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  • 1
    Publication Date: 2014-02-15
    Description: The vertebrate body forms from a multipotent stem cell-like progenitor population that progressively contributes newly differentiated cells to the most posterior end of the embryo. How the progenitor population balances proliferation and other cellular functions is unknown due to the difficulty of analyzing cell division in vivo. Here, we show that proliferation is compartmentalized at the posterior end of the embryo during early zebrafish development by the regulated expression of cdc25a , a key controller of mitotic entry. Through the use of a transgenic line that misexpresses cdc25a , we show that this compartmentalization is critical for the formation of the posterior body. Upon misexpression of cdc25a , several essential T-box transcription factors are abnormally expressed, including Spadetail/Tbx16, which specifically prevents the normal onset of myoD transcription, leading to aberrant muscle formation. Our results demonstrate that compartmentalization of proliferation during early embryogenesis is critical for both extension of the vertebrate body and differentiation of the multipotent posterior progenitor cells to the muscle cell fate.
    Print ISSN: 0890-9369
    Topics: Biology
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  • 2
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    Oxford University Press
    Publication Date: 2018-03-06
    Description: We develop a theory of minors for alternating dimaps—orientably embedded digraphs where, at each vertex, the incident edges (taken in the order given by the embedding) are directed alternately into, and out of, the vertex. We show that they are related by the triality relation of Tutte. They do not commute in general, though do in many circumstances, and we characterize the situations where they do. We give a characterization of alternating dimaps of at most a given genus, using a finite set of excluded minors. We also use the minor operations to define simple Tutte invariants for alternating dimaps and characterize them. We establish a connection with the Tutte polynomial, and pose the problem of characterizing universal Tutte-like invariants for alternating dimaps based on these minor operations.
    Print ISSN: 0033-5606
    Electronic ISSN: 1464-3847
    Topics: Mathematics
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  • 3
    Publication Date: 2012-04-04
    Description: Context Leucovorin, fluorouracil, and oxaliplatin (FOLFOX) is the standard adjuvant therapy for resected stage III colon cancer. Adding cetuximab to FOLFOX benefits patients with metastatic wild-type KRAS but not mutated KRAS colon cancer. Objective To assess the potential benefit of cetuximab added to the modified sixth version of the FOLFOX regimen (mFOLFOX6) in patients with resected stage III wild-type KRAS colon cancer. Design, Setting, and Participants A randomized trial of 2686 patients aged 18 years or older at multiple institutions across North America enrolled following resection and informed consent between February 10, 2004, and November 25, 2009. The primary randomized comparison was 12 biweekly cycles of mFOLFOX6 with and without cetuximab. KRAS mutation status was centrally determined. The trial was halted after a planned interim analysis of 48% of predicted events (246/515) occurring in 1863 (of 2070 planned) patients with tumors having wild-type KRAS . A total of 717 patients with mutated KRAS and 106 with indeterminate KRAS were accrued. The 2070 patients with wild-type KRAS provided 90% power to detect a hazard ratio (HR) of 1.33 (2-sided α = .05), with planned interim efficacy analyses after 25%, 50%, and 75% of expected relapses. Main Outcome Measures Disease-free survival in patients with wild-type KRAS mutations. Secondary end points included overall survival and toxicity. Results Median (range) follow-up was 28 (0-68) months. The trial demonstrated no benefit when adding cetuximab. Three-year disease-free survival for mFOLFOX6 alone was 74.6% vs 71.5% with the addition of cetuximab (HR, 1.21; 95% CI, 0.98-1.49; P  = .08) in patients with wild-type KRAS , and 67.1% vs 65.0% (HR, 1.12; 95% CI, 0.86-1.46; P  = .38) in patients with mutated KRAS , with no significant benefit in any subgroups assessed. Among all patients, grade 3 or higher adverse events (72.5% vs 52.3%; odds ratio [OR], 2.4; 95% CI, 2.1-2.8; P  〈 .001) and failure to complete 12 cycles (33% vs 23%; OR, 1.6; 95% CI, 1.4-1.9; P  〈 .001) were significantly higher with cetuximab. Increased toxicity and greater detrimental differences in all outcomes were observed in patients aged 70 years or older. Conclusion Among patients with stage III resected colon cancer, the use of cetuximab with adjuvant mFOLFOX6 compared with mFOLFOX6 alone did not result in improved disease-free survival. Trial Registration clinicaltrials.gov Identifier: NCT00079274
    Keywords: Oncology, Colon Cancer, Surgery, Surgical Interventions, Colorectal Surgery, Randomized Controlled Trial, Prognosis/ Outcomes, Drug Therapy
    Print ISSN: 0098-7484
    Electronic ISSN: 1538-3598
    Topics: Medicine
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  • 4
    Publication Date: 2015-07-22
    Description: Cortney M. Bouldin, Alyssa J. Manning, Yu-Hsuan Peng, Gist H. Farr III, King L. Hung, Alice Dong, and David Kimelman Anterior to posterior growth of the vertebrate body is fueled by a posteriorly located population of bipotential neuro-mesodermal progenitor cells. These progenitors have a limited rate of proliferation and their maintenance is crucial for completion of the anterior-posterior axis. How they leave the progenitor state and commit to differentiation is largely unknown, in part because widespread modulation of factors essential for this process causes organism-wide effects. Using a novel assay, we show that zebrafish Tbx16 (Spadetail) is capable of advancing mesodermal differentiation cell-autonomously. Tbx16 locks cells into the mesodermal state by not only activating downstream mesodermal genes, but also by repressing bipotential progenitor genes, in part through a direct repression of sox2 . We demonstrate that tbx16 is activated as cells move from an intermediate Wnt environment to a high Wnt environment, and show that Wnt signaling activates the tbx16 promoter. Importantly, high-level Wnt signaling is able to accelerate mesodermal differentiation cell-autonomously, just as we observe with Tbx16. Finally, because our assay for mesodermal commitment is quantitative we are able to show that the acceleration of mesodermal differentiation is surprisingly incomplete, implicating a potential separation of cell movement and differentiation during this process. Together, our data suggest a model in which high levels of Wnt signaling induce a transition to mesoderm by directly activating tbx16 , which in turn acts to irreversibly flip a bistable switch, leading to maintenance of the mesodermal fate and repression of the bipotential progenitor state, even as cells leave the initial high-Wnt environment.
    Print ISSN: 0950-1991
    Electronic ISSN: 1477-9129
    Topics: Biology
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  • 5
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    Alimentary pharmacology & therapeutics 20 (2004), S. 0 
    ISSN: 1365-2036
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background : Insulin sensitizing agents may be useful in treatment of non-alcoholic fatty liver disease.Aim : A pilot study to evaluate the efficacy and safety of metformin in non-alcoholic fatty liver disease.Methods : In an open labelled study, patients with histologically confirmed non-alcoholic fatty liver disease were given metformin (20 mg/kg) for 1 year. Insulin resistance (by log homeostasis assessment model analysis for insulin resistance and Quantitative Insulin Sensitivity Check Index) and post-treatment hepatic histology were compared with pre-treatment histology.Results : Fifteen patients completed 1 year of treatment. During the initial 3 months, there was improvement in alanine aminotransferase and aspartate aminotransferase (P-value 0.01 and 0.02, respectively) along with improvement in insulin sensitivity. However, after 3 months, there was no further improvement in insulin sensitivity and there was gradual rise in aspartate aminotransferase and alanine aminotransferase back to pre-treatment levels. Among the 10 patients with post-treatment biopsy, three (33%), showed improvement in steatosis, two (20%) showed improvement in inflammation score and one (10%) showed improvement in fibrosis.Conclusion : Metformin treatment was associated with only a transient improvement in liver chemistries. A progressive, sustainable reduction in insulin sensitivity was not noted during treatment.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Bulletin of environmental contamination and toxicology 57 (1996), S. 236 -241 
    ISSN: 1432-0800
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Medicine
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Advances in contraception 11 (1995), S. 23-24 
    ISSN: 1573-7195
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1573-7195
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Resumé On pense qu'un bon nombre des légers risques de contracter une affection pelvienne inflammatoire liée à l'utilisation d'un dispositif intra-utérin est sans doute dû à une contamination bactérienne de la cavité utérine au moment de l'insertion. Les recherches précédentes semblen indiquer que l'administration d'antibiotiques à titre prophylactique immédiatement avant l'insertion d'un DIU peut réduire le risque de telles inflammations. Ce document présente les résultats d'un essai clinique randomisé sur 1485 femmes effectué à Ibadan (Nigéria) en vue d'évaluer l'efficacité de 200 mg de la doxycycline (comparée à un placebo), administrés par voie buccale au moment de l'insertion du DIU, pour réduire l'incidence des affections pelviennes inflammatoires pendant les trois premiers mois d'utilisation d'un DIU. Le pourcentage d'infection dans le groupe des femmes traitées à la doxycycline n'étaiet pas significativement moins élevé que celui du groupe traité au placebo. Le pourcentage de consultations imprévues à la clinique pour des raisons liées au DIU n'étaient pas non plus significativement moins élevé pour le groupe traité à la doxycycline. Toutefois, l'incidence d'affections pelviennes inflammatoires étaiet faible (21 cas) pour les deux groupes étudiés. Il est possible que les conditions d'aseptie pendant l'insertion du DIU, les visites de suivi à intervalles rapprochés pour contrôler l'état de santé, ainsi que le traitement d'infections intercurrentes aient réduit l'eventualité de telles affections inflammatoires dans cette population.
    Abstract: Resumen Se piensa que una gran parte de los pequeños riesgos de contraer una afección pélvica inflamatoria relacionada con la utilización de un dispositivo intrauterino parece haber sido causada por una contaminación bacteriana de la cavidad uterina en el momento de la colocación. Las investigaciones anteriores parecen indicar que la administración de antibióticos a título profiláctico inmediatamente antes de la colocación de un DIU reducir el riesgo de tales inflamaciones. En este documento se presentan los resultados de un ensayo clínico al azar realizado con 1,485 mujeres de Ibadán, Nigeria, a los efectos de evaluar la eficacia de 200 mg de doxiciclina (en comparación con un placebo) administrada por vía oral en el momento de colocar el DIU, para reducir la incidencia de afecciones pélvicas inflamatorias durante los primeros tres meses de utilización de un DIU. El porcentaje de infección en el grupo de mujeres tratadas con doxiciclina no era significativamente menos elevado que en el grupo tratado con un placebo). El porcentaje de consultas imprevistas en la clínica por motivos relacionados con el tampoco era significativamente menos elevado en el caso del grupo tratado con doxiciclina. Sin embargo, la incidencia de afecciones pélvicas inflamatorias era baja (21 casos) en los dos grupos estudiados. Es posible que las condiciones de asepsia durante la colocación del DIU, las visitas de seguimiento a intervalos cortos para controlar el estado de salud, así como el tratamiento de infecciones intercurrentes, hayan reducido la posibilidad de tales afecciones inflamatorias en esta población.
    Notes: Abstract It is believed that much of the small increased risk for developing pelvic inflammatory disease (PID) associated with the use of an intrauterine device (IUD) appears to be caused by bacterial contamination of the endometrial cavity at the time of insertion. Previous research suggests that use of prophylactic antibiotics immediately prior to IUD insertion may reduce the risk of developing PID. This paper presents results from a randomized clinical trial of 1485 women in Ibadan, Nigeria evaluating the effectiveness of 200 mg of doxycycline (versus placebo) given orally at the time of IUD insertion in reducing the incidence of PID during the first three months of IUD use. Rate of PID infection in the doxycycline-treated group was not significantly lower than that in the placebo-treated group. The rate of unscheduled IUD-related visits to the clinic also was not significantly lower among the doxycyclinetreated group. However, the incidence of PID was low (21 cases) for both study groups. Aseptic conditions during IUD insertion, follow-up visits with short intervals to monitor health, and treatment of opportunistic infections may have reduced the potential of PID within this population.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Advances in contraception 5 (1989), S. 127-146 
    ISSN: 1573-7195
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Resumé La mise en place d'un dispositif intra-utérin (DIU) après un accouchement, alors que les femmes se trouvent encore à l'hôpital, présente un certain nombre d'avantages. Toutefois, dans des rapports antérieurs, cette pratique a généralement été associée à des taux de rejet élevés. D'autre part, des études récentes ont montré que si l'insertion du DIU de fait immédiatement après l'expulsion du placenta (dans les 10 minutes qui suivent), cette méthode est sûre et efficace. Certains centres expérimentés ont rapporté des taux de rejet relativement faibles. La présente étude passe en revue les expériences décrites dans des études internationales sur les insertions des DIU après le post-partum, résume les enseignements tirés de ces expériences et suggère des orientations pour les recherches futures.
    Abstract: Resumen La inserción de un dispositivo intrauterino (DIU) después des parto, mientras las mujeres continúan hospitalizadas, presenta cierto número de ventajas. Sin embargo, en informes anteriores, esta práctica estuvo asociada generalmente con tasas elevadas de rechazo. Por otra parte, estudios recientes señalaron que si la inserción del DIU se realiza immediatamente después de la expulsión de la placenta (dentro de los 10 minutos siguientes), este método es seguro y eficaz. Ciertos centros experimentados señalaron tasas de rechazo relativamente bajas. En este estudio se examinan las experiencias descritas en estudios internacionales sobre las inserciones posparto de DIU, se resumen las lecciones aprendidas de estas experiencias y se sugieren orientaciones para futuras investigaciones.
    Notes: Abstract Postpartum insertion of intrauterine contraceptive devices (IUDs) performed while women are still in hospital has a number of advantages. Earlier reports, however, generally associated this procedure with high expulsion rates. Recent studies, on the other hand, have shown that if IUDs are inserted immediately (within 10 minutes) after placental delivery, it is safe and effective. In some experienced centers, fairly low expulsion rates are reported. In this paper the experiences with postplacental IUD insertions from international studies are reviewed, the lessons we have learned from these experiences summarized, and future research directions suggested.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Advances in contraception 10 (1994), S. 271-285 
    ISSN: 1573-7195
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Resumé Les essais cliniques ont invariablement montré que le DIU libérant chaque jour 20 μg de lévonorgestrel (LNG-IUD-20) a une utilité contraceptive comparable, sinon supérieure, à celle des dispositifs Copper T380 et Multiload Copper-375. Le présent article est axé non seulement sur les effets non contraceptifs du dispositif, ceux qui sont bénéfiques, tels qu'une réduction de la ménorragie, un effet thérapeutique sur la dysménorrhée, la prévention des grossesses ectopiques, mais aussi sur les effets délétères tels que l'aménorrhée, les microrragies et les pertes sanguines irrégulières, les effets hormonaux secondaires et les kystes fonctionnels ovariens. Y est examinée aussi la possibilité d'un effet préventif des maladies pelviennes inflammatories, les effets du DIU chez les femmes lors du post-partum et de la lactation, le retour à la fécondité après le retrait et d'autres aspects de sécurité. En général, les avantages non contraceptifs du LNG-IUD-20 sont considérables, ont d'importantes incidences médicales et en matière de santé publique, et compensent très largement les effets délétères du dispositif, lesquels sont soit bénins du point de vue médical soit passagers et peuvent en général être convenablement surmontés en demandant conseil. Une meilleure connaissance des effets, bénéfiques et délétères, de ce DIU libérant des hormones devrait permettre de mieux conseiller les patientes, ce qui devrait du même coup améliorer la qualité de la vie des utilisatrices, réduire au minimum les retraits inutiles du dispositif et maximaliser la poursuite de son utilisation.
    Abstract: Resumen Los ensayos clínicos realizados señalaron sistemáticamente que el DIU que descarga 20 μg de levonorgestrel diariamente (LNG-DIU-20) tiene una eficacia anticonceptiva similar o incluso superior a la de los DIU CuT380 y Multiload Cu375. Este examen se centra en los efectos no anticonceptivos del dispositivo, los benéficos, tales como la reducción de la menorragia, el efecto terapéutico sobre la dismenorrea y la prevención del embarazo ectópico, así como los perjudiciales, por ejemplo, la amenorrea, las pérdidas y el sangrado irregular, los efectos secundarios hormonales y los quistes ováricos funcionales. También se examina la posibilidad de un efecto preventivo de la enfermedad inflamatoria pélvica (PID), los efectos del DIU sobre mujeres de posparto/lactantes, el retorno de la fecundidad después del retiro y otras cuestiones de seguridad. En general, los beneficios no anticonceptivos de los LNG-DIU-20 son significativos, tienen importantes repercusiones médicas y de salud pública, y compensan con creces los efectos perjudiciales del dispositivo, que son médicamente ligeros o bien de naturaleza pasajera, y pueden ser manejados satisfactoriamente, en términos generales, mediante un asesoramiento adecuado. Una mejor comprensión de los efectos, tanto benéficos como perjudiciales, de estos DIU de descarga hormonal habrá de llevar a un mayor asesoramiento de pacientes, lo cual, a su vez, mejorará la calidad de vida de las usuarias, reducirá al mínimo los retiros innecesarios y aumentará al máximo la continuación del uso.
    Notes: Abstract Clinical trials have consistently shown that the IUD that releases 20 μg levonorgestrel daily (LNG-IUD-20) has a contraceptive efficacy comparable to, if not surpassing, the Copper T380 and the Multiload Copper-375 IUDs. The focus of this review is the device's non-contraceptive effects — the beneficial ones, such as reduction of menorrhagia, a therapeutic effect on dysmenorrhea, and prevention of ectopic pregnancy, as well as the deleterious ones, such as amenorrhea, spotting and irregular bleeding, hormonal side-effects, and functional ovarian cysts. Also discussed are the possibility of a preventive effect on pelvic inflammatory disease, the effects of the IUD on postpartum/lactating women, fertility return after removal and other safety issues. In general, the LNG-IUD-20's non-contraceptive benefits are substantive, carry important medical and public health implications, and far outweigh the device's deleterious effects, which are either medically mild or transient in nature, and can usually be managed satisfactorily by counseling. A better understanding of these effects, both beneficial and deleterious, of this hormone-releasing IUD should lead to more effective patient counseling, which, in turn, should improve user quality of life, minimize unnecessary removals, and maximize continuation of use.
    Type of Medium: Electronic Resource
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