Functional magnetic resonance imaging in oncology: state of the art

In the investigation of tumors with conventional magnetic resonance imaging, both quantitative characteristics, such as size, edema, necrosis, and presence of metastases, and qualitative characteristics, such as contrast enhancement degree, are taken into consideration. However, changes in cell metabolism and tissue physiology which precede morphological changes cannot be detected by the conventional technique. The development of new magnetic resonance imaging techniques has enabled the functional assessment of the structures in order to obtain information on the different physiological processes of the tumor microenvironment, such as oxygenation levels, cellularity and vascularity. The detailed morphological study in association with the new functional imaging techniques allows for an appropriate approach to cancer patients, including the phases of diagnosis, staging, response evaluation and follow-up, with a positive impact on their quality of life and survival rate.

Versatile methodology to hydrate alkynes, in the presence of a wide variety of functional groups, with Mercury(II) p-Toluensulfonamidate, under catalytic, mild and neutral conditions

A method to generate carbonylic compounds from alkynes under mild and neutral conditions, with excellent functional group compatibility and high yields, is described. Hydration takes place under catalytic conditions by using from 0.1 to 0.2 equivalents of the easily available and inexpensive mercury(II) p-toluensulfonamidate in a hydroalcoholic solution. After use the catalyst is iner tized and/or recycled ...

Weakened functional connectivity in patients with psychogenic non-epileptic seizures (PNES) converges on basal ganglia.

BACKGROUND: Psychogenic non-epileptic seizures (PNES) are involuntary paroxysmal events that are unaccompanied by epileptiform EEG discharges. We hypothesised that PNES are a disorder of distributed brain networks resulting from their functional disconnection.The disconnection may underlie a dissociation mechanism that weakens the influence of unconsciously presented traumatising information but exerts maladaptive effects leading to episodic failures of behavioural control manifested by psychogenic 'seizures'. METHODS: To test this hypothesis, we compared functional connectivity (FC) derived from resting state high-density EEGs of 18 patients with PNES and 18 age-matched and gender-matched controls. To this end, the EEGs were transformed into source space using the local autoregressive average inverse solution. FC was estimated with a multivariate measure of lagged synchronisation in the θ, α and β frequency bands for 66 brain sites clustered into 18 regions. A multiple comparison permutation test was applied to deduce significant between-group differences in inter-regional and intraregional FC. RESULTS: The significant effect of PNES-a decrease in lagged FC between the basal ganglia and limbic, prefrontal, temporal, parietal and occipital regions-was found in the α band. CONCLUSION: We believe that this finding reveals a possible neurobiological substrate of PNES, which explains both attenuation of the effect of potentially disturbing mental representations and the occurrence of PNES episodes. By improving understanding of the aetiology of this condition, our results suggest a potential refinement of diagnostic criteria and management principles.

Functional EF-hands in neuronal calcium sensor GCAP2 determine its phosphorylation state and subcellular distribution in vivo, and are essential for photoreceptor cell integrity

The neuronal calcium sensor proteins GCAPs (guanylate cyclase activating proteins) switch between Ca2+-free and Ca2+-bound conformational states and confer calcium sensitivity to guanylate cyclase at retinal photoreceptor cells. They play a fundamental role in light adaptation by coupling the rate of cGMP synthesis to the intracellular concentration of calcium. Mutations in GCAPs lead to blindness. The importance of functional EF-hands in GCAP1 for photoreceptor cell integrity has been well established. Mutations in GCAP1 that diminish its Ca2+ binding affinity lead to cell damage by causing unabated cGMP synthesis and accumulation of toxic levels of free cGMP and Ca2+. We here investigate the relevance of GCAP2 functional EF-hands for photoreceptor cell integrity. By characterizing transgenic mice expressing a mutant form of GCAP2 with all EF-hands inactivated (EF(-)GCAP2), we show that GCAP2 locked in its Ca2+-free conformation leads to a rapid retinal degeneration that is not due to unabated cGMP synthesis. We unveil that when locked in its Ca2+-free conformation in vivo, GCAP2 is phosphorylated at Ser201 and results in phospho-dependent binding to the chaperone 14-3-3 and retention at the inner segment and proximal cell compartments. Accumulation of phosphorylated EF(-)GCAP2 at the inner segment results in severe toxicity. We show that in wildtype mice under physiological conditions, 50% of GCAP2 is phosphorylated correlating with the 50% of the protein being retained at the inner segment. Raising mice under constant light exposure, however, drastically increases the retention of GCAP2 in its Ca2+-free form at the inner segment. This study identifies a new mechanism governing GCAP2 subcellular distribution in vivo, closely related to disease. It also identifies a pathway by which a sustained reduction in intracellular free Ca2+ could result in photoreceptor damage, relevant for light damage and for those genetic disorders resulting in 'equivalent-light'' scenarios.

Anoxic-ischemic encephalopathy: association of predictors with the vital and functional prognosis of patients

Improve the prediction of the vital and functional prognosis of comatose patients suffering from anoxic-ischemic encephalopathy after successful resuscitation from a cardiac arrest, addmitted to the Intensive Care and Coronary Units of the Dr. Josep Trueta Hospital, based on clinical, neurophysiological and biochemical results.The results of these different tests, revised and combined all together, will improve the prediction of the patients' prognosis, leading to an accurate vital and functional outcome, as they only have been studied separately so far. Anoxia is the third most frequent cause of coma, and the most common cause of post-anoxic coma in adults is the cardiac arrest. The incidence of hypoxic-ischemic brain injury is not well known, but it is certain that cardiac arrest, the most common cause of post-anoxic coma, affects approximately 24000 to 50000 Spanish people every year, most of them occuring out of the hospital. A cardiac arrest is the abrupt cessation of normal circulation of the blood due to failure of the heart to contract effectively during systole. It is different from, but may be caused by, a heart attack or myocardial infarction, where blood flow to the still-beating heart is interrupted. Arrested blood circulation prevents delivery of oxygen to all parts of the body. Cerebral hypoxia, or lack of oxygen supply to the brain, causes victims to lose consciousness and to stop normal breathing, although agonal breathing may still occur. Brain injury is likely if cardiac arrest is untreated for more than five minutes

Microstructural Brain Differences Predict Functional Hemodynamic Responses in a Reward Processing Task

Many aspects of human behavior are driven by rewards, yet different people are differentially sensitive to rewards and punishment. In this study, we showthat white matter microstructure inthe uncinate/inferiorfronto-occipitalfasciculus, defined byfractional anisotropy values derived from diffusion tensor magnetic resonance images, correlates with both short-term (indexed by the fMRI blood oxygenation level-dependent response to reward in the nucleus accumbens) and long-term (indexed by the trait measure sensitivity to punishment) reactivityto rewards.Moreover,traitmeasures of reward processingwere also correlatedwith reward-relatedfunctional activation in the nucleus accumbens. The white matter tract revealed by the correlational analysis connects the anterior temporal lobe with the medial and lateral orbitofrontal cortex and also supplies the ventral striatum. The pattern of strong correlations suggests an intimate relationship betweenwhitematter structure and reward-related behaviorthatmay also play a rolein a number of pathological conditions, such as addiction and pathological gambling.

Pilot study about the effect of rt-PA administration on the excitotoxicity mediated brain damage and its repercussion on the functional prognosis of patients with ischaemic stroke: research protocol

Fibrinolytic therapy with Recombinant Tissue-Plasminogen Activator (rt-PA) is currently the only effective treatment for ischaemic stroke in its acute phase. Even though its use generally improves the prognosis of those patients likely to receive it, rt-PA administration is associated to several risks, such as haemorrhagic transformation ofthe ischaemic lesion and activation of excitotoxic mechanisms that may contribute to an increase in mortality or to a poor outcome in certain occasions, specially when arterial recanalization is not achieved or the rt-PA is lately administrated. Since in the last few years the role of glutamate in the neurotoxicity associated toischaemia has been widely studied and it is known that high plasma glutamate levels are predictors of ischaemic lesion growth and poor neurological outcome, it is necessary to find out which factors can contribute to glutamate release in the brain. The aim of this study is to determine if rt-PA administration is related to an increase in plasma glutamate levels, as well as to define if higher plasma glutamate levels at admission are related to different evolution and prognosis of our patients, both in those in which recanalisation is achieved and not. A series of cases of patients with hemispheric cerebral infarction admitted in our hospital during a year will be studied, and the data obtained from them will be compared to the data obtained from a control group, the samples of wich were takenyears ago, before rt-PA was routinely used

Highly functional binding surface for miniaturised solid-phase immunoassays. - A spot story -

Several bioaffinity assays are based on the detection of an analyte which is bound on a solid substrate via biochemical interaction. These so called solid phase assays are based on the adhesion of the primary binding partner on a solid surface, which then binds the analyte to be detected. In this thesis work a novel solid phase based assay technology, known as spot technology, was developed. The spot technology is based on combination of high-capacity solid phases, concentrated in a spot format, utilising modified streptavidin molecules and recombinant antibody fragments. The reduction of the solid phase binding surface to a size of a spot enabled denser binding of the target molecules, providing improved signal intensities and signal-to-background ratio when applied in different solid phase immunoassays. Streptavidin-biotin interactions are commonly utilised in numerous different bioaffinity assays and the ultimate nature of streptavidin to bind biotin is among the strongest non-covalent interaction reported between two biomolecules. In this study native core streptavidin was chemically modified to provide polymerised streptavidin molecules with altered adsorption properties. These streptavidin conjugates, when coated onto polystyrene surface, provided enhanced biotin binding capacity and surface stability when compared to a reference coating constructed with native streptavidin. Furthermore, the combination of chemically modified streptavidin, sitespecifically biotinylated antibody fragments and the spot coating technology provided highly dense solid phase coating with improved binding properties. The performance of the spot assay technology was further demonstrated in different immunoassay configurations. Human thyroid stimulating hormone (TSH) and human cardiac troponin I (cTnI) were used as model analytes to show the applicability of the highly sensitive spot-based solid-phase immunoassay for detection of very low levels of analytes. It was demonstrated that the spot technology provided an assay concept with enhanced sensitivity and short turn-around times, characteristics that are highly suitable for point-of-care applications.

Functional diversity of macrophyte communities within and between Pyrenean lakes

Submersed vegetation is a common feature in about 70% Pyrene an high mountain (>1500 m a.s.l.) lakes. Isoetids and soft-water elodeids are common elements of this underw ater flora and can form distinct vegetation units (i.e. patches of vegetation dominated by different species) within complex mosaics of vegetation in shallow waters (<7 m). Since is oetids exert a strong influence on sediment biogeochemistry due to high radial oxygen loss, we examined the small scale characteristics of the lake environment (water and sediment) associated to vegetation patches in order to ascertain potential functional differences among them. To do so, we characterised the species composition and biomass of the main vegetation units from 11 lakes, defined plant communities based on biomass data, and then related each community with sediment properties (redox and dissolved nutrient concentration in the pore water) and water nutrient concentration within plant canopy. We also characterised lake water and sediment in areas without vegetation as a reference. A total of twenty-one vegetation units were identified, ranging from one to five per lake. A cluster analysis on biomass species composition suggested seven different macrophyte communities that were named after the most dominant species:Nitella sp.,Potamogeton praelongus, Myriophyllum alterniflorum, Sparganium angustifolium , Isoetes echinospora,Isoetes lacustris and Carex rostrata . Coupling between macrophyte communities and their immediate environment (overlying water and sediment) was manifested mainly as variation in sediment redox conditions and the dominant form of inorganic nitrogen in pore-water. These effects depended on the specific compositi on of the community, and on the allocation between above- and belowground biomass, and could be predicted with a model relating the average and standard deviation of sediment redox potential from 0 down to -20 cm, across macrophyte communities. Differences in pore-water total dissolved phosphorus were related to the trophic state of the lakes. There was no correlation between sediment and water column dissolved nutrients. However, nitrate concentrations tended to be lower in the water overlaying isoetid communities, in apparent contradiction to the patterns of dissolved nitrates in the pore-water. These tendencies were robust even when comparing the water over laying communities within the same lake, thus pointing towards a potential effect of isoetids in reducing dissolved nitrogen in the lakes.

Music-supported training is more efficient than functional motor training for recovery of fine motor skills in stroke patients

MOTOR IMPAIRMENTS ARE COMMON AFTER STROKE but efficacious therapies for these dysfunctions are scarce. Extending an earlier study on the effects of music-supported training (MST), behavioral indices of motor function were obtained before and after a series of training sessions to assess whether this new treatment leads to improved motor functions. Furthermore, music-supported training was contrasted to functional motor training according to the principles of constraint-induced therapy (CIT). In addition to conventional physiotherapy, 32 stroke patients with moderately impaired motor function and no previous musical experience received 15 sessions of MST over a period of three weeks, using a manualized, step-bystep approach. A control group consisting of 15 patients received 15 sessions of CIT in addition to conventional physiotherapy. A third group of 30 patients received exclusively conventional physiotherapy and served as a control group for the other three groups. Fine as well as gross motor skills were trained by using either a MIDI-piano or electronic drum pads programmed to emit piano tones. Motor functions were assessed by an extensive test battery. MST yielded significant improvement in fine as well as gross motor skills with respect to speed, precision, and smoothness of movements. These improvements were greater than after CIT or conventional physiotherapy. In conclusion, with equal treatment intensity, MST leads to more pronounced improvements of motor functions after stroke than CIT.

Functional neuroanatomy of contextual acquisition of concrete and abstract words

The meaning of a novel word can be acquired by extracting it from linguistic context. Here we simulated word learning of new words associated to concrete and abstract concepts in a variant of the human simulation paradigm that provided linguistic context information in order to characterize the brain systems involved. Native speakers of Spanish read pairs of sentences in order to derive the meaning of a new word that appeared in the terminal position of the sentences. fMRI revealed that learning the meaning associated to concrete and abstract new words was qualitatively different and recruited similar brain regions as the processing of real concrete and abstract words. In particular, learning of new concrete words selectively boosted the activation of the ventral anterior fusiform gyrus, a region driven by imageability, which has previously been implicated in the processing of concrete words.

Essential factors for control of the equilibrium in the reversible rearrangement of M3N@Ih-C80 fulleropyrrolidines: Exohedral functional groups versus endohedral metal clusters

The effects of exohedral moieties and endohedral metal clusters on the isomerization of M3N@Ih-C80 products from the Prato reaction through [1,5]-sigmatropic rearrangement were systematically investigated by using three types of fulleropyrrolidine derivatives and four different endohedral metal clusters. As a result, all types of derivatives provided the same ratios of the isomers for a given trimetallic nitride template (TNT) as the thermodynamic products, thus indicating that the size of the endohedral metal clusters inside C80 was the single essential factor in determining the equilibrium between the [6,6]-isomer (kinetic product) and the [5,6]-isomer. In all the derivatives, the [6,6]- and [5,6]-Prato adducts with larger metal clusters, such as Y3N and Gd3N, were equally stable, which is in good agreement with DFT calculations. The reaction rate of the rearrangement was dependent on both the substituent of exohedral functional groups and the endohedral metal-cluster size. Further DFT calculations and 13C NMR spectroscopic studies were employed to rationalize the equilibrium in the rearrangement between the [6,6]- and [5,6]-fulleropyrrolidines

Functional connectivity of reward processing in the brain

Controversial results have been reported concerning the neural mechanisms involved in the processing of rewards and punishments. On the one hand, there is evidence suggesting that monetary gains and losses activate a similar fronto-subcortical network. On the other hand, results of recent studies imply that reward and punishment may engage distinct neural mechanisms. Using functional magnetic resonance imaging (fMRI) we investigated both regional and interregional functional connectivity patterns while participants performed a gambling task featuring unexpectedly high monetary gains and losses. Classical univariate statistical analysis showed that monetary gains and losses activated a similar fronto-striatallimbic network, in which main activation peaks were observed bilaterally in the ventral striatum. Functional connectivity analysis showed similar responses for gain and loss conditions in the insular cortex, the amygdala, and the hippocampus that correlated with the activity observed in the seed region ventral striatum, with the connectivity to the amygdala appearing more pronounced after losses. Larger functional connectivity was found to the medial orbitofrontal cortex for negative outcomes. The fact that different functional patterns were obtained with both analyses suggests that the brain activations observed in the classical univariate approach identifi es the involvement of different functional networks in the current task. These results stress the importance of studying functional connectivity in addition to standard fMRI analysis in reward-related studies.

Functional neuroanatomy of meaning acquisition from context

An important issue in language learning is how new words are integrated in the brain representations that sustain language processing. To identify the brain regions involved in meaning acquisition and word learning, we conducted a functional magnetic resonance imaging study. Young participants were required to deduce the meaning of a novel word presented within increasingly constrained sentence contexts that were read silently during the scanning session. Inconsistent contexts were also presented in which no meaning could be assigned to the novel word. Participants showed meaning acquisition in the consistent but not in the inconsistent condition. A distributed brain network was identified comprising the left anterior inferior frontal gyrus (BA 45), the middle temporal gyrus (BA 21), the parahippocampal gyrus, and several subcortical structures (the thalamus and the striatum). Drawing on previous neuroimaging evidence, we tentatively identify the roles of these brain areas in the retrieval, selection, and encoding of the meaning.