BOLD functional MRI in disease and pharmacological studies: room for improvement?

In the past decade the use of blood oxygen level-dependent (BOLD) fMRI to investigate the effect of diseases and pharmacological agents on brain activity has increased greatly. BOLD fMRI does not measure neural activity directly, but relies on a cascade of physiological events linking neural activity to the generation of MRI signal. However, most of the disease and pharmacological studies performed so far have interpreted changes in BOLD fMRI as "brain activation," ignoring the potential confounds that can arise through drug- or disease-induced modulation of events downstream of the neural activity. This issue is especially serious in diseases (like multiple sclerosis, brain tumours and stroke) and drugs (like anaesthetics or those with a vascular action) that are known to influence these physiological events. Here we provide evidence that, to extract meaningful information on brain activity in patient and pharmacological BOLD fMRI studies, it is important to identify, characterise and possibly correct these influences that potentially confound the results. We suggest a series of experimental measures to improve the interpretability of BOLD fMRI studies. We have ranked these according to their potential information and current practical feasibility. First-line, necessary improvements consist of (1) the inclusion of one or more control tasks, and (2) the recording of physiological parameters during scanning and subsequent correction of possible between-group differences. Second-line, highly recommended important aim to make the results of a patient or drug BOLD study more interpretable and include the assessment of (1) baseline brain perfusion, (2) vascular reactivity, (3) the inclusion of stimulus-related perfusion fMRI and (4) the recording of electrophysiological responses to the stimulus of interest. Finally, third-line, desirable improvements consist of the inclusion of (1) simultaneous EEG-fMRI, (2) cerebral blood volume and (3) rate of metabolic oxygen consumption measurements and, when relevant, (4) animal studies investigating signalling between neural cells and blood vessels.     

What Are the Roles of Hydrogen in Infinite-Layer Nickelates?

<正>Even after more than 30 years of intensive effort,the understanding of physical origin accounting for the high-temperature superconductivity in cuprates remains the open question in condensed matter physics. A possible way to solve this long-standing question is to find other cuprate-analogous structures.     

Error and attack tolerance of synchronization in Hindmarsh–Rose neural networks with community structure

Synchronization is one of the most important features observed in large-scale complex networks of interacting dynamical systems. As is well known, there is a close relation between the network topology and the network synchronizability. Using the coupled Hindmarsh–Rose neurons with community structure as a model network, in this paper we explore how failures of the nodes due to random errors or intentional attacks affect the synchronizability of community networks. The intentional attacks are realized by removing a fraction of the nodes with high values in some centrality measure such as the centralities of degree, eigenvector, betweenness and closeness. According to the master stability function method, we employ the algebraic connectivity of the considered community network as an indicator to examine the network synchronizability. Numerical evidences show that the node failure strategy based on the betweenness centrality has the most influence on the synchronizability of community networks. With this node failure strategy for a given network with a fixed number of communities, we find that the larger the degree of communities, the worse the network synchronizability; however, for a given network with a fixed degree of communities, we observe that the more the number of communities, the better the network synchronizability.     

Should abbreviated breast MRI be compliant with American College of Radiology requirements for MRI accreditation?

ObjectiveTo evaluate non-inferiority and diagnostic performance of an American College of Radiology compliant abbreviated MRI protocol (AB-MRI) compared with standard-of-care breast MRI (SOC-BMRI) in patients with increased breast cancer risk.Material and methodsWomen with increased lifetime breast cancer risk by American Cancer Society guidelines underwent breast MRI at a single institution between October 2015 and February 2018. AB-MRI was acquired at 3.0 T with T2-weighted extended fast spin echo triple-echo Dixon and pre- and post-contrast 3D dual-echo fast spoiled gradient echo two-point Dixon sequences with an 8-channel breast coil 1–7 days after SOC-BMRI. Three readers independently reviewed AB-MRI and assigned BI-RADS categories for maximum intensity projection images (AB1), dynamic contrast-enhanced (DCE) images (AB2), and DCE and non-contrast T2 and fat-only images (AB3). These scores were compared to those from SOC-BMRI.ResultsCancer yield was 14 per 1000 (women-years) in 73 women aged 26–75 years (mean 53.5 years). AB-MRI acquisition times (mean 9.63 min) and table times (mean 15.07 min) were significantly shorter than those of SOC-BMRI (means 19.46 and 36.3 min, respectively) (p < .001). Accuracy, sensitivity, specificity, and positive and negative predictive values were identical for AB3 and SOC-BMRI (93%, 100%, 93%, 16.7%, and 100%, respectively). AB-MRI with AB1 and AB2 had significantly lower specificity (AB1 = 73.6%, AB2 = 77.8%), positive predictive values (AB1 = 5%, AB2 = 5.9%), and accuracy (AB1 = 74%, AB2 = 78%) than those of SOC-BMRI (p = .002 for AB1, p = .01 for AB2).ConclusionAB-MRI was acquired significantly faster than SOC-BMRI and its diagnostic performance was non-inferior. Inclusion of T2 and fat-only images was necessary to achieve non-inferiority by multireader evaluation.     

Use of fat suppression in R₂ relaxometry with MRI for the quantification of tissue iron overload in beta-thalassemic patients

Purpose

To assess the performance and results of R₂ relaxometry using a fat-suppressed (FS) multiecho sequence and compare these to conventional R₂ relaxometry in estimating tissue iron overload.

Materials and Methods

Relaxation rate values (R₂=1/T2) of the liver, spleen, pancreas and vertebral bone marrow (VBM) were estimated in 21 patients with β-thalassemia major, using a respiratory-triggered 16-echo Carr-Purcell-Meiboom-Gill (CPMG) spin-echo sequence before (R₂) and after (R₂ FS) the application of chemically selective fat suppression.

Results

Hepatic and splenic R₂ FS values correlated with respective R₂ values (r=0.98 and r=0.96, P<.001), whereas correlations between R₂ FS and R₂ values for pancreas and VBM were not statistically significant. Bland–Altman plots show disagreement between R₂ and R₂ FS values, particularly for pancreas and VBM. Hepatic, pancreatic and VBM R₂ FS values correlated with serum ferritin (r=0.88, P<.001; r=0.51, P<.003; and r=0.75, P<.002, respectively). Hepatic R₂ FS values correlated with splenic R₂ FS (r=0.77, P<.03), pancreatic R₂ FS (r=0.61, P<.006) and VBM R₂ FS values (r=0.70, P<.001), whereas pancreatic R₂ FS values correlated also with VMB R₂ FS values. On the contrary, among the R₂ values of the above tissues, obtained without fat suppression, only hepatic R₂ values correlated with serum ferritin, whereas no correlation was documented between hepatic and pancreatic or VBM R₂ values. The application of fat suppression did not improve breathing or flow artifacts.

Conclusion

Application of fat suppression in the standard CPMG sequence improved the capability of MRI in noninvasive quantification of iron, particularly in lipid-rich tissues, such as vertebral bone marrow (VBM) and pancreas.     

Role of Brans-Dicke Theory with?or?without?Self-Interacting Potential in?Cosmic?Acceleration

In this work we have studied the possibility of obtaining cosmic acceleration in Brans-Dicke theory with varying or constant ω (Brans-Dicke parameter) and with or without self-interacting potential, the background fluid being barotropic fluid or Generalized Chaplygin Gas. Here we take the power law form of the scale factor and the scalar field. We show that accelerated expansion can also be achieved for high values of ω for closed Universe.     

Determination of the kinetic parameters of radical pairs with heavy atom substitutions in micellar solution by optical detected × and Ku band ESR

A study is reported of the dynamics of radical pairs formed by the photochemical reaction of benzophenone and its heavy atom substitutions, dichlorobenzophenone and bromobenzophe-none, in a sodium dodecylsulphate micellar solution. Changes were observed in the time profiles of the transient absorptions and in the yields of the escaping radicals induced by the irradiation of an × (9.15 GHz) or Ku band (17.44 GHz) microwave short pulse. From these experiments, the hydrogen abstraction reaction rates, the recombination rates of the singlet radical pairs, the relaxation rates, the escape rates, the decay rates of the radical pairs without the external magnetic field, and the intersystem recombination rates due to the spin-orbit coupling were determined.     

What is the recall rate of breast MRI when used for screening asymptomatic women at high risk?

Breast screening acceptability is dependent on sensitivity and recall rate. We aimed to establish the recall rate for MRI and mammography, separately and together, when screening a cohort of women at high genetic risk. Women aged 35-49 years in the MARIBS study form the cohort. We analysed the recall rate, the number of extra tests and their effectiveness. Wilcoxon Rank test was used to estimate the effect of age and logistic regression with robust variance the effect of mammographic density on recall rates. The first 726 screening studies took place in 415 women. Following 86 of these recall occurred, comprising 140 additional investigations. 28 of the cases were resolved without further MRI, and 18 women had more than 2 additional tests. Neither age nor mammographic density was associated with recall. MRI had a recall of rate of 10.19%, and mammography 4.00%. The two techniques largely recalled different cases and 10 cases only (11.62% of those recalled) were abnormal by both tests. The two together had a recall rate of 11.85%. Recall rates varied widely between centres of the study. Breast MRI in asymptomatic high-risk women age 35-49 years largely recalls different women from mammography. The combined figure of approximately 12% may be acceptable for screening and will be useful for planning similar studies.     

Is gadoxetic acid-enhanced MRI limited in tumor characterization for patients with chronic liver disease?

Purpose

There are pros and cons to the use of gadoxetic acid in hepatocellular carcinoma (HCC) workup due to the potential for high false positive diagnosis. This study was conducted to investigate the preoperative diagnostic performance of gadoxetic acid-enhanced MRI protocol including diffusion-weighted imaging (DWI) with emphasis on tumor characterization developed in high risk HCC patients.

Materials and methods

We included 144 patients (102 men, 42 women; age range 33–74 years) with chronic viral hepatitis or cirrhosis and 183 focal hepatic tumors (size range, 0.4–11.0 cm; mean, 3.2 cm), including 148 HCCs, 13 cholangiocarcinomas, 12 hemangiomas, three hepatocellular adenomas, two focal nodular hyperplasias, and five other tumors. All patients underwent gadoxetic acid-enhanced MRI protocol with DWI. MRIs were independently interpreted by three observers for the detection and characterization of hepatic tumors.

Results

Sensitivities for detecting all 183 liver tumors were 98.4%, 97.8%, and 96.2% for each observer, respectively, with a 97.5% for pooled data. Among 183 hepatic tumors, 91.3% (n = 167), 87.4% (n = 160), and 86.9% (n = 159) were correctly characterized according to their reference standard by each observer, respectively. In 13 cholangiocarcinomas, one to three were misinterpreted as HCC, and the remaining tumors were correctly characterized by each observer. The accuracies (Az) of MRI for HCC diagnosis were 0.952 for observer 1, 0.906 for observer 2, and 0.910 for observer 3, with 0.922 for pooled data. There was good inter-observer agreement.

Conclusion

The gadoxetic acid-enhanced MRI including DWI showed a reasonable performance for tumor characterization with high sensitivity for tumor detection in patients with chronic liver disease, despite concerns of high false positive diagnosis of hypervascular tumors.     

Are there sterile neutrinos in the flux of solar neutrinos on the earth?

It is shown that the future SNO and Super-Kamiokande experiments, in which high energy⁸B neutrinos will be detected through the observation of CC, NC and –e elastic scattering processes, could allow to reveal in a model independent way the presence of sterile neutrinos in the flux of solar neutrinos on the earth. Lower bounds for different averaged values of the probability of transition of solar v^e'S into sterile states and for the total flux of⁸B neutrinos are derived in terms of measurable quantities. The possibilities to reveal the presence of v and/or v in the solar neutrino flux on the earth are also considered and the case of transitions of solar v^e'S only into sterile states is discussed. Some numerical results for a simple model with v–v^s mixing are given.     

Are the structures of twist grain boundaries in silicon ordered at 0 K?

Contrary to previous simulation results on the existence of amorphous intergranular films at high-angle twist grain boundaries (GBs) in elemental solids such as silicon, recent experimental results imply structural order in some high-angle boundaries. With a novel protocol for simulating twist GBs, which allows the number of atoms at the boundary to vary, we have found new low-energy ordered structures. We give a detailed exposition of the results for the simplest boundary. The validity of our results is confirmed by first-principles calculations.     

Are the evidences of forensic entomology preserved in ethanol suitable for SEM studies?

In forensic practice, the use of arthropod evidences to estimate the postmortem interval is a very good approach when the elapsed time from death is long, but it requires the correct identification of the specimens. This is a crucial step, not always easy to achieve, in particular when dealing with immature specimens. In this case, scanning electronic microscopy (SEM) can be useful, but the techniques used to preserve specimens in forensic practice are usually different from those used to prepare specimens for SEM studies. To determine whether forensic evidences preserving techniques are also compatible with SEM analysis, we have compared specimens of all the immature stages of Calliphora vicina Robineau-Desvoidy, 1830 (Diptera, Calliphoridae) preserved in 70% ethanol, with others prepared with aldehydic fixative techniques that are more appropriate for SEM studies. At the same time, two drying techniques have also been compared with both fixative techniques, the critical point drying and air-drying following with hexamethyldisilizane treatment (HMDS). Our results indicate that there are not basis against recommending the use of ethanol to preserve forensic entomological evidences and that both drying methods appear to offer good results for second and third instar larvae, although HMDS behaves better with eggs and pupae.     

Detection of combined changes in interaural time and intensity differences: Segregated mechanisms in cue type and in operating frequency range?

Although physiological studies have revealed segregated binaural pathways, namely the medial and lateral superior olives, it is unclear whether the human auditory system has separate mechanisms for different cue types (interaural time and intensity differences; ITD and IID, respectively) and for operating frequency ranges. This study hypothesized "channels" for ITD and IID processing, and examined channel interaction at low and high frequencies based on the signal detection theory. The stimuli were a 125- or 500-Hz tone and a 4-kHz tone amplitude-modulated with a half-wave-rectified 125-Hz sinusoid, presented dichotically with various baseline ITDs and IIDs. The detectability indices, d('), for ITD and IID changes, imposed individually or simultaneously in the same direction, were derived from the results of a forced-choice task. The degree of channel interaction was estimated by comparing d(') for combined cues with those for individual cues. The estimated interaction showed little effect of baseline ITD or IID. The results generally exhibited nonzero interaction, indicating that the cue processes are not completely independent. The interaction was stronger for high frequencies than for low frequencies. The results can be interpreted as indicating the involvement of different binaural mechanisms for different frequency regions.     

Towards reconciliation of structure with function in plasmodesmata-who is the gatekeeper?

Whilst the structure of higher plant plasmodesmata was first described by Robards (1963. Desmotubule—a plasmodesmatal substructure. Nature 218, 784), and despite many subsequent intensive investigations, there is still much that remains unclear relating to their ultrastructure and functioning in higher plants. We have examined chemically fixed plant material, and suggest that the conformational changes seen in plasmodesmatal substructure, particularly the deposition of electron-dense extra-plasmodesmal material, is linked to either manipulation of the hormonal balance (as in Avocado fruit), or of osmotic potential in leaf blade material. These changes result in the deposition of β 1,3-glucan (callose) at the neck region of these plasmodesmata. This electron-dense material is deposited at the neck region of plasmodesmata, and forms a collar-like structure. The formation of a collar is shown to be coupled with loss of lucence within the cytoplasmic sleeve. The formation of a collar at the plasmodesmatal orifice thus results in encapsulation and closure of the plasmodesmatal orifice. Closure of the orifice coincides with a loss of electron-lucence and a lack of resolution of the desmotubule. These ultrastructural changes are potentially significant and could contribute to, result in, or assist in the down-regulation of cell to cell trafficking via plasmodesmata.     

Structural and magnetic properties of bimetallic Con ? 1Cr clusters with density functional theory

We have investigated the structural and magnetic properties of small bimetallic Co _{n − 1}Cr (n = 2 − 9) clusters by means of spin-polarized density functional theory approach. We found the ground state structures of Co _{n − 1}Cr were very similar to those of pure Co _n except n = 3,6. The clusters were of high stability at n = 6. Magnetic moments showed an interesting size-dependent variation: the magnetic moments of Co _{n − 1}Cr can be obtained by minus 7μB for n = 2, 4, 6–9 or by plus 1μB for n = 5 from those of the Co _n counterparts. The different magnetic behavior stems from ferromagnetic alignment or ferrimagnetic alignment of Co and Cr atoms in Co _{n − 1}Cr, associated with their longer or shorter interatomic distances.      

Production of medical radioisotopes with high specific activity in?photonuclear reactions with γ-beams of high intensity and?large brilliance

We study the production of radioisotopes for nuclear medicine in (γ,xn+yp) photonuclear reactions or (γ,γ′) photoexcitation reactions with high-flux [(10¹³–10¹⁵)γ/s], small diameter ∼(100 μm)² and small bandwidth (ΔE/E≈10⁻³–10⁻⁴) γ beams produced by Compton back-scattering of laser light from relativistic brilliant electron beams. We compare them to (ion,xn+yp) reactions with (ion = p,d,α) from particle accelerators like cyclotrons and (n,γ) or (n,f) reactions from nuclear reactors. For photonuclear reactions with a narrow γ-beam the energy deposition in the target can be managed by using a stack of thin target foils or wires, hence avoiding direct stopping of the Compton and pair electrons (positrons). However, for ions with a strong atomic stopping only a fraction of less than 10⁻² leads to nuclear reactions resulting in a target heating, which is at least 10⁵ times larger per produced radioactive ion and often limits the achievable activity. In photonuclear reactions the well defined initial excitation energy of the compound nucleus leads to a small number of reaction channels and enables new combinations of target isotope and final radioisotope. The narrow bandwidth γ excitation may make use of the fine structure of the Pygmy Dipole Resonance (PDR) or fluctuations in γ-width leading to increased cross sections. Within a rather short period compared to the isotopic half-life, a target area of the order of (100 μm)² can be highly transmuted, resulting in a very high specific activity. (γ,γ′) isomer production via specially selected γ cascades allows to produce high specific activity in multiple excitations, where no back-pumping of the isomer to the ground state occurs. We discuss in detail many specific radioisotopes for diagnostics and therapy applications. Photonuclear reactions with γ-beams allow to produce certain radioisotopes, e.g. ⁴⁷Sc, ⁴⁴Ti, ⁶⁷Cu, ¹⁰³Pd, ^117m Sn, ¹⁶⁹Er, ^195m Pt or ²²⁵Ac, with higher specific activity and/or more economically than with classical methods. This will open the door for completely new clinical applications of radioisotopes. For example ^195m Pt could be used to verify the patient’s response to chemotherapy with platinum compounds before a complete treatment is performed. Also innovative isotopes like ⁴⁷Sc, ⁶⁷Cu and ²²⁵Ac could be produced for the first time in sufficient quantities for large-scale application in targeted radionuclide therapy.     

Are "pinholes" the cause of excess current in superconducting tunnel junctions? A study of Andreev current in highly resistive junctions

In highly resistive superconducting tunnel junctions, excess subgap current is usually observed and is often attributed to microscopic pinholes in the tunnel barrier. We have studied the subgap current in superconductor-insulator-superconductor (SIS) and superconductor-insulator-normal-metal (SIN) junctions. In Al/AlO(x)/Al junctions, we observed a decrease of 2 orders of magnitude in the current upon the transition from the SIS to the SIN regime, where it then matched theory. In Al/AlO(x)/Cu junctions, we also observed generic features of coherent diffusive Andreev transport in a junction with a homogenous barrier. We use the quasiclassical Keldysh-Green function theory to quantify single- and two-particle tunneling and find good agreement with experiment over 2 orders of magnitude in transparency. We argue that our observations rule out pinholes as the origin of the excess current.