1,223 research outputs found

    PHP5 JUDICIALIZAÇÃO DO ACESSO AO TRATAMENTO DE DOENÇAS RARAS: DOENÇA DE FABRY NO ESTADO DO RIO GRANDE DO SUL

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    The contribution of DNA ploidy to radiation sensitivity in human tumour cell lines

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    The contribution of DNA ploidy to radiation sensitivity was investigated in a group of eight human tumour cell lines. As previous studies suggest, while more aneuploid tumours tend to be more radioresistant, there is no significant relationship between ploidy and radiation sensitivity (SF2). The failure to observe a significant effect of ploidy on radiation sensitivity is due to the complex and multifactorial basis of radiation sensitivity. When we determined the relationship between survival and radiation-induced chromosome aberration frequency, a measure independent of most other modifiers of sensitivity, we observed a direct relationship between ploidy and mean lethal aberration frequency. The mean lethal frequency of aberrations increased from about 1 for diploid cells to about 2 for tetraploid cells. The mean lethal frequency of aberrations was independent of DNA repair variations. These observations demonstrate that changes in DNA ploidy are an important contributor to radiation sensitivity variations in human tumour cell lines. Therefore, any battery of predictive assays should include DNA ploidy measurements. © 1999 Cancer Research Campaig

    Checkpoints are blind to replication restart and recombination intermediates that result in gross chromosomal rearrangements

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    Replication fork inactivation can be overcome by homologous recombination, but this can cause gross chromosomal rearrangements that subsequently missegregate at mitosis, driving further chromosome instability. It is unclear when the chromosome rearrangements are generated and whether individual replication problems or the resulting recombination intermediates delay the cell cycle. Here we have investigated checkpoint activation during HR-dependent replication restart using a site-specific replication fork-arrest system. Analysis during a single cell cycle shows that HR-dependent replication intermediates arise in S phase, shortly after replication arrest, and are resolved into acentric and dicentric chromosomes in G2. Despite this, cells progress into mitosis without delay. Neither the DNA damage nor the intra-S phase checkpoints are activated in the first cell cycle, demonstrating that these checkpoints are blind to replication and recombination intermediates as well as to rearranged chromosomes. The dicentrics form anaphase bridges that subsequently break, inducing checkpoint activation in the second cell cycle

    Genomic analysis of the function of the transcription factor gata3 during development of the Mammalian inner ear

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    We have studied the function of the zinc finger transcription factor gata3 in auditory system development by analysing temporal profiles of gene expression during differentiation of conditionally immortal cell lines derived to model specific auditory cell types and developmental stages. We tested and applied a novel probabilistic method called the gamma Model for Oligonucleotide Signals to analyse hybridization signals from Affymetrix oligonucleotide arrays. Expression levels estimated by this method correlated closely (p<0.0001) across a 10-fold range with those measured by quantitative RT-PCR for a sample of 61 different genes. In an unbiased list of 26 genes whose temporal profiles clustered most closely with that of gata3 in all cell lines, 10 were linked to Insulin-like Growth Factor signalling, including the serine/threonine kinase Akt/PKB. Knock-down of gata3 in vitro was associated with a decrease in expression of genes linked to IGF-signalling, including IGF1, IGF2 and several IGF-binding proteins. It also led to a small decrease in protein levels of the serine-threonine kinase Akt2/PKB beta, a dramatic increase in Akt1/PKB alpha protein and relocation of Akt1/PKB alpha from the nucleus to the cytoplasm. The cyclin-dependent kinase inhibitor p27(kip1), a known target of PKB/Akt, simultaneously decreased. In heterozygous gata3 null mice the expression of gata3 correlated with high levels of activated Akt/PKB. This functional relationship could explain the diverse function of gata3 during development, the hearing loss associated with gata3 heterozygous null mice and the broader symptoms of human patients with Hearing-Deafness-Renal anomaly syndrome

    Disorder Effects on Exciton-Polariton Condensates

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    The impact of a random disorder potential on the dynamical properties of Bose Einstein condensates is a very wide research field. In microcavities, these studies are even more crucial than in the condensates of cold atoms, since random disorder is naturally present in the semiconductor structures. In this chapter, we consider a stable condensate, defined by a chemical potential, propagating in a random disorder potential, like a liquid flowing through a capillary. We analyze the interplay between the kinetic energy, the localization energy, and the interaction between particles in 1D and 2D polariton condensates. The finite life time of polaritons is taken into account as well. In the first part, we remind the results of [G. Malpuech et al. Phys. Rev. Lett. 98, 206402 (2007).] where we considered the case of a static condensate. In that case, the condensate forms either a glassy insulating phase at low polariton density (strong localization), or a superfluid phase above the percolation threshold. We also show the calculation of the first order spatial coherence of the condensate versus the condensate density. In the second part, we consider the case of a propagating non-interacting condensate which is always localized because of Anderson localization. The localization length is calculated in the Born approximation. The impact of the finite polariton life time is taken into account as well. In the last section we consider the case of a propagating interacting condensate where the three regimes of strong localization, Anderson localization, and superfluid behavior are accessible. The localization length is calculated versus the system parameters. The localization length is strongly modified with respect to the non-interacting case. It is infinite in the superfluid regime whereas it is strongly reduced if the fluid flows with a supersonic velocity.Comment: chapter for a book "Exciton Polaritons in Microcavities: New Frontiers" by Springer (2012), the original publication is available at http://www.springerlink.co

    A rare case of complete C2–C3 dislocation with mild neurological symptoms

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    The authors report a rare case of complete C2–C3 dislocation with unexpectedly mild neurological symptoms in a 57 year old man involved in a motor vehicle accident, who had previously undergone posterior laminectomy from C3 through C7. A retrospective chart analysis and a thorough radiographic review were performed. X-rays and CT of the cervical spine demonstrated a complete dislocation at the C2–C3 level. Computed tomographic angiography revealed disruption of both vertebral arteries; however, blood flow was evident in the basilar artery. After radiologically guided placement in cervical traction with tongs that reduced the subluxation by approximately 50% the patient had spontaneous eye opening and was able to follow commands. A two-stage 360(o) stabilization and fusion was performed and the patient was finally discharged 24 days after admission with his neurological status essentially unchanged. In conclusion, our patient presented with surprisingly mild neurological symptoms. The previously performed laminectomy could have both predisposed to injury as well as protected his spinal cord from potentially fatal trauma

    A Novel and Lethal De Novo LQT-3 Mutation in a Newborn with Distinct Molecular Pharmacology and Therapeutic Response

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    SCN5A encodes the alpha-subunit (Na(v)1.5) of the principle Na(+) channel in the human heart. Genetic lesions in SCN5A can cause congenital long QT syndrome (LQTS) variant 3 (LQT-3) in adults by disrupting inactivation of the Na(v)1.5 channel. Pharmacological targeting of mutation-altered Na(+) channels has proven promising in developing a gene-specific therapeutic strategy to manage specifically this LQTS variant. SCN5A mutations that cause similar channel dysfunction may also contribute to sudden infant death syndrome (SIDS) and other arrhythmias in newborns, but the prevalence, impact, and therapeutic management of SCN5A mutations may be distinct in infants compared with adults.Here, in a multidisciplinary approach, we report a de novo SCN5A mutation (F1473C) discovered in a newborn presenting with extreme QT prolongation and differential responses to the Na(+) channel blockers flecainide and mexiletine. Our goal was to determine the Na(+) channel phenotype caused by this severe mutation and to determine whether distinct effects of different Na(+) channel blockers on mutant channel activity provide a mechanistic understanding of the distinct therapeutic responsiveness of the mutation carrier. Sequence analysis of the proband revealed the novel missense SCN5A mutation (F1473C) and a common variant in KCNH2 (K897T). Patch clamp analysis of HEK 293 cells transiently transfected with wild-type or mutant Na(+) channels revealed significant changes in channel biophysics, all contributing to the proband's phenotype as predicted by in silico modeling. Furthermore, subtle differences in drug action were detected in correcting mutant channel activity that, together with both the known genetic background and age of the patient, contribute to the distinct therapeutic responses observed clinically.The results of our study provide further evidence of the grave vulnerability of newborns to Na(+) channel defects and suggest that both genetic background and age are particularly important in developing a mutation-specific therapeutic personalized approach to manage disorders in the young

    Is the impact of hospital performance data greater in patients who have compared hospitals?

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    <p>Abstract</p> <p>Background</p> <p>Public information on average has limited impact on patients' hospital choice. However, the impact may be greater in consumers who have compared hospitals prior to their hospital choice. We therefore assessed whether patients who have compared hospitals based their hospital choice mainly on public information, rather than e.g. advice of their general practitioner and consider other information important than patients who have not compared hospitals.</p> <p>Methods</p> <p>337 new surgical patients completed an internet-based questionnaire. They were asked whether they had compared hospitals prior to their hospital choice and which factors influenced their choice. They were also asked to select between four and ten items of hospital information (total: 41 items) relevant for their future hospital choice. These were subsequently used in a hospital choice experiment in which participants were asked to compare hospitals in an Adaptive Choice-Based Conjoint analysis to estimate which of the hospital characteristics had the highest Relative Importance (RI).</p> <p>Results</p> <p>Patients who have compared hospitals more often used public information for their hospital choice than patients who have not compared hospitals (12.7% vs. 1.5%, p < 0.001). However, they still mostly relied on their own (47.9%) and other people's experiences (31%) rather than to base their decision on public information. Both groups valued physician's expertise (RI 20.2 [16.6-24.8] in patients comparing hospitals vs. 16.5 [14.2-18.8] in patients not comparing hospitals) and waiting time (RI 15.1 [10.7-19.6] vs. 15.6 [13.2-17.9] respectively) as most important public information. Patients who have compared hospitals assigned greater importance to information on wound infections (p = 0.010) and respect for patients (p = 0.022), but lower importance to hospital distance (p = 0.041).</p> <p>Conclusion</p> <p>Public information has limited impact on patient's hospital choice, even in patients who have actually compared hospitals prior to hospital choice.</p
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