Flow targeted 3D steady-state free-precession coronary MR angiography: comparison of three different imaging approaches.

PURPOSE: To compare 3 different flow targeted magnetization preparation strategies for coronary MR angiography (cMRA), which allow selective visualization of the vessel lumen. MATERIAL AND METHODS: The right coronary artery of 10 healthy subjects was investigated on a 1.5 Tesla MR system (Gyroscan ACS-NT, Philips Healthcare, Best, NL). A navigator-gated and ECG-triggered 3D radial steady-state free-precession (SSFP) cMRA sequence with 3 different magnetization preparation schemes was performed referred to as projection SSFP (selective labeling of the aorta, subtraction of 2 data sets), LoReIn SSFP (double-inversion preparation, selective labeling of the aorta, 1 data set), and inflow SSFP (inversion preparation, selective labeling of the coronary artery, 1 data set). Signal-to-noise ratio (SNR) of the coronary artery and aorta, contrast-to-noise ratio (CNR) between the coronary artery and epicardial fat, vessel length and vessel sharpness were analyzed. RESULTS: All cMRA sequences were successfully obtained in all subjects. Both projection SSFP and LoReIn SSFP allowed for selective visualization of the coronary arteries with excellent background suppression. Scan time was doubled in projection SSFP because of the need for subtraction of 2 data sets. In inflow SSFP, background suppression was limited to the tissue included in the inversion volume. Projection SSFP (SNR(coro): 25.6 +/- 12.1; SNR(ao): 26.1 +/- 16.8; CNR(coro-fat): 22.0 +/- 11.7) and inflow SSFP (SNR(coro): 27.9 +/- 5.4; SNR(ao): 37.4 +/- 9.2; CNR(coro-fat): 24.9 +/- 4.8) yielded significantly increased SNR and CNR compared with LoReIn SSFP (SNR(coro): 12.3 +/- 5.4; SNR(ao): 11.8 +/- 5.8; CNR(coro-fat): 9.8 +/- 5.5; P < 0.05 for both). Longest visible vessel length was found with projection SSFP (79.5 mm +/- 18.9; P < 0.05 vs. LoReIn) whereas vessel sharpness was best in inflow SSFP (68.2% +/- 4.5%; P < 0.05 vs. LoReIn). Consistently good image quality was achieved using inflow SSFP likely because of the simple planning procedure and short scanning time. CONCLUSION: Three flow targeted cMRA approaches are presented, which provide selective visualization of the coronary vessel lumen and in addition blood flow information without the need of contrast agent administration. Inflow SSFP yielded highest SNR, CNR and vessel sharpness and may prove useful as a fast and efficient approach for assessing proximal and mid vessel coronary blood flow, whereas requiring less planning skills than projection SSFP or LoReIn SSFP.

Transvaginal specimen extraction in colorectal surgery: current state of the art.

Aim  Background The expected benefit of transvaginal specimen extraction is reduced incision-related morbidity. Objectives A systematic review of transvaginal specimen extraction in colorectal surgery was carried out to assess this expectation. Method  Search strategy The following keywords, in various combinations, were searched: NOSE (natural orifices specimen extraction), colorectal, colon surgery, transvaginal, right hemicolectomy, left hemicolectomy, low anterior resection, sigmoidectomy, ileocaecal resection, proctocolectomy, colon cancer, sigmoid diverticulitis and inflammatory bowel diseases. Selection criteria Selection criteria included large bowel resection with transvaginal specimen extraction, laparoscopic approach, human studies and English language. Exclusion criteria were experimental studies and laparotomic approach or local excision. All articles published up to February 2011 were included. Results  Twenty-three articles (including a total of 130 patients) fulfilled the search criteria. The primary diagnosis was colorectal cancer in 51% (67) of patients, endometriosis in 46% (60) of patients and other conditions in the remaining patients. A concurrent gynaecological procedure was performed in 17% (22) of patients. One case of conversion to laparotomy was reported. In two patients, transvaginal extraction failed. In left- and right-sided resections, the rate of severe complications was 3.7% and 2%, respectively. Two significant complications, one of pelvic seroma and one of rectovaginal fistula, were likely to have been related to transvaginal extraction. The degree of follow up was specified in only one study. Harvested nodes and negative margins were adequate and reported in 70% of oncological cases. Conclusion  Vaginal extraction of a colorectal surgery specimen shows potential benefit, particularly when associated with a gynaecological procedure. Data from prospective randomized trials are needed to support the routine use of this technique.

MRI of coronary vessel walls using radial k-space sampling and steady-state free precession imaging.

OBJECTIVE: The objective of our study was to investigate the impact of radial k-space sampling and steady-state free precession (SSFP) imaging on image quality in MRI of coronary vessel walls. SUBJECTS AND METHODS: Eleven subjects were examined on a 1.5-T MR system using three high-resolution navigator-gated and cardiac-triggered 3D black blood sequences (cartesian gradient-echo [GRE], radial GRE, and radial SSFP) with identical spatial resolution (0.9 x 0.9 x 2.4 mm3). The signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), vessel wall sharpness, and motion artifacts were analyzed. RESULTS: The mean SNR and CNR of the coronary vessel wall were improved using radial imaging and were best using radial k-space sampling combined with SSFP imaging. Vessel border definition was similar for all three sequences. Radial k-space sampling was found to be less sensitive to motion. Consistently good image quality was seen with the radial GRE sequence. CONCLUSION: Radial k-space sampling in MRI of coronary vessel walls resulted in fewer motion artifacts and improved SNR and CNR. The use of SSFP imaging, however, did not result in improved coronary vessel wall visualization.

Markers for sepsis diagnosis in the forensic setting: state of the art.

Reliable diagnoses of sepsis remain challenging in forensic pathology routine despite improved methods of sample collection and extensive biochemical and immunohistochemical investigations. Macroscopic findings may be elusive and have an infectious or non-infectious origin. Blood culture results can be difficult to interpret due to postmortem contamination or bacterial translocation. Lastly, peripheral and cardiac blood may be unavailable during autopsy. Procalcitonin, C-reactive protein, and interleukin-6 can be measured in biological fluids collected during autopsy and may be used as in clinical practice for diagnostic purposes. However, concentrations of these parameters may be increased due to etiologies other than bacterial infections, indicating that a combination of biomarkers could more effectively discriminate non-infectious from infectious inflammations. In this article, we propose a review of the literature pertaining to the diagnostic performance of classical and novel biomarkers of inflammation and bacterial infection in the forensic setting.

Rufinamide Attenuates Mechanical Allodynia in a Model of Neuropathic Pain in the Mouse and Stabilizes Voltage-gated Sodium Channel Inactivated State.

BACKGROUND:: Voltage-gated sodium channels dysregulation is important for hyperexcitability leading to pain persistence. Sodium channel blockers currently used to treat neuropathic pain are poorly tolerated. Getting new molecules to clinical use is laborious. We here propose a drug already marketed as anticonvulsant, rufinamide. METHODS:: We compared the behavioral effect of rufinamide to amitriptyline using the Spared Nerve Injury neuropathic pain model in mice. We compared the effect of rufinamide on sodium currents using in vitro patch clamp in cells expressing the voltage-gated sodium channel Nav1.7 isoform and on dissociated dorsal root ganglion neurons to amitriptyline and mexiletine. RESULTS:: In naive mice, amitriptyline (20 mg/kg) increased withdrawal threshold to mechanical stimulation from 1.3 (0.6-1.9) (median [95% CI]) to 2.3 g (2.2-2.5) and latency of withdrawal to heat stimulation from 13.1 (10.4-15.5) to 30.0 s (21.8-31.9), whereas rufinamide had no effect. Rufinamide and amitriptyline alleviated injury-induced mechanical allodynia for 4 h (maximal effect: 0.10 ± 0.03 g (mean ± SD) to 1.99 ± 0.26 g for rufinamide and 0.25 ± 0.22 g to 1.92 ± 0.85 g for amitriptyline). All drugs reduced peak current and stabilized the inactivated state of voltage-gated sodium channel Nav1.7, with similar effects in dorsal root ganglion neurons. CONCLUSIONS:: At doses alleviating neuropathic pain, amitriptyline showed alteration of behavioral response possibly related to either alteration of basal pain sensitivity or sedative effect or both. Side-effects and drug tolerance/compliance are major problems with drugs such as amitriptyline. Rufinamide seems to have a better tolerability profile and could be a new alternative to explore for the treatment of neuropathic pain.

Hyperuricaemia and gout: state of the art and future perspectives.

Major progress has been made in the past decade in understanding the pathogenesis and treatment of gout. These advances include identification of the genetic and environmental risk factors for gout, recognition that gout is an important risk factor for cardiovascular disease, elucidation of the pathways regulating the acute gout attack and the development of novel therapeutic agents to treat both the acute and chronic phases of the disease. This review summarises these advances and highlights the research agenda for the next decade.

Characterization of cerebral glucose dynamics in vivo with a four-state conformational model of transport at the blood-brain barrier.

Determination of brain glucose transport kinetics in vivo at steady-state typically does not allow distinguishing apparent maximum transport rate (T(max)) from cerebral consumption rate. Using a four-state conformational model of glucose transport, we show that simultaneous dynamic measurement of brain and plasma glucose concentrations provide enough information for independent and reliable determination of the two rates. In addition, although dynamic glucose homeostasis can be described with a reversible Michaelis-Menten model, which is implicit to the large iso-inhibition constant (K(ii)) relative to physiological brain glucose content, we found that the apparent affinity constant (K(t)) was better determined with the four-state conformational model of glucose transport than with any of the other models tested. Furthermore, we confirmed the utility of the present method to determine glucose transport and consumption by analysing the modulation of both glucose transport and consumption by anaesthesia conditions that modify cerebral activity. In particular, deep thiopental anaesthesia caused a significant reduction of both T(max) and cerebral metabolic rate for glucose consumption. In conclusion, dynamic measurement of brain glucose in vivo in function of plasma glucose allows robust determination of both glucose uptake and consumption kinetics.

Classifying minimally disabled multiple sclerosis patients from resting state functional connectivity.

Multiple sclerosis (MS), a variable and diffuse disease affecting white and gray matter, is known to cause functional connectivity anomalies in patients. However, related studies published to-date are post hoc; our hypothesis was that such alterations could discriminate between patients and healthy controls in a predictive setting, laying the groundwork for imaging-based prognosis. Using functional magnetic resonance imaging resting state data of 22 minimally disabled MS patients and 14 controls, we developed a predictive model of connectivity alterations in MS: a whole-brain connectivity matrix was built for each subject from the slow oscillations (<0.11Hz) of region-averaged time series, and a pattern recognition technique was used to learn a discriminant function indicating which particular functional connections are most affected by disease. Classification performance using strict cross-validation yielded a sensitivity of 82% (above chance at p<0.005) and specificity of 86% (p<0.01) to distinguish between MS patients and controls. The most discriminative connectivity changes were found in subcortical and temporal regions, and contralateral connections were more discriminative than ipsilateral connections. The pattern of decreased discriminative connections can be summarized post hoc in an index that correlates positively (ρ=0.61) with white matter lesion load, possibly indicating functional reorganisation to cope with increasing lesion load. These results are consistent with a subtle but widespread impact of lesions in white matter and in gray matter structures serving as high-level integrative hubs. These findings suggest that predictive models of resting state fMRI can reveal specific anomalies due to MS with high sensitivity and specificity, potentially leading to new non-invasive markers.

Nonenhanced arterial spin labeled carotid MR angiography using three-dimensional radial balanced steady-state free precession imaging.

PURPOSE: To optimize and preliminarily evaluate a three-dimensional (3D) radial balanced steady-state free precession (bSSFP) arterial spin labeled (ASL) sequence for nonenhanced MR angiography (MRA) of the extracranial carotid arteries. MATERIALS AND METHODS: The carotid arteries of 13 healthy subjects and 2 patients were imaged on a 1.5 Tesla MRI system using an undersampled 3D radial bSSFP sequence providing a scan time of ∼4 min and 1 mm(3) isotropic resolution. A hybridized scheme that combined pseudocontinuous and pulsed ASL was used to maximize arterial coverage. The impact of a post label delay period, the sequence repetition time, and radiofrequency (RF) energy configuration of pseudocontinuous labeling on the display of the carotid arteries was assessed with contrast-to-noise ratio (CNR) measurements. Faster, higher undersampled 2 and 1 min scans were tested. RESULTS: Using hybridized ASL MRA and a 3D radial bSSFP trajectory, arterial CNR was maximized with a post label delay of 0.2 s, repetition times ≥ 2.5 s (P < 0.05), and by eliminating RF energy during the pseudocontinuous control phase (P < 0.001). With higher levels of undersampling, the carotid arteries were displayed in ≤ 2 min. CONCLUSION: Nonenhanced MRA using hybridized ASL with a 3D radial bSSFP trajectory can display long lengths of the carotid arteries with 1 mm(3) isotropic resolution. J. Magn. Reson. Imaging 2015;41:1150-1156. © 2014 Wiley Periodicals, Inc.

Blood culture-based diagnosis of bacteraemia: state of the art.

Blood culture remains the best approach to identify the incriminating microorganisms when a bloodstream infection is suspected, and to guarantee that the antimicrobial treatment is adequate. Major improvements have been made in the last years to increase the sensitivity and specificity and to reduce the time to identification of microorganisms recovered from blood cultures. Among other factors, the introduction in clinical microbiology laboratories of the matrix-assisted laser desorption ionization time-of-flight mass spectrometry technology revolutionized the identification of microorganisms whereas the introduction of nucleic-acid-based methods, such as DNA hybridization or rapid PCR-based test, significantly reduce the time to results. Together with traditional antimicrobial susceptibility testing, new rapid methods for the detection of resistance mechanisms respond to major epidemiological concerns such as methicillin-resistant Staphylococcus aureus, extended-spectrum β-lactamase or carbapenemases. This review presents and discusses the recent developments in microbial diagnosis of bloodstream infections based on blood cultures.

Antihypertensive Combination Treatment: State of the Art.

An adequate control of blood pressure is essential to reduce the risk of target organ damages and cardiovascular events in patients with hypertension. Yet, it is well recognized that a substantial proportion of treated patients remain hypertensive despite treatment. Several reasons have been evoked to explain why so many patients are not adequately controlled. Among them, medical inertia, a poor long-term adherence, and the need to prescribe several antihypertensive drugs to reach the target blood pressure have been identified as major limitations to the success of antihypertensive therapy. In this context, the use of single-pill combinations (SPC) containing two or three drugs in one pill has an important role in reducing the impact of some of these issues. Indeed, the use of SPC enables to reduce the pill burden and to improve the treatment efficacy without increasing the incidence of side effects. However, besides their major advantages, SPC have also some limitations such as a possible lack of flexibility or a higher cost. The purpose of this review is to discuss the place of SPC in the actual management of hypertension. The active development of new single-pill combinations in last years can be considered as a significant improvement in the physicians' capacity to treat hypertension effectively.

Computational modeling of resting-state activity demonstrates markers of normalcy in children with prenatal or perinatal stroke.

Children who sustain a prenatal or perinatal brain injury in the form of a stroke develop remarkably normal cognitive functions in certain areas, with a particular strength in language skills. A dominant explanation for this is that brain regions from the contralesional hemisphere "take over" their functions, whereas the damaged areas and other ipsilesional regions play much less of a role. However, it is difficult to tease apart whether changes in neural activity after early brain injury are due to damage caused by the lesion or by processes related to postinjury reorganization. We sought to differentiate between these two causes by investigating the functional connectivity (FC) of brain areas during the resting state in human children with early brain injury using a computational model. We simulated a large-scale network consisting of realistic models of local brain areas coupled through anatomical connectivity information of healthy and injured participants. We then compared the resulting simulated FC values of healthy and injured participants with the empirical ones. We found that the empirical connectivity values, especially of the damaged areas, correlated better with simulated values of a healthy brain than those of an injured brain. This result indicates that the structural damage caused by an early brain injury is unlikely to have an adverse and sustained impact on the functional connections, albeit during the resting state, of damaged areas. Therefore, these areas could continue to play a role in the development of near-normal function in certain domains such as language in these children.

TLR3-Mediated CD8+ Dendritic Cell Activation Is Coupled with Establishment of a Cell-Intrinsic Antiviral State.

Because of their unique capacity to cross-present Ags to CD8(+) T cells, mouse lymphoid tissue-resident CD8(+) dendritic cells (DCs) and their migratory counterparts are critical for priming antiviral T cell responses. High expression of the dsRNA sensor TLR3 is a distinctive feature of these cross-presenting DC subsets. TLR3 engagement in CD8(+) DCs promotes cross-presentation and the acquisition of effector functions required for driving antiviral T cell responses. In this study, we performed a comprehensive analysis of the TLR3-induced antiviral program and cell-autonomous immunity in CD8(+) DC lines and primary CD8(+) DCs. We found that TLR3-ligand polyinosinic-polycytidylic acid and human rhinovirus infection induced a potent antiviral protection against Sendai and vesicular stomatitis virus in a TLR3 and type I IFN receptor-dependent manner. Polyinosinic-polycytidylic acid-induced antiviral genes were identified by mass spectrometry-based proteomics and transcriptomics in the CD8(+) DC line. Nanostring nCounter experiments confirmed that these antiviral genes were induced by TLR3 engagement in primary CD8(+) DCs, and indicated that many are secondary TLR3-response genes requiring autocrine IFN-β stimulation. TLR3-activation thus establishes a type I IFN-dependent antiviral program in a DC subtype playing crucial roles in priming adaptive antiviral immune responses. This mechanism is likely to shield the priming of antiviral responses against inhibition or abrogation by the viral infection. It could be particularly relevant for viruses detected mainly by TLR3, which may not trigger type I IFN production by DCs that lack TLR3, such as plasmacytoid DCs or CD8(-) DCs.

The Human Acid-Sensing Ion Channel ASIC1a: Evidence for a Homotetrameric Assembly State at the Cell Surface.

The chicken acid-sensing ion channel ASIC1 has been crystallized as a homotrimer. We address here the oligomeric state of the functional ASIC1 in situ at the cell surface. The oligomeric states of functional ASIC1a and mutants with additional cysteines introduced in the extracellular pore vestibule were resolved on SDS-PAGE. The functional ASIC1 complexes were stabilized at the cell surface of Xenopus laevis oocytes or CHO cells either using the sulfhydryl crosslinker BMOE, or sodium tetrathionate (NaTT). Under these different crosslinking conditions ASIC1a migrates as four distinct oligomeric states that correspond by mass to multiples of a single ASIC1a subunit. The relative importance of each of the four ASIC1a oligomers was critically dependent on the availability of cysteines in the transmembrane domain for crosslinking, consistent with the presence of ASIC1a homo-oligomers. The expression of ASIC1a monomers, trimeric or tetrameric concatemeric cDNA constructs resulted in functional channels. The resulting ASIC1a complexes are resolved as a predominant tetramer over the other oligomeric forms, after stabilization with BMOE or NaTT and SDS-PAGE/western blot analysis. Our data identify a major ASIC1a homotetramer at the surface membrane of the cell expressing functional ASIC1a channel.

CNDOL: A fast and reliable method for the calculation of electronic properties of very large systems. Applications to retinal binding pocket in rhodopsin and gas phase porphine.

Very large molecular systems can be calculated with the so called CNDOL approximate Hamiltonians that have been developed by avoiding oversimplifications and only using a priori parameters and formulas from the simpler NDO methods. A new diagonal monoelectronic term named CNDOL/21 shows great consistency and easier SCF convergence when used together with an appropriate function for charge repulsion energies that is derived from traditional formulas. It is possible to obtain a priori molecular orbitals and electron excitation properties after the configuration interaction of single excited determinants with reliability, maintaining interpretative possibilities even being a simplified Hamiltonian. Tests with some unequivocal gas phase maxima of simple molecules (benzene, furfural, acetaldehyde, hexyl alcohol, methyl amine, 2,5 dimethyl 2,4 hexadiene, and ethyl sulfide) ratify the general quality of this approach in comparison with other methods. The calculation of large systems as porphine in gas phase and a model of the complete retinal binding pocket in rhodopsin with 622 basis functions on 280 atoms at the quantum mechanical level show reliability leading to a resulting first allowed transition in 483 nm, very similar to the known experimental value of 500 nm of "dark state." In this very important case, our model gives a central role in this excitation to a charge transfer from the neighboring Glu(-) counterion to the retinaldehyde polyene chain. Tests with gas phase maxima of some important molecules corroborate the reliability of CNDOL/2 Hamiltonians.