An unusually powerful mode of low-frequency sound interference due to defective hair bundles of the auditory outer hair cells

International audienceA detrimental perceptive consequence of damaged auditory sen-sory hair cells consists in a pronounced masking effect exerted by low-frequency sounds, thought to occur when auditory threshold elevation substantially exceeds 40 dB. Here, we identified the submembrane scaffold protein Nherf1 as a hair-bundle component of the differentiating outer hair cells (OHCs). Nherf1 −/− mice dis-played OHC hair-bundle shape anomalies in the mid and basal co-chlea, normally tuned to mid-and high-frequency tones, and mild (22–35 dB) hearing-threshold elevations restricted to midhigh sound frequencies. This mild decrease in hearing sensitivity was, however, discordant with almost nonresponding OHCs at the co-chlear base as assessed by distortion-product otoacoustic emissions and cochlear microphonic potentials. Moreover, unlike wild-type mice, responses of Nherf1 −/− mice to high-frequency (20–40 kHz

Multiple sclerosis lesions and atrophy in the spinal cord: Distribution across vertebral levels and correlation with disability

Background: The vast majority of magnetic resonance imaging (MRI) studies on multiple sclerosis (MS) covered the spinal cord (SC), if at all, incompletely.Objective: To assess SC involvement in MS, as detectable by whole SC MRI, with regard to distribution across vertebral levels and relation to clinical phenotypes and disability.Methods: We investigated SC MRI with sagittal and axial coverage. Analyzed were brain and SC MRI scans of 17 healthy controls (HC) and of 370 patients with either clinically isolated syndrome (CIS, 27), relapsing remitting MS (RRMS, 303) or progressive MS (PMS, 40). Across vertebral levels, cross-sectional areas were semiautomatically segmented, and lesions manually delineated.Results: The frequency of SC lesions was highest at the level C3-4. The volume of SC lesions increased from CIS to RRMS, and from RRMS to PMS whereas lesion distribution across SC levels did not differ. SC atrophy was demonstrated in RRMS and, to a higher degree, in PMS;apart from an accentuation at the level C3-4, it was evenly distributed across SC levels. SC lesions and atrophy volume were not correlated with each other and were independently associated with disability.Conclusion: SC lesions and atrophy already exist at the stage of RRMS in the whole SC with an accentuation in the cervical enlargement;SC lesions and atrophy are more pronounced in the stage of PMS. Both contribute to the clinical picture but are largely independent

Irradiation-Induced Up-Regulation of HLA-E on Macrovascular Endothelial Cells Confers Protection against Killing by Activated Natural Killer Cells

BACKGROUND: Apart from the platelet/endothelial cell adhesion molecule 1 (PECAM-1, CD31), endoglin (CD105) and a positive factor VIII-related antigen staining, human primary and immortalized macro- and microvascular endothelial cells (ECs) differ in their cell surface expression of activating and inhibitory ligands for natural killer (NK) cells. Here we comparatively study the effects of irradiation on the phenotype of ECs and their interaction with resting and activated NK cells. METHODOLOGY/PRINCIPAL FINDINGS: Primary macrovascular human umbilical vein endothelial cells (HUVECs) only express UL16 binding protein 2 (ULBP2) and the major histocompatibility complex (MHC) class I chain-related protein MIC-A (MIC-A) as activating signals for NK cells, whereas the corresponding immortalized EA.hy926 EC cell line additionally present ULBP3, membrane heat shock protein 70 (Hsp70), intercellular adhesion molecule ICAM-1 (CD54) and HLA-E. Apart from MIC-B, the immortalized human microvascular endothelial cell line HMEC, resembles the phenotype of EA.hy926. Surprisingly, primary HUVECs are more sensitive to Hsp70 peptide (TKD) plus IL-2 (TKD/IL-2)-activated NK cells than their immortalized EC counterpatrs. This finding is most likely due to the absence of the inhibitory ligand HLA-E, since the activating ligands are shared among the ECs. The co-culture of HUVECs with activated NK cells induces ICAM-1 (CD54) and HLA-E expression on the former which drops to the initial low levels (below 5%) when NK cells are removed. Sublethal irradiation of HUVECs induces similar but less pronounced effects on HUVECs. Along with these findings, irradiation also induces HLA-E expression on macrovascular ECs and this correlates with an increased resistance to killing by activated NK cells. Irradiation had no effect on HLA-E expression on microvascular ECs and the sensitivity of these cells to NK cells remained unaffected. CONCLUSION/SIGNIFICANCE: These data emphasize that an irradiation-induced, transient up-regulation of HLA-E on macrovascular ECs might confer protection against NK cell-mediated vascular injury

Diagnostic Potential of Pulsed Arterial Spin Labeling in Alzheimer's Disease

Alzheimers disease (AD) is the most common cause of dementia. Although the underlying pathology is still not completely understood, several diagnostic methods are available. Frequently, the most accurate methods are also the most invasive. The present work investigates the diagnostic potential of Pulsed Arterial Spin Labeling (PASL) for AD: a non-invasive, MRI-based technique for the quantification of regional cerebral blood flow (rCBF). In particular, we propose a pilot computer aided diagnostic (CAD) procedure able to discriminate between healthy and diseased subjects, and at the same time, providing visual informative results. This method encompasses the creation of a healthy model, the computation of a voxel-wise likelihood function as comparison between the healthy model and the subject under examination, and the correction of the likelihood function via prior distributions. The discriminant analysis is carried out to maximize the accuracy of the classification. The algorithm has been trained on a dataset of 81 subjects and achieved a sensitivity of 0.750 and a specificity of 0.875. Moreover, in accordance with the current pathological knowledge, the parietal lobe, and limbic system are shown to be the main discriminant factors

The potency of selatogrel, a reversible antagonist of the P2Y12 receptor, is affected by calcium concentration

Here, we report the in vitro characterization of the P2Y12 receptor antagonist selatogrel (ACT-246475). Binding studies with radiolabeled selatogrel demonstrated that selatogrel is a competitive antagonist of ADP binding to the P2Y12 receptor with a fast onset of action. Consequently, selatogrel was confirmed to be a potent inhibitor of P2Y12-mediated intra-platelet signaling and ADP-induced platelet activation. Characterization of selatogrel in platelet-rich plasma in vitro demonstrated that the mode of anti-coagulation affected the anti-platelet potency. Specifically, in platelet-rich plasma containing physiological calcium concentration (anticoagulated with a direct thrombin inhibitor), selatogrel achieved half-maximal inhibition of ADP-induced platelet aggregation at a 3-fold lower concentration than in conditions with low calcium concentration (anticoagulated with citrate). Furthermore, calcium-dependent reduction in selatogrel potency was observed in whole blood platelet aggregation using the VerifyNow™ system with a 3.7-fold potency loss in low calcium conditions. A comparable potency loss was also observed with the reversible P2Y12 receptor antagonists ticagrelor, cangrelor and elinogrel. Furthermore, receptor-binding experiments using radiolabeled selatogrel confirmed a 3-fold lowering of selatogrel binding affinity to the P2Y12 receptor in low calcium conditions. In conclusion, our data suggest that in low calcium conditions (i.e., citrate-anticoagulated blood), there is a risk of underestimating the potency of reversible P2Y12 receptor antagonists. To avoid overdosing, and a potential increase in bleeding risk, we propose that the ex vivo evaluation of reversible P2Y12 receptor antagonists should be performed with platelet assay systems containing physiological calcium concentration

Pre-contrast T1-weighted imaging of the spinal cord may be unnecessary in patients with multiple sclerosis

Objectives!#!Multiple sclerosis (MS) is an inflammatory disease frequently involving the spinal cord, which can be assessed by magnetic resonance imaging (MRI). Here, we hypothesize that pre-contrast T1-w imaging does not add diagnostic value to routine spinal MRI for the follow-up of patients with MS.!##!Methods!#!3-T MRI scans including pre- and post-contrast T1-w as well as T2-w images of 265 consecutive patients (mean age: 40 ± 13 years, 169 women) with (suspected) MS were analyzed retrospectively. Images were assessed in two separate reading sessions, first excluding and second including pre-contrast T1-w images. Two independent neuroradiologists rated the number of contrast-enhancing (ce) lesions as well as diagnostic confidence (1 = unlikely to 5 = very high), overall image quality, and artifacts. Results were compared using Wilcoxon matched-pairs signed-rank tests and weighted Cohen's kappa (κ).!##!Results!#!Fifty-six ce lesions were found in 43 patients. There were no significant differences in diagnostic confidence between both readings for both readers (reader 1: p = 0.058; reader 2: p = 0.317). Inter-rater concordance was both moderate regarding artifacts (κ = 0.418) and overall image quality (κ = 0.504). Thirty-one black holes were found in 25 patients with high diagnostic confidence (reader 1: 4.04 ± 0.81; reader 2: 3.80 ± 0.92) and substantial inter-rater concordance (κ = 0.700).!##!Conclusions!#!Availability of pre-contrast T1-w images did not significantly increase diagnostic confidence or detection rate of ce lesions in the spinal cord in patients with MS. Thus, pre-contrast T1-w sequences might be omitted in routine spinal MRI for follow-up exams, however not in special unclear clinical situations in which certainty on contrast enhancement is required.!##!Key points!#!Availability of pre-contrast T1-w images does not increase diagnostic confidence or detection rate of contrast-enhancing lesions in the spinal cord of MS patients. Excluding pre-contrast T1-w sequences reduces scan time, thus providing more time for other sequences or increasing the patients' compliance

Iodine images in dual energy CT: A monocentric study benchmarking quantitative iodine concentration values of the healthy liver.

Dual energy computed tomography (DECT) allows the quantification of specific materials such as iodine contrast agent in human body tissue, potentially providing additional diagnostic data. Yet full diagnostic value can only be achieved if physiological normal values for iodine concentrations are known. We retrospectively evaluated abdominal DECT scans of 105 patients with healthy liver between March and August 2018 (age 17 to 86 years, 43 female and 62 male). The iodine concentrations within ROIs of the liver parenchyma as well as of the abdominal aorta and main portal vein were obtained. We evaluated the absolute iodine concentration and blood-normalized iodine concentrations relating the measured iodine concentration of the liver parenchyma to those of the supplying vessels. The influence of age and gender on the iodine uptake was assessed. The absolute iodine concentration was significantly different for the male and female cohort, but the difference was eliminated by the blood-normalized values. The average blood-normalized iodine concentrations were 2.107 mg/ml (+/- 0.322 mg/ml), 2.125 mg/ml (+/- 0.426 mg/ml) and 2.103 mg/ml (+/- 0.317 mg/ml) for the portal vein normalized, aorta normalized and mixed blood normalized iodine concentrations, respectively. A significant negative correlation between the patients' age and the iodine concentration was detected only for the blood-normalized values. A physiological range for iodine concentration in portal venous phase contrast enhanced DECT images can be defined for absolute and blood-normalized values. Deviations of blood-normalized iodine concentration values might be a robust biomarker for diagnostic evaluation. Patient age but not the gender influences the blood-normalized iodine concentrations in healthy liver parenchyma

Low-dose MDCT: evaluation of the impact of systematic tube current reduction and sparse sampling on the detection of degenerative spine diseases

Objectives!#!To investigate potential radiation dose reduction for multi-detector computed tomography (MDCT) exams of the spine by using sparse sampling and virtually lowered tube currents combined with statistical iterative reconstruction (SIR).!##!Methods!#!MDCT data of 26 patients (68.9 ± 11.7 years, 42.3% males) were retrospectively simulated as if the scans were acquired at 50%, 10%, 5%, and 3% of the original X-ray tube current or number of projections, using SIR for image reconstructions. Two readers performed qualitative image evaluation considering overall image quality, artifacts, and contrast and determined the number and type of degenerative changes. Scoring was compared between readers and virtual low-dose and sparse-sampled MDCT, respectively.!##!Results!#!Image quality and contrast decreased with virtual lowering of tube current and sparse sampling, but all degenerative changes were correctly detected in MDCT with 50% of tube current as well as MDCT with 50% of projections. Sparse-sampled MDCT with only 10% of initial projections still enabled correct identification of all degenerative changes, in contrast to MDCT with virtual tube current reduction by 90% where non-calcified disc herniations were frequently missed (R1: 23.1%, R2: 21.2% non-diagnosed herniations). The average volumetric CT dose index (CTDI!##!Conclusions!#!MDCT with 50% of original tube current or projections using SIR still allowed for accurate diagnosis of degenerative changes. Sparse sampling may be more promising for further radiation dose reductions since no degenerative changes were missed with 10% of initial projections.!##!Key points!#!• Most common degenerative changes of the spine can be diagnosed in multi-detector CT with 50% of tube current or number of projections. • Sparse-sampled multi-detector CT with only 10% of initial projections still enables correct identification of degenerative changes, in contrast to imaging with 10% of original tube current. • Sparse sampling may be a promising option for distinct lowering of radiation dose, reducing the CTD

Subtraction Maps Derived from Longitudinal Magnetic Resonance Imaging in Patients with Glioma Facilitate Early Detection of Tumor Progression

Progression of glioma is frequently characterized by increases or enhanced spread of a hyperintensity in fluid attenuated inversion recovery (FLAIR) sequences. However, changes in FLAIR signal over time can be subtle, and conventional (CONV) visual reading is time-consuming. The purpose of this monocentric, retrospective study was to compare CONV reading to reading of subtraction maps (SMs) for serial FLAIR imaging. FLAIR datasets of cranial 3-Tesla magnetic resonance imaging (MRI), acquired at two different time points (mean inter-scan interval: 5.4 ± 1.9 months), were considered per patient in a consecutive series of 100 patients (mean age: 49.0 ± 13.7 years) diagnosed with glioma (19 glioma World Health Organization [WHO] grade I and II, 81 glioma WHO grade III and IV). Two readers (R1 and R2) performed CONV and SM reading by assessing overall image quality and artifacts, alterations in tumor-associated FLAIR signal over time (stable/unchanged or progressive) including diagnostic confidence (1—very high to 5—very low diagnostic confidence), and time needed for reading. Gold-standard (GS) reading, including all available clinical and imaging information, was performed by a senior reader, revealing progressive FLAIR signal in 61 patients (tumor progression or recurrence in 38 patients, pseudoprogression in 10 patients, and unclear in the remaining 13 patients). SM reading used an officially certified and commercially available algorithm performing semi-automatic coregistration, intensity normalization, and color-coding to generate individual SMs. The approach of SM reading revealed FLAIR signal increases in a larger proportion of patients according to evaluations of both readers (R1: 61 patients/R2: 60 patients identified with FLAIR signal increase vs. R1: 45 patients/R2: 44 patients for CONV reading) with significantly higher diagnostic confidence (R1: 1.29 ± 0.48, R2: 1.26 ± 0.44 vs. R1: 1.73 ± 0.80, R2: 1.82 ± 0.85; p < 0.0001). This resulted in increased sensitivity (99.9% vs. 73.3%) with maintained high specificity (98.1% vs. 98.8%) for SM reading when compared to CONV reading. Furthermore, the time needed for SM reading was significantly lower compared to CONV assessments (p < 0.0001). In conclusion, SM reading may improve diagnostic accuracy and sensitivity while reducing reading time, thus potentially enabling earlier detection of disease progression