A critical review of the molecular pathophysiology of lenalidomide sensitivity in 5q - myelodysplastic syndromes.

Abstract The 5q deletion is a chromosomal abnormality that is observed in a subset of myelodysplastic syndromes (MDS). When isolated, this abnormality defines a specific clinical syndrome termed MDS associated with isolated deletion 5q, presenting with macrocytic anemia, normal platelet count or slight thrombocytosis, hypolobated megakaryocytes and fewer than 5% blasts in the bone marrow. MDS with the 5q deletion have a particular sensitivity to treatment with lenalidomide, a thalidomide analog. In this article, molecular changes in 5q- MDS derived from haploinsufficiency of genes encoded from the deleted region in 5q are reviewed, and mechanisms that link these molecular lesions with lenalidomide sensitivity are proposed.

Lung microbiota promotes tolerance to allergens in neonates via PD-L1.

Epidemiological data point toward a critical period in early life during which environmental cues can set an individual on a trajectory toward respiratory health or disease. The neonatal immune system matures during this period, although little is known about the signals that lead to its maturation. Here we report that the formation of the lung microbiota is a key parameter in this process. Immediately following birth, neonatal mice were prone to develop exaggerated airway eosinophilia, release type 2 helper T cell cytokines and exhibit airway hyper-responsiveness following exposure to house dust mite allergens, even though their lungs harbored high numbers of natural CD4(+)Foxp3(+)CD25(+)Helios(+) regulatory T (Treg) cells. During the first 2 weeks after birth, the bacterial load in the lungs increased, and representation of the bacterial phyla shifts from a predominance of Gammaproteobacteria and Firmicutes towards Bacteroidetes. The changes in the microbiota were associated with decreased aeroallergen responsiveness and the emergence of a Helios(-) Treg cell subset that required interaction with programmed death ligand 1 (PD-L1) for development. Absence of microbial colonization(10) or blockade of PD-L1 during the first 2 weeks postpartum maintained exaggerated responsiveness to allergens through to adulthood. Adoptive transfer of Treg cells from adult mice to neonates before aeroallergen exposure ameliorated disease. Thus, formation of the airway microbiota induces regulatory cells early in life, which, when dysregulated, can lead to sustained susceptibility to allergic airway inflammation in adulthood.

Interactions between respiration and systemic hemodynamics. Part II: practical implications in critical care.

In Part I of this review, we have covered basic concepts regarding cardiorespiratory interactions. Here, we put this theoretical framework to practical use. We describe mechanisms underlying Kussmaul's sign and pulsus paradoxus. We review the literature on the use of respiratory variations of blood pressure to evaluate volume status. We show the possibilities of attaining the latter aim by investigating with ultrasonography how the geometry of great veins fluctuates with respiration. We provide a Guytonian analysis of the effects of PEEP on cardiac output. We terminate with some remarks on the potential of positive pressure breathing to induce acute cor pulmonale, and on the cardiovascular mechanisms that at times may underly the failure to wean a patient from the ventilator.

Hexyl Aminolevulinate-Guided Fluorescence Cystoscopy in the Diagnosis and Follow-up of Patients with Non-Muscle-invasive Bladder Cancer: A Critical Review of the Current Literature.

CONTEXT: Controversy exists regarding the therapeutic benefit and cost effectiveness of photodynamic diagnosis (PDD) with 5-aminolevulinic acid (5-ALA) or hexyl aminolevulinate (HAL) in addition to white-light cystoscopy (WLC) in the management of non-muscle-invasive bladder cancer (NMIBC). OBJECTIVE: To systematically evaluate evidence regarding the therapeutic benefits and economic considerations of PDD in NMIBC detection and treatment. EVIDENCE ACQUISITION: We performed a critical review of PubMed/Medline, Embase, and the Cochrane Library in October 2012 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Identified reports were reviewed according to the Consolidated Standards of Reporting Trials (CONSORT) and Standards for the Reporting of Diagnostic Accuracy Studies (STARD) criteria. Forty-four publications were selected for inclusion in this analysis. EVIDENCE SYNTHESIS: Included reports used 5-ALA (in 26 studies), HAL (15 studies), or both (three studies) as photosensitising agents. PDD increased the detection of both papillary tumours (by 7-29%) and flat carcinoma in situ (CIS; by 25-30%) and reduced the rate of residual tumours after transurethral resection of bladder tumour (TURBT; by an average of 20%) compared to WLC alone. Superior recurrence-free survival (RFS) rates and prolonged RFS intervals were reported for PDD, compared to WLC in most studies. PDD did not appear to reduce disease progression. Our findings are limited by tumour heterogeneity and a lack of NMIBC risk stratification in many reports or adjustment for intravesical therapy use in most studies. Although cost effectiveness has been demonstrated for 5-ALA, it has not been studied for HAL. CONCLUSIONS: Moderately strong evidence exists that PDD improves tumour detection and reduces residual disease after TURBT compared with WLC. This has been shown to improve RFS but not progression to more advanced disease. Further work to evaluate cost effectiveness of PDD is required.

Waveform inversion of crosshole georadar data: influence of source wavelet variability and the suitability of a single wavelet assumption

Waveform-based tomographic imaging of crosshole georadar data is a powerful method to investigate the shallow subsurface because of its ability to provide images of electrical properties in near-surface environments with unprecedented spatial resolution. A critical issue with waveform inversion is the a priori unknown source signal. Indeed, the estimation of the source pulse is notoriously difficult but essential for the effective application of this method. Here, we explore the viability and robustness of a recently proposed deconvolution-based procedure to estimate the source pulse during waveform inversion of crosshole georadar data, where changes in wavelet shape with location as a result of varying near-field conditions and differences in antenna coupling may be significant. Specifically, we examine whether a single, average estimated source current function can adequately represent the pulses radiated at all transmitter locations during a crosshole georadar survey, or whether a separate source wavelet estimation should be performed for each transmitter gather. Tests with synthetic and field data indicate that remarkably good tomographic reconstructions can be obtained using a single estimated source pulse when moderate to strong variability exists in the true source signal with antenna location. Only in the case of very strong variability in the true source pulse are tomographic reconstructions clearly improved by estimating a different source wavelet for each transmitter location.

Critical appraisal of single port access cholecystectomy.

BACKGROUND: Single port access (SPA) cholecystectomy is a new concept in laparoscopic surgery. A review of existing results was performed to evaluate critically the current state of SPA with specific reference to feasibility, safety, learning curve, indications and cost-effectiveness. METHODS: All papers identified in MEDLINE until 15 February 2010 and all other relevant papers obtained from cited references were reviewed, without any language restriction. Case reports and series of fewer than three patients were excluded. RESULTS: After selection, 24 studies including 895 patients were analysed. None was randomized. Feasibility seems to be established, with a conversion rate of 2 per cent. SPA was not standardized and there was much technical variation. The learning curve could not be determined. Median follow-up time was 3 (range 0.25-12) months. The overall published complication rate was 5.4 per cent and the biliary complication rate 0.7 per cent. The rate of umbilical complications ranged from 2 to 10 per cent. CONCLUSION: SPA cholecystectomy seems feasible, but standardization, safety and the real benefits for patients need further assessment. Uncontrolled wide adoption of this approach may be responsible for a rise in biliary complications.

The influence of drugs used in cardiac anaesthesia and critical care on multiple electrode aggregometry: an in-vitro volunteer study.

BACKGROUND: Multiple electrode aggregometry (MEA) is a point-of-care test evaluating platelet function and the efficacy of platelet inhibitors. In MEA, electrical impedance of whole blood is measured after addition of a platelet activator. Reduced impedance implies platelet dysfunction or the presence of platelet inhibitors. MEA plays an increasingly important role in the management of perioperative platelet dysfunction. In vitro, midazolam, propofol, lidocaine and magnesium have known antiplatelet effects and these may interfere with MEA interpretation. OBJECTIVE: To evaluate the extent to which MEA is modified in the presence of these drugs. DESIGN: An in-vitro study using blood collected from healthy volunteers. SETTING: Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, 2010 to 2011. PATIENTS: Twenty healthy volunteers. INTERVENTION: Measurement of baseline MEA was using four activators: arachidonic acid, ADP, TRAP-6 and collagen. The study drugs were then added in three increasing, clinically relevant concentrations. MAIN OUTCOME MEASURE: MEA was compared with baseline for each study drug. RESULTS: Midazolam, propofol and lidocaine showed no effect on MEA at any concentration. Magnesium at 2.5 mmol l had a significant effect on the ADP and TRAP tests (31 ± 13 and 96 ± 39 AU, versus 73 ± 21 and 133 ± 28 AU at baseline, respectively), and a less pronounced effect at 1 mmol l on the ADP test (39 ± 0 AU). CONCLUSION: Midazolam, propofol and lidocaine do not interfere with MEA measurement. In patients treated with high to normal doses of magnesium, MEA results for ADP and TRAP-tests should be interpreted with caution. TRIAL REGISTRATION: Clinicaltrials.gov (no. NCT01454427).

Brownian dynamics simulation of DNA condensation.

DNA condensation observed in vitro with the addition of polyvalent counterions is due to intermolecular attractive forces. We introduce a quantitative model of these forces in a Brownian dynamics simulation in addition to a standard mean-field Poisson-Boltzmann repulsion. The comparison of a theoretical value of the effective diameter calculated from the second virial coefficient in cylindrical geometry with some experimental results allows a quantitative evaluation of the one-parameter attractive potential. We show afterward that with a sufficient concentration of divalent salt (typically approximately 20 mM MgCl(2)), supercoiled DNA adopts a collapsed form where opposing segments of interwound regions present zones of lateral contact. However, under the same conditions the same plasmid without torsional stress does not collapse. The condensed molecules present coexisting open and collapsed plectonemic regions. Furthermore, simulations show that circular DNA in 50% methanol solutions with 20 mM MgCl(2) aggregates without the requirement of torsional energy. This confirms known experimental results. Finally, a simulated DNA molecule confined in a box of variable size also presents some local collapsed zones in 20 mM MgCl(2) above a critical concentration of the DNA. Conformational entropy reduction obtained either by supercoiling or by confinement seems thus to play a crucial role in all forms of condensation of DNA.

Comparison of C-reactive protein and white blood cell count with differential in neonates at risk for septicaemia.

We prospectively compared the diagnostic value of C-reactive protein (CRP) and white blood cell counts for detection of neonatal septicaemia. Sensitivity and specifity in receiver operating characteristics, and positive and negative predictive value of CRP and white blood cell count were compared in 195 critically ill preterm and term newborns clinically suspected of infection. Blood cultures were positive in 33 cases. During the first 3 days after birth CRP elevation (sensitivity 75%, specifity 86%), leukopenia (67%/90%), neutropenia (78%/80%) and immature to total neutrophil count (I/T) ratio (78%/73%) were good diagnostic parameters, as opposed to band forms with absolute count (84%/66%) or percentage (79%/71%), thrombocytopenia (65%/57%) and toxic granulations (44%/94%). Beyond 3 days of age elevated CRP (88%/87%) was the best parameter. Increased total (84%/66%) or percentage band count (79%/71%) were also useful. Leukocytosis (74%/56%), increased neutrophils (67%/65%), I/T ratio (79%/47%), thrombocytopenia (65%/57%) and toxic granulations had a low specifity. The positive predictive value of CRP was 32% before and 37% after 3 days of age, that of leukopenia was 37% in the first 3 days. CONCLUSION: During the first 3 days of life CRP, leukopenia and neutropenia were comparably good tests while after 3 days of life CRP was the best single test in early detection of neonatal septicaemia. Serial CRP estimations confirm the diagnosis, monitor the course of infection and the efficacy of antibiotic treatment.

An improved trap design for decoupling multinuclear RF coils.

PURPOSE: Multinuclear magnetic resonance spectroscopy and imaging require a radiofrequency probe capable of transmitting and receiving at the proton and non-proton frequencies. To minimize coupling between probe elements tuned to different frequencies, LC (inductor-capacitor) traps blocking current at the (1) H frequency can be inserted in non-proton elements. This work compares LC traps with LCC traps, a modified design incorporating an additional capacitor, enabling control of the trap reactance at the low frequency while maintaining (1) H blocking. METHODS: Losses introduced by both types of trap were analysed using circuit models. Radiofrequency coils incorporating a series of LC and LCC traps were then built and evaluated at the bench. LCC trap performance was then confirmed using (1) H and (13) C measurements in a 7T human scanner. RESULTS: LC and LCC traps both effectively block interaction between non-proton and proton coils at the proton frequency. LCC traps were found to introduce a sensitivity reduction of 5±2%, which was less than half of that caused by LC traps. CONCLUSION: Sensitivity of non-proton coils is critical. The improved trap design, incorporating one extra capacitor, significantly reduces losses introduced by the trap in the non-proton coil. Magn Reson Med 72:584-590, 2014. © 2013 Wiley Periodicals, Inc.

Mutational and computational analysis of the alpha(1b)-adrenergic receptor. Involvement of basic and hydrophobic residues in receptor activation and G protein coupling.

To investigate their role in receptor coupling to G(q), we mutated all basic amino acids and some conserved hydrophobic residues of the cytosolic surface of the alpha(1b)-adrenergic receptor (AR). The wild type and mutated receptors were expressed in COS-7 cells and characterized for their ligand binding properties and ability to increase inositol phosphate accumulation. The experimental results have been interpreted in the context of both an ab initio model of the alpha(1b)-AR and of a new homology model built on the recently solved crystal structure of rhodopsin. Among the twenty-three basic amino acids mutated only mutations of three, Arg(254) and Lys(258) in the third intracellular loop and Lys(291) at the cytosolic extension of helix 6, markedly impaired the receptor-mediated inositol phosphate production. Additionally, mutations of two conserved hydrophobic residues, Val(147) and Leu(151) in the second intracellular loop had significant effects on receptor function. The functional analysis of the receptor mutants in conjunction with the predictions of molecular modeling supports the hypothesis that Arg(254), Lys(258), as well as Leu(151) are directly involved in receptor-G protein interaction and/or receptor-mediated activation of the G protein. In contrast, the residues belonging to the cytosolic extensions of helices 3 and 6 play a predominant role in the activation process of the alpha(1b)-AR. These findings contribute to the delineation of the molecular determinants of the alpha(1b)-AR/G(q) interface.

'Toxic' and 'Nontoxic': confirming critical terminology concepts and context for clear communication

If 'the dose makes the poison', and if the context of an exposure to a hazard shapes the risk as much as the innate character of the hazard itself, then what is 'toxic' and what is 'nontoxic'? This article is intended to help readers and communicators: anticipate that concepts such as 'toxic' and 'nontoxic' may have different meanings to different stakeholders in different contexts of general use, commerce, science, and the law; recognize specific situations in which terms and related information could potentially be misperceived or misinterpreted; evaluate the relevance, reliability, and other attributes of information for a given situation; control actions, assumptions, interpretations, conclusions, and decisions to avoid flaws and achieve a desired outcome; and confirm that the desired outcome has been achieved. To meet those objectives, we provide some examples of differing toxicology terminology concepts and contexts; a comprehensive decision-making framework for understanding and managing risk; along with a communication and education message and audience-planning matrix to support the involvement of all relevant stakeholders; a set of CLEAR-communication assessment criteria for use by both readers and communicators; example flaws in decision-making; a suite of three tools to assign relevance vs reliability, align know vs show, and refine perception vs reality aspects of information; and four steps to foster effective community involvement and support. The framework and supporting process are generally applicable to meeting any objective.