based on results of initial surveys, subjects were classified as seronegative, moderately seropositive or strongly seropositive using both DAT and rK39. Based on the combination of first and second survey results we identified seroconvertors for both markers. Seroconvertors were subdivided in high and low titer convertors. Subjects were followed up for at least one year following the second survey. Incident VL cases were recorded and verified. RESULTS: We assessed a total of 32,529 enrolled subjects, for a total follow-up time of 72,169 person years. Altogether 235 incident VL cases were documented. The probability of progression to disease was strongly associated with initial serostatus and with seroconversion; this was particularly the case for those with high titers and most prominently among seroconvertors. For high titer DAT convertors the hazard ratio reached as high as 97.4 when compared to non-convertors. The strengths of the associations varied between cohorts and between markers but similar trends were observed between the four cohorts and the two markers. DISCUSSION: There is a strongly increased risk of progressing to disease among DAT and/or rK39 seropositives with high titers. The options for prophylactic treatment for this group merit further investigation, as it could be of clinical benefit if it prevents progression to disease. Prophylactic treatment might also have a public health benefit if it can be corroborated that these asymptomatically infected individuals are infectious

  19. Phenotype and clinical course in a family with a new de novo Twinkle gene mutation

    DEFF Research Database (Denmark)

    Jeppesen, Tina Dysgaard; Schwartz, M.; Colding-Jorgensen, E.;

    2008-01-01

    The Twinkle gene product is important for mtDNA replication. Only a few reports have investigated the clinically effect of mutations in this gene. We describe a new de novo mutation (1110C > A) in the PEO1 gene in a mother and her two sons. The mother had progressive ophthalmoplegia, limb weakness...

  20. Synovial tissue rank ligand expression and radiographic progression in rheumatoid arthritis: observations from a proof-of-concept randomized clinical trial of cytokine blockade.

    LENUS (Irish Health Repository)

    Rooney, Terence

    2012-02-01

    The objective of the study was to evaluate synovial tissue receptor activator of nuclear factor-kappabeta ligand (RANKL) and osteoprotegerin (OPG) as biomarkers of disease activity, progressive joint damage, and therapeutic response, during cytokine blockade in rheumatoid arthritis (RA). Patients with active RA entered a randomized open-label 12-month study of anakinra 100 mg\\/day, administered as monotherapy or in combination with pegsunercept 800 mug\\/kg twice weekly. Arthroscopic synovial tissue biopsies were obtained at baseline, at 4 weeks and at the final time point. Following immunohistochemical staining, RANKL and OPG expression was quantified using digital image analysis. Radiographic damage was evaluated using the van der Heijde modification of the Sharp scoring system. Twenty-two patients were randomized. Baseline expression of RANKL, but not OPG, correlated significantly with baseline CRP levels (r = 0.61, P < 0.01). While a significant reduction in OPG expression following treatment was observed in clinical responders at the final time point (P < 0.05 vs. baseline), RANKL levels did not change, and the RANKL:OPG ratio remained unaltered, even at the highest levels of clinical response. When potential predictors of radiographic outcome were evaluated, baseline RANKL expression correlated with erosive progression at 1 year (r = 0.71, P < 0.01). Distinct, though related, pathophysiologic processes mediate joint inflammation and destruction in RA. Elevated synovial tissue RANKL expression is associated with progressive joint erosion, and may be independent of the clinical response to targeted therapy. The potential therapeutic importance of modulating RANKL in RA is highlighted, if radiographic arrest is to be achieved.

  1. Assessment of Local Control after Laser-Induced Thermotherapy of Liver Metastases from Colorectal Cancer: Contribution of FDG-PET in Patients with Clinical Suspicion of Progressive Disease

    Energy Technology Data Exchange (ETDEWEB)

    Denecke, T.; Steffen, I.; Hildebrandt, B.; Ruehl, R.; Streitparth, F.; Lehmk uhl, L.; Langrehr, J.; Ricke, J.; Amthauer, H.; Lopez Haenninen, E. [Klinik fuer Strahlenheilkunde, Bereiche Radiologie und Nuklearmedizin, Medizinische Klinik mit Schwerpunkt Haematologie Onkologie, and Klinik fuer Allgemein-, Viszeral-, und T ransplantationschirurgie, Campus Virchow-Klinikum, Charite - Universitaetsmedizi n Berlin, (Germany)

    2007-10-15

    Background: Management of patients after locally ablative treatment of liver metastases requires exact information about local control and systemic disease status. To fulfill these requirements, whole-body imaging using positron emission tomography with {sup 18}F-fluorodeoxyglucose (FDG-PET) is a promising alternative to morphologic imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI). Purpose: To evaluate FDG-PET for the assessment of local control and systemic disease in patients with clinical suspicion of tumor progression after laser-induced thermotherapy (LITT) of colorectal liver metastases. Material and Methods: In 21 patients with suspicion of progressive disease after LITT, whole-body FDG-PET was performed. The presence of viable tumor within treated lesions, new liver metastases, and extrahepatic disease was evaluated visually and semi quantitatively (maximal standard uptake value [SUVmax], tumor-to-normal ratio [T/N]). The standard of reference was histopathology (n = 25 lesions) and/or clinical follow-up (>12 months) including contrast-enhanced MRI of the liver. Results: Among 54 metastases treated with LITT, 29 had residual tumor. Receiver operating characteristic (ROC) analysis of SUVmax (area under the curve (AUC) 0.990) and T/N (AUC 0.968) showed a significant discrimination level of negative or positive lesion status with an equal accuracy of 94% (51/54). The overall accuracy of visual FDG-PET was 96% (52/54), with one false-negative lesion among six examined within 3 days after LITT, and one false-positive lesion examined 54 days after LITT. In the detection of new intra- and extrahepatic lesions, FDG-PET resulted in correct alteration of treatment strategy in 43% of patients (P = 0.007). Conclusion: FDG-PET is a promising tool for the assessment of local control and whole-body restaging in patients with clinical suspicion of tumor progression after locally ablative treatment of colorectal liver metastases with

  2. Progress with Drug-Eluting Stent Technology from Early to New Generation Devices : A comprehensive clinical and intravascular imaging evaluation

    NARCIS (Netherlands)

    L. Räber (Lorenz)

    2014-01-01

    markdownabstract__Abstract__ Percutaneous coronary interventions (PCI) are among the most frequently performed medical interventions worldwide reflecting the large burden of coronary atherosclerosis. Bare metal stents were associated with a high rate of repeat revascularization due to clinical

  3. Review of progresses on clinical applications of ion selective electrodes for electrolytic ion tests: from conventional ISEs to graphene-based ISEs

    Directory of Open Access Journals (Sweden)

    Rongguo Yan

    2016-10-01

    Full Text Available There exist several positively and negatively charged electrolytes or ions in human blood, urine, and other body fluids. Tests that measure the concentration of these ions in clinics are performed using a more affordable, portable, and disposable potentiometric sensing method with few sample volumes, which requires the use of ion-selective electrodes (ISEs and reference electrodes. This review summarily descriptively presents progressive developments and applications of ion selective electrodes in medical laboratory electrolytic ion tests, from conventional ISEs, solid-contact ISEs, carbon nanotube based ISEs, to graphene-based ISEs.

  4. 小肠淋巴瘤临床与治疗进展%Progress of small bowel lymphoma in clinical treatment

    Institute of Scientific and Technical Information of China (English)

    陈春球; 范跃祖

    2008-01-01

    对小肠淋巴瘤的病因、临床表现、病理分期、治疗和预后研究进展进行综述,为早期明确诊断小肠淋巴瘤,选择有效的治疗方案提供依据.%To review the progress of small bowel lymphoma in,Pathoyeny pathology,clinical treatment and prognosis,which can effectively provide scheme for early diagnosis and therapy of small bowel lymphoma.

  5. CD8+ Lymphocytes Can Control HIV Infection in vitro by Suppressing Virus Replication

    Science.gov (United States)

    Walker, Christopher M.; Moody, Dewey J.; Stites, Daniel P.; Levy, Jay A.

    1986-12-01

    Lymphocytes bearing the CD8 marker were shown to suppress replication of human immunodeficiency virus (HIV) in peripheral blood mononuclear cells. The effect was dose-dependent and most apparent with autologous lymphocytes; it did not appear to be mediated by a cytotoxic response. This suppression of HIV replication could be demonstrated by the addition of CD8+ cells at the initiation of virus production as well as after several weeks of virus replication by cultured cells. The observations suggest a potential approach to therapy in which autologous CD8 lymphocytes could be administered to individuals to inhibit HIV replication and perhaps progression of disease.

  6. Shell Separation for Mirror Replication

    Science.gov (United States)

    1999-01-01

    NASA's Space Optics Manufacturing Center has been working to expand our view of the universe via sophisticated new telescopes. The Optics Center's goal is to develop low-cost, advanced space optics technologies for the NASA program in the 21st century - including the long-term goal of imaging Earth-like planets in distant solar systems. To reduce the cost of mirror fabrication, Marshall Space Flight Center (MSFC) has developed replication techniques, the machinery, and materials to replicate electro-formed nickel mirrors. Optics replication uses reusable forms, called mandrels, to make telescope mirrors ready for final finishing. MSFC optical physicist Bill Jones monitors a device used to chill a mandrel, causing it to shrink and separate from the telescope mirror without deforming the mirror's precisely curved surface.

  7. Detection of HIV drug resistance during antiretroviral treatment and clinical progression in a large European cohort study

    DEFF Research Database (Denmark)

    Cozzi-Lepri, Alessandro; Phillips, Andrew N; Clotet, Bonaventura;

    2008-01-01

    OBJECTIVE(S): To investigate the relationship between detection of HIV drug resistance by 2 years from starting antiretroviral therapy and the subsequent risk of progression to AIDS and death. DESIGN: Virological failure was defined as experiencing two consecutive viral loads of more than 400......-up. We observed 829 AIDS events and 571 deaths during 38,814 person-years of follow-up resulting in an overall incidence of new AIDS and death of 3.6 per 100 person-years of follow-up [95% confidence interval (CI):3.4-3.8]. By 96 months from baseline, the proportion of patients with a new AIDS diagnosis...

  8. Personality and Academic Motivation: Replication, Extension, and Replication

    Science.gov (United States)

    Jones, Martin H.; McMichael, Stephanie N.

    2015-01-01

    Previous work examines the relationships between personality traits and intrinsic/extrinsic motivation. We replicate and extend previous work to examine how personality may relate to achievement goals, efficacious beliefs, and mindset about intelligence. Approximately 200 undergraduates responded to the survey with a 150 participants replicating…

  9. Multiple sclerosis: integration of modeling with biology, clinical and imaging measures to provide better monitoring of disease progression and prediction of outcome.

    Science.gov (United States)

    Goodwin, Shikha Jain

    2016-12-01

    Multiple Sclerosis (MS) is a major cause of neurological disability in adults and has an annual cost of approximately $28 billion in the United States. MS is a very complex disorder as demyelination can happen in a variety of locations throughout the brain; therefore, this disease is never the same in two patients making it very hard to predict disease progression. A modeling approach which combines clinical, biological and imaging measures to help treat and fight this disorder is needed. In this paper, I will outline MS as a very heterogeneous disorder, review some potential solutions from the literature, demonstrate the need for a biomarker and will discuss how computational modeling combined with biological, clinical and imaging data can help link disparate observations and decipher complex mechanisms whose solutions are not amenable to simple reductionism.

  10. Weight as predictors of clinical progression and treatment failure: Results from the TREAT Asia Pediatric HIV Observational Database (TApHOD)

    Science.gov (United States)

    Kariminia, Azar; Durier, Nicolas; Jourdain, Gonzague; Saghayam, Suneeta; Do, Chau V.; Van Nguyên, Lam; Hansudewechakul, Rawiwan; Lumbiganon, Pagakrong; Chokephaibulkit, Kulkanya; Truong, Khanh Huu; Sirisanthana, Virat; Ung, Vibol; Vonthanak, Saphonn; Ananworanich, Jintanat; Yusoff, Nik Khairulddin N.; Kurniati, Nia; Razali, Kamarul Azahar; Fong, Moy Siew; Nallusamy, Revathy; Wati, Dewi Kumara

    2014-01-01

    Objective To evaluate the value of time-updated weight and height in predicting clinical progression, immunological and virological failure in children receiving combination antiretroviral therapy (cART). Methods We used Cox regression to analyse data of a cohort of Asian children. Results 2608 children were included; median age at cART was 5.7 years. Time-updated weight for age Z score <−3 was associated with mortality (P < 0.001) independent of CD4%; and <−2 was associated with immunological failure (P ≤ 0.03) independent of age at cART. Conclusion Weight monitoring provides useful data to inform clinical management of children on cART in resource-limited settings. PMID:24872132

  11. A protocol for evaluating progressive levels of simulation fidelity in the development of technical skills, integrated performance and woman centred clinical assessment skills in undergraduate midwifery students.

    Science.gov (United States)

    Brady, Susannah; Bogossian, Fiona; Gibbons, Kristen; Wells, Andrew; Lyon, Pauline; Bonney, Donna; Barlow, Melanie; Jackson, Anne

    2013-05-24

    Simulation as a pedagogical approach has been used in health professional education to address the need to safely develop effective clinical skills prior to undertaking clinical practice. However, evidence for the use of simulation in midwifery is largely anecdotal, and research evaluating the effectiveness of different levels of simulation fidelity are lacking.Woman centred care is a core premise of the midwifery profession and describes the behaviours of an individual midwife who demonstrates safe and effective care of the individual woman. Woman centred care occurs when the midwife modifies the care to ensure the needs of each individual woman are respected and addressed. However, a review of the literature demonstrates an absence of a valid and reliable tool to measure the development of woman centred care behaviours. This study aims to determine which level of fidelity in simulated learning experiences provides the most effective learning outcomes in the development of woman centred clinical assessment behaviors and skills in student midwives. Three-arm, randomised, intervention trial.In this research we plan to:a) trial three levels of simulation fidelity - low, medium and progressive, on student midwives performing the procedure of vaginal examination;b) measure clinical assessment skills using the Global Rating Scale (GRS) and Integrated Procedural Performance Instrument (IPPI); andc) pilot the newly developed Woman Centred Care Scale (WCCS) to measure clinical behaviors related to Woman-Centredness. This project aims to enhance knowledge in relation to the appropriate levels of fidelity in simulation that yield the best educational outcomes for the development of woman centred clinical assessment in student midwives. The outcomes of this project may contribute to improved woman centred clinical assessment for student midwives, and more broadly influence decision making regarding education resource allocation for maternity simulation.

  12. 多囊卵巢综合征的临床治疗研究进展%Research Progress in Clinical Treatments of Polycystic Ovary Syndrome

    Institute of Scientific and Technical Information of China (English)

    杨艳; 李海燕

    2016-01-01

    Polycystic ovary syndrome (PCOS) isone of the disease more and more attended by all of us which troubled the childbearing-aged women. The main clinical features are infertility amenorrhea, obesity, hairy acne and so on, belonging to an endocrine disorder. As the research progresses of its pathogenesis, now the methods for the clinical treatments of polycystic ovary syndrome is not a few. These methods mainly through such as Inducing ovulation, lowering androgen levels , improving insulin resistance and so on to cure clinical symptoms. Learning about its treatments presented in this review, we discussed the progress in clinical treatments of it from ifve aspects: the general treatments, drug therapies, surgical treatments,Integrated therapies Chinese-western medicine and assisted reproductive technology.%多囊卵巢综合症(PCOS)作为困扰育龄期妇女的疾病之一越来越受到大家的重视,其临床特征主要为不孕、闭经、肥胖以及多毛痤疮等,属于内分泌紊乱性疾病。随着对其发病机制的研究进展,目前临床上治疗多囊卵巢综合症的方法较多,主要是通过诱发排卵、降低雄激素水平以及改善胰岛素抵抗等展开对症治疗。本文就其治疗情况进行了解,从一般治疗、药物治疗、手术治疗、中西医联合治疗及辅助生殖技术等方面进行了综述。

  13. Noninvasive visualization of adenovirus replication with a fluorescent reporter in the E3 region.

    Science.gov (United States)

    Ono, Hidetaka A; Le, Long P; Davydova, Julia G; Gavrikova, Tatyana; Yamamoto, Masato

    2005-11-15

    To overcome the inefficacy and undesirable side effects of current cancer treatment strategies, conditionally replicative adenoviruses have been developed to exploit the unique mechanism of oncolysis afforded by tumor-specific viral replication. Despite rapid translation into clinical trials and the established safety of oncolytic adenoviruses, the in vivo function of these agents is not well understood due to lack of a noninvasive detection system for adenovirus replication. To address this issue, we propose the expression of a reporter from the adenovirus E3 region as a means to monitor replication. Adenovirus replication reporter vectors were constructed with the enhanced green fluorescent protein (EGFP) gene placed in the deleted E3 region under the control of the adenoviral major late promoter while retaining expression of the adenovirus death protein to conserve the native oncolytic capability of the virus. Strong EGFP fluorescence was detected from these vectors in a replication-dependent manner, which correlated with viral DNA replication. Fluorescence imaging in vivo confirmed the ability to noninvasively detect fluorescent signal during replication, which generally corresponded with the underlying level of viral DNA replication. EGFP representation of viral replication was further confirmed by Western blot comparison with the viral DNA content in the tumors. Imaging reporter expression controlled by the adenoviral major late promoter provides a viable approach to noninvasively monitor adenovirus replication in preclinical studies and has the potential for human application with clinically relevant imaging reporters.

  14. New histone supply regulates replication fork speed and PCNA unloading

    DEFF Research Database (Denmark)

    Mejlvang, Jakob; Feng, Yunpeng; Alabert, Constance;

    2014-01-01

    Correct duplication of DNA sequence and its organization into chromatin is central to genome function and stability. However, it remains unclear how cells coordinate DNA synthesis with provision of new histones for chromatin assembly to ensure chromosomal stability. In this paper, we show...... that replication fork speed is dependent on new histone supply and efficient nucleosome assembly. Inhibition of canonical histone biosynthesis impaired replication fork progression and reduced nucleosome occupancy on newly synthesized DNA. Replication forks initially remained stable without activation...... of conventional checkpoints, although prolonged histone deficiency generated DNA damage. PCNA accumulated on newly synthesized DNA in cells lacking new histones, possibly to maintain opportunity for CAF-1 recruitment and nucleosome assembly. Consistent with this, in vitro and in vivo analysis showed that PCNA...

  15. The lag time in initiating clinical testing of new drugs in combination with radiation therapy, a significant barrier to progress?

    Science.gov (United States)

    Blumenfeld, P; Pfeffer, R M; Symon, Z; Den, R B; Dicker, A P; Raben, D; Lawrence, Y R

    2014-01-01

    Background: The clinical development of new drugs with radiation appears to be limited. We hypothesised that phase I clinical trials with radiation therapy (RT) are initiated too late into a new drug's lifetime, impeding the ability to complete RT–drug development programmes before patent expiration. Methods: We identified novel drug–radiation phase I combination trials performed between 1980 and 2012 within the PubMed and ClinicalTrials.gov databases. Data gathered for each drug included: date the initial phase I trial with/without RT was opened/published, date of the published positive phase III trials, and patent expiration dates. Lag time was defined as the interval between opening of the phase I trial without RT and the opening of the phase I with RT. Linear regression was used to model how the lag time has changed over time. Results: The median lag time was 6 years. The initial phase I trial with RT was typically published 2 years after the first published positive phase III trial and 11 years before patent expiration. Using a best-fit linear model, lag time decreased from 10 years for phase I trials published in 1990 to 5 years in 2005 (slope significantly non-zero, P<0.001). Conclusions: Clinical drug development with RT commences late in the life cycle of anti-cancer agents. Taking into account the additional time required for late-phase clinical trials, the delay in initiating clinical testing of drug–RT combinations discourages drug companies from further pursuing RT-based development. Encouragingly, lag time appears to be decreasing. Further reduction in lag time may accelerate RT-based drug development, potentially improving patient outcomes. PMID:25117813

  16. Replication-selective oncolytic viruses in the treatment of cancer.

    Science.gov (United States)

    Everts, Bart; van der Poel, Henk G

    2005-02-01

    In the search for novel strategies, oncolytic virotherapy has recently emerged as a viable approach to specifically kill tumor cells. Unlike conventional gene therapy, it uses replication competent viruses that are able to spread through tumor tissue by virtue of viral replication and concomitant cell lysis. Recent advances in molecular biology have allowed the design of several genetically modified viruses, such as adenovirus and herpes simplex virus that specifically replicate in, and kill tumor cells. On the other hand, viruses with intrinsic oncolytic capacity are also being evaluated for therapeutic purposes. In this review, an overview is given of the general mechanisms and genetic modifications by which these viruses achieve tumor cell-specific replication and antitumor efficacy. However, although generally the oncolytic efficacy of these approaches has been demonstrated in preclinical studies the therapeutic efficacy in clinical trails is still not optimal. Therefore, strategies are evaluated that could further enhance the oncolytic potential of conditionally replicating viruses. In this respect, the use of tumor-selective viruses in conjunction with other standard therapies seems most promising. However, still several hurdles regarding clinical limitations and safety issues should be overcome before this mode of therapy can become of clinical relevance.

  17. Chk1 inhibits replication factory activation but allows dormant origin firing in existing factories

    Science.gov (United States)

    Ge, Xin Quan

    2010-01-01

    Replication origins are licensed by loading MCM2-7 hexamers before entry into S phase. However, only ∼10% of licensed origins are normally used in S phase, with the others remaining dormant. When fork progression is inhibited, dormant origins initiate nearby to ensure that all of the DNA is eventually replicated. In apparent contrast, replicative stress activates ataxia telangiectasia and rad-3–related (ATR) and Chk1 checkpoint kinases that inhibit origin firing. In this study, we show that at low levels of replication stress, ATR/Chk1 predominantly suppresses origin initiation by inhibiting the activation of new replication factories, thereby reducing the number of active factories. At the same time, inhibition of replication fork progression allows dormant origins to initiate within existing replication factories. The inhibition of new factory activation by ATR/Chk1 therefore redirects replication toward active factories where forks are inhibited and away from regions that have yet to start replication. This minimizes the deleterious consequences of fork stalling and prevents similar problems from arising in unreplicated regions of the genome. PMID:21173116

  18. Regulation of Replication Recovery and Genome Integrity

    DEFF Research Database (Denmark)

    Colding, Camilla Skettrup

    facilitate replication recovery after MMS-induced replication stress. Our data reveal that control of Mrc1 turnover through the interplay between posttranslational modifications and INQ localization adds another layer of regulation to the replication checkpoint. We also add replication recovery to the list...... is mediated by Mrc1, which ensures Mec1 presence at the stalled replication fork thus facilitating Rad53 phosphorylation. When replication can be resumed safely, the replication checkpoint is deactivated and replication forks restart. One mechanism for checkpoint deactivation is the ubiquitin......-targeted proteasomal degradation of Mrc1. In this study, we describe a novel nuclear structure, the intranuclear quality control compartment (INQ), which regulates protein turnover and is important for recovery after replication stress. We find that upon methyl methanesulfonate (MMS)-induced replication stress, INQ...

  19. Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial.

    Science.gov (United States)

    Grignani, Giovanni; Palmerini, Emanuela; Ferraresi, Virginia; D'Ambrosio, Lorenzo; Bertulli, Rossella; Asaftei, Sebastian Dorin; Tamburini, Angela; Pignochino, Ymera; Sangiolo, Dario; Marchesi, Emanuela; Capozzi, Federica; Biagini, Roberto; Gambarotti, Marco; Fagioli, Franca; Casali, Paolo Giovanni; Picci, Piero; Ferrari, Stefano; Aglietta, Massimo

    2015-01-01

    Results of previous study showed promising but short-lived activity of sorafenib in the treatment of patients with unresectable advanced and metastatic osteosarcoma. This treatment failure has been attributed to the mTOR pathway and might therefore be overcome with the addition of mTOR inhibitors. We aimed to investigate the activity of sorafenib in combination with everolimus in patients with inoperable high-grade osteosarcoma progressing after standard treatment. We did this non-randomised phase 2 trial in three Italian Sarcoma Group centres. We enrolled adults (≥18 years) with relapsed or unresectable osteosarcoma progressing after standard treatment (methotrexate, cisplatin, and doxorubicin, with or without ifosfamide). Patients received 800 mg sorafenib plus 5 mg everolimus once a day until disease progression or unacceptable toxic effects. The primary endpoint was 6 month progression-free survival (PFS). All analyses were intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01804374. We enrolled 38 patients between June 16, 2011, and June 4, 2013. 17 (45%; 95% CI 28-61) of 38 patients were progression free at 6 months. Toxic effects led to dose reductions, or short interruptions, or both in 25 (66%) of 38 patients and permanent discontinuation for two (5%) patients. The most common grade 3-4 adverse events were lymphopenia and hypophosphataemia each in six (16%) patients, hand and foot syndrome in five (13%), thrombocytopenia in four (11%), and fatigue, oral mucositis, diarrhoea, and anaemia each in two (5%). One patient (3%) had a grade 3 pneumothorax that required trans-thoracic drainage, and that recurred at the time of disease progression. This was reported as a serious adverse event related to the study drugs in both instances. No other serious adverse events were reported during the trial. There were no treatment-related deaths. Although the combination of sorafenib and everolimus showed activity as a further-line treatment

  20. Cytokine profile during latent and slowly progressive primary tuberculosis: a possible role for interleukin-15 in mediating clinical disease.

    Science.gov (United States)

    Abebe, F; Mustafa, T; Nerland, A H; Bjune, G A

    2006-01-01

    Recently, mouse models for latent (LTB) and slowly progressive primary tuberculosis (SPTB) have been established. However, cytokine profiles during the two models are not well established. Using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) we studied the expression levels of interleukin (IL)-2, IL-4, IL-10, IL-12, IL-15, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha during the course of LTB and SPTB in the lungs and spleens of B6D2F1Bom mice infected with the H37Rv strain of Mycobacterium tuberculosis (Mtb). The results show that, except for IL-4, cytokine expression levels were significantly higher during SPTB than LTB in both the lungs and spleens. During LTB, all the cytokines (except IL-2 in the lungs) had higher expression levels during the initial period of infection both in the lungs and spleens. During SPTB, the expression levels of IL-15 increased significantly from phases 1 to 3 in the lungs. The expression levels of IL-10, IL-12 and IFN-gamma increased significantly from 2 to 3 in the lungs. IL-10 and IL-15 increased significantly from phases 2 to 3, whereas that of TNF-alpha decreased significantly and progressively from phases 1 to 3 in the spleens. Over-expression of proinflammatory cytokines during active disease has been well documented, but factor(s) underlying such over-expression is not known. In the present study, there was a progressive and significant increase in the expression levels of IL-15, together with Th1 cytokines (IL-12 and IFN-gamma) during SPTB but a significant decrease during LTB. IL-15 is known to up-regulate the production of proinflammatory cytokines, IL-1beta, IL-8, IL-12, IL-17, IFN-gamma and TNF-alpha and has an inhibitory effect on activation-induced cell death. IL-15 is known to be involved in many proinflammatory disease states such as rheumatoid arthritis, sarcoidosis, inflammatory bowel diseases, autoimmune diabetes, etc. Our results, together with the above observations

  1. Autologous Bone Marrow Stromal Cell Transplantation for Central Nervous System Disorders – Recent Progress and Perspective for Clinical Application

    Directory of Open Access Journals (Sweden)

    Kuroda S

    2011-01-01

    Full Text Available There is increasing evidence that the transplanted BMSC significantly promote functional recovery after CNS damage in the animal models of various kinds of CNS disorders, including cerebral infarct, traumatic brain injury and spinal cord injury. However, there are several shortages of information when considering clinical application of BMSC transplantation for patients with CNS disorders. In this review, therefore, we discuss what we should clarify to establish cell transplantation therapy as the scientifically proven entity in clinical situation and describe our recent works for this purpose. The BMSC have the ability to alter their gene expression profile and phenotype in response to the surrounding circumstances and to protect the neurons by producing some neurotrophic factors. They also promote neurite extension and rebuild the neural circuits in the injured CNS. The BMSC can be expanded in vitro using the animal serum-free medium. Pharmacological modulation may accelerate the in vitro proliferation of the BMSC. Using in vivo optical imaging technique, the transplanted BMSC can non-invasively be tracked in the living animals for at least 8 weeks after transplantation. It is urgent issues to develop clinical imaging technique to track the transplanted cells in the CNS and evaluate the therapeutic significance of BMSC transplantation in order to establish it as a definite therapeutic strategy in clinical situation in the future.

  2. Clinical symptoms of right ventricular failure in experimental chronic pressure load are associated with progressive diastolic dysfunction

    NARCIS (Netherlands)

    Borgdorff, Marinus A. J.; Koop, Anne-Marie C.; Bloks, Vincent W.; Dickinson, Michael G.; Steendijk, Paul; Sillje, Herman H. W.; van Wiechen, Maarten P. H.; Berger, Rolf M. F.; Bartelds, Beatrijs

    2015-01-01

    Background: Right ventricular failure (RVF) due to pressure load is a major cause of death in congenital heart diseases and pulmonary hypertension. The mechanisms of RVF are unknown. We used an experimental approach based upon clinical signs of RVF to delineate functional and biological processes as

  3. The diagnostic challenge of progressive pseudorheumatoid dysplasia (PPRD): a review of clinical features, radiographic features, and WISP3 mutations in 63 affected individuals.

    Science.gov (United States)

    Garcia Segarra, Nuria; Mittaz, Laureane; Campos-Xavier, Ana Belinda; Bartels, Cynthia F; Tuysuz, Beyhan; Alanay, Yasemin; Cimaz, Rolando; Cormier-Daire, Valerie; Di Rocco, Maja; Duba, Hans-Christoph; Elcioglu, Nursel H; Forzano, Francesca; Hospach, Toni; Kilic, Esra; Kuemmerle-Deschner, Jasmin B; Mortier, Geert; Mrusek, Sonja; Nampoothiri, Sheela; Obersztyn, Ewa; Pauli, Richard M; Selicorni, Angelo; Tenconi, Romano; Unger, Sheila; Utine, G Eda; Wright, Michael; Zabel, Bernhard; Warman, Matthew L; Superti-Furga, Andrea; Bonafé, Luisa

    2012-08-15

    Progressive pseudorheumatoid dysplasia (PPRD) is a genetic, non-inflammatory arthropathy caused by recessive loss of function mutations in WISP3 (Wnt1-inducible signaling pathway protein 3; MIM 603400), encoding for a signaling protein. The disease is clinically silent at birth and in infancy. It manifests between the age of 3 and 6 years with joint pain and progressive joint stiffness. Affected children are referred to pediatric rheumatologists and orthopedic surgeons; however, signs of inflammation are absent and anti-inflammatory treatment is of little help. Bony enlargement at the interphalangeal joints progresses leading to camptodactyly. Spine involvement develops in late childhood and adolescence leading to short trunk with thoracolumbar kyphosis. Adult height is usually below the 3rd percentile. Radiographic signs are relatively mild. Platyspondyly develops in late childhood and can be the first clue to the diagnosis. Enlargement of the phalangeal metaphyses develops subtly and is usually recognizable by 10 years. The femoral heads are large and the acetabulum forms a distinct "lip" overriding the femoral head. There is a progressive narrowing of all articular spaces as articular cartilage is lost. Medical management of PPRD remains symptomatic and relies on pain medication. Hip joint replacement surgery in early adulthood is effective in reducing pain and maintaining mobility and can be recommended. Subsequent knee joint replacement is a further option. Mutation analysis of WISP3 allowed the confirmation of the diagnosis in 63 out of 64 typical cases in our series. Intronic mutations in WISP3 leading to splicing aberrations can be detected only in cDNA from fibroblasts and therefore a skin biopsy is indicated when genomic analysis fails to reveal mutations in individuals with otherwise typical signs and symptoms. In spite of the first symptoms appearing in early childhood, the diagnosis of PPRD is most often made only in the second decade and affected

  4. Self-replicating alphavirus RNA vaccines.

    Science.gov (United States)

    Ljungberg, Karl; Liljeström, Peter

    2015-02-01

    Recombinant nucleic acids are considered as promising next-generation vaccines. These vaccines express the native antigen upon delivery into tissue, thus mimicking live attenuated vaccines without having the risk of reversion to pathogenicity. They also stimulate the innate immune system, thus potentiating responses. Nucleic acid vaccines are easy to produce at reasonable cost and are stable. During the past years, focus has been on the use of plasmid DNA for vaccination. Now mRNA and replicon vaccines have come into focus as promising technology platforms for vaccine development. This review discusses self-replicating RNA vaccines developed from alphavirus expression vectors. These replicon vaccines can be delivered as RNA, DNA or as recombinant virus particles. All three platforms have been pre-clinically evaluated as vaccines against a number of infectious diseases and cancer. Results have been very encouraging and propelled the first human clinical trials, the results of which have been promising.

  5. 临床无肌病性皮肌炎生物学标记物研究进展%Research progress on biomarkers in clinically amyopathic dermatomyositis

    Institute of Scientific and Technical Information of China (English)

    左瑜; 安媛(综述); 栗占国(审校)

    2015-01-01

    Clinically amyopathic dermatomyositis (CADM)is a unique subset of idiopathic inflammatory myositis .Atypical clin-ical manifestations and associated ILD /malignancy often result in rapid progress and poor prognosis in some patients with CADM .Thus, the detection of biomarkers and treatment monitor indexes is very important for early diagnosis and treatment of the disease .This review will discuss the epidemiologic status ,and relative biomarkers and their clinical significance in the disease .%临床无肌病性皮肌炎(clinically amyopathic dermatomyositis, CADM)作为炎性肌病中亚型之一,临床上较难识别,并可合并肺间质病变及恶性肿瘤,部分患者病情进展迅速,预后较差。因此,通过测定生物标记物及病情活动监测指标对CADM 患者早期诊断及治疗具有重要意义。本文对 CADM 的流行病学情况、相关生物学标记物及其临床意义进行讨论。

  6. [The clinical and forensic psychiatric assessment of attack-like progressive schizophrenia with the Kandinsky-Clérambault syndrome].

    Science.gov (United States)

    Vasil'ev, V D

    1992-01-01

    Overall 200 patients suffering from attack-like progressive schizophrenia associated with Kandinsky-Clérambault syndrome were examined. All the patients underwent compulsory treatment at the psychiatric hospitals. Two varieties of schizophrenia associated with Kandinsky-Clérambault syndrome were distinguished: psychotic (127 persons) and psychopath-like (73 persons). The psychotic variety is characterized by the growth of personality disintegration because of changes to a greater degree in the thinking sphere, whereas the psychopath-like variety is marked by alterations in the affective volitional sphere. The psychopathological mechanisms of socially dangerous action of the patients at the preproductive and productive stages of endogenous process are described depending on the varieties distinguished.

  7. A clinical and laboratory study evaluating the profile of cytokine levels in relapsing remitting and secondary progressive multiple sclerosis.

    Science.gov (United States)

    Pasquali, Livia; Lucchesi, Cinzia; Pecori, Chiara; Metelli, Maria Rita; Pellegrini, Silvia; Iudice, Alfonso; Bonuccelli, Ubaldo

    2015-01-15

    The main aim of the study was to evaluate levels of cytokines IL-1ra, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, TNF-alfa, TGB-beta1 and IFN-gamma in 30 patients with relapsing remitting (RRMS) compared to 30 secondary progressive multiple sclerosis (SPMS) in a peripheral blood sample. Statistical analysis showed significant higher levels of IL-17 and INF-gamma, which are cytokines with pro-inflammatory properties, and lower levels of TGF-beta1, a molecule with immunosuppressant activity, in RRMS compared to SPMS. These results underline the existence of a different cytokines dysregulation in RRMS compared to SPMS phases with higher pro-inflammatory activity in RRMS.

  8. Hyperthermia stimulates HIV-1 replication.

    Directory of Open Access Journals (Sweden)

    Ferdinand Roesch

    Full Text Available HIV-infected individuals may experience fever episodes. Fever is an elevation of the body temperature accompanied by inflammation. It is usually beneficial for the host through enhancement of immunological defenses. In cultures, transient non-physiological heat shock (42-45°C and Heat Shock Proteins (HSPs modulate HIV-1 replication, through poorly defined mechanisms. The effect of physiological hyperthermia (38-40°C on HIV-1 infection has not been extensively investigated. Here, we show that culturing primary CD4+ T lymphocytes and cell lines at a fever-like temperature (39.5°C increased the efficiency of HIV-1 replication by 2 to 7 fold. Hyperthermia did not facilitate viral entry nor reverse transcription, but increased Tat transactivation of the LTR viral promoter. Hyperthermia also boosted HIV-1 reactivation in a model of latently-infected cells. By imaging HIV-1 transcription, we further show that Hsp90 co-localized with actively transcribing provirus, and this phenomenon was enhanced at 39.5°C. The Hsp90 inhibitor 17-AAG abrogated the increase of HIV-1 replication in hyperthermic cells. Altogether, our results indicate that fever may directly stimulate HIV-1 replication, in a process involving Hsp90 and facilitation of Tat-mediated LTR activity.

  9. Hyperthermia stimulates HIV-1 replication.

    Science.gov (United States)

    Roesch, Ferdinand; Meziane, Oussama; Kula, Anna; Nisole, Sébastien; Porrot, Françoise; Anderson, Ian; Mammano, Fabrizio; Fassati, Ariberto; Marcello, Alessandro; Benkirane, Monsef; Schwartz, Olivier

    2012-01-01

    HIV-infected individuals may experience fever episodes. Fever is an elevation of the body temperature accompanied by inflammation. It is usually beneficial for the host through enhancement of immunological defenses. In cultures, transient non-physiological heat shock (42-45°C) and Heat Shock Proteins (HSPs) modulate HIV-1 replication, through poorly defined mechanisms. The effect of physiological hyperthermia (38-40°C) on HIV-1 infection has not been extensively investigated. Here, we show that culturing primary CD4+ T lymphocytes and cell lines at a fever-like temperature (39.5°C) increased the efficiency of HIV-1 replication by 2 to 7 fold. Hyperthermia did not facilitate viral entry nor reverse transcription, but increased Tat transactivation of the LTR viral promoter. Hyperthermia also boosted HIV-1 reactivation in a model of latently-infected cells. By imaging HIV-1 transcription, we further show that Hsp90 co-localized with actively transcribing provirus, and this phenomenon was enhanced at 39.5°C. The Hsp90 inhibitor 17-AAG abrogated the increase of HIV-1 replication in hyperthermic cells. Altogether, our results indicate that fever may directly stimulate HIV-1 replication, in a process involving Hsp90 and facilitation of Tat-mediated LTR activity.

  10. Cellular Responses to Replication Problems

    NARCIS (Netherlands)

    M. Budzowska (Magdalena)

    2008-01-01

    textabstractDuring every S-phase cells need to duplicate their genomes so that both daughter cells inherit complete copies of genetic information. It is a tremendous task, given the large sizes of mammalian genomes and the required precision of DNA replication. A major threat to the accuracy and eff

  11. Covert Reinforcement: A Partial Replication.

    Science.gov (United States)

    Ripstra, Constance C.; And Others

    A partial replication of an investigation of the effect of covert reinforcement on a perceptual estimation task is described. The study was extended to include an extinction phase. There were five treatment groups: covert reinforcement, neutral scene reinforcement, noncontingent covert reinforcement, and two control groups. Each subject estimated…

  12. Clinical significance of SOX9 in human non-small cell lung cancer progression and overall patient survival

    Directory of Open Access Journals (Sweden)

    Zhou Chun-Hui

    2012-03-01

    Full Text Available Abstract Background Sex determining region Y (SRY-related high mobility groupbox 9 (SOX9 is an important transcription factor required for development, which regulates the expression of target genes in the associated pathway. The aim of this study was to describe the expression of SOX9 in human non-small cell lung cancer (NSCLC and to investigate the association between SOX9 expression and progression of NSCLC. Methods SOX9 protein and mRNA expression in normal human pneumonocytes, lung cancer cell lines, and eight pairs of matched lung cancer tissues and their adjacent normal lung tissues were detected by Western blotting and real-time reverse transcription-polymerase chain reaction (RT-PCR. Immunohistochemistry was used to determine SOX9 protein expression in 142 cases of histologically characterized NSCLC. Statistical analyses were applied to test for prognostic and diagnostic associations. Results SOX9 in lung cancer cell lines was upregulated at both mRNA and protein levels, and SOX9 mRNA and protein were also elevated in NSCLC tissues compared with levels in corresponding adjacent non-cancerous lung tissues. Immunohistochemical analysis demonstrated a high expression of SOX9 in 74/142 (52.1% paraffin-embedded archival lung cancer biopsies. Statistical analysis indicated that upregulation of SOX9 was significantly correlated with the histological stage of NSCLC (P = 0.017 and that patients with a high SOX9 level exhibited a shorter survival time (P Conclusions This work shows that SOX9 may serve as a novel and prognostic marker for NSCLC, and play a role during the development and progression of the disease.

  13. 含临床病毒株聚合酶逆转录酶区的乙肝病毒DNA稳定复制细胞系的构建%Establishment of a Stable Cell Line Replicating Hepatitis B Virus DNA Carrying the Reverse Transcriptase Region Derived from a Clinical Isolate

    Institute of Scientific and Technical Information of China (English)

    向明确; 蔡雪飞; 张文露; 黄爱龙; 胡接力

    2013-01-01

    目的 构建含有临床病毒株聚合酶逆转录酶(RT)区的乙肝病毒(HBV) DNA稳定复制细胞系.方法 采用巢式PCR从患者血清扩增HBV DNA片段,利用片段置换反应将该片段克隆到HBV DNA复制载体,并在该载体上引入新霉素抗性基因,在确认该重组DNA体外可复制后,将其转染HepG2细胞,G418筛选,采用real-time PCR结合ELISA及Southern blot检测初筛和鉴定HBV DNA稳定复制细胞系.结果 从患者血清扩增出的HBV DNA片段nt55~1654被成功置换到HBV复制质粒pLL相应区域,得到质粒p11;新霉素抗性基因表达片段被克隆到p11中HBV DNA下游,获得质粒p11-neo,Southern blot检测证实p11-neo可支持体外复制;p11-neo转染HepG2后,经筛选鉴定,获得了可支持HBV DNA稳定复制的细胞系3-10.结论 建立了含有临床病毒株聚合酶RT区的HBV DNA稳定复制细胞系,real-time PCR结合ELISA有助于HBV DNA稳定复制细胞系的快速初筛鉴定.%Objective To establish a stable cell line that can replicate hepatitis B virus (HBV) DNA carrying the reverse transcriptase sequence derived from a clinical isolate. Methods Nested PCR was used to amplify the HBV DNA fragment from the serum. The fragment was cloned into a plasmid that can support HBV replication in vitro by fragment substitution reaction ( FSR) , followed by the cloning of the neomycin expressing fragment downstream from HBV DNA. G418 selection was conducted after the transfection of HepG2 cells with the recombinant DNA. Real-time PCR and enzyme linked immunosorbent assay (ELISA) were used to screen stable cell lines that can replicate HBV DNA, and the replication of HBV DNA by the cell line was confirmed by using Southern blot analysis. Results Fragment nt55-1654 amplified from the serum DNA was substituted to the plasmid pLL, generating the plasmid p11. The neomycin fragment was cloned into p11 , leading to the plasmid pll-neo, and pll-neo was confirmed to be HBV-replication-competent. A stable

  14. Crinivirus replication and host interactions

    Directory of Open Access Journals (Sweden)

    Zsofia A Kiss

    2013-05-01

    Full Text Available Criniviruses comprise one of the genera within the family Closteroviridae. Members in this family are restricted to the phloem and rely on whitefly vectors of the genera Bemisia and/or Trialeurodes for plant-to-plant transmission. All criniviruses have bipartite, positive-sense ssRNA genomes, although there is an unconfirmed report of one having a tripartite genome. Lettuce infectious yellows virus (LIYV is the type species of the genus, the best studied so far of the criniviruses and the first for which a reverse genetics system was available. LIYV RNA 1 encodes for proteins predicted to be involved in replication, and alone is competent for replication in protoplasts. Replication results in accumulation of cytoplasmic vesiculated membranous structures which are characteristic of most studied members of the Closteroviridae. These membranous structures, often referred to as BYV-type vesicles, are likely sites of RNA replication. LIYV RNA 2 is replicated in trans when co-infecting cells with RNA 1, but is temporally delayed relative to RNA1. Efficient RNA 2 replication also is dependent on the RNA 1-encoded RNA binding protein, P34. No LIYV RNA 2-encoded proteins have been shown to affect RNA replication, but at least four, CP, CPm, Hsp70h, and p59 are virion structural components and CPm is a determinant of whitefly transmissibility. Roles of other LIYV RNA 2-encoded proteins are largely as yet unknown, but P26 is a non-virion protein that accumulates in cells as characteristic plasmalemma deposits which in plants are localized within phloem parenchyma and companion cells over plasmodesmata connections to sieve elements. The two remaining crinivirus-conserved RNA 2-encoded proteins are P5 and P9. P5 is 39 amino acid protein and is encoded at the 5’ end of RNA 2 as ORF1 and is part of the hallmark closterovirus gene array. The orthologous gene in BYV has been shown to play a role in cell-to-cell movement and indicated to be localized to the

  15. The LMO2 oncogene regulates DNA replication in hematopoietic cells.

    Science.gov (United States)

    Sincennes, Marie-Claude; Humbert, Magali; Grondin, Benoît; Lisi, Véronique; Veiga, Diogo F T; Haman, André; Cazaux, Christophe; Mashtalir, Nazar; Affar, El Bachir; Verreault, Alain; Hoang, Trang

    2016-02-02

    Oncogenic transcription factors are commonly activated in acute leukemias and subvert normal gene expression networks to reprogram hematopoietic progenitors into preleukemic stem cells, as exemplified by LIM-only 2 (LMO2) in T-cell acute lymphoblastic leukemia (T-ALL). Whether or not these oncoproteins interfere with other DNA-dependent processes is largely unexplored. Here, we show that LMO2 is recruited to DNA replication origins by interaction with three essential replication enzymes: DNA polymerase delta (POLD1), DNA primase (PRIM1), and minichromosome 6 (MCM6). Furthermore, tethering LMO2 to synthetic DNA sequences is sufficient to transform these sequences into origins of replication. We next addressed the importance of LMO2 in erythroid and thymocyte development, two lineages in which cell cycle and differentiation are tightly coordinated. Lowering LMO2 levels in erythroid progenitors delays G1-S progression and arrests erythropoietin-dependent cell growth while favoring terminal differentiation. Conversely, ectopic expression in thymocytes induces DNA replication and drives these cells into cell cycle, causing differentiation blockade. Our results define a novel role for LMO2 in directly promoting DNA synthesis and G1-S progression.

  16. Design and Outcomes of a Comprehensive Care Experience Level System to Evaluate and Monitor Dental Students' Clinical Progress.

    Science.gov (United States)

    Teich, Sorin T; Roperto, Renato; Alonso, Aurelio A; Lang, Lisa A

    2016-06-01

    A Comprehensive Care Experience Level (CCEL) system that is aligned with Commission on Dental Accreditation (CODA) standards, promotes comprehensive care and prevention, and addresses flaws observed in previous Relative Value Units (RVU)-based programs has been implemented at the School of Dental Medicine, Case Western Reserve University since 2011. The purpose of this article is to report on the design, implementation, and preliminary outcomes of this novel clinical evaluation system. With the development of the CCEL concept, it was decided not to award points for procedures performed on competency exams. The reason behind this decision was that exams are not learning opportunities and are evaluated with summative tools. To determine reasonable alternative requirements, production data from previous classes were gathered and translated into CCEL points. These RVU points had been granted selectively only for restorative procedures completed after the initial preparation stage of the treatment plan, and achievement of the required levels was checked at multiple points during the clinical curriculum. Results of the CCEL system showed that low performing students increased their productivity, overall production at graduation increased significantly, and fluoride utilization to prevent caries rose by an order of magnitude over the RVU system. The CCEL program also allowed early identification and remediation of students having difficulty in the clinic. This successful implementation suggests that the CCEL concept has the potential for widespread adoption by dental schools. This method also can be used as a behavior modification tool to achieve specific patient care or clinical educational goals as illustrated by the way caries prevention was promoted through the program.

  17. Progression and survival in prostatic adenocarcinoma: a comparison of clinical stage, Gleason grade, S-phase fraction and DNA ploidy.

    OpenAIRE

    Vesalainen, S.; Nordling, S; Lipponen, P.; Talja, M.; Syrjänen, K

    1994-01-01

    Clinical data were reviewed in 325 patients with prostatic adenocarcinoma followed up for a mean of 13 years. Paraffin-embedded tumour biopsy specimens from the primary tumours were available for flow cytometry (FCM) in 273 cases. Intra-tumour heterogeneity in DNA index (DI) was found in 4% of the tumours (54 cases were analysed). S-phase fraction (SPF) and DNA ploidy were significantly interrelated. Aneuploidy and high SPF were significantly related to both a high T category and high Gleason...

  18. Longitudinal Study of the Relationship among Craniocervical Morphology, Clinical Progression, and Syringomyelia in a Cohort of Cavalier King Charles Spaniels

    OpenAIRE

    Cerda‐Gonzalez, S.; Olby, N.J.; Griffith, E.H.

    2016-01-01

    Background Craniocervical junction (CCJ) anomalies and secondary syringomyelia are commonly diagnosed in Cavalier King Charles spaniel (CKCS). Familiarity with the natural history of these abnormalities is vital to understanding the disease syndrome. Objective To evaluate magnetic resonance imaging (MRI) predictors of worsening clinical signs, syringomyelia, and morphology in CKCS longitudinally. Animals Fifty‐four client‐owned CKCS, 5–13 years old; 50% currently symptomatic. Methods Longitud...

  19. Global profiling of DNA replication timing and efficiency reveals that efficient replication/firing occurs late during S-phase in S. pombe.

    Directory of Open Access Journals (Sweden)

    Majid Eshaghi

    Full Text Available BACKGROUND: During S. pombe S-phase, initiation of DNA replication occurs at multiple sites (origins that are enriched with AT-rich sequences, at various times. Current studies of genome-wide DNA replication profiles have focused on the DNA replication timing and origin location. However, the replication and/or firing efficiency of the individual origins on the genomic scale remain unclear. METHODOLOGY/PRINCIPAL FINDINGS: Using the genome-wide ORF-specific DNA microarray analysis, we show that in S. pombe, individual origins fire with varying efficiencies and at different times during S-phase. The increase in DNA copy number plotted as a function of time is approximated to the near-sigmoidal model, when considering the replication start and end timings at individual loci in cells released from HU-arrest. Replication efficiencies differ from origin to origin, depending on the origin's firing efficiency. We have found that DNA replication is inefficient early in S-phase, due to inefficient firing at origins. Efficient replication occurs later, attributed to efficient but late-firing origins. Furthermore, profiles of replication timing in cds1Delta cells are abnormal, due to the failure in resuming replication at the collapsed forks. The majority of the inefficient origins, but not the efficient ones, are found to fire in cds1Delta cells after HU removal, owing to the firing at the remaining unused (inefficient origins during HU treatment. CONCLUSIONS/SIGNIFICANCE: Taken together, our results indicate that efficient DNA replication/firing occurs late in S-phase progression in cells after HU removal, due to efficient late-firing origins. Additionally, checkpoint kinase Cds1p is required for maintaining the efficient replication/firing late in S-phase. We further propose that efficient late-firing origins are essential for ensuring completion of DNA duplication by the end of S-phase.

  20. Tendinopathy: Investigating the Intersection of Clinical and Animal Research to Identify Progress and Hurdles in the Field

    Science.gov (United States)

    Titan, Ashley; Andarawis-Puri, Nelly

    2017-01-01

    Biological treatments, surgical interventions, and rehabilitation exercises have been successfully used to treat tendinopathy, but the development of effective treatments has been hindered by the lack of mechanistic data regarding the pathogenesis of the disease.While insightful, clinical studies are limited in their capacity to provide data regarding the pathogenesis of tendinopathies, emphasizing the value of animal models and cell culture studies to fill this essential gap in knowledge.Clinical pathological findings from imaging studies or histological analysis are not universal across patients with tendinopathy and have not been clearly associated with the onset of symptoms.There are several unresolved controversies, including the cellular changes that accompany the tendinopathic disease state and the role of inflammation.Additional research is needed to correlate the manifestations of the disease with its pathogenesis, with the goal of reaching a field-wide consensus on the pathology of the disease state. Such a consensus will allow standardized clinical practices to more effectively diagnose and treat tendinopathy. PMID:27792676

  1. Luciferase imaging for evaluation of oncolytic adenovirus replication in vivo.

    Science.gov (United States)

    Guse, K; Dias, J D; Bauerschmitz, G J; Hakkarainen, T; Aavik, E; Ranki, T; Pisto, T; Särkioja, M; Desmond, R A; Kanerva, A; Hemminki, A

    2007-06-01

    Oncolytic viruses kill cancer cells by tumor-selective replication. Clinical data have established the safety of the approach but also the need of improvements in potency. Efficacy of oncolysis is linked to effective infection of target cells and subsequent productive replication. Other variables include intratumoral barriers, access to target cells, uptake by non-target organs and immune response. Each of these aspects relates to the location and degree of virus replication. Unfortunately, detection of in vivo replication has been difficult, labor intensive and costly and therefore not much studied. We hypothesized that by coinfection of a luciferase expressing E1-deleted virus with an oncolytic virus, both viruses would replicate when present in the same cell. Photon emission due to conversion of D-Luciferin is sensitive and penetrates tissues well. Importantly, killing of animals is not required and each animal can be imaged repeatedly. Two different murine xenograft models were used and intratumoral coinjections of luciferase encoding virus were performed with eight different oncolytic adenoviruses. In both models, we found significant correlation between photon emission and infectious virus production. This suggests that the system can be used for non-invasive quantitation of the amplitude, persistence and dynamics of oncolytic virus replication in vivo, which could be helpful for the development of more effective and safe agents.

  2. A Blm-Recql5 partnership in replication stress response

    Institute of Scientific and Technical Information of China (English)

    Xincheng Lu; Hua Lou; Guangbin Luo

    2011-01-01

    Deficiencies in DNA damage response and repair not only can result in genome instability and cancer predisposition, but also can render the cancer cells intrinsically more vulnerable to certain types of DNA damage insults. Particularly, replication stress is both a hallmark of human cancers and a common instigator for genome instability and cell death. Here, we review our work based on the genetic knockout studies on Blm and Recql5, two members of the mammalian RecQ helicase family. These studies have uncovered a unique partnership between these two helicases in the implementation of proper mitigation strategies under different circumstances to promote DNA replication and cell survival and suppress genome instability and cancer. In particular, current studies have revealed the presence of a novel Recql5/RECQL5-dependent mechanism for suppressing replication fork collapse in response to global replication fork stalling following exposure to camptothecin (CPT), a topoisomerase I inhibitor, and a potent inhibitor of DNA replication. The unique partnership between Blm and Recql5 in coping with the challenge imposed by replication stress is discussed. In addition, given that irinotecan and topotecan, two CPT derivatives, are currently used in clinic for treating human cancer patients with very promising results, the potential implication of the new findings from these studies in anticancer treatments is also discussed.

  3. Functional amyloids as inhibitors of plasmid DNA replication

    Science.gov (United States)

    Molina-García, Laura; Gasset-Rosa, Fátima; Moreno-del Álamo, María; Fernández-Tresguerres, M. Elena; Moreno-Díaz de la Espina, Susana; Lurz, Rudi; Giraldo, Rafael

    2016-01-01

    DNA replication is tightly regulated to constrain the genetic material within strict spatiotemporal boundaries and copy numbers. Bacterial plasmids are autonomously replicating DNA molecules of much clinical, environmental and biotechnological interest. A mechanism used by plasmids to prevent over-replication is ‘handcuffing’, i.e. inactivating the replication origins in two DNA molecules by holding them together through a bridge built by a plasmid-encoded initiator protein (Rep). Besides being involved in handcuffing, the WH1 domain in the RepA protein assembles as amyloid fibres upon binding to DNA in vitro. The amyloid state in proteins is linked to specific human diseases, but determines selectable and epigenetically transmissible phenotypes in microorganisms. Here we have explored the connection between handcuffing and amyloidogenesis of full-length RepA. Using a monoclonal antibody specific for an amyloidogenic conformation of RepA-WH1, we have found that the handcuffed RepA assemblies, either reconstructed in vitro or in plasmids clustering at the bacterial nucleoid, are amyloidogenic. The replication-inhibitory RepA handcuff assembly is, to our knowledge, the first protein amyloid directly dealing with DNA. Built on an amyloid scaffold, bacterial plasmid handcuffs can bring a novel molecular solution to the universal problem of keeping control on DNA replication initiation. PMID:27147472

  4. 发笑癫(痫)发病机制与临床治疗研究进展%Study progress of pathogenesis and clinical treatment of gelastic epilepsy

    Institute of Scientific and Technical Information of China (English)

    余金泉; 吴至凤; 赵聪敏

    2015-01-01

    Gelastic epilepsy is a special refractory epilepsy accompany with ictal laughing and/or crying which can be divided into cortical induced gelastic epilepsy and hypothalamic hamartomas induced gelastic epilepsy according to their epileptogenic focus.Currently, domestic scholars had lack of systematic understanding of the mechanism and clinical treatment involved in gelastic epilepsy.Recently, foreign scholars had achieved great progress in the research of gelastic epilepsy which included the ictal laughing mechanism in gelastic epilepsy, the primary molecular mechanism in hypothalamic hamartomas induced gelastic epilepsy, the secondary epileptogenesis mechanism in hypothalamic hamartomas induced gelastic epilepsy and the clinical treatment of gelastic epilepsy.Now, the study progress of pathogenesis and clinical treatment of gelastic epilepsy were reviewed.%发笑癫(痫)是一种伴发作性哭笑的特殊的难治性癫(痫),按其癫(痫)源带的不同可以分为皮质源性发笑癫(痫)和下丘脑错构瘤源性发笑癫(痫).目前,国内学者对发笑癫(痫)涉及的发病机制与临床治疗缺乏系统的认识.近年来,国外学者对发笑癫(痫)的研究取到不少进展,这些进展包括发笑癫(痫)中的发笑机制,下丘脑错构瘤源性发笑癫(痫)的原发性致(痫)分子机制,下丘脑错构瘤源性发笑癫(痫)中的继发性致(痫)源机制以及发笑癫(痫)的临床治疗.现对发笑癫(痫)发病机制与临床治疗研究进展做一综述.

  5. 小儿氨基酸联合用药的临床进展%Clinical Progress of Combined Use of AminoAcids in Children

    Institute of Scientific and Technical Information of China (English)

    蒋英蓝; 王琦; 刘婷; 柯刚; 李荣; 李洁; 曾敬怀

    2016-01-01

    ABSTRACT:Objective The clinical progress of combined use of amino acids in children was reviewed, which provided a reference for further application.Methods To consult some clinical research related to the combination of“pediatric amino acids”The clinical progress of three aspects of the combined treatment of pediatric amino acids in the treatment of infantile rotavirus enteritis, refractory diarrhea, pediatric Staphylococcus scald syndrome were reviewed. Results and conclusion The combined application of Paediatric Amino acid Compound Injection and other drugs, can supply the body’s amino acids in children, improve the immunity and treatment effect, help improve the prognosis of children, which is worthy of application in the treatment of diseases in children.%目的:对小儿氨基酸联合用药的临床进展进行综述,为其进一步应用研究提供参考。方法查阅与“小儿氨基酸联合用药”相关的临床研究,从治疗轮状病毒性肠炎、难治性腹泻、小儿葡萄球菌烫伤杨皮肤综合征三个方面对小儿氨基酸联合用药的临床进展进行综述。结果与结论联合应用小儿氨基酸注射液和其他药物,可以补充小儿机体所需的氨基酸,提高其机体免疫力和治疗效果,有助于小儿预后的改善,值得在儿童疾病治疗中应用。

  6. Analysis of JC virus DNA replication using a quantitative and high-throughput assay

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Jong; Phelan, Paul J.; Chhum, Panharith; Bashkenova, Nazym; Yim, Sung; Parker, Robert [Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111 (United States); Gagnon, David [Institut de Recherches Cliniques de Montreal (IRCM), 110 Pine Avenue West, Montreal, Quebec, Canada H2W 1R7 (Canada); Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Quebec (Canada); Gjoerup, Ole [Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111 (United States); Archambault, Jacques [Institut de Recherches Cliniques de Montreal (IRCM), 110 Pine Avenue West, Montreal, Quebec, Canada H2W 1R7 (Canada); Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Quebec (Canada); Bullock, Peter A., E-mail: Peter.Bullock@tufts.edu [Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111 (United States)

    2014-11-15

    Progressive Multifocal Leukoencephalopathy (PML) is caused by lytic replication of JC virus (JCV) in specific cells of the central nervous system. Like other polyomaviruses, JCV encodes a large T-antigen helicase needed for replication of the viral DNA. Here, we report the development of a luciferase-based, quantitative and high-throughput assay of JCV DNA replication in C33A cells, which, unlike the glial cell lines Hs 683 and U87, accumulate high levels of nuclear T-ag needed for robust replication. Using this assay, we investigated the requirement for different domains of T-ag, and for specific sequences within and flanking the viral origin, in JCV DNA replication. Beyond providing validation of the assay, these studies revealed an important stimulatory role of the transcription factor NF1 in JCV DNA replication. Finally, we show that the assay can be used for inhibitor testing, highlighting its value for the identification of antiviral drugs targeting JCV DNA replication. - Highlights: • Development of a high-throughput screening assay for JCV DNA replication using C33A cells. • Evidence that T-ag fails to accumulate in the nuclei of established glioma cell lines. • Evidence that NF-1 directly promotes JCV DNA replication in C33A cells. • Proof-of-concept that the HTS assay can be used to identify pharmacological inhibitor of JCV DNA replication.

  7. Widening Disparity and its Suppression in a Stochastic Replicator Model

    CERN Document Server

    Sakaguchi, Hidetsugu

    2016-01-01

    Winner-take-all phenomena are observed in various competitive systems. We find similar phenomena in replicator models with randomly fluctuating growth rates. The disparity between winners and losers increases indefinitely, even if all elements are statistically equivalent. A lognormal distribution describes well the nonstationary time evolution. If a nonlinear load corresponding to progressive taxation is introduced, a stationary distribution is obtained and disparity widening is suppressed.

  8. Replication-Uncoupled Histone Deposition during Adenovirus DNA Replication

    OpenAIRE

    Komatsu, Tetsuro; Nagata, Kyosuke

    2012-01-01

    In infected cells, the chromatin structure of the adenovirus genome DNA plays critical roles in its genome functions. Previously, we reported that in early phases of infection, incoming viral DNA is associated with both viral core protein VII and cellular histones. Here we show that in late phases of infection, newly synthesized viral DNA is also associated with histones. We also found that the knockdown of CAF-1, a histone chaperone that functions in the replication-coupled deposition of his...

  9. REPLICATION TOOL AND METHOD OF PROVIDING A REPLICATION TOOL

    DEFF Research Database (Denmark)

    2016-01-01

    structured master surface (3a, 3b, 3c, 3d) having a lateral master pattern and a vertical master profile. The microscale structured master surface (3a, 3b, 3c, 3d) has been provided by localized pulsed laser treatment to generate microscale phase explosions. A method for producing a part with microscale......The invention relates to a replication tool (1, 1a, 1b) for producing a part (4) with a microscale textured replica surface (5a, 5b, 5c, 5d). The replication tool (1, 1a, 1b) comprises a tool surface (2a, 2b) defining a general shape of the item. The tool surface (2a, 2b) comprises a microscale...... energy directors on flange portions thereof uses the replication tool (1, 1a, 1b) to form an item (4) with a general shape as defined by the tool surface (2a, 2b). The formed item (4) comprises a microscale textured replica surface (5a, 5b, 5c, 5d) with a lateral arrangement of polydisperse microscale...

  10. Clinical research progress of polycystic liver disease%多囊肝临床研究进展

    Institute of Scientific and Technical Information of China (English)

    靳松; 崔凯; 孙自强; 李胜

    2013-01-01

    多囊肝全称为常染色体显性遗传性多囊肝病,目前以外科治疗为主.随着对多囊肝病因的研究深入到分子基因水平,分子诊断为实现症状前诊断提供可能.本文主要介绍多囊肝的病因、发病机制、诊断、治疗等方面的研究进展.%The full name of the polycystic liver disease is autosomald ominant polycystic liver disease.Surgical treatment is the main method to deal with it at present.With the deep study of the polycystic liver disease into the molecular genetic level,it is possible for molecular diagnostics to achieve presymptomatic and prenatal diagnosis.The article mainly introduce the research progress of the polycystic liver disease's etiology,pathogenesis,diagnosis,treatment,and so on.

  11. Molecular mechanisms and clinical applications of miR-22 in regulating malignant progression in human cancer (Review)

    Science.gov (United States)

    Wang, Jingyu; Li, Yuan; Ding, Meiman; Zhang, Honghe; Xu, Xiaoming; Tang, Jinlong

    2017-01-01

    miRNAs (microRNAs) have been validated to play fateful roles in the occurrence and development of cancers by post-transcriptionally targeting 3′-untranslated regions of the downstream gene mRNAs to repress mRNA expression. Mounting investigations forcefully document that not only does miR-22 biologically impinge on the processes of senescence, energy supply, angiogenesis, EMT (epithelial-mesenchymal transition), proliferation, migration, invasion, metastasis and apoptosis, but also it genetically or epigenetically exerts dual (inhibitory/promoting cancer) effects in various cancers via CNAs (copy number alterations), SNPs (single nucleotide polymorphisms), methylation, acetylation and even more momentously hydroxymethylation. Additionally, miR-22 expression may fluctuate with cancer progression in the body fluids of cancer patients and miR-22 could amplify its inhibitory or promoting effects through partaking in positive or negative feedback loops and interplaying with many other related miRNAs in the cascade of events, making it possible for miR-22 to be a promising and complementary or even independent cancer biomarker in some cancers and engendering profound influences on the early diagnosis, therapeutics, supervising curative effects and prognosis. PMID:28000852

  12. An evaluation of the various aspects of the progress in clinical applications of laser driven ionizing radiation

    Science.gov (United States)

    Hideghéty, K.; Szabó, E. R.; Polanek, R.; Szabó, Z.; Ughy, B.; Brunner, S.; Tőkés, T.

    2017-03-01

    There has been a vast development of laser-driven particle acceleration (LDPA) using high power lasers. This has initiated by the radiation oncology community to use the dose distribution and biological advantages of proton/heavy ion therapy in cancer treatment with a much greater accessibility than currently possible with cyclotron/synchrotron acceleration. Up to now, preclinical experiments have only been performed at a few LDPA facilities; technical solutions for clinical LDPA have been theoretically developed but there is still a long way to go for the clinical introduction of LDPA. Therefore, to explore the further potential bio-medical advantages of LDPA has pronounced importance. The main characteristics of LDPA are the ultra-high beam intensity, the flexibility in beam size reduction and the potential particle and energy selection whilst conventional accelerators generate single particle, quasi mono-energetic beams. There is a growing number of studies on the potential advantages and applications of Energy Modulated X-ray Radiotherapy, Modulated Electron Radiotherapy and Very High Energy Electron (VHEE) delivery system. Furthermore, the ultra-high space and/or time resolution of super-intense beams are under intensive investigation at synchrotrons (microbeam radiation and very high dose rate (> 40 Gy/s) electron accelerator flash irradiation) with growing evidence of significant improvement of the therapeutic index. Boron Neutron Capture Therapy (BNCT) is an advanced cell targeted binary treatment modality. Because of the high linear energy transfer (LET) of the two particles (7Li and 4He) released by 10BNC reaction, all of the energy is deposited inside the tumour cells, killing them with high probability, while the neighbouring cells are not damaged. The limited availability of appropriate neutron sources, prevent the more extensive exploration of clinical benefit of BNCT. Another boron-based novel binary approach is the 11B-Proton Fusion, which result in

  13. Existing data sources for clinical epidemiology: Scandinavian Cohort for osteonecrosis of the jaw – work in progress and challenges

    Directory of Open Access Journals (Sweden)

    Schiodt M

    2015-01-01

    Full Text Available Morten Schiodt,1 Cecilia Larsson Wexell,2,3 Bente Brokstad Herlofson,4 Karen Marie Giltvedt,4 Sven Erik Norholt,5 Vera Ehrenstein61Department of Oral and Maxillofacial Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; 2Department of Oral and Maxillofacial Surgery, Södra Älvsborg Hospital, Region Västra Götaland, Borås, 3Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 4Department of Oral Surgery and Oral Medicine, Faculty of Dentistry, University of Oslo, Oslo, Norway; 5Department of Oral and Maxillofacial Surgery, Aarhus University and University Hospital, 6Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, DenmarkAbstract: Osteonecrosis of the jaw (ONJ is a severe side effect associated with antiresorptive treatment. Monitoring of ONJ using routine databases in Scandinavian countries is a challenge owing to lack of valid algorithms and to heterogeneous referral practices. The aim of this paper is to describe the process of establishing a Scandinavian ONJ Cohort enrolling all ONJ cases related to antiresorptive treatment arising in Denmark, Norway, and Sweden between 2011 and 2019. The initial purpose of the cohort is to support an ongoing pharmacovigilance study of denosumab and zoledronic acid in Denmark, Norway, and Sweden. The three countries, with their 199 clinics, departments, and units of oral and maxillofacial surgery, both hospital-based and freestanding, differ somewhat in referral practices of the ONJ patients. By directly contacting all providers of care to ONJ patients in the three countries, we established a network for reporting incident cases to each country's research database directly or through a member of the Scandinavian ONJ task force as a liaison. The task force includes a Scandinavian coordinator and three national coordinators collaborating directly with the clinics. A uniform ONJ

  14. 干扰素γ临床应用新进展%Progress in the clinical application of interferon gamma

    Institute of Scientific and Technical Information of China (English)

    盖晴; 单风平

    2015-01-01

    干扰素γ(IFN-γ)属于Ⅱ型干扰素,是一种具有抗肿瘤,抗病毒,免疫调节等生物学功能的细胞因子,已经应用于医学研究和临床多种疾病的治疗.近年来,IFN-γ在抗肿瘤,抗感染和治疗自身免疫病方面有了更广泛的应用,然而也有报道称IFN-γ可以促进某些疾病的发生.因此分析总结IFN-γ在一些疾病中的作用机制及作用效果,对于临床应用具有重要的指导意义.%Interferon gamma(IFN-γ),belonging to type Ⅱ interferon,is a kind of cytokine with antitumor,antiviral,immune regulatory as well as other biological effects.IFN-γ has been applied to medical research and clinical treatment for various diseases.In recent years,IFN-γ has wide applications in antitumor,anti-infection and the treatment of autoimmune diseases.However,it has also been reported that IFN-γmay promote the occurance of certain diseases.Therefore,we summarized the recent reports and expectation of IFN-γ in the clinical application.

  15. RESEARCH PROGRESS OF CLINICAL APPLICATION OF METAPEX PASTE%Metapex糊剂临床应用研究进展

    Institute of Scientific and Technical Information of China (English)

    李志芳; 牛一山

    2016-01-01

    随着口腔材料学的发展,Metapex糊剂(韩国META公司生产)在临床中的应用越来越广泛,作为根管充填糊剂、根管内消毒药物和根尖诱导成形药物分别用于乳牙根管治疗、恒牙根管内消毒和牙根未发育完成的年轻恒牙,取得了一定疗效,值得在临床上推广使用。%With the development of dental materials,Metapex paste is used more and more widely in clinic. For example Metapex paste is regarded as root canal filling material,intracanal medicaments and apexfication medicaments applied to root canal therapy of children's primary teeth, root canal disinfection of permanent teeth and immature young permanent teeth, acquired a certain therapeutic effect and deservesed clinical popularization.

  16. 抗骨质疏松药物临床应用的研究进展%Research progress of anti-osteoporosis drug clinical application

    Institute of Scientific and Technical Information of China (English)

    陈萌萌; 包利; 唐海

    2015-01-01

    随着我国人口老龄化的加剧,骨质疏松的发病率逐年增加,髋部及椎体骨折的发病率呈现快速增长趋势,给患者及社会都带来极大的痛苦及经济负担.目前临床上存在多种抗骨质疏松药物,从多方面干扰骨质疏松的发展进程,减轻患者症状,提高生活质量.本文就抗骨质疏松药物临床应用的研究进展做一综述.%With the increasingly aging population,osteoporosis morbidity had been gradually increased and the incidence of the hips and vertebral fractures showed a trend of rapid growth,which brought great pain and economic burden to patients and society.There were a variety of anti-osteoporosis drugs clinically,which interfere with the development of osteoporosis via multi-approaches to reduce the clinical symptoms and improve their quality of life.In this paper,the author aimed to make a review of the research progress of anti-osteoporosis drug clinical application.

  17. Progress of clinical indicators in the diagnosis of neonatal sepsis%新生儿败血症临床检测指标的研究进展

    Institute of Scientific and Technical Information of China (English)

    崔雪薇

    2015-01-01

    新生儿败血症起病隐匿,进展迅速,临床症状缺乏特异性,极易发生休克、多器官功能损伤等严重并发症,因此,早期诊断是降低败血症新生儿病死率及改善预后的关键.目前,有关新生儿败血症临床检测指标包括细菌培养、急性时相反应蛋白、细胞因子、细胞表面抗原及细菌基因检测等.该文将对上述指标在新生儿败血症的早期诊断、病情评估、治疗监测中的临床意义进行综述.%Neonatal sepsis progresses very fast,and its clinical signs are non-specific,and it can cause severe complications,such as shock,MODS.Therefore,early diagnosis is key to reduce mortality and improve prognosis.The clinical indicators in diagnosis of neonatal sepsis includ bacterial culture,peripheral hemogram,acute phase reaction proteins,cytokines,cell surface antigen and bacterial gene detection.This article reviews the clinical significance of these indicators in the early diagnosis,condition assessment,treatment monitoring of neonatal sepsis.

  18. CLINICAL PROGRESS IN CORONARY ARTERY BYPASS GRAFT%冠状动脉搭桥术的临床应用进展

    Institute of Scientific and Technical Information of China (English)

    姚建民; 成杞润

    2001-01-01

    Conventional coronary artery bypass graft performed through median sternotomy with hypothermic extracorporeal circulation and saphenous vein grafts is both saft and effective.To reduce perioperative morbidity further,and promote earlier hospital discharge and long-term graft patency rate,great efforts have ben recently made in coronary surgery.we reviewed the literature relevent to clinical progress in minimally invasive coronary bypass graft,total arterial revascularization and coronary operation in advanced age,and discussed their surgical indications,operative techniques and clinical results.Studies about off pump,thoracoscope or axial flow pump-assisted myocardial revacularization have demonstrated favourable results such as reduced systemic inflammatory respones,avoiding ischemia-prefusion injury,lower cost and shorter hospital stay.Clinical practice also showed that patients who received two arterial graft or total arterial revascularization had decreased risk of death,reoperation and angioplasty,and that advanced age in and of itself should not be a contraindication to an coronary bypass operation,although morbidity,mortality and cost may be higher.

  19. 根尖外科治疗的临床进展%Clinical progress in periapical surgery

    Institute of Scientific and Technical Information of China (English)

    王密; 尹仕海

    2009-01-01

    根尖外科手术是对根管治疗术无法治愈患牙的有效保存治疗手段,具有较高的治疗成功率.根尖外科治疗从理念、技术、方法到材料、设备等方面都在不断的发展,其明显的标志是:由传统手术方法、器械,逐步引入根尖显微外科、根尖激光外科和根尖超声预备等新技术;由单纯的刮净根尖肉芽组织和根尖倒充填,转入到对骨组织的诱导再生和封闭材料的生物相容性;手术设计由充分暴露病变区到微创性和美观性的考虑.该文就根尖外科治疗的临床新进展和如何应对一些临床问题作一综述.%Periapical surgery is an effective way of high success rate to preserve teeth that can't be treated by routine RCT. Recently, it has developments in concepts, technologies, methods , materials and equipments, etc. For instance, the apical micro/laser surgery and ultrasonic apical preparation have been introduced into traditional sur gical instruments; bone tissue regeneration and biocompatibility of materials are emphasized based on the simple curet tage of granulation tissure and root -end filling; aesthetics and minimal invasion are taken into consideration compared with the traditional surgery design. This article reviews the progress in periaical surgery and gives some suggestion for treating different cilinic situations.

  20. Replicator dynamics in value chains

    DEFF Research Database (Denmark)

    Cantner, Uwe; Savin, Ivan; Vannuccini, Simone

    2016-01-01

    The pure model of replicator dynamics though providing important insights in the evolution of markets has not found much of empirical support. This paper extends the model to the case of firms vertically integrated in value chains. We show that i) by taking value chains into account, the replicator...... dynamics may revert its effect. In these regressive developments of market selection, firms with low fitness expand because of being integrated with highly fit partners, and the other way around; ii) allowing partner's switching within a value chain illustrates that periods of instability in the early...... stage of industry life-cycle may be the result of an 'optimization' of partners within a value chain providing a novel and simple explanation to the evidence discussed by Mazzucato (1998); iii) there are distinct differences in the contribution to market selection between the layers of a value chain...

  1. Regulation of DNA replication by the S-phase DNA damage checkpoint

    Directory of Open Access Journals (Sweden)

    Rhind Nicholas

    2009-07-01

    Full Text Available Abstract Cells slow replication in response to DNA damage. This slowing was the first DNA damage checkpoint response discovered and its study led to the discovery of the central checkpoint kinase, Ataxia Telangiectasia Mutated (ATM. Nonetheless, the manner by which the S-phase DNA damage checkpoint slows replication is still unclear. The checkpoint could slow bulk replication by inhibiting replication origin firing or slowing replication fork progression, and both mechanisms appear to be used. However, assays in various systems using different DNA damaging agents have produced conflicting results as to the relative importance of the two mechanisms. Furthermore, although progress has been made in elucidating the mechanism of origin regulation in vertebrates, the mechanism by which forks are slowed remains unknown. We review both past and present efforts towards determining how cells slow replication in response to damage and try to resolve apparent conflicts and discrepancies within the field. We propose that inhibition of origin firing is a global checkpoint mechanism that reduces overall DNA synthesis whenever the checkpoint is activated, whereas slowing of fork progression reflects a local checkpoint mechanism that only affects replisomes as they encounter DNA damage and therefore only affects overall replication rates in cases of high lesion density.

  2. Alphavirus polymerase and RNA replication.

    Science.gov (United States)

    Pietilä, Maija K; Hellström, Kirsi; Ahola, Tero

    2017-01-16

    Alphaviruses are typically arthropod-borne, and many are important pathogens such as chikungunya virus. Alphaviruses encode four nonstructural proteins (nsP1-4), initially produced as a polyprotein P1234. nsP4 is the core RNA-dependent RNA polymerase but all four nsPs are required for RNA synthesis. The early replication complex (RC) formed by the polyprotein P123 and nsP4 synthesizes minus RNA strands, and the late RC composed of fully processed nsP1-nsP4 is responsible for the production of genomic and subgenomic plus strands. Different parts of nsP4 recognize the promoters for minus and plus strands but the binding also requires the other nsPs. The alphavirus polymerase has been purified and is capable of de novo RNA synthesis only in the presence of the other nsPs. The purified nsP4 also has terminal adenylyltransferase activity, which may generate the poly(A) tail at the 3' end of the genome. Membrane association of the nsPs is vital for replication, and alphaviruses induce membrane invaginations called spherules, which form a microenvironment for RNA synthesis by concentrating replication components and protecting double-stranded RNA intermediates. The RCs isolated as crude membrane preparations are active in RNA synthesis in vitro, but high-resolution structure of the RC has not been achieved, and thus the arrangement of viral and possible host components remains unknown. For some alphaviruses, Ras-GTPase-activating protein (Src-homology 3 (SH3) domain)-binding proteins (G3BPs) and amphiphysins have been shown to be essential for RNA replication and are present in the RCs. Host factors offer an additional target for antivirals, as only few alphavirus polymerase inhibitors have been described.

  3. Sequential steps in DNA replication are inhibited to ensure reduction of ploidy in meiosis.

    Science.gov (United States)

    Hua, Hui; Namdar, Mandana; Ganier, Olivier; Gregan, Juraj; Méchali, Marcel; Kearsey, Stephen E

    2013-03-01

    Meiosis involves two successive rounds of chromosome segregation without an intervening S phase. Exit from meiosis I is distinct from mitotic exit, in that replication origins are not licensed by Mcm2-7 chromatin binding, but spindle disassembly occurs during a transient interphase-like state before meiosis II. The absence of licensing is assumed to explain the block to DNA replication, but this has not been formally tested. Here we attempt to subvert this block by expressing the licensing control factors Cdc18 and Cdt1 during the interval between meiotic nuclear divisions. Surprisingly, this leads only to a partial round of DNA replication, even when these factors are overexpressed and effect clear Mcm2-7 chromatin binding. Combining Cdc18 and Cdt1 expression with modulation of cyclin-dependent kinase activity, activation of Dbf4-dependent kinase, or deletion of the Spd1 inhibitor of ribonucleotide reductase has little additional effect on the extent of DNA replication. Single-molecule analysis indicates this partial round of replication results from inefficient progression of replication forks, and thus both initiation and elongation replication steps may be inhibited in late meiosis. In addition, DNA replication or damage during the meiosis I-II interval fails to arrest meiotic progress, suggesting absence of checkpoint regulation of meiosis II entry.

  4. Progress in the capture, manipulation, and delivery of medical media and its impact on education, clinical care, and research.

    Science.gov (United States)

    Bernardo, Theresa M; Malinowski, Robert P

    2005-01-01

    In this article, advances in the application of medical media to education, clinical care, and research are explored and illustrated with examples, and their future potential is discussed. Impact is framed in terms of the Sloan Consortium's five pillars of quality education: access; student and faculty satisfaction; learning effectiveness; and cost effectiveness. (Hiltz SR, Zhang Y, Turoff M. Studies of effectiveness of learning networks. In Bourne J, Moore J, ed. Elements of Quality Online Education. Needham, MA: Sloan-Consortium, 2002:15-45). The alternatives for converting analog media (text, photos, graphics, sound, video, animations, radiographs) to digital media and direct digital capture are covered, as are options for storing, manipulating, retrieving, and sharing digital collections. Diagnostic imaging is given particular attention, clarifying the difference between computerized radiography and digital radiography and explaining the accepted standard (DICOM) and the advantages of Web PACS. Some novel research applications of medical media are presented.

  5. Progress in the Clinical Treatment of Muscle Spasm%肌肉痉挛的临床治疗进展

    Institute of Scientific and Technical Information of China (English)

    赵晔; 郭义

    2011-01-01

    分析近3年来国、内外相关文献,对国内、外学者在肌肉痉挛临床治疗方面的有益探索进行综述,指出对于肌肉痉挛的临床治疗应以常规物理治疗为基础,综合多种治疗手段,鼓励采取良性体位,以提高疗效.%This article reviewed the useful explorafion of scholars domestic and foreign on the clinical treatment of muscle spasm by the analysis of the literature domestic and foreign for the last 3 years,pointed that the clhnical treatment of muscle spasm should at the basis of regular physical therapy, synthesized variety of treatments, encouraged healthy position, to improve the efficacy.

  6. General Survey and Progress in Clinical Trials Abroad over Kanglaite Injection(康莱特注射液)

    Institute of Scientific and Technical Information of China (English)

    李大鹏

    2004-01-01

    @@ Kanglaite (康莱特, KLT) is made of a lipolytic and efficacious anti-cancer ingredient isolated from Chinese herb Semen Coix lacryma-jobi, an anti-cancer emulsion made with international advanced technology for intravenous and intra-arterial injection, which has obvious efficacy in treating many primary malignant tumors such as lung cancer, liver cancer, gastric cancer, breast cancer etc.and could markedly elevate immune function, as it is a biphasic broad spectrum anti-cancer agent;KLT combined with radiotherapy or chemotherapy could alleviate toxicity and raise their efficacy, and before surgical operation could facilitate cancer cell necrosis, apoptosis, prevent diffusion and metastasis, effectively act against cachexia, control cancer pain, increase body weight, improve quality of life and extend survival period of cancer patients in the advanced stage. Since came to market, KLT has been used in over 2 000 large and medium hospitals at home, and 300 000 cancer patients have benefited clinically from it.

  7. Aloe Vera External Use and Clinical Use Research Progress%芦荟临床外用研究进展

    Institute of Scientific and Technical Information of China (English)

    刘学华; 赵红影

    2011-01-01

    To research Aloe vera external use function of the clinical study on the review.Aloe vera has medical and health care, hairdressing, eating, and other functions, known as the "drug" and "natural beautician" and "family doctor", "miracle" laudatory name.In recent years, with the number of natural medicine research, Aloe become increasingly common attention of world medicine, especially the multipurpose development and research articles, application scope, increasing economic value.%对芦荟外用功能的临床应用研究进展进行了综述.芦荟具有医疗、保健、美容、食用、现赏等多种功能,近年来芦荟外用品的开发研究,倍受青睐,应用范围日趋扩大,成为全世界关注的药食多用植物.

  8. 渗透树脂的临床应用进展%Progress in clinical application of resin penetration

    Institute of Scientific and Technical Information of China (English)

    徐云龙; 周洲; 于金华

    2016-01-01

    渗透树脂材料是近年来出现的牙科修复材料,因其具有微创、无痛、美学效果好、渗透性能佳等优点,正在临床工作中广泛运用。该文就渗透树脂在早期龋、釉质白斑及其联合运用方面进行综述。%The resin infiltration is an important dental restorative material in endodontic practice. This approach is minimally invasive, painless, aesthetic, and permeable. Therefore, it is widely used in clinic. In this paper, the resin infiltration in treating ini⁃tial enamel caries and enamel white spots and the combination application with other approaches are extensively reviewed.

  9. Dynamic replication of Web contents

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The phenomenal growth of the World Wide Web has brought huge increase in the traffic to the popular web sites.Long delays and denial of service experienced by the end-users,especially during the peak hours,continues to be the common problem while accessing popular sites.Replicating some of the objects at multiple sites in a distributed web-server environment is one of the possible solutions to improve the response time/Iatency. The decision of what and where to replicate requires solving a constraint optimization problem,which is NP-complete in general.In this paper, we consider the problem of placing copies of objects in a distributed web server system to minimize the cost of serving read and write requests when the web servers have Iimited storage capacity.We formulate the problem as a 0-1 optimization problem and present a polynomial time greedy algorithm with backtracking to dynamically replicate objects at the appropriate sites to minimize a cost function.To reduce the solution search space,we present necessary condi tions for a site to have a replica of an object jn order to minimize the cost function We present simulation resuIts for a variety of problems to illustrate the accuracy and efficiency of the proposed algorithms and compare them with those of some well-known algorithms.The simulation resuIts demonstrate the superiority of the proposed algorithms.

  10. Clinical Research Progress of Ivabradine%伊伐布雷定的临床研究进展

    Institute of Scientific and Technical Information of China (English)

    马奎影; 侯春霞; 邱祥春

    2014-01-01

    伊伐布雷定是高度特异性超极化激活的环核苷酸门控通道(I f通道)阻滞剂,以剂量依赖性方式抑制If电流降低窦房结节律,由此减慢心率,而对心内传导、心肌收缩力、左室收缩功能或心室复极化无影响。目前许多临床研究表明,伊伐布雷定对冠状动脉粥样硬化性心脏病(冠心病)、心力衰竭患者的临床症状以及预后有明确的改善作用,对快速型窦性心律失常疗效确切。现对伊伐布雷定在冠心病的诊断及治疗、心力衰竭和不适当性窦性心动过速中的应用进行综述。%Ivabradine is a high specificity inhibitor of hyperpolarization activated cyclic nucleotide-gated channels (If channel), which can inhibit If current in a dose-dependent manner, and reduce heart rate, but it does not affect the myocardial contractility, conduction, left ventricular systolic function or ventricular repolarization. At present, many clinical studies have shown that ivabradine can obviously improve the clinical symptoms and prognosis for the patients with coronary heart disease, heart failure, and that it has a definite curative effect on inappropriate sinus tachycardia. This article summarizes the application of ivabradine in treatment or diagnosis of coronary heart disease, heart failure and inappropriate sinus tachycardia.

  11. Replication domains are self-interacting structural chromatin units of human chromosomes

    Science.gov (United States)

    Arneodo, Alain

    2011-03-01

    In higher eukaryotes, the absence of specific sequence motifs marking the origins of replication has been a serious hindrance to the understanding of the mechanisms that regulate the initiation and the maintenance of the replication program in different cell types. In silico analysis of nucleotide compositional skew has predicted the existence, in the germline, of replication N-domains bordered by putative replication origins and where the skew decreases rather linearly as the signature of a progressive inversion of the average fork polarity. Here, from the demonstration that the average fork polarity can be directly extracted from the derivative of replication timing profiles, we develop a wavelet-based pattern recognition methodology to delineate replication U-domains where the replication timing profile is shaped as a U and its derivative as a N. Replication U-domains are robustly found in seven cell lines as covering a significant portion (40-50%) of the human genome where the replication timing data actually displays some plasticity between cell lines. The early replication initiation zones at U-domains borders are found to be hypersensitive to DNase I cleavage, to be associated with transcriptional activity and to present a significant enrichment in insular-binding proteins CTCF, the hallmark of an open chromatin structure. A comparative analysis of genome-wide chromatin interaction (HiC) data shows that replication-U domains correspond to self-interacting structural high order chromatin units of megabase characteristic size. Taken together, these findings provide evidence that the epigenetic compartmentalization of the human genome into autonomous replication U-domains comes along with an extensive remodelling of the threedimensional chromosome architecture during development or in specific diseases. The observed cell specific conservation of the replication timing between the human and mouse genomes strongly suggests that this chromosome organization into

  12. Clinical progress and its significance in current apical surgery%根尖手术的临床进展和意义

    Institute of Scientific and Technical Information of China (English)

    王霄

    2012-01-01

    Enormous progress has been made and the success of treatment has been improved in apical surgery by using the surgical microscopy, ultrasound equipment, and new materials in recent years. The purpose of this article is to review the clinical progress and significance in current concepts, operating equipments, surgical techniques, root-end filling materials, and the application of the guide tissue regeneration in apical surgery.%近来,口腔显微镜、超声器械和新材料等应用于根管外科领域,给根尖手术带来了巨大的变化,提高了手术的成功率.本文就当前的根尖手术现状、手术器械、手术技术、根尖倒充填材料和引导组织再生术在根尖手术中的应用等临床进展和意义作一综述.

  13. 糖尿病肾病中医药临床研究进展%Clinical Research Progress of Traditional Chinese Medicine on Treatment of Diabetic Nephropathy

    Institute of Scientific and Technical Information of China (English)

    张萌佳; 张洁

    2009-01-01

    从中医病因病机、中医辨证分型、中药复方、单味药及提取物几个方面入手阐述了近十年来中医药在糖尿病肾病方面的临床研究情况,提示中医药治疗糖尿病在早期疗效较好,值得推广.%Clinical research progress of Traditional Chinese Medicine(TCM) on treatment of diabetic nephropathy in recent ten years was explained from aspects of pathogen and pathogenesis, patterns classification of TCM, Chinese herbal Compound, single drug and the extractive. And the result showed a good therapeutic effect on early stage of TCM treatment for diabetes mellitus which was worthy to be popularized.

  14. Clinical Research Progress orthopedic postoperative pain treatment%骨科术后疼痛处理的概况

    Institute of Scientific and Technical Information of China (English)

    何健

    2016-01-01

    fracture is a bone fracture or structural part of the structure is completely broken,or long -term repeated strain due to the fracture site,indirect violence and other causes,can occur in patients after the onset of muscle soreness,difficulty moving the main.Currently,the clinical fracture more for surgical treatment,which can improve the clinical efficacy and ease symptoms.Howev-er,some patients with a higher incidence of postoperative pain,it is an objective and emotions people feel uncomfortable on experi-ence,along with tissue injury has a greater impact on the prognosis of patients after surgery.This will be the impact of postoperative pain as a starting point,the analysis methods of pain assessment,treatment and care measures,to provide a scientific basis for the de-velopment of rational orthopedic postoperative pain measures.%骨折是指骨头部分结构断裂或结构完全断裂,或者由于骨折部位长期反复劳损、间接暴力等引起,患者发病后可出现肌肉酸痛、活动不便等症状。目前,临床上对于骨折更多的以手术治疗为主,该方法能够提高临床疗效,缓解患者症状。但是,部分患者术后疼痛发生率较高,并伴随着组织损伤,对患者术后预后具有较大影响。文中以疼痛对患者术后的影响为起点,分析疼痛评估的方法、治疗方法及护理措施等,以期为制定合理的骨科术后疼痛措施提供科学依据。

  15. Evidence That Onset of Clinical Psychosis Is an Outcome of Progressively More Persistent Subclinical Psychotic Experiences: An 8-Year Cohort Study

    Science.gov (United States)

    Dominguez, M.D.G.; Wichers, Marieke; Lieb, Roselind; Wittchen, Hans-Ulrich; van Os, Jim

    2011-01-01

    This study examined the hypothesis that developmental expression of psychometric risk in the form of subclinical psychotic experiences in the general population is usually transitory but in some instances may become abnormally persistent and progress to a clinical psychotic state. A prospective cohort study was conducted in a general population sample of 845 adolescents, aged 14–17 years, in Munich, Germany (Early Developmental Stages of Psychopathology Study). Expression of psychosis was assessed 4 times (T0–T3) over a period of 8.4 years. Transition from subclinical psychosis at T0–T2 to clinical psychosis in terms of impairment at T3 was examined as a function of the level of prior persistence of subclinical psychosis (present never, once, twice, or thrice). The more the subclinical psychosis persisted over the period T0–T2, the greater the risk of transition to clinical psychosis at T3 in a dose-response fashion (subclinical psychosis expression once over T0–T2: odds ratio [OR] = 1.5 [95% confidence interval {CI} = 0.6–3.7], posttest probability [PP] = 5%; twice: OR = 5.0 [95% CI = 1.6–15.9], PP = 16%; at all 3 measurements: OR = 9.9 [95% CI = 2.5–39.8], PP = 27%). Of all clinical psychosis at T3, more than a third (38.3%) was preceded by subclinical psychotic experiences at least once and a fifth (19.6%) at least twice. Consequently, a significant proportion of psychotic disorder may be conceptualized as the rare poor outcome of a common developmental phenotype characterized by persistence of psychometrically detectable subclinical psychotic experiences. This may be summarized descriptively as a psychosis proneness-persistence-impairment model of psychotic disorder. PMID:19460881

  16. Evaluating replicability of laboratory experiments in economics.

    Science.gov (United States)

    Camerer, Colin F; Dreber, Anna; Forsell, Eskil; Ho, Teck-Hua; Huber, Jürgen; Johannesson, Magnus; Kirchler, Michael; Almenberg, Johan; Altmejd, Adam; Chan, Taizan; Heikensten, Emma; Holzmeister, Felix; Imai, Taisuke; Isaksson, Siri; Nave, Gideon; Pfeiffer, Thomas; Razen, Michael; Wu, Hang

    2016-03-25

    The replicability of some scientific findings has recently been called into question. To contribute data about replicability in economics, we replicated 18 studies published in the American Economic Review and the Quarterly Journal of Economics between 2011 and 2014. All of these replications followed predefined analysis plans that were made publicly available beforehand, and they all have a statistical power of at least 90% to detect the original effect size at the 5% significance level. We found a significant effect in the same direction as in the original study for 11 replications (61%); on average, the replicated effect size is 66% of the original. The replicability rate varies between 67% and 78% for four additional replicability indicators, including a prediction market measure of peer beliefs.

  17. Mutant, wild type, or overall p53 expression: freedom from clinical progression in tumours of astrocytic lineage.

    Science.gov (United States)

    Pardo, F S; Hsu, D W; Zeheb, R; Efird, J T; Okunieff, P G; Malkin, D M

    2004-11-01

    Abnormalities of the p53 tumor-suppressor gene are found in a significant proportion of astrocytic brain tumours. We studied tumour specimens from 74 patients evaluated over 20 years at the Massachusetts General Hospital, where clinical outcome could be determined and sufficient pathologic material was available for immunostaining. p53 expression studies employed an affinity-purified p53 monoclonal antibody, whose specificity was verified in absorption studies and, in a minority of cases, a second antibody recognising a different epitope of p53. Significant overexpression of p53 protein was found in 48% of the 74 tumours included in this series and high levels of expression were associated with higher mortality from astrocytic tumours (Pexpression of p53 plays an important role in the pathobiology of these tumours. In a subset of 36 cases, coding regions of the p53 gene were completely sequenced via SSCP and direct DNA sequencing, revealing that overexpression of p53 protein is not always associated with point mutations in conserved exons of the p53 gene. Finally, we confirmed p53 protein expression in early-passage human glioma cell lines of known p53 mutational status and immunostaining scores. Although grade continues to be the strongest prognostic variable, the use of p53 staining as a prognostic indicator, in contrast to mutational DNA analyses, may be a useful adjunct in identifying patients at higher risk of treatment failure.

  18. 山莨菪碱的临床应用进展%Progress in clinical applications of anisodamine

    Institute of Scientific and Technical Information of China (English)

    张华林; 兰芬; 胡晋红

    2013-01-01

    Anisodamine,a typical acetylcholine M receptor antagonist,is mainly used in treatment of gastrointestinal smooth muscle spasm and infective toxic shock.Recently,anisodamine is also used in treatment of sudden deafness,acute otitis media,anaphylactoid purpura,acute alcoholism,myocardial infarction and bronchial asthma,etc.This paper makes a comprehensive review on the clinical application of anisodamine.%山莨菪碱是M胆碱受体拮抗剂,主要用于胃肠道平滑肌痉挛和感染中毒性休克.近年来,山莨菪碱在突发性耳聋、急性中耳炎、过敏性紫癜、急性酒精中毒、心肌梗死和支气管哮喘等疾病治疗中也有应用,本文对该药的临床应用情况做一综述.

  19. Progress on pharmacology and clinical research of eribulin mesylate%eribulin mesylate的药理与临床研究

    Institute of Scientific and Technical Information of China (English)

    倪倩; 封宇飞; 傅得兴; 孙春华

    2012-01-01

    By literature review, pharmacology, pharmacokinetics, clinical study, and safety of eribulin mesylate in the treatment of metastatic breast cancer ( MBC) were evaluated in the paper. As a microtuhule inhibitor, eribulin mesylate has a good effect on multiple drug resistance of chemotherapy medicines in patients with MBC. The main adverse drug reaction is neutropenia. Eribulin mesylate could extend overall survival in patients with MBC. However, further studies should be conducted.%通过文献回顾,评价eribulin mesylate治疗转移性乳腺癌中的药理作用、药动学、临床研究和安全性.本品作为微管抑制剂,临床试验结果显示,对化疗药物产生多重耐药性的转移性乳腺癌具有很好的疗效,主要的不良反应为中性粒细胞减少症.本品可延长转移性乳腺癌患者的总存活时间,更多的研究有待进一步的评价.

  20. Hepatitis Delta Virus: Replication Strategy and Upcoming Therapeutic Options for a Neglected Human Pathogen

    Science.gov (United States)

    Lempp, Florian A.; Urban, Stephan

    2017-01-01

    The human Hepatitis Delta Virus (HDV) is unique among all viral pathogens. Encoding only one protein (Hepatitis Delta Antigen; HDAg) within its viroid-like self-complementary RNA, HDV constitutes the smallest known virus in the animal kingdom. To disseminate in its host, HDV depends on a helper virus, the human Hepatitis B virus (HBV), which provides the envelope proteins required for HDV assembly. HDV affects an estimated 15–20 million out of the 240 million chronic HBV-carriers and disperses unequally in disparate geographical regions of the world. The disease it causes (chronic Hepatitis D) presents as the most severe form of viral hepatitis, leading to accelerated progression of liver dysfunction including cirrhosis and hepatocellular carcinoma and a high mortality rate. The lack of approved drugs interfering with specific steps of HDV replication poses a high burden for gaining insights into the molecular biology of the virus and, consequently, the development of specific novel medications that resiliently control HDV replication or, in the best case, functionally cure HDV infection or HBV/HDV co-infection. This review summarizes our current knowledge of HBV molecular biology, presents an update on novel cell culture and animal models to study the virus and provides updates on the clinical development of the three developmental drugs Lonafarnib, REP2139-Ca and Myrcludex B. PMID:28677645

  1. Clinical progress of human papillomavirus genotypes and their persistent infection in subjects with atypical squamous cells of undetermined significance cytology: Statistical and latent Dirichlet allocation analysis.

    Science.gov (United States)

    Kim, Yee Suk; Lee, Sungin; Zong, Nansu; Kahng, Jimin

    2017-06-01

    The present study aimed to investigate differences in prognosis based on human papillomavirus (HPV) infection, persistent infection and genotype variations for patients exhibiting atypical squamous cells of undetermined significance (ASCUS) in their initial Papanicolaou (PAP) test results. A latent Dirichlet allocation (LDA)-based tool was developed that may offer a facilitated means of communication to be employed during patient-doctor consultations. The present study assessed 491 patients (139 HPV-positive and 352 HPV-negative cases) with a PAP test result of ASCUS with a follow-up period ≥2 years. Patients underwent PAP and HPV DNA chip tests between January 2006 and January 2009. The HPV-positive subjects were followed up with at least 2 instances of PAP and HPV DNA chip tests. The most common genotypes observed were HPV-16 (25.9%, 36/139), HPV-52 (14.4%, 20/139), HPV-58 (13.7%, 19/139), HPV-56 (11.5%, 16/139), HPV-51 (9.4%, 13/139) and HPV-18 (8.6%, 12/139). A total of 33.3% (12/36) patients positive for HPV-16 had cervical intraepithelial neoplasia (CIN)2 or a worse result, which was significantly higher than the prevalence of CIN2 of 1.8% (8/455) in patients negative for HPV-16 (P<0.001), while no significant association was identified for other genotypes in terms of genotype and clinical progress. There was a significant association between clearance and good prognosis (P<0.001). Persistent infection was higher in patients aged ≥51 years (38.7%) than in those aged ≤50 years (20.4%; P=0.036). Progression from persistent infection to CIN2 or worse (19/34, 55.9%) was higher than clearance (0/105, 0.0%; P<0.001). In the LDA analysis, using symmetric Dirichlet priors α=0.1 and β=0.01, and clusters (k)=5 or 10 provided the most meaningful groupings. Statistical and LDA analyses produced consistent results regarding the association between persistent infection of HPV-16, old age and long infection period with a clinical progression of CIN2 or worse

  2. Rationale and design of the DIPAK 1 study: a randomized controlled clinical trial assessing the efficacy of lanreotide to Halt disease progression in autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Meijer, Esther; Drenth, Joost P H; d'Agnolo, Hedwig; Casteleijn, Niek F; de Fijter, Johan W; Gevers, Tom J; Kappert, Peter; Peters, Dorien J M; Salih, Mahdi; Soonawala, Darius; Spithoven, Edwin M; Torres, Vicente E; Visser, Folkert W; Wetzels, Jack F M; Zietse, Robert; Gansevoort, Ron T

    2014-03-01

    There are limited therapeutic options to slow the progression of autosomal dominant polycystic kidney disease (ADPKD). Recent clinical studies indicate that somatostatin analogues are promising for treating polycystic liver disease and potentially also for the kidney phenotype. We report on the design of the DIPAK 1 (Developing Interventions to Halt Progression of ADPKD 1) Study, which will examine the efficacy of the somatostatin analogue lanreotide on preservation of kidney function in ADPKD. The DIPAK 1 Study is an investigator-driven, randomized, multicenter, controlled, clinical trial. We plan to enroll 300 individuals with ADPKD and estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73 m(2) who are aged 18-60 years. Patients will be randomly assigned (1:1) to standard care or lanreotide, 120 mg, subcutaneously every 28 days for 120 weeks, in addition to standard care. Main study outcome is the slope through serial eGFR measurements starting at week 12 until end of treatment for lanreotide versus standard care. Secondary outcome parameters include change in eGFR from pretreatment versus 12 weeks after treatment cessation, change in kidney volume, change in liver volume, and change in quality of life. Blood and urine will be collected and questionnaires will be filled in following a fixed scheme. Magnetic resonance imaging will be performed for assessment of kidney and liver volume. Assuming an average change in eGFR of 5.2 ± 4.3 (SD) mL/min/1.73 m(2) per year in untreated patients, 150 patients are needed in each group to detect a 30% reduction in the rate of kidney function loss between treatment groups with 80% power, 2-sided α = 0.05, and 20% protocol violators and/or dropouts. The design is an open randomized controlled trial and measurement of our primary end point does not begin at randomization. The DIPAK 1 Study will show whether subcutaneous administration of lanreotide every 4 weeks attenuates disease progression in patients with ADPKD

  3. Adenovirus sequences required for replication in vivo.

    OpenAIRE

    Wang, K.; Pearson, G D

    1985-01-01

    We have studied the in vivo replication properties of plasmids carrying deletion mutations within cloned adenovirus terminal sequences. Deletion mapping located the adenovirus DNA replication origin entirely within the first 67 bp of the adenovirus inverted terminal repeat. This region could be further subdivided into two functional domains: a minimal replication origin and an adjacent auxillary region which boosted the efficiency of replication by more than 100-fold. The minimal origin occup...

  4. Initiation of chromosomal replication in predatory bacterium Bdellovibrio bacteriovorus

    Directory of Open Access Journals (Sweden)

    Lukasz Makowski

    2016-11-01

    Full Text Available Bdellovibrio bacteriovorus is a small Gram-negative predatory bacterium that attacks other Gram-negative bacteria, including many animal, human, and plant pathogens. This bacterium exhibits a peculiar biphasic life cycle during which two different types of cells are produced: non-replicating highly motile cells (the free-living phase and replicating cells (the intracellular-growth phase. The process of chromosomal replication in B. bacteriovorus must therefore be temporally and spatially regulated to ensure that it is coordinated with cell differentiation and cell cycle progression. Recently, B. bacteriovorus has received considerable research interest due to its intriguing life cycle and great potential as a prospective antimicrobial agent. Although we know that chromosomal replication in bacteria is mainly regulated at the initiation step, no data exists about this process in B. bacteriovorus. We report the first characterization of key elements of initiation of chromosomal replication – DnaA protein and oriC region from the predatory bacterium, B. bacteriovorus. In vitro studies using different approaches demonstrate that the B. bacteriovorus oriC (BdoriC is specifically bound and unwound by the DnaA protein. Sequence comparison of the DnaA-binding sites enabled us to propose a consensus sequence for the B. bacteriovorus DnaA box (5’-NN(A/TTCCACA-3’. Surprisingly, in vitro analysis revealed that BdoriC is also bound and unwound by the host DnaA proteins (relatively distantly related from B. bacteriovorus. We compared the architecture of the DnaA–oriC complexes (orisomes in homologous (oriC and DnaA from B. bacteriovorus and heterologous (BdoriC and DnaA from prey, E. coli or P. aeruginosa systems. This work provides important new entry points toward improving our understanding of the initiation of chromosomal replication in this predatory bacterium.

  5. Spectral CT: Clinical application and research progress%能谱CT的临床应用与研究进展

    Institute of Scientific and Technical Information of China (English)

    雷立昌; 陈建宇

    2013-01-01

    多排螺旋CT技术的广泛应用及计算机后处理技术的不断发展,使能谱CT成像从理论走向实践.能谱CT从球管和探测器等方面进行革新,尽可能同时、同相位获得两个不同能量水平的图像,从而重建出40~140 keV的高清单能量图像、多种基础物质密度图像、虚拟图像以及特异能谱曲线,为疾病的早期发现、定性甚至定量诊断提供可靠依据,为临床实践和科研提供更为广阔的发展空间.%Advances in multi-detector technology and computer processing technology have made spectral CT imaging possible. On the basis of the improvement of X-ray tubes and X-ray detectors, spectral CT can obtain two images at different levels of energy at the same time and at the same phase to reconstruct high-definition and monochromatic images from 40 keV to 140 keV and even generate 3-materials decomposition images, virtual non-contrast images and specific spectrum curve. These imaging technologies provide reliable information to diagnose disease earlier and more accurately. Spectral CT is a promising technique with clinical application potential.

  6. The Progress of Composite Mesh in Clinical Application%复合补片临床应用进展

    Institute of Scientific and Technical Information of China (English)

    杨凯; 纪艳超; 姜龙; 崔磊(综述); 刘昶(审校)

    2015-01-01

    复合补片是由多种材料复合在一起,可以避免单一材料功能、性能的单一性,集多种材料的优点于一身。复合补片具有与组织相容性良好;其特殊结构有利于补片自然撑开展平,使补片放置更加容易,能有效防止粘连;可有效防止感染及疝复发等优势。复合补片临床应用广泛,在疝外科应用较为成熟且疗效确切,在整形美容等众多领域也得到较好应用,然而其更多性能还有待于进一步开发研究。%Composite patch(composite mesh) is a composite of a variety of materials, to avoid the sin-gularity of a single materiale,and be equipped with the advantages of multiple materials.Composite patch has good compatibility with tissues,and its special structure is easy to open flat naturally, which makes it easier to place the patch and can effectively prevent adhesion , infection and hernia recurrence .The composite patches are widely used in clinical,and the application is more mature and accurate in hernia repair,while cosmetic surgery is also a good application field.However,further studies and development are still needed for the application of the materials.

  7. 下丘脑性肥胖临床研究进展%Clinical progress in hypothalamic obesity

    Institute of Scientific and Technical Information of China (English)

    吴蔚; 杨叶虹; 李益明

    2014-01-01

    Hypothalamic obesity is defined as the significant polyphagia and rapid weight gain due to a variety of structural or functional damage to the hypothalamic regulatory centers of energy homeostasis.Its clinical characteristics also include reduced energy expenditure,multiple deficits of hypothalamic-pituitary function and metabolic disturbances of blood glucose,lipid profile and blood pressure.Some patients may as well develop abnormal circadian rhythms,impaired regulation of body temperature,thirst perception and mood.The pathogenetic mechanisms underlying hypothalamic obesity include defects in the hypothalamic weightregulating pathways,dysfunction of afferent peripheral humoral signals in the central nervous system,such as leptin,insulin,ghrelin,etc,and autonomic imbalance.The treatment of hypothalamic obesity includes conventional lifestyle modifications,several agents and bariatric surgery.%下丘脑性肥胖是指下丘脑能量稳态调节系统结构或功能损伤引起的食欲亢进和短期内体重显著增加综合征.其临床特征还包括能量消耗下降、合并多种下丘脑-垂体功能减退以及血糖、血脂、血压等代谢改变,部分可合并昼夜节律、体温、渴感及情绪调节异常.发病机制涉及下丘脑能量调节通路受损,胰岛素、瘦素、ghrelin等体液因子在中枢作用异常,自主神经功能紊乱等方面.其治疗包括常规生活方式干预、药物治疗及减重手术等.

  8. Replication Origin Specification Gets a Push.

    Science.gov (United States)

    Plosky, Brian S

    2015-12-03

    During the gap between G1 and S phases when replication origins are licensed and fired, it is possible that DNA translocases could disrupt pre-replicative complexes (pre-RCs). In this issue of Molecular Cell, Gros et al. (2015) find that pre-RCs can be pushed along DNA and retain the ability to support replication.

  9. Unscheduled DNA replication origin activation at inserted HPV 18 sequences in a HPV-18/MYC amplicon.

    Science.gov (United States)

    Conti, Chiara; Herrick, John; Bensimon, Aaron

    2007-08-01

    Oncogene amplification is a critical step leading to tumorigenesis, but the underlying mechanisms are still poorly understood. Despite data suggesting that DNA replication is a major source of genomic instability, little is known about replication origin usage and replication fork progression in rearranged regions. Using a single DNA molecule approach, we provide here the first study of replication kinetics on a previously characterized MYC/papillomavirus (HPV18) amplicon in a cervical cancer. Using this amplicon as a model, we investigated the role DNA replication control plays in generating amplifications in human cancers. The data reveal severely perturbed DNA replication kinetics in the amplified region when compared with other regions of the same genome. It was found that DNA replication is initiated from both genomic and viral sequences, resulting in a higher median frequency of origin firings. In addition, it was found that the higher initiation frequency was associated with an equivalent increase in the number of stalled replication forks. These observations raise the intriguing possibility that unscheduled replication origin activation at inserted HPV-18 viral DNA sequences triggers DNA amplification in this cancer cell line and the subsequent overexpression of the MYC oncogene.

  10. Top2 and Sgs1-Top3 Act Redundantly to Ensure rDNA Replication Termination.

    Directory of Open Access Journals (Sweden)

    Kamilla Mundbjerg

    2015-12-01

    Full Text Available Faithful DNA replication with correct termination is essential for genome stability and transmission of genetic information. Here we have investigated the potential roles of Topoisomerase II (Top2 and the RecQ helicase Sgs1 during late stages of replication. We find that cells lacking Top2 and Sgs1 (or Top3 display two different characteristics during late S/G2 phase, checkpoint activation and accumulation of asymmetric X-structures, which are both independent of homologous recombination. Our data demonstrate that checkpoint activation is caused by a DNA structure formed at the strongest rDNA replication fork barrier (RFB during replication termination, and consistently, checkpoint activation is dependent on the RFB binding protein, Fob1. In contrast, asymmetric X-structures are formed independent of Fob1 at less strong rDNA replication fork barriers. However, both checkpoint activation and formation of asymmetric X-structures are sensitive to conditions, which facilitate fork merging and progression of replication forks through replication fork barriers. Our data are consistent with a redundant role of Top2 and Sgs1 together with Top3 (Sgs1-Top3 in replication fork merging at rDNA barriers. At RFB either Top2 or Sgs1-Top3 is essential to prevent formation of a checkpoint activating DNA structure during termination, but at less strong rDNA barriers absence of the enzymes merely delays replication fork merging, causing an accumulation of asymmetric termination structures, which are solved over time.

  11. Construction of a subgenomic CV-B3 replicon expressing emerald green fluorescent protein to assess viral replication of a cardiotropic enterovirus strain in cultured human cells.

    Science.gov (United States)

    Wehbe, Michel; Huguenin, Antoine; Leveque, Nicolas; Semler, Bert L; Hamze, Monzer; Andreoletti, Laurent; Bouin, Alexis

    2016-04-01

    Coxsackieviruses B (CV-B) (Picornaviridae) are a common infectious cause of acute myocarditis in children and young adults, a disease, which is a precursor to 10-20% of chronic myocarditis and dilated cardiomyopathy (DCM) cases. The mechanisms involved in the disease progression from acute to chronic myocarditis phase and toward the DCM clinical stage are not fully understood but are influenced by both viral and host factors. Subgenomic replicons of CV-B can be used to assess viral replication mechanisms in human cardiac cells and evaluate the effects of potential antiviral drugs on viral replication activities. Our objectives were to generate a reporter replicon from a cardiotropic prototype CV-B3/28 strain and to characterize its replication properties into human cardiac primary cells. To obtain this replicon, a cDNA plasmid containing the full CV-B3/28 genome flanked by a hammerhead ribozyme sequence and an MluI restriction site was generated and used as a platform for the insertion of sequences encoding emerald green fluorescent protein (EmGFP) in place of those encoding VP3. In vitro transcribed RNA from this plasmid was transfected into HeLa cells and human primary cardiac cells and was able to produce EmGFP and VP1-containing polypeptides. Moreover, non-structural protein biological activity was assessed by the specific cleavage of eIF4G1 by viral 2A(pro). Viral RNA replication was indirectly demonstrated by inhibition assays, fluoxetine was added to cell culture and prevented the EmGFP synthesis. Our results indicated that the EmGFP CV-B3 replicon was able to replicate and translate as well as the CV-B3/28 prototype strain. Our EmGFP CV-B3 replicon will be a valuable tool to readily investigate CV-B3 replication activities in human target cell models.

  12. Do HIV-1 non-B subtypes differentially impact resistance mutations and clinical disease progression in treated populations? Evidence from a systematic review

    Directory of Open Access Journals (Sweden)

    Madhavi Bhargava

    2014-07-01

    Full Text Available There are 31 million adults living with HIV-1 non-B subtypes globally, and about 10 million are on antiretroviral therapy (ART. Global evidence to guide clinical practice on ART response in HIV-1 non-B subtypes remains limited. We systematically searched 11 databases for the period 1996 to 2013 for evidence. Outcomes documented included time to development of AIDS and/or death, resistance mutations, opportunistic infections, and changes in CD4 cell counts and viral load. A lack of consistent reporting of all clinical end points precluded a meta-analysis. In sum, genetic diversity that precipitated differences in disease progression in ART-naïve populations was minimized in ART-experienced populations, although variability in resistance mutations persisted across non-B subtypes. To improve the quality of patient care in global settings, recording HIV genotypes at baseline and at virologic failure with targeted non-B subtype-based point-of-care resistance assays and timely phasing out of resistance-inducing ART regimens is recommended.