Neuroinflammation and structural injury of the fetal ovine brain following intra-amniotic Candida albicans exposure.

BackgroundIntra-amniotic Candida albicans (C. Albicans) infection is associated with preterm birth and high morbidity and mortality rates. Survivors are prone to adverse neurodevelopmental outcomes. The mechanisms leading to these adverse neonatal brain outcomes remain largely unknown. To better understand the mechanisms underlying C. albicans-induced fetal brain injury, we studied immunological responses and structural changes of the fetal brain in a well-established translational ovine model of intra-amniotic C. albicans infection. In addition, we tested whether these potential adverse outcomes of the fetal brain were improved in utero by antifungal treatment with fluconazole.MethodsPregnant ewes received an intra-amniotic injection of 10(7) colony-forming units C. albicans or saline (controls) at 3 or 5 days before preterm delivery at 0.8 of gestation (term ~ 150 days). Fetal intra-amniotic/intra-peritoneal injections of fluconazole or saline (controls) were administered 2 days after C. albicans exposure. Post mortem analyses for fungal burden, peripheral immune activation, neuroinflammation, and white matter/neuronal injury were performed to determine the effects of intra-amniotic C. albicans and fluconazole treatment.ResultsIntra-amniotic exposure to C. albicans caused a severe systemic inflammatory response, illustrated by a robust increase of plasma interleukin-6 concentrations. Cerebrospinal fluid cultures were positive for C. albicans in the majority of the 3-day C. albicans-exposed animals whereas no positive cultures were present in the 5-day C. albicans-exposed and fluconazole-treated animals. Although C. albicans was not detected in the brain parenchyma, a neuroinflammatory response in the hippocampus and white matter was seen which was characterized by increased microglial and astrocyte activation. These neuroinflammatory changes were accompanied by structural white matter injury. Intra-amniotic fluconazole reduced fetal mortality but did not attenuate neuroinflammation and white matter injury.ConclusionsIntra-amniotic C. albicans exposure provoked acute systemic and neuroinflammatory responses with concomitant white matter injury. Fluconazole treatment prevented systemic inflammation without attenuating cerebral inflammation and injury

Brain tumour diagnostics using a DNA methylation-based classifier as a diagnostic support tool

Aims: Methylation profiling (MP) is increasingly incorporated in the diagnostic process of central nervous system (CNS) tumours at our centres in The Netherlands and Scandinavia. We aimed to identify the benefits and challenges of MP as a support tool for CNS tumour diagnostics. Methods: About 502 CNS tumour samples were analysed using (850 k) MP. Profiles were matched with the DKFZ/Heidelberg CNS Tumour Classifier. For each case, the final pathological diagnosis was compared to the diagnosis before MP. Results: In 54.4% (273/502) of all analysed cases, the suggested methylation class (calibrated score ≥0.9) corresponded with the initial pathological diagnosis. The diagnosis of 24.5% of these cases (67/273) was more refined after incorporation of the MP result. In 9.8% of cases (49/502), the MP result led to a new diagnosis, resulting in an altered WHO grade in 71.4% of these cases (35/49). In 1% of cases (5/502), the suggested class based on MP was initially disregarded/interpreted as misleading, but in retrospect, the MP result predicted the right diagnosis for three of these cases. In six cases, the suggested class was interpreted as ‘discrepant but noncontributory’. The remaining 33.7% of cases (169/502) had a calibrated score <0.9, including 7.8% (39/502) for which no class indication was given at all (calibrated score <0.3). Conclusions: MP is a powerful tool to confirm and fine-tune the pathological diagnosis of CNS tumours, and to avoid misdiagnoses. However, it is crucial to interpret the results in the context of clinical, radiological, histopathological and other molecular information

Activating mutations of the GNAQ gene: a frequent event in primary melanocytic neoplasms of the central nervous system

Primary melanocytic neoplasms of the central nervous system (CNS) are uncommon neoplasms derived from melanocytes that normally can be found in the leptomeninges. They cover a spectrum of malignancy grades ranging from low-grade melanocytomas to lesions of intermediate malignancy and overtly malignant melanomas. Characteristic genetic alterations in this group of neoplasms have not yet been identified. Using direct sequencing, we investigated 19 primary melanocytic lesions of the CNS (12 melanocytomas, 3 intermediate-grade melanocytomas, and 4 melanomas) for hotspot oncogenic mutations commonly found in melanocytic tumors of the skin (BRAF, NRAS, and HRAS genes) and uvea (GNAQ gene). Somatic mutations in the GNAQ gene at codon 209, resulting in constitutive activation of GNAQ, were detected in 7/19 (37%) tumors, including 6/12 melanocytomas, 0/3 intermediate-grade melanocytomas, and 1/4 melanomas. These GNAQ-mutated tumors were predominantly located around the spinal cord (6/7). One melanoma carried a BRAF point mutation that is frequently found in cutaneous melanomas (c.1799 T>A, p.V600E), raising the question whether this is a metastatic rather than a primary tumor. No HRAS or NRAS mutations were detected. We conclude that somatic mutations in the GNAQ gene at codon 209 are a frequent event in primary melanocytic neoplasms of the CNS. This finding provides new insight in the pathogenesis of these lesions and suggests that GNAQ-dependent mitogen-activated kinase signaling is a promising therapeutic target in these tumors. The prognostic and predictive value of GNAQ mutations in primary melanocytic lesions of the CNS needs to be determined in future studies

Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease

Accumulation of autophagosomes because of impaired autophagy during valosin-containing protein (VCP)–linked dementia is explained by the absence or reduced activity of VCP

Protocol analysis modulo combination of theories: A case study in Maude-NPA

There is a growing interest in formal methods and tools to analyze cryptographic protocols modulo algebraic properties of their underlying cryptographic functions. It is well-known that an intruder who uses algebraic equivalences of such functions can mount attacks that would be impossible if the cryptographic functions did not satisfy such equivalences. In practice, however, protocols use a collection of well-known functions, whose algebraic properties can naturally be grouped together as a union of theories E 1... ¿ n. Reasoning symbolically modulo the algebraic properties E 1... ¿ n requires performing (E 1... ¿ n)-unification. However, even if a unification algorithm for each individual E i is available, this requires combining the existing algorithms by methods that are highly non-deterministic and have high computational cost. In this work we present an alternative method to obtain unification algorithms for combined theories based on variant narrowing. Although variant narrowing is less efficient at the level of a single theory E i, it does not use any costly combination method. Furthermore, it does not require that each E i has a dedicated unification algorithm in a tool implementation. We illustrate the use of this method in the Maude-NPA tool by means of a well-known protocol requiring the combination of three distinct equational theories. © 2011 Springer-Verlag.R. Sasse and J. Meseguer have been partially supported by NSF Grants CNS0716638, CNS-0831064 and CNS-0904749. S. Escobar has been partially supported by the EU (FEDER) and the Spanish MEC/MICINN under grant TIN 2007-68093- C02-02. C. Meadows has been partially supported by NSF Grant CNS-0904749National Science Foundation, EEUUSasse, R.; Escobar Román, S.; Meadows, C.; Meseguer, J. (2011). Protocol analysis modulo combination of theories: A case study in Maude-NPA. En Security and Trust Management. Springer Verlag (Germany). 6710:163-178. doi:10.1007/978-3-642-22444-7_11S1631786710Abadi, M., Cortier, V.: Deciding knowledge in security protocols under equational theories. Theoretical Computer Science 367(1-2), 2–32 (2006)Armando, A., Basin, D.A., Boichut, Y., Chevalier, Y., Compagna, L., Cuéllar, J., Drielsma, P.H., Héam, P.-C., Kouchnarenko, O., Mantovani, J., Mödersheim, S., von Oheimb, D., Rusinowitch, M., Santiago, J., Turuani, M., Viganò, L., Vigneron, L.: The avispa tool for the automated validation of internet security protocols and applications. In: Etessami, K., Rajamani, S.K. (eds.) CAV 2005. LNCS, vol. 3576, pp. 281–285. Springer, Heidelberg (2005)Baader, F., Schulz, K.U.: Unification in the union of disjoint equational theories: Combining decision procedures. In: Kapur, D. (ed.) CADE 1992. LNCS, vol. 607, pp. 50–65. Springer, Heidelberg (1992)Basin, D.A., Mödersheim, S., Viganò, L.: An on-the-fly model-checker for security protocol analysis. In: Snekkenes, E., Gollmann, D. (eds.) ESORICS 2003. LNCS, vol. 2808, pp. 253–270. Springer, Heidelberg (2003)Baudet, M., Cortier, V., Delaune, S.: YAPA: A generic tool for computing intruder knowledge. In: Treinen, R. (ed.) RTA 2009. LNCS, vol. 5595, pp. 148–163. Springer, Heidelberg (2009)Blanchet, B.: An efficient cryptographic protocol verifier based on prolog rules. In: CSFW, pp. 82–96. IEEE Computer Society, Los Alamitos (2001)Bursuc, S., Comon-Lundh, H.: Protocol security and algebraic properties: Decision results for a bounded number of sessions. In: Treinen, R. (ed.) RTA 2009. LNCS, vol. 5595, pp. 133–147. Springer, Heidelberg (2009)Chevalier, Y., Küsters, R., Rusinowitch, M., Turuani, M.: An NP decision procedure for protocol insecurity with XOR. In: LICS, pp. 261–270. IEEE Computer Society, Los Alamitos (2003)Chevalier, Y., Rusinowitch, M.: Hierarchical combination of intruder theories. Inf. Comput. 206(2-4), 352–377 (2008)Chevalier, Y., Rusinowitch, M.: Symbolic protocol analysis in the union of disjoint intruder theories: Combining decision procedures. Theor. Comput. Sci. 411(10), 1261–1282 (2010)Ciobâcă, Ş., Delaune, S., Kremer, S.: Computing knowledge in security protocols under convergent equational theories. In: Schmidt, R.A. (ed.) CADE-22. LNCS, vol. 5663, pp. 355–370. Springer, Heidelberg (2009)Comon-Lundh, H., Delaune, S.: The finite variant property: How to get rid of some algebraic properties. In: Giesl, J. (ed.) RTA 2005. LNCS, vol. 3467, pp. 294–307. Springer, Heidelberg (2005)Cortier, V., Delaitre, J., Delaune, S.: Safely composing security protocols. In: Arvind, V., Prasad, S. (eds.) FSTTCS 2007. LNCS, vol. 4855, pp. 352–363. Springer, Heidelberg (2007)Cremers, C.J.F.: The scyther tool: Verification, falsification, and analysis of security protocols. In: Gupta, A., Malik, S. (eds.) CAV 2008. LNCS, vol. 5123, pp. 414–418. Springer, Heidelberg (2008)Escobar, S., Meadows, C., Meseguer, J.: A rewriting-based inference system for the NRL protocol analyzer and its meta-logical properties. Theoretical Computer Science 367(1-2), 162–202 (2006)Escobar, S., Meadows, C., Meseguer, J.: Maude-NPA: Cryptographic protocol analysis modulo equational properties. In: Aldini, A., Barthe, G., Gorrieri, R. (eds.) FOSAD 2007/2008/2009 Tutorial Lectures. LNCS, vol. 5705, pp. 1–50. Springer, Heidelberg (2009)Escobar, S., Meseguer, J., Sasse, R.: Effectively checking or disproving the finite variant property. Technical Report UIUCDCS-R-2008-2960, Department of Computer Science - University of Illinois at Urbana-Champaign (April 2008)Escobar, S., Meseguer, J., Sasse, R.: Effectively checking the finite variant property. In: Voronkov, A. (ed.) RTA 2008. LNCS, vol. 5117, pp. 79–93. Springer, Heidelberg (2008)Escobar, S., Meseguer, J., Sasse, R.: Variant narrowing and equational unification. Electr. Notes Theor. Comput. Sci. 238(3), 103–119 (2009)Escobar, S., Sasse, R., Meseguer, J.: Folding variant narrowing and optimal variant termination. In: Ölveczky, P.C. (ed.) WRLA 2010. LNCS, vol. 6381, pp. 52–68. Springer, Heidelberg (2010)Fabrega, F.J.T., Herzog, J., Guttman, J.: Strand Spaces: What Makes a Security Protocol Correct? Journal of Computer Security 7, 191–230 (1999)Guo, Q., Narendran, P.: Unification and matching modulo nilpotence. In: CADE-13. LNCS, vol. 1104, pp. 261–274. Springer, Heidelberg (1996)Harkins, D., Carrel, D.: The Internet Key Exchange (IKE), IETF RFC 2409, (November 1998)Jouannaud, J.-P., Kirchner, C., Kirchner, H.: Incremental construction of unification algorithms in equational theories. In: Díaz, J. (ed.) ICALP 1983. LNCS, vol. 154, pp. 361–373. Springer, Heidelberg (1983)Küsters, R., Truderung, T.: Reducing protocol analysis with xor to the xor-free case in the Horn theory based approach. 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LNCS, vol. 1376, pp. 18–61. Springer, Heidelberg (1998)Meseguer, J., Thati, P.: Symbolic reachability analysis using narrowing and its application to verification of cryptographic protocols. Higher-Order and Symbolic Computation 20(1–2), 123–160 (2007)Ohlebusch, E.: Advanced Topics in Term Rewriting. Springer, Heidelberg (2002)Santiago, S., Talcott, C.L., Escobar, S., Meadows, C., Meseguer, J.: A graphical user interface for Maude-NPA. Electr. Notes Theor. Comput. Sci. 258(1), 3–20 (2009)Schmidt-Schauß, M.: Unification in a combination of arbitrary disjoint equational theories. J. Symb. Comput. 8(1/2), 51–99 (1989)Terese (ed.): Term Rewriting Systems. Cambridge University Press, Cambridge (2003)Turuani, M.: The CL-atse protocol analyser. In: Pfenning, F. (ed.) RTA 2006. LNCS, vol. 4098, pp. 277–286. Springer, Heidelberg (2006

Insulin Glargine in the Intensive Care Unit: A Model-Based Clinical Trial Design

Online 4 Oct 2012Introduction: Current succesful AGC (Accurate Glycemic Control) protocols require extra clinical effort and are impractical in less acute wards where patients are still susceptible to stress-induced hyperglycemia. Long-acting insulin Glargine has the potential to be used in a low effort controller. However, potential variability in efficacy and length of action, prevent direct in-hospital use in an AGC framework for less acute wards. Method: Clinically validated virtual trials based on data from stable ICU patients from the SPRINT cohort who would be transferred to such an approach are used to develop a 24-hour AGC protocol robust to different Glargine potencies (1.0x, 1.5x and 2.0x regular insulin) and initial dose sizes (dose = total insulin over prior 12, 18 and 24 hours). Glycemic control in this period is provided only by varying nutritional inputs. Performance is assessed as %BG in the 4.0-8.0mmol/L band and safety by %BG<4.0mmol/L. Results: The final protocol consisted of Glargine bolus size equal to insulin over the previous 18 hours. Compared to SPRINT there was a 6.9% - 9.5% absolute decrease in mild hypoglycemia (%BG<4.0mmol/L) and up to a 6.2% increase in %BG between 4.0 and 8.0mmol/L. When the efficacy is known (1.5x assumed) there were reductions of: 27% BG measurements, 59% insulin boluses, 67% nutrition changes, and 6.3% absolute in mild hypoglycemia. Conclusion: A robust 24-48 clinical trial has been designed to safely investigate the efficacy and kinetics of Glargine as a first step towards developing a Glargine-based protocol for less acute wards. Ensuring robustness to variability in Glargine efficacy significantly affects the performance and safety that can be obtained

SCALA: In situ calibration for integral field spectrographs

International audienceThe scientific yield of current and future optical surveys is increasingly limited by systematic uncertainties in the flux calibration. This is the case for Type Ia supernova (SN Ia) cosmology programs, where an improved calibration directly translates into improved cosmological constraints. Current methodology rests on models of stars. Here we aim to obtain flux calibration that is traceable to state-of-the-art detector-based calibration. We present the SNIFS Calibration Apparatus (SCALA), a color (relative) flux calibration system developed for the SuperNova Integral Field Spectrograph (SNIFS), operating at the University of Hawaii 2.2 m (UH 88) telescope. By comparing the color trend of the illumination generated by SCALA during two commissioning runs, and to previous laboratory measurements, we show that we can determine the light emitted by SCALA with a long-term repeatability better than 1%. We describe the calibration procedure necessary to control for system aging. We present measurements of the SNIFS throughput as estimated by SCALA observations. The SCALA calibration unit is now fully deployed at the UH\,88 telescope, and with it color-calibration between 4000 {\AA} and 9000 {\AA} is stable at the percent level over a one-year baseline

Integrin α7 Mutations Are Associated With Adult-Onset Cardiac Dysfunction in Humans and Mice.

Background Integrin α7β1 is a major laminin receptor in skeletal and cardiac muscle. In skeletal muscle, integrin α7β1 plays an important role during muscle development and has been described as an important modifier of skeletal muscle diseases. The integrin α7β1 is also highly expressed in the heart, but its precise role in cardiac function is unknown. Mutations in the integrin α7 gene (ITGA7) have been reported in children with congenital myopathy. Methods and Results In this study, we described skeletal and cardiac muscle pathology in Itga7-/- mice and 5 patients from 2 unrelated families with ITGA7 mutations. Proband in family 1 presented a homozygous c.806_818del [p.S269fs] variant, and proband in family 2 was identified with 2 intron variants in the ITGA7 gene. The complete absence of the integrin α7 protein in muscle supports the ITGA7 mutations are pathogenic. We performed electrocardiography, echocardiography, or cardiac magnetic resonance imaging, and histological biopsy analyses in patients with ITGA7 deficiency and Itga7-/- mice. The patients exhibited cardiac dysrhythmia and dysfunction from the third decade of life and late-onset respiratory insufficiency, but with relatively mild limb muscle involvement. Mice demonstrated corresponding abnormalities in cardiac conduction and contraction as well as diaphragm muscle fibrosis. Conclusions Our data suggest that loss of integrin α7 causes a novel form of adult-onset cardiac dysfunction indicating a critical role for the integrin α7β1 in normal cardiac function and highlights the need for long-term cardiac monitoring in patients with ITGA7-related congenital myopathy

The amount of preoperative endometrial tissue surface in relation to final endometrial cancer classification

OBJECTIVETo evaluate whether the amount of preoperative endometrial tissue surface is related to the degree of concordance with final low- and high-grade endometrial cancer (EC). In addition, to determine whether discordance is influenced by sampling method and impacts outcome.METHODSA retrospective cohort study within the European Network for Individualized Treatment of Endometrial Cancer (ENITEC). Surface of preoperative endometrial tissue samples was digitally calculated using ImageJ. Tumor samples were classified into low-grade (grade 1-2 endometrioid EC (EEC)) and high-grade (grade 3 EEC + non-endometroid EC).RESULTSThe study cohort included 573 tumor samples. Overall concordance between pre- and postoperative diagnosis was 60.0%, and 88.8% when classified into low- and high-grade EC. Upgrading (preoperative low-grade, postoperative high-grade EC) was found in 7.8% and downgrading (preoperative high-grade, postoperative low-grade EC) in 26.7%. The median endometrial tissue surface was significantly lower in concordant diagnoses when compared to discordant diagnoses, respectively 18.7 mm2 and 23.5 mm2 (P = 0.022). Sampling method did not influence the concordance in tumor classification. Patients with preoperative high-grade and postoperative low-grade showed significant lower DSS compared to patients with concordant low-grade EC (P = 0.039).CONCLUSIONThe amount of preoperative endometrial tissue surface was inversely related to the degree of concordance with final tumor low- and high-grade. Obtaining higher amount of preoperative endometrial tissue surface does not increase the concordance between pre- and postoperative low- and high-grade diagnosis in EC. Awareness of clinically relevant down- and upgrading is crucial to reduce subsequent over- or undertreatment with impact on outcome.</p