Nitroxide-nitroxide and nitroxide-metal distance measurements in transition metal complexes with two or three paramagnetic centres give access to thermodynamic and kinetic stabilities.

Fundamentally, the stability of coordination complexes and of templated (bio)macromolecular assemblies depends on the thermodynamic and kinetic properties of the intermediates and final complexes formed. Here, we used pulse EPR (electron paramagnetic resonance) spectroscopy to determine the stabilities of nanoscopic assemblies formed between one or two nitroxide spin-labelled tridentate 2,2':6',2''-terpyridine (tpy) ligands and divalent metal ions (FeII, ZnII, CoII and CuII). In three distinct approaches we exploited (a) the modulation depth of pulsed electron-electron double resonance (PELDOR) experiments in samples with increasing metal-to-ligand ratios, (b) the frequencies of PELDOR under broadband excitation using shaped pulses and (c) the distances recovered from well-resolved PELDOR data in fully deuterated solvents measured at 34 GHz. The results demonstrate that PELDOR is highly sensitive to resolving the stability of templated dimers and allows to readily distinguish anti-cooperative binding (for CuII ions) from cooperative binding (for CoII or FeII ions). In the case of paramagnetic ions (CoII and CuII) the use of broadband PELDOR allowed to identify the cooperativity of binding from the time domain and distance data. By using a second labelled tpy ligand and by mixing two homoleptic complexes of the same metal centre we could probe the kinetic stability on a timescale of tens of seconds. Here, tpy complexes of CuII and ZnII were found to be substitutionally labile, CoII showed very slow exchange and FeII was inert under our conditions. Not only do our chemical models allow studying metal-ligand interactions via PELDOR spectroscopy, the design of our study is directly transferable to (bio)macromolecular systems for determining the kinetic and thermodynamic stabilities underpinning (templated) multimerisation. Considering the limited methods available to obtain direct information on the composition and stability of complex assemblies we believe our approach to be a valuable addition to the armoury of methods currently used to study these systems.

Electronic nature of zwitterionic alkali metal methanides, silanides and germanides - a combined experimental and computational approach.

Zwitterionic group 14 complexes of the alkali metals of formula [C(SiMe2OCH2CH2OMe)3M], (M-1), [Si(SiMe2OCH2CH2OMe)3M], (M-2), [Ge(SiMe2OCH2CH2OMe)3M], (M-3), where M = Li, Na or K, have been prepared, structurally characterized and their electronic nature was investigated by computational methods. Zwitterions M-2 and M-3 were synthesized via reactions of [Si(SiMe2OCH2CH2OMe)4] (2) and [Ge(SiMe2OCH2CH2OMe)4] (3) with MOBu t (M = Li, Na or K), resp., in almost quantitative yields, while M-1 were prepared from deprotonation of [HC(SiMe2OCH2CH2OMe)3] (1) with LiBu t , NaCH2Ph and KCH2Ph, resp. X-ray crystallographic studies and DFT calculations in the gas-phase, including calculations of the NPA charges confirm the zwitterionic nature of these compounds, with the alkali metal cations being rigidly locked and charge separated from the anion by the internal OCH2CH2OMe donor groups. Natural bond orbital (NBO) analysis and the second order perturbation theory analysis of the NBOs reveal significant hyperconjugative interactions in M-1-M-3, primarily between the lone pair and the antibonding Si-O orbitals, the extent of which decreases in the order M-1 > M-2 > M-3. The experimental basicities and the calculated gas-phase basicities of M-1-M-3 reveal the zwitterionic alkali metal methanides M-1 to be significantly stronger bases than the analogous silanides M-2 and germanium M-3.

Phenotyping Sunflower Genetic Resources for Sclerotinia Head Rot Response: Assessing Variability for Disease Resistance Breeding.

Sclerotinia head rot (SHR) is one of the most serious constraints to sunflower (Helianthus annuus L. var. macrocarpus) production worldwide. Here, we evaluated the response to SHR in a sunflower inbred panel from a large INTA germplasm collection, consisting of 137 inbred lines (ILs). Field trials were performed over five consecutive seasons using a twice-replicated randomized complete-block design. Disease incidence, disease severity, incubation period, and area under disease progress curve for disease incidence and severity were determined after controlled inoculation with the pathogen. Statistical analysis using mixed-effect models detected significant differences among ILs for all variables (P < 0.001). In addition, principal component analysis (PCA) and distance-based methods were used to classify the ILs according to their response to SHR, with ILs ALB2/5261 and 5383 emerging as the most resistant. Broad-sense heritability estimates ranged from 20.64% for disease severity to 10.58% for incubation period. The ample phenotypic variability of our collection, along with the moderate heritability estimates, highlight the importance of molecular breeding approaches to gain new insights into the genetic basis of sunflower resistance to SHR. The exhaustive phenotypic characterization presented here provides a reliable set of variables to comprehensively evaluate the disease and identifies two new sources of resistance to SHR.

Correction: Assessing dimerisation degree and cooperativity in a biomimetic small-molecule model by pulsed EPR.

Correction for 'Assessing dimerisation degree and cooperativity in a biomimetic small-molecule model by pulsed EPR' by K. Ackermann et al., Chem. Commun., 2015, 51, 5257-5260.

Assessing dimerisation degree and cooperativity in a biomimetic small-molecule model by pulsed EPR.

Pulsed electron paramagnetic resonance (EPR) spectroscopy is gaining increasing importance as a complementary biophysical technique in structural biology. Here, we describe the synthesis, optimisation, and EPR titration studies of a spin-labelled terpyridine Zn(II) complex serving as a small-molecule model system for tuneable dimerisation.

BOLD-fMRI of PTZ-induced seizures in rats.

PURPOSE: To develop a non-invasive method for exploring seizure initiation and propagation in the brain of intact experimental animals. METHODS: We have developed and applied a model-independent statistical method--Hierarchical Cluster Analysis (HCA)--for analyzing BOLD-fMRI data following administration of pentylenetetrazol (PTZ) to intact rats. HCA clusters voxels into groups that share similar time courses and magnitudes of signal change, without any assumptions about when and/or where the seizure begins. RESULTS: Epileptiform spiking activity was monitored by EEG (outside the magnet) following intravenous PTZ (IV-PTZ; n=4) or intraperitoneal PTZ administration (IP-PTZ; n=5). Onset of cortical spiking first occurred at 29+/-16 s (IV-PTZ) and 147+/-29 s (IP-PTZ) following drug delivery. HCA of fMRI data following IV-PTZ (n=4) demonstrated a single dominant cluster, involving the majority of the brain and first activating at 27+/-23s. In contrast, IP-PTZ produced multiple, relatively small, clusters with heterogeneous time courses that varied markedly across animals (n=5); activation of the first cluster (involving cortex) occurred at 130+/-59 s. With both routes of PTZ administration, the timing of the fMRI signal increase correlated with onset of EEG spiking. CONCLUSIONS: These experiments demonstrate that fMRI activity associated with seizure activity can be analyzed with a model-independent statistical method. HCA indicated that seizure initiation in the IV- and IP-PTZ models involves multiple regions of sensitivity that vary with route of drug administration and that show significant variability across animal subjects. Even given this heterogeneity, fMRI shows clear differences that are not apparent with typical EEG monitoring procedures, in the activation patterns between IV and IP-PTZ models. These results suggest that fMRI can be used to assess different models and patterns of seizure activation.

Test-retest precision of functional magnetic resonance imaging processed with independent component analysis.

This study was designed to compare the test-retest precision of functional magnetic resonance imaging (fMRI) data processed with independent component analysis (ICA) and the same data analyzed with a conventional model-dependent method (Student's- t mapping). Volunteers underwent two or three iterations of visual and auditory stimuli, while data were collected for fMRI scans. The scan data were separately processed with ICA and with Student's- t mapping (STM). As a measure of test-retest precision, concurrence ratios were calculated for each subject and each task as the number of voxels that were activated by two iterations of a task divided by the average number of voxels activated in each repetition. In 28 test-retest comparisons, the average concurrence ratio was 0.69+/-0.10 for ICA and 0.65+/-0.13 for the conventional method, a statistically insignificant difference. In fMR image data of block stimulus paradigms, ICA had similar test-retest precision to a conventional model-dependent method.

Frequencies contributing to functional connectivity in the cerebral cortex in "resting-state" data.

BACKGROUND AND PURPOSE: In subjects performing no specific cognitive task ("resting state"), time courses of voxels within functionally connected regions of the brain have high cross-correlation coefficients ("functional connectivity"). The purpose of this study was to measure the contributions of low frequencies and physiological noise to cross-correlation maps. METHODS: In four healthy volunteers, task-activation functional MR imaging and resting-state data were acquired. We obtained four contiguous slice locations in the "resting state" with a high sampling rate. Regions of interest consisting of four contiguous voxels were selected. The correlation coefficient for the averaged time course and every other voxel in the four slices was calculated and separated into its component frequency contributions. We calculated the relative amounts of the spectrum that were in the low-frequency (0 to 0.1 Hz), the respiratory-frequency (0.1 to 0.5 Hz), and cardiac-frequency range (0.6 to 1.2 Hz). RESULTS: For each volunteer, resting-state maps that resembled task-activation maps were obtained. For the auditory and visual cortices, the correlation coefficient depended almost exclusively on low frequencies (<0.1 Hz). For all cortical regions studied, low-frequency fluctuations contributed more than 90% of the correlation coefficient. Physiological (respiratory and cardiac) noise sources contributed less than 10% to any functional connectivity MR imaging map. In blood vessels and cerebrospinal fluid, physiological noise contributed more to the correlation coefficient. CONCLUSION: Functional connectivity in the auditory, visual, and sensorimotor cortices is characterized predominantly by frequencies slower than those in the cardiac and respiratory cycles. In functionally connected regions, these low frequencies are characterized by a high degree of temporal coherence.

Effect of focal and nonfocal cerebral lesions on functional connectivity studied with MR imaging.

BACKGROUND AND PURPOSE: Functional connectivity MR (fcMR) imaging is used to map regions of brain with synchronous, regional, slow fluctuations in cerebral blood flow. We tested the hypothesis that focal cerebral lesions do not eradicate expected functional connectivity. METHODS: Functional MR (fMR) and fcMR maps were acquired for 12 patients with focal cerebral tumors, cysts, arteriovenous malformations, or in one case, agenesis of the corpus callosum. Task activation secondary to text listening, finger tapping, and word generation was mapped by use of fMR imaging. Functional connectivity was measured by selecting "seed" voxels in brain regions showing activation (based on the fMR data) and cross correlating with every other voxel (based on data acquired while the subject performed no task). Concurrence of the fMR and fcMR maps was measured by comparing the location and number of voxels selected by both methods. RESULTS: Technically adequate fMR and fcMR maps were obtained for all patients. In patients with focal lesions, the fMR and fcMR maps correlated closely. The fcMR map generated for the patient with agenesis of the corpus callosum failed to reveal functional connectivity between blood flow in the left and right sensorimotor cortices and in the frontal lobe language regions. Nonetheless, synchrony between blood flow in the auditory cortices was preserved. On average, there was 40% concurrence between all fMR and fcMR maps. CONCLUSION: Patterns of functional connectivity remain intact in patients with focal cerebral lesions. Disruption of major neuronal networks, such as agenesis of the corpus callosum, may diminish the normal functional connectivity patterns. Therefore, functional connectivity in such patients cannot be fully demonstrated with fcMR imaging.

Assessing the economic return of specializing in orthodontics or oral and maxillofacial surgery.

BACKGROUND: The authors determined the economic returns from an educational investment in the specialties of orthodontics and oral an maxillofacial surgery. They also addressed problems found in previous studies. METHODS: The marginal return for specializing in orthodontics or oral and maxillofacial surgery was determined using net present value and internal rate of return, or IRR, with the income of the general dentist serving as the common opportunity cost. Extreme scenario, threshold and one-way sensitivity analyses were used to account for variation in the data. RESULTS: The median group of orthodontists broke even 5.9 years after specialty training and had a working lifetime net return of $271,536 above that of general dentists; the IRR for them was 10.36 percent. The median group of oral and maxillofacial surgeons broke even 2.3 years after training and had a working lifetime net return of $587,563 above that of general dentists; the IRR for them was 25.30 percent. CONCLUSIONS: Under the most likely conditions, the authors found a positive economic return to dentists in both specialties from their additional dental training. PRACTICE IMPLICATIONS: The positive financial returns brought by specialization indicate that the demand for additional dental education should continue within an environment of increased educational investment costs.

Compensation of susceptibility-induced signal loss in echo-planar imaging for functional applications.

Functional magnetic resonance imaging favors the use of multi-slice gradient-recalled echo-planar imaging due to its short image acquisition times, whole brain coverage and sensitivity to BOLD contrast. However, despite its advantages, gradient-recalled echo-planar imaging also is sensitive to static magnetic field gradients arising primarily from air-tissue interfaces. This can lead to image artifacts such as voxel shifts and complete signal loss. A method to recover signal loss by adjusting the refocusing gradient amplitude in the slice-select direction, preferably axially, is proposed. This method is implemented as an automated computer algorithm that partitions echo-planar images into regions of recoverable signal intensities using a histogram analysis and determines each region's proper refocusing gradient amplitude. As an example, different refocusing gradient amplitudes are interleaved in a fMRI acquisition to maximize the signal to noise ratio and obtain functional activation in normal and dropout regions. The effectiveness of this method is demonstrated by recovering signal voids in the orbitofrontal cortex, parahippocampal/amygdala region, and inferior visual association cortex near the cerebellum.

Combining independent component analysis and correlation analysis to probe interregional connectivity in fMRI task activation datasets.

A new approach in studying interregional functional connectivity using functional magnetic resonance imaging (fMRI) is presented. Functional connectivity may be detected by means of cross correlating time course data from functionally related brain regions. These data exhibit high temporal coherence of low frequency fluctuations due to synchronized blood flow changes. In the past, this fMRI technique for studying functional connectivity has been applied to subjects that performed no prescribed task ("resting" state). This paper presents the results of applying the same method to task-related activation datasets. Functional connectivity analysis is first performed in areas not involved with the task. Then a method is devised to remove the effects of activation from the data using independent component analysis (ICA) and functional connectivity analysis is repeated. Functional connectivity, which is demonstrated in the "resting brain," is not affected by tasks which activate unrelated brain regions. In addition, ICA effectively removes activation from the data and may allow us to study functional connectivity even in the activated regions.

Whole-brain functional MR imaging activation from a finger-tapping task examined with independent component analysis.

BACKGROUND AND PURPOSE: Independent component analysis (ICA), unlike other methods for processing functional MR (fMR) imaging data, requires no a priori assumptions about the hemodynamic response to the task. The purpose of this study was to analyze the temporal characteristics and the spatial mapping of the independent components identified by ICA when the subject performs a finger-tapping task. METHODS: Ten healthy subjects performed variations of the finger-tapping task conventionally used to map the sensorimotor cortex. The scan data were processed with ICA, and the temporal configuration of the components and their spatial localizations were studied. The locations with activation were tabulated and compared with locations known to be involved in the organization of motor functions in the brain. RESULTS: Components were identified that correlated to varying degrees with the conventional boxcar reference function. One or more of these components mapped to the sensorimotor cortex, supplementary motor area (SMA), putamen, and thalamus. By means of ICA components, sensorimotor cortex, supplementary motor area, and superior cerebellar activation were identified bilaterally in 100% of the subjects; thalamus activation was contralateral to the active hand in 80%; and putamen activation was contralateral to the active hand in 60%. CONCLUSION: ICA processing of multislice fMR imaging data acquired during finger tapping identifies the sensorimotor cortex, SMA, cerebellar, putamen, and thalamic activation. ICA appears to be a method that provides information on both the temporal and spatial characteristics of activation. Multiple task-related components can be identified by ICA, and specific activation maps can be derived from each separate component.

Mapping functionally related regions of brain with functional connectivity MR imaging.

BACKGROUND AND PURPOSE: In subjects who are performing no prescribed cognitive task, functional connectivity mapped with MR imaging (fcMRI) shows regions with synchronous fluctuations of cerebral blood flow. When specific tasks are performed, functional MR imaging (fMRI) can map locations in which regional cerebral blood flow increases synchronously with the performance of the task. We tested the hypothesis that fcMRI maps, based on the synchrony of low-frequency blood flow fluctuations, identify brain regions that show activation on fMRI maps of sensorimotor, visual, language, and auditory tasks. METHODS: In four volunteers, task-activation fMRI and functional connectivity (resting-state) fcMRI data were acquired. A small region of interest (in an area that showed maximal task activation) was chosen, and the correlation coefficient of the corresponding resting-state signal with the signal of all other voxels in the resting data set was calculated. The correlation coefficient was decomposed into frequency components and its distribution determined for each fcMRI map. The fcMRI maps were compared with the fMRI maps. RESULTS: For each task, fcMRI maps based on one to four seed voxel(s) produced clusters of voxels in regions of eloquent cortex. For each fMRI map a closely corresponding fcMRI map was obtained. The frequencies that predominated in the cross-correlation coefficients for the functionally related regions were below 0.1 Hz. CONCLUSION: Functionally related brain regions can be identified by means of their synchronous slow fluctuations in signal intensity. Such blood flow synchrony can be detected in sensorimotor areas, expressive and receptive language regions, and the visual cortex by fcMRI. Regions identified by the slow synchronous fluctuations are similar to those activated by motor, language, or visual tasks.

Functional connectivity in the thalamus and hippocampus studied with functional MR imaging.

BACKGROUND AND PURPOSE: With functional connectivity functional MR imaging, co-variance in signal intensity has been shown in functionally related regions of brain in participants instructed to perform no cognitive task. These changes are thought to represent synchronous fluctuations in blood flow, which imply neuronal connections between the regions. The purpose of this study was to map functional connectivity in subcortical nuclei with functional connectivity functional MR imaging. METHODS: Imaging data were acquired with an echo-planar sequence from six volunteers who performed no specific cognitive task. For functional connectivity functional MR imaging, a "seed" voxel or group of voxels was selected from the resting data set in the thalamus or in the hippocampus. Control voxels in gray matter presumed not to be eloquent cortex were also chosen. The correlation coefficient of the seed voxels and the control voxels with every other voxel in the resting data set was calculated. The voxels with correlation coefficients greater than or equal to 0.5 were mapped onto anatomic images for the functional connectivity functional MR images. The anatomic location of these voxels was determined by conventional parcellation methods. RESULTS: For each participant, functional connectivity functional MR imaging maps based on four seed voxels in the thalamus or hippocampus showed clusters of voxels in the ipsilateral and contralateral thalamus or hippocampus. For control voxels, few voxels in the hippocampus or thalamus showed significant correlation. Significantly more pixels in the ipsilateral hippocampus correlated with the seed voxel than in the contralateral hippocampus. The differences between numbers of functionally connected voxels in ipsilateral thalamus and those in contralateral thalamus were not significant. CONCLUSIONS: The thalamus and hippocampus show functional connectivity, presumably representing synchronous changes in blood flow.

Functional MR imaging activation after finger tapping has a shorter duration in the basal ganglia than in the sensorimotor cortex.

BACKGROUND AND PURPOSE: Repetitive motor tasks that produce sustained neuronal activity in the sensorimotor cortex produce transient neuronal activity in subcortical regions. We tested the hypothesis that a reference function modeling a transient hemodynamic response would more reliably detect activation in the basal ganglia than would a conventional reference function, which models a sustained hemodynamic response. METHODS: Functional MR imaging data were acquired in eight subjects performing an alternating-hand finger-tapping task. Postprocessing was performed by cross-correlation to two types of reference functions: one that models a sustained hemodynamic response to finger tapping and one that models an initial transient hemodynamic response. Activation in the sensorimotor cortex, supplementary motor area, cerebellum, thalamus, and corpus striatum was tabulated for each reference function. RESULTS: With the conventional boxcar reference function, activation was detected in the sensorimotor cortex, supplementary motor area, and cerebellum, but intermittently in the corpus striatum in all subjects. With the reference function for a transient response, activation in the corpus striatum was not detected in all subjects. CONCLUSION: In the corpus striatum, activation is detected more frequently with a reference function that models a transient response. Activated cortical and subcortical regions can be mapped with an alternating-hand finger-tapping paradigm and a combination of reference functions.

Self-care strategies for symptom management in patients with chronic heart failure.

BACKGROUND: The troublesome symptoms experienced by patients with chronic heart failure are associated with diminished quality of life, frequent hospitalizations, and mortality. OBJECTIVES: To describe the symptoms experienced by patients with heart failure, to detail the self-care strategies used by these patients in managing their symptoms, and to categorize the self-care strategies. METHODS: Six focus groups were used with 23 patients who had heart failure, along with six focus groups with 18 family members of the patients. Data analysis was performed by transcription of audiotape recordings of the group sessions and review of field notes. RESULTS: The patients reported a large number of troublesome symptoms, many consistent with past empirical findings, but some not reported in previous studies. Self-care strategies to manage the symptoms clustered into 11 categories. CONCLUSIONS: Results from this study provided direction for future studies to (a) identify the prevalence, severity, and etiologies of the commonly reported symptoms, particularly cognitive impairment, loss of balance, and depression; (b) evaluate the emotions reported by women with heart failure; and (c) test the strategies as part of an intervention program to improve symptom management in patients with heart failure.

Spontaneous pericardial hematoma in an infant.

The finding of a pericardial hematoma is rare in the pediatric population. Its occurrence in an otherwise healthy 3-month-old infant is unprecedented in the literature. The hematoma was initially identified by echocardiography. Computerized tomography and magnetic resonance imaging did not contribute to the identification of the mass. An exploratory thoracotomy was necessary to rule out a neoplastic process. The final diagnosis of hemorrhagic pericarditis was made.

Basic concepts of functional magnetic resonance imaging and arteriovenous malformations

Cortical mapping is an important adjunct to the workup of patients with arteriovenous malformation (AVMs) near eloquent cortical regions. Task activation imaging can be performed that clearly identifies primary cortical regions. Although current methods require considerable postprocessing, advances in hardware and software will likely make functional MR imaging a routing examination before surgical resection of AVMs in the near future.

Basic concepts of functional arteriovenous MR imaging malformations.

This article reviews the technical features of functional MR imaging. Examples are presented demonstrating how MR imaging may be used to identify primary cortical regions adjacent to AVMs. Preliminary results suggest that cortical functions may undergo translocation when the AVM involves eloquent cortex. This finding underscores the importance of cortical mapping prior to surgical excision.