From individual to collective 3D cancer dissemination: roles of collagen concentration and TGF-ß.

Cancer cells have the ability to migrate from the primary (original) site to other places in the body. The extracellular matrix affects cancer cell migratory capacity and has been correlated with tissue-specific spreading patterns. However, how the matrix orchestrates these behaviors remains unclear. Here, we investigated how both higher collagen concentrations and TGF-ß regulate the formation of H1299 cell (a non-small cell lung cancer cell line) spheroids within 3D collagen-based matrices and promote cancer cell invasive capacity. We show that at low collagen concentrations, tumor cells move individually and have moderate invasive capacity, whereas when the collagen concentration is increased, the formation of cell clusters is promoted. In addition, when the concentration of TGF-ß in the microenvironment is lower, most of the clusters are aggregates of cancer cells with a spheroid-like morphology and poor migratory capacity. In contrast, higher concentrations of TGF-ß induced the formation of clusters with a notably higher invasive capacity, resulting in clear strand-like collective cell migration. Our results show that the concentration of the extracellular matrix is a key regulator of the formation of tumor clusters that affects their development and growth. In addition, chemical factors create a microenvironment that promotes the transformation of idle tumor clusters into very active, invasive tumor structures. These results collectively demonstrate the relevant regulatory role of the mechano-chemical microenvironment in leading the preferential metastasis of tumor cells to specific tissues with high collagen concentrations and TFG-ß activity.

Quantifying 3D chemotaxis in microfluidic-based chips with step gradients of collagen hydrogel concentrations.

Cell migration is an essential process involved in crucial stages of tissue formation, regeneration or immune function as well as in pathological processes including tumor development or metastasis. During the last few years, the effect of gradients of soluble molecules on cell migration has been widely studied, and complex systems have been used to analyze cell behavior under simultaneous mechano-chemical stimuli. Most of these chemotactic assays have, however, focused on specific substrates in 2D. The aim of the present work is to develop a novel microfluidic-based chip that allows the long-term chemoattractant effect of growth factors (GFs) on 3D cell migration to be studied, while also providing the possibility to analyze the influence of the interface generated between different adjacent hydrogels. Namely, 1.5, 2, 2.5 and 4 mg ml-1 concentrations of collagen type I were alternatively combined with 5, 10 or 50 ng ml-1 concentrations of PDGF and VEGF (as a negative control). To achieve this goal, we have designed a new microfluidic device including three adjacent chambers to introduce hydrogels that allow the generation of a collagen concentration step gradient. This versatile and simple platform was tested by using dermal human fibroblasts embedded in 3D collagen matrices. Images taken over a week were processed to quantify the number of cells in each zone. We found, in terms of cell distribution, that the presence of PDGF, especially in small concentrations, was a strong chemoattractant for dermal human fibroblasts across the gels regardless of their collagen concentration and step gradient direction, whereas the effects of VEGF or collagen step gradient concentrations alone were negligible.

Subsurface imaging of silicon nanowire circuits and iron oxide nanoparticles with sub-10 nm spatial resolution.

Non-destructive subsurface characterization of nanoscale structures and devices is of significant interest in nanolithography and nanomanufacturing. In those areas, the accurate location of the buried structures and their nanomechanical properties are relevant for optimization of the nanofabrication process and the functionality of the system. Here we demonstrate the capabilities of bimodal and trimodal force microscopy for imaging silicon nanowire devices buried under an ultrathin polymer film. We resolve the morphology and periodicities of silicon nanowire pairs. We report a spatial resolution in the sub-10 nm range for nanostructures buried under a 70 nm thick polymer film. By using numerical simulations we explain the role of the excited modes in the subsurface imaging process. Independent of the bimodal or trimodal atomic force microscopy approach, the fundamental mode is the most suitable for tracking the topography while the higher modes modulate the interaction of the tip with the buried nanostructures and provide subsurface contrast.

Continuous-wavelet-transform analysis of the multifocal ERG waveform in glaucoma diagnosis.

The vast majority of multifocal electroretinogram (mfERG) signal analyses to detect glaucoma study the signals' amplitudes and latencies. The purpose of this paper is to investigate application of wavelet analysis of mfERG signals in diagnosis of glaucoma. This analysis method applies the continuous wavelet transform (CWT) to the signals, using the real Morlet wavelet. CWT coefficients resulting from the scale of maximum correlation are used as inputs to a neural network, which acts as a classifier. mfERG recordings are taken from the eyes of 47 subjects diagnosed with chronic open-angle glaucoma and from those of 24 healthy subjects. The high sensitivity in the classification (0.894) provides reliable detection of glaucomatous sectors, while the specificity achieved (0.844) reflects accurate detection of healthy sectors. The results obtained in this paper improve on the previous findings reported by the authors using the same visual stimuli and database.

Improved measurement of intersession latency in mfVEPs.

PURPOSE: The purpose of the study is to present a method (Selfcorr) by which to measure intersession latency differences between multifocal VEP (mfVEP) signals. METHODS: The authors compared the intersession latency difference obtained using a correlation method (Selfcorr) against that obtained using a Template method. While the Template method cross-correlates the subject's signals with a reference database, the Selfcorr method cross-correlates traces across subsequent recordings taken from the same subject. RESULTS: The variation in latency between intersession signals was 0.8 ± 13.6 and 0.5 ± 5.0 ms for the Template and Selfcorr methods, respectively, with a coefficient of variability CV_TEMPLATE = 15.83 and CV_SELFCORR = 5.68 (n = 18, p = 0.0002, Wilcoxon). The number of analyzable sectors with the Template and Selfcorr methods was 36.7 ± 8.5 and 45.3 ± 8.7, respectively (p = 0.0001, paired t test, two tailed). CONCLUSIONS: The Selfcorr method produces smaller intersession mfVEP delays and variability over time than the Template method.

Paroxysmal MEG activity in obsessive compulsive patients without SSRIs therapy.

We describe a fronto-temporal paroxysmal rhythmic activity registered by magnetoencephalography (MEG) in two patients with obsessive compulsive disorder (OCD) without SSRIs treatment. The localization of the activity involves cingulate cortex and frontal areas. We think that these MEG findings are related to the disease itself, rather than representing pharmacological SSRIs effect.

Síntomas de epilepsia parietal probablemente asociados al uso de topiramato en un caso de epilepsia temporal / Symptoms of parietal epilepsy probably associated to the use of topiramate in a case of temporal epilepsy

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[Frontal seizures recorded by magnetoencephalography. Case report]. / Crisis frontales registradas mediante magnetoencefalografía. Caso clínico.

INTRODUCTION: This paper reports the usefulness of magnetoencephalography (MEG) in the anatomical localization of the onset and spread of seizures. CASE REPORT: In a 34-year-old male patient who suffered from drug-resistant complex partial seizures (sometimes generalized) with loss of awareness, magnetic resonance imaging revealed a probable left frontobasal cortical dysplasia. Ictal scalp electroencephalogram showed left frontotemporal theta waves. Electrocorticography (ECoG) registered interictal polyspike discharges and located the seizure onset in the lateral orbital side of the left frontal lobe. Three seizures were registered by MEG, clinically similar to the ones usually experienced by the patient. MEG ictal spike dipole location showed seizure onset coming from the left inferior frontal gyrus (as the ECoG), spreading on to other frontal areas, insula and temporal lobe, all in the left hemisphere. CONCLUSION: MEG may be considered as a useful diagnosis modality in the study of partial seizure physiopathology as well as in its presurgical evaluation.

Crisis frontales registradas mediante magnetoencefalografía. Caso clínico / Frontal seizures recorded by magnetoencephalography. Case report

Introducción. Este artículo expone un ejemplo de la utilidadde la magnetoencefalografía (MEG) en la localización anatómicadel inicio y la propagación de las crisis epilépticas. Caso clínico.Se trata de un paciente de 34 años con crisis parciales complejas farmacorresistentes.La resonancia magnética presenta una probabledisplasia cortical frontobasal izquierda. El electroencefalograma ictalde superficie revela ondas theta frontotemporales izquierdas. Enel registro con electrodos subdurales se demuestra la existencia deanomalías epileptiformes interictales durante el sueño, entre las quepredominan las polipuntas, y crisis de inicio focal en la cara lateroorbitariadel lóbulo frontal izquierdo. La MEG registra tres crisis clínicamentesimilares a las experimentadas por el paciente y permitelocalizar el inicio de las crisis en la circunvolución frontal inferiorizquierda, con propagación a otras áreas frontales, la ínsula y ellóbulo temporal, todo ello en el hemisferio izquierdo. Conclusión. LaMEG puede considerarse como un elemento diagnóstico útil en el estudiode la fisiopatología de las crisis parciales, así como en la evaluaciónprequirúrgica

Introduction. This paper reports the usefulness of magnetoencephalography (MEG) in the anatomical localization ofthe onset and spread of seizures. Case report. In a 34-year-old male patient who suffered from drug-resistant complex partialseizures (sometimes generalized) with loss of awareness, magnetic resonance imaging revealed a probable left frontobasalcortical dysplasia. Ictal scalp electroencephalogram showed left frontotemporal theta waves. Electrocorticography (ECoG)registered interictal polyspike discharges and located the seizure onset in the lateral orbital side of the left frontal lobe. Threeseizures were registered by MEG, clinically similar to the ones usually experienced by the patient. MEG ictal spike dipolelocation showed seizure onset coming from the left inferior frontal gyrus (as the ECoG), spreading on to other frontal areas,insula and temporal lobe, all in the left hemisphere. Conclusion. MEG may be considered as a useful diagnosis modality in thestudy of partial seizure physiopathology as well as in its presurgical evaluation

Profiles of brain magnetic activity during a memory task in patients with Alzheimer's disease and in non-demented elderly subjects, with or without depression.

The presence of depression is common among the elderly and it often complicates the early diagnosis of Alzheimer's disease (AD). In this study, we searched for brain activity measures that characterise AD. We compared brain magnetic activity profiles during a memory task, obtained from patients with AD, elderly patients with late onset depression, and age matched volunteers without history of neurological or psychiatric disease. AD patients showed significantly reduced activity in left temporal lobe regions during late portions of the event related magnetic response (400 ms or later after stimulus onset), compared with both groups of patients who did not present with serious cognitive decline. This finding highlights the potential usefulness of MEG protocols supporting the differential diagnosis of AD and major depression related cognitive decline in the elderly.

[A magnetoencephalographic study of generalised developmental disorders. A new proposal for their classification]. / Estudio mediante magnetoencefalografia de los trastornos generalizados del desarrollo. Nueva propuesta de clasificacion.

INTRODUCTION: Autistic spectrum disorders (ASD) is a term that is not included in DSM IV or in ICD 10, which are the diagnostic tools most commonly used by clinical professionals but can offer problems in research when it comes to finding homogenous groups. DEVELOPMENT: From a neuropaediatric point of view, there is a need for a classification of the generalised disorders affecting development and for this purpose we used Wing's triad, which defines the continuum of the autistic spectrum, and the information provided by magnetoencephalography (MEG) as grouping elements. Specific generalised developmental disorders were taken as being those syndromes that partially expressed some autistic trait, but with their own personality so that they could be considered to be a specific disorder. ASD were classified as being primary, cryptogenic or secondary. The primary disorders, in turn, express a continuum that ranges from Savant syndrome to Asperger's syndrome and the different degrees of early infantile autism. MEG is a functional neuroimaging technique that has enabled us to back up this classification.

Cortical organization for receptive language functions in Chinese, English, and Spanish: a cross-linguistic MEG study.

Chinese differs from Indo-European languages in both its written and spoken forms. Being a tonal language, tones convey lexically meaningful information. The current study examines patterns of neurophysiological activity in temporal and temporoparietal brain areas as speakers of two Indo-European languages (Spanish and English) and speakers of Mandarin-Chinese were engaged in a spoken-word recognition task that is used clinically for the presurgical determination of hemispheric dominace for receptive language functions. Brain magnetic activation profiles were obtained from 92 healthy adult volunteers: 30 monolingual native speakers of Mandarin-Chinese, 20 Spanish-speaking, and 42 native speakers of American English. Activation scans were acquired in two different whole-head MEG systems using identical testing methods. Results indicate that (a) the degree of hemispheric asymmetry in the duration of neurophysiological activity in temporal and temporoparietal regions was reduced in the Chinese group, (b) the proportion of individuals who showed bilaterally symmetric activation was significantly higher in this group, and (c) group differences in functional hemispheric asymmetry were first noted after the initial sensory processing of the word stimuli. Furthermore, group differences in the degree of hemispheric asymmetry were primarily due to greater degree of activation in the right temporoparietal region in the Chinese group, suggesting increased participation of this region in the spoken word recognition in Mandarin-Chinese.

Estudio mediante magnetoencefalografía de los trastornos generalizados del desarrollo. Nueva propuesta de clasificación / A magnetoencephalographic study of generalised developmental disorders. A new proposal for their classification

Introducción. ‘Trastornos del espectro autista’ (TEA) constituye un término no incluido en DSM-IV ni en ICD-10, instrumentos de diagnóstico utilizados ampliamente por los profesionales clínicos, pero que en investigación pueden ocasionar problemas a la hora de encontrar grupos homogéneos. Desarrollo. Desde el punto de vista neuropediátrico es necesaria una clasificación de los trastornos generalizados del desarrollo, y para ello hemos utilizado como elementos de agrupación la tríada de Wing, que define el continuo del espectro autista, y la información proporcionada por la magnetoencefalografía (MEG). Se han considerado trastornos generalizados del desarrollo específicos aquellos síndromes que en parte expresaban algún rasgo autista, pero con personalidad propia para considerarse un trastorno específico. Los TEA se han clasificado en primarios, criptogenéticos y secundarios. Los primarios, a su vez expresan, un continuo desde síndrome de savant hasta síndrome de Asperger y autismo infantil precoz en sus diversos grados. La MEG es una técnica de neuroimagen funcional que nos ha permitido apoyar esta clasificación (AU)

Introduction. Autistic spectrum disorders (ASD) is a term that is not included in DSM-IV or in ICD-10, which are the diagnostic tools most commonly used by clinical professionals but can offer problems in research when it comes to finding homogenous groups. Development. From a neuropaediatric point of view, there is a need for a classification of the generalised disorders affecting development and for this purpose we used Wing’s triad, which defines the continuum of the autistic spectrum, and the information provided by magnetoencephalography (MEG) as grouping elements. Specific generalised developmental disorders were taken as being those syndromes that partially expressed some autistic trait, but with their own personality so that they could be considered to be a specific disorder. ASD were classified as being primary, cryptogenic or secondary. The primary disorders, in turn, express a continuum that ranges from Savant syndrome to Asperger’s syndrome and the different degrees of early infantile autism. MEG is a functional neuroimaging technique that has enabled us to back up this classification (AU)

[Cognition and neural networks, a new perspective based on functional neuroimaging]. / Cognición y redes neurales, una nueva perspectiva desde la neuroimagen funcional.

AIM: We went through a critical review of the current status of neuroimaging studies of cognition. Thus, we argue why the use of a neuronal network perspective could led us to a better understanding of cognition than a localizationism perspective. METHOD: The question about how cognitive functions are organized in the brain, comes from the very early lesions studies. Electrocortical stimulation and the intracorotid amytal procedure collaborate together with lesions studies to increase the knowledge about the organization of cognitive functions in the brain. Functional neuroimaging could help to this issue answering the following questions: where, when and how the activity is produced in the brain. Many of the functional neuroimaging studies have addressed the question of where the activity is located, but very few has been concentrated into describe the spatio temporal profiles of brain activity, and then how the neural networks which support cognition are organized. Taking into account just one of this perspectives (where or when) we could achieve a reductionism view of the problem. CONCLUSIONS: Executive function, memory or language are more distributed than located in just one area, even the different subprocesses that are included in each of this functions are supported by a network rather than a particular area. We analyze the current available functional neuroimaging techniques under this view and its possibilities to describe the neural networks which support cognition.

[Associations of allergic and asthmatic patients in Europe]. / Asociaciones de pacientes alérgicos y asmáticos en Europa.

Patients' associations are NGOs that emerge as a result of the needs of patients with chronic diseases that cannot be solved in the doctor's surgery. At the start, the role of the health personnel, in guiding and collaborating with them, was fundamental, and their aims and interests coincided to a high degree. Their healthy operation favored both the patients and, indirectly, the health professionals related to them. However, we must bear in mind that those interests are not identical and, on occasion, can be clearly divergent. This is why the independence of these associations cannot be renounced upon, and they are managed according to the growth in their size and social influence.

[Neuromagnetic correlates of dyslexia]. / Correlatos neuromagnéticos de la dislexia.

Dyslexia was first described over a century ago and since then many theories have been put forward to explain it, but we still do not have one single unified theory that explains the problem. Furthermore, over the years a great deal of research work has also been carried out that relates dyslexia with disorders in different brain structures, and yet we still do not have a clear idea of exactly which neurophysiological mechanisms are involved. It has been claimed, however, that the disorder may be caused by specific deficits in the left frontotemporal region or atypical asymmetries in the left perisylvian regions. Lastly, neuroimaging techniques, such as functional magnetic resonance or mapping of the electrical activity in the brain, have helped to further studies into dyslexia over the last decade. Recently, the introduction of magnetoencephalography in the study of the brain has opened up a whole new range of possibilities that will allow most of the controversial points raised by research into dyslexia using neuroimaging techniques to be resolved empirically.

[The neuromagnetic correlates of language]. / Correlatos neuromagnéticos del lenguaje.

Studies of language using different functional neuroimaging techniques have shown the cortical structures to be involved in the functions of language, both in control subjects and in patients with different neurological pathologies who are to undergo brain surgery. Magnetoencephalography (MEG) is a totally non-invasive technique that measures the magnetic fields generated by the flow of intracellular current produced in the dendrites of the pyramidal neurones. MEG also offers the possibility of lateralizing language, so enabling us to know which areas of language lie within the dominant hemisphere and to establish the temporal patterns that reveal the organisation, either in sequence or in parallel, of the different areas that are activated. This will provide us with a deeper understanding of the physiological foundations upholding both language and other cognitive processes.

[Clinical features of epilepsy in autism spectrum disorders]. / Clínica de la epilepsia en los trastornos del espectro autista.

Autism is a rare disease, but is currently in vogue. An incidence of 1/1,000 has been estimated for early childhood autism, but in autism spectrum the incidence can reach 30/1,000. The clinical characteristics of autism are cognitive language disorders, lack of social interaction, obsessive behaviours with stereotypic movements and epilepsy. For some authors it is an associated symptom while for others it is a cardinal symptom of the disease. Epilepsy in autism, as an association, was reported as early as 1944 by Leo Kanner, in describing his initial work involving 11 cases and how one of them suffered from epilepsy. In 1960, the prevalence of epilepsy among autistic patients was evaluated and found to be much higher than in the normal population. The figures differ from author to author, but really they depend on age: the higher the age, the greater the prevalence of epilepsy. It was in fact this detail that drew our attention to this issue, and triggered the first questions in our research into autism and epilepsy. The series vary from 4 to 86%, depending on the methodology used to confirm the epilepsy. In our casuistics, between the ages of 1 and 18 years, 20% of these children with autism spectrum disorders suffer some kind of epileptic seizures, and 80% suffer what other researchers call subclinical seizures . In this paper, the symptomatology of the most important subclinical seizures that have been observed in these children is presented; the diseases associated with autism are commented on; the concept of primary and secondary autism is discussed; we explain why seizures occur in autism and their consequences as a neurodevelopmental disorder, and we put forward an interesting hypothesis within our general theory of autism. We also comment on the importance that the use of functional magnetic images in the study of autism has in our research.