CEREBROVASCULAR CARBON DIOXIDE REACTIVITY DURING EXPOSURE TO EQUIPOTENT ISOFLURANE AND ISOFLURANE IN NITROUS OXIDE ANAESTHESIA

We have studied the effects of hypocapnia on cerebrovascular changes in two MAC-equivalent anaesthetic regimens, using the transcranial Doppler technique as an index of cerebral blood flow (CBF) in 24healthy ASA I patients undergoing spinal surgery. Eight of the patients were subjected to carbon dioxide reactivity challenges in the awake state. Before surgery, the other 16 patients received, in random order, either 1.15% isoflurane in oxygen or 0.5% isoflurane with 70% nitrous oxide. Carbon dioxide reactivity was calculated for each group as the increase in flow velocity per kPa change in PÉCO2 (cm s−1 kPa−1). It was significantly greater for the isoflurane group (14.09 (SD 2.44) cm s−1 kPa−1) and significantly less for the isoflurane—nitrous oxide group (7.95 (1.32) cm s-−1 kPa−1) compared with the awake group (11.24 (0.95) cm s−1 kPa−1). We conclude that cerebrovascular responsiveness to changes in arterial carbon dioxide concentration is influenced markedly by the anaesthetic procedure. Hyperventilation is more likely to affect CBF during isoflurane anaesthesia than during an MAC-equivalent isoflurane—nitrous oxide anaesthesi

Pencil beam characteristics of the next-generation proton scanning gantry of PSI: design issues and initial commissioning results

In this paper we report on the main design features, on the realization process and on selected first results of the initial commissioning of the new Gantry 2 of PSI for the delivery of proton therapy with new advanced pencil beam scanning techniques. We present briefly the characteristics of the new gantry system with main emphasis on the beam optics, on the characterization of the pencil beam used for scanning and on the performance of the scanning system. The idea is to give an overview of the major components of the whole system. The main long-term technical goal of the new equipment of Gantry 2 is to expand the use of pencil beam scanning to the whole spectrum of clinical indications including moving targets. We report here on the initial experience and problems encountered in the development of the system with selected preliminary results of the ongoing commissioning of Gantry

Structural dissimilarity of large-scale structures in turbulent flows over wavy walls

Turbulent flows over a wavy wall are investigated in channels with a wavy bottom and a flat top with different channel heights. Flow structures are determined from proper orthogonal decompositions of velocity fields measured with particle image velocimetry. Three different channel heights are considered, which are characterized by blockage ratios β (half channel height to wave amplitude ratio) 3.3, 6.7, and 10. Measurements are evaluated at comparable Reynolds numbers (Re) around 10 000. Structural similarity of large-scale structures, which is valid at β = 6.7 and 10, no longer holds at β = 3.3. Furthermore, characteristic regions of flows over wavy walls exhibit different locations in the case of the smallest channel height

Impact of loss of high-molecular-weight von Willebrand factor multimers on blood loss after aortic valve replacement

Background Severe aortic stenosis is associated with loss of the largest von Willebrand factor (vWF) multimers, which could affect primary haemostasis. We hypothesized that the altered multimer structure with the loss of the largest multimers increases postoperative bleeding in patients undergoing aortic valve replacement. Methods We prospectively included 60 subjects with severe aortic stenosis. Before and after aortic valve replacement, vWF antigen, activity, and multimer structure were determined and platelet function was measured by impedance aggregometry. Blood loss from mediastinal drainage and the use of blood and haemostatic products were evaluated perioperatively. Results Before operation, the altered multimer structure was present in 48 subjects (80%). Baseline characteristics and laboratory data were similar in all subjects. The median blood loss after 6 h was 250 (105-400) and 145 (85-240) ml in the groups with the altered and normal multimer structures, respectively (P=0.182). After 24 h, the cumulative loss was 495 (270-650) and 375 (310-600) ml in the groups with the altered and normal multimer structures, respectively (P=0.713). Multivariable analysis revealed no significant influence of multimer structure and platelet function on bleeding volumes after 6 and 24 h. After 24 h, there was no obvious difference in vWF antigen, activity, and multimer structure in subjects with and without the altered multimer structure before operation or in subjects with and without perioperative plasma transfusion. Conclusions The altered vWF multimer structure before operation was not associated with increased bleeding after aortic valve replacement. Our findings might be explained by perioperative release of vWF and rapid recovery of the largest vWF multimer

Telomerase activity in human leukemic cells with or without monosomy 7 or 7q-

BACKGROUND: In bone marrow material from patients with various leukemias we noted that samples with either a deletion on the long arm of one chromosome 7 (7q-) or a monosomy 7 had a higher telomerase activity. Considering that introduction of a chromosome 7 into a cancer cell line had been reported to eliminate telomerase activity, that 7q- is a common negative prognostic finding in cancers, and that the deleted segment (band 7q31) contains an unidentified tumor suppressor gene, we wondered if this gene might be a telomerase inhibitor. RESULTS: We found no significant difference in telomerase activity between the three groups of patient samples. In contrast to reports on tumor cell lines we observed no amplification of the telomerase genes. METHODS: We analyzed telomerase activity and copy number of the telomerase genes hTERT and hTR in frozen archival bone marrow samples from leukemia patients with a referral diagnosis of AML, and either a monosomy for chromosome 7, a deletion on the long arm of chromosome 7 (7q-), or none of these aberrations. Telomerase activity was measured with a commercially available kit, and the copy number of the telomerase genes was tested by FISH. CONCLUSIONS: We found no evidence of a telomerase inhibitor in band 7q31. The lack of telomerase gene amplification found in cell lines from solid tumors could reflect that this amplification is a property of solid tumors, not of hematological cancers

Differential expression of THOC1 and ALY mRNP biogenesis/export factors in human cancers

<p>Abstract</p> <p>Background</p> <p>One key step in gene expression is the biogenesis of mRNA ribonucleoparticle complexes (mRNPs). Formation of the mRNP requires the participation of a number of conserved factors such as the THO complex. THO interacts physically and functionally with the Sub2/UAP56 RNA-dependent ATPase, and the Yra1/REF1/ALY RNA-binding protein linking transcription, mRNA export and genome integrity. Given the link between genome instability and cancer, we have performed a comparative analysis of the expression patterns of THOC1, a THO complex subunit, and ALY in tumor samples.</p> <p>Methods</p> <p>The mRNA levels were measured by quantitative real-time PCR and hybridization of a tumor tissue cDNA array; and the protein levels and distribution by immunostaining of a custom tissue array containing a set of paraffin-embedded samples of different tumor and normal tissues followed by statistical analysis.</p> <p>Results</p> <p>We show that the expression of two mRNP factors, THOC1 and ALY are altered in several tumor tissues. THOC1 mRNA and protein levels are up-regulated in ovarian and lung tumors and down-regulated in those of testis and skin, whereas ALY is altered in a wide variety of tumors. In contrast to THOC1, ALY protein is highly detected in normal proliferative cells, but poorly in high-grade cancers.</p> <p>Conclusions</p> <p>These results suggest a differential connection between tumorogenesis and the expression levels of human THO and ALY. This study opens the possibility of defining mRNP biogenesis factors as putative players in cell proliferation that could contribute to tumor development.</p

Effect of promoter architecture on the cell-to-cell variability in gene expression

According to recent experimental evidence, the architecture of a promoter, defined as the number, strength and regulatory role of the operators that control the promoter, plays a major role in determining the level of cell-to-cell variability in gene expression. These quantitative experiments call for a corresponding modeling effort that addresses the question of how changes in promoter architecture affect noise in gene expression in a systematic rather than case-by-case fashion. In this article, we make such a systematic investigation, based on a simple microscopic model of gene regulation that incorporates stochastic effects. In particular, we show how operator strength and operator multiplicity affect this variability. We examine different modes of transcription factor binding to complex promoters (cooperative, independent, simultaneous) and how each of these affects the level of variability in transcription product from cell-to-cell. We propose that direct comparison between in vivo single-cell experiments and theoretical predictions for the moments of the probability distribution of mRNA number per cell can discriminate between different kinetic models of gene regulation.Comment: 35 pages, 6 figures, Submitte

A Distinct DNA Methylation Shift in a Subset of Glioma CpG Island Methylator Phenotypes during Tumor Recurrence

Glioma diagnosis is based on histomorphology and grading; however, such classification does not have predictive clinical outcome after glioblastomas have developed. To date, no bona fide biomarkers that significantly translate into a survival benefit to glioblastoma patients have been identified. We previously reported that the IDH mutant G-CIMP-high subtype would be a predecessor to the G-CIMP-low subtype. Here, we performed a comprehensive DNA methylation longitudinal analysis of diffuse gliomas from 77 patients (200 tumors) to enlighten the epigenome-based malignant transformation of initially lower-grade gliomas. Intra-subtype heterogeneity among G-CIMP-high primary tumors allowed us to identify predictive biomarkers for assessing the risk of malignant recurrence at early stages of disease. G-CIMP-low recurrence appeared in 9.5% of all gliomas, and these resembled IDH-wild-type primary glioblastoma. G-CIMP-low recurrence can be characterized by distinct epigenetic changes at candidate functional tissue enhancers with AP-1/SOX binding elements, mesenchymal stem cell-like epigenomic phenotype, and genomic instability. Molecular abnormalities of longitudinal G-CIMP offer possibilities to defy glioblastoma progression