Validation of less-invasive hemodynamic monitoring with Pulsioflex in critically ill patients

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Varicella-zoster virus infections in immunocompromised patients - a single centre 6-years analysis

Background: Infection with varicella-zoster virus (VZV) contemporaneously with malignant disease or immunosuppression represents a particular challenge and requires individualized decisions and treatment. Although the increasing use of varicella-vaccines in the general population and rapid initiation of VZVimmunoglobulins and acyclovir in case of exposure has been beneficial for some patients, immunocompromised individuals are still at risk for unfavourable courses. Methods: In this single center, 6-year analysis we review incidence, hospitalization and complication rates of VZVinfections in our center and compare them to published data. Furthermore, we report three instructive cases. Results: Hospitalization rate of referred children with VZV-infections was 45%, among these 17% with malignancies and 9% under immunosuppressive therapy. Rate of complications was not elevated in these two high-risk cohorts, but one ALL-patient died due to VZV-related complications. We report one 4-year old boy with initial diagnosis of acute lymphoblastic leukemia who showed a rapidly fatal outcome of his simultaneous varicella-infection, one 1.8-year old boy with an identical situation but a mild course of his disease, and an 8.5-year old boy with a steroiddependent nephrotic syndrome. This boy developed severe hepatic involvement during his varicella-infection but responded to immediate withdrawl of steroids and administration of acyclovir plus single-dose cidofovir after nonresponse to acyclovir after 48 h. Conclusion: Our data show that patients with malignant diseases or immunosuppressive therapy should be hospitalized and treated immediately with antiviral agents. Despite these measures the course of VZV-infections can be highly variable in these patients. We discuss aids to individual decision-making for these difficult situations

Peaks and Troughs of Three-Dimensional Vestibulo-ocular Reflex in Humans

The three-dimensional vestibulo-ocular reflex (3D VOR) ideally generates compensatory ocular rotations not only with a magnitude equal and opposite to the head rotation but also about an axis that is collinear with the head rotation axis. Vestibulo-ocular responses only partially fulfill this ideal behavior. Because animal studies have shown that vestibular stimulation about particular axes may lead to suboptimal compensatory responses, we investigated in healthy subjects the peaks and troughs in 3D VOR stabilization in terms of gain and alignment of the 3D vestibulo-ocular response. Six healthy upright sitting subjects underwent whole body small amplitude sinusoidal and constant acceleration transients delivered by a six-degree-of-freedom motion platform. Subjects were oscillated about the vertical axis and about axes in the horizontal plane varying between roll and pitch at increments of 22.5° in azimuth. Transients were delivered in yaw, roll, and pitch and in the vertical canal planes. Eye movements were recorded in with 3D search coils. Eye coil signals were converted to rotation vectors, from which we calculated gain and misalignment. During horizontal axis stimulation, systematic deviations were found. In the light, misalignment of the 3D VOR had a maximum misalignment at about 45°. These deviations in misalignment can be explained by vector summation of the eye rotation components with a low gain for torsion and high gain for vertical. In the dark and in response to transients, gain of all components had lower values. Misalignment in darkness and for transients had different peaks and troughs than in the light: its minimum was during pitch axis stimulation and its maximum during roll axis stimulation. We show that the relatively large misalignment for roll in darkness is due to a horizontal eye movement component that is only present in darkness. In combination with the relatively low torsion gain, this horizontal component has a relative large effect on the alignment of the eye rotation axis with respect to the head rotation axis

The additional value of TGFβ1 and IL-7 to predict the course of prostate cancer progression

Background: Given the fact that prostate cancer incidence will increase in the coming years, new prognostic biomarkers are needed with regard to the biological aggressiveness of the prostate cancer diagnosed. Since cytokines have been associated with the biology of cancer and its prognosis, we determined whether transforming growth factor beta 1 (TGFβ1), interleukin-7 (IL-7) receptor and IL-7 levels add additional prognostic information with regard to prostate cancer

Fusion transcripts and their genomic breakpoints in polyadenylated and ribosomal RNA-minus RNA sequencing data

BACKGROUND: Fusion genes are typically identified by RNA sequencing (RNA-seq) without elucidating the causal genomic breakpoints. However, non–poly(A)-enriched RNA-seq contains large proportions of intronic reads that also span genomic breakpoints. RESULTS: We have developed an algorithm, Dr. Disco, that searches for fusion transcripts by taking an entire reference genome into account as search space. This includes exons but also introns, intergenic regions, and sequences that do not meet splice junction motifs. Using 1,275 RNA-seq samples, we investigated to what extent genomic breakpoints can be extracted from RNA-seq data and their implications regarding poly(A)-enriched and ribosomal RNA–minus RNA-seq data. Comparison with whole-genome sequencing data revealed that most genomic breakpoints are not, or minimally, transcribed while, in contrast, the genomic breakpoints of all 32 TMPRSS2-ERG–positive tumours were present at RNA level. We also revealed tumours in which the ERG breakpoint was located before ERG, which co-existed with additional deletions and messenger RNA that incorporated intergenic cryptic exons. In breast cancer we identified rearrangement hot spots near CCND1 and in glioma near CDK4 and MDM2 and could directly associate this with increased expression. Furthermore, in all datasets we find fusions to intergenic regions, often spanning multiple cryptic exons that potentially encode neo-antigens. Thus, fusion transcripts other than classical gene-to-gene fusions are prominently present and can be identified using RNA-seq. CONCLUSION: By using the full potential of non–poly(A)-enriched RNA-seq data, sophisticated analysis can reliably identify expressed genomic breakpoints and their transcriptional effects

Modulation of Androgen Receptor Signaling in Hormonal Therapy-Resistant Prostate Cancer Cell Lines

Background: Prostate epithelial cells depend on androgens for survival and function. In (early) prostate cancer (PCa) androgens also regulate tumor growth, which is exploited by hormonal therapies in metastatic disease. The aim of the present study was to characterize the androgen receptor (AR) response in hormonal therapy-resistant PC346 cells and identify potential disease markers. Methodology/Principal Findings: Human 19K oligoarrays were used to establish the androgen-regulated expression profile of androgen-responsive PC346C cells and its derivative therapy-resistant sublines: PC346DCC (vestigial AR levels), PC346Flu1 (AR overexpression) and PC346Flu2 (T877A AR mutation). In total, 107 transcripts were differentially-expressed in PC346C and derivatives after R1881 or hydroxyflutamide stimulations. The AR-regulated expression profiles reflected the AR modifications of respective therapy-resistant sublines: AR overexpression resulted in stronger and broader transcriptional response to R1881 stimulation, AR down-regulation correlated with deficient response of AR-target genes and the T877A mutation resulted in transcriptional response to both R1881 and hydroxyflutamide. This AR-target signature was linked to multiple publicly available cell line and tumor derived PCa databases, revealing that distinct functional clusters were differentially modulated during PCa progression. Differentiation and secretory functions were up-regulated in primary PCa but repressed i