Targeted and untargeted serum NMR metabolomics to reveal initial kidney disease in diabetes mellitus.

Serum 1H NMR metabolomics has been used as a diagnostic tool for screening type 2 diabetes (T2D) with chronic kidney disease (CKD) as comorbidity. This work aimed to evaluate 1H NMR data to detect the initial kidney damage and CKD in T2D subjects, through multivariate statistical analysis. Clinical data and biochemical parameters were obtained for classifying five experimental groups using KDIGO guidelines: Control (healthy subjects), T2D, T2D-CKD-mild, T2D-CKD-moderate, and T2D-CKD-severe. Serum 1H NMR spectra were recorded to follow two strategies: one based on metabolite-to-creatinine (Met/Cr) ratios as targeted metabolomics, and the second one based on untargeted metabolomics from the 1H NMR profile. A prospective biomarkers panel of the early stage of T2D-CKD based in metabolite-to-creatinine ratio (ornithine/Cr, serine/Cr, mannose/Cr, acetate/Cr, acetoacetate/Cr, formate/Cr, and glutamate/Cr) was proposed. Later, a statistical model based on non-targeted metabolomics was used to predict initial CKD, and its metabolic pathway analysis allowed identifying the most affected pathways: phenylalanine, tyrosine, and tryptophan biosynthesis; valine, leucine, and isoleucine degradation; glyoxylate and dicarboxylate metabolism; glycine, serine, and threonine metabolism; and histidine metabolism. Nonetheless, further studies with a larger cohort are advised to precise ranges in metabolite-to-creatinine ratios and evaluate the prediction pertinency to detect initial CKD in T2D patients in both statistical models proposed.

Is the tendency to maximise energy distribution an optimal collective activity for biological purposes? A proposal for a global principle of biological organization.

Our purpose is to address the biological problem of finding foundations of the organization in the collective activity among cell networks in the nervous system, at the meso/macroscale, giving rise to cognition and consciousness. But in doing so, we encounter another problem related to the interpretation of methods to assess the neural interactions and organization of the neurodynamics, because thermodynamic notions, which have precise meaning only under specific conditions, have been widely employed in these studies. The consequence is that apparently contradictory results appear in the literature, but these contradictions diminish upon the considerations of the specific circumstances of each experiment. After clarifying some of these controversial points and surveying some experimental results, we propose that a necessary condition for cognition/consciousness to emerge is to have available enough energy, or cellular activity; and a sufficient condition is the multiplicity of configurations in which cell networks can communicate, resulting in non-uniform energy distribution, the generation and dissipation of energy gradients due to the constant activity. The diversity of sensorimotor processing of higher animals needs a flexible, fluctuating web on neuronal connections, and we review results supporting such multiplicity of configurations among brain regions associated with conscious awareness and healthy brain states. These ideas may reveal possible fundamental principles of brain organization that could be extended to other natural phenomena and how healthy activity may derive to pathological states.

Latin American Registry of Idiopathic Pulmonary Fibrosis (REFIPI): Clinical Characteristics, Evolution and Treatment.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible and frequently fatal disease. Currently there are national and multinational registries in Europe, United States, Australia and China to better understand the magnitude of the problem and the characteristics of the IPF patients. However, there are no national or regional registries in Latin America, so the objective of this study was to carry out a Latin American registry that would allow the identification of IPF patients in our region. METHODOLOGY: A system consisting of 3 levels of control was designed, ensuring that patients met the diagnostic criteria for IPF according to international guidelines ATS/ERS/ALAT/JRS 2011. Demographic, clinical, serological, functional, tomographic, histological and treatment variables were recorded through a digital platform. RESULTS: 761 IPF patients from 14 Latin American countries were included for analysis, 74.7% were male, with a mean age of 71.9+8.3 years. In general there was a long period of symptoms before definitive diagnosis (median 1 year). In functional tests, an average reduction of FVC (70.9%) and DLCO (53.7%) was detected. 72% received at least one antifibrotic drug (pirfenidone or nintedanib) and 11.2% of the patients had an acute exacerbation, of which 38 (45.2%) died from this cause. CONCLUSIONS: Like other registries, we found that there is difficulty in the recognition and excessive delay in the diagnosis of IPF in Latin America. Most of the patients in REFIPI received antifibrotics; these were well tolerated and associated with fewer adverse events than those reported in clinical trials.

Using nuclear magnetic resonance urine metabolomics to develop a prediction model of early stages of renal disease in subjects with type 2 diabetes.

Type 2 diabetes mellitus (DM2) is a multimorbidity, long-term condition, and one of the worldwide leading causes of chronic kidney disease (CKD) -a silent disease, usually detected when non-reversible renal damage have already occurred. New strategies and more effective laboratory methods are needed for more opportune diagnosis of DM2-CKD. This study comprises clinical parameters and nuclear magnetic resonance (NMR)-based urine metabolomics data from 60 individuals (20-65 years old, 67.7% females), sorted in 5 experimental groups (healthy subjects; diabetic patients without any clinical sign of CKD; and patients with mild, moderate, and severe DM2-CKD), according to KDIGO. DM2-CKD produces a continuous variation of the urine metabolome, characterized by an increase/decrement of a group of metabolites that can be used to monitor CKD progression (trigonelline, hippurate, phenylalanine, glycolate, dimethylamine, alanine, 2-hydroxybutyrate, lactate, and citrate). NMR profiles were used to obtain a statistical model, based on partial least squares analysis (PLS-DA) to discriminate among groups. The PLS-DA model yielded good validation parameters (sensitivity, specificity, and area under the curve (AUC) of the receiver operating characteristic curve (ROC) plot: 0.692, 0.778 and 0.912, respectively) and, thus, it can differentiate between subjects with DM2-CKD in early stages, from subjects with a mild or severe condition. This metabolic signature exhibits a molecular variation associated to DM2-CKD, and data suggests it can be used to predict risk of DM2-CKD in patients without clinical signs of renal disease, offering a new alternative to current diagnosis methods.

Consciousness as an Emergent Phenomenon: A Tale of Different Levels of Description.

One of the biggest queries in cognitive sciences is the emergence of consciousness from matter. Modern neurobiological theories of consciousness propose that conscious experience is the result of interactions between large-scale neuronal networks in the brain, traditionally described within the realm of classical physics. Here, we propose a generalized connectionist framework in which the emergence of "conscious networks" is not exclusive of large brain areas, but can be identified in subcellular networks exhibiting nontrivial quantum phenomena. The essential feature of such networks is the existence of strong correlations in the system (classical or quantum coherence) and the presence of an optimal point at which the system's complexity and energy dissipation are maximized, whereas free-energy is minimized. This is expressed either by maximization of the information content in large scale functional networks or by achieving optimal efficiency through the quantum Goldilock effect.

On the emergence of cognition: from catalytic closure to neuroglial closure.

In an analogous manner as occurred during the development of a connected metabolism that at some point reached characteristics associated with what is called "life"-due mainly to a catalytic closure phenomenon when chemicals started to autocatalyze themselves forming a closed web of chemical reactions-it is here proposed that cognition and consciousness (or features associated with them) arose as a consequence of another type of closure within the nervous system, the brain especially. Proper brain function requires an efficient web of connections and once certain complexity is attained due to the number and coordinated activities of the brain cell networks, the emergent properties of cognition and consciousness take place. Seeking to identify main features of the nervous system organization for optimal function, it is here proposed that while catalytic closure yielded life, neuroglial closure produced cognition/consciousness.

CapsidMesh: Atomic-detail structured mesh representation of icosahedral viral capsids and the study of their mechanical properties.

Viruses are the most abundant pathogens affecting all forms of life. A major component of a virus is a protein shell, known as the viral capsid, that encapsulates the genomic material. The fundamental functions of the capsid are to protect and transport the viral genome and recognize the host cell. Descriptions of this macromolecular complex have been proposed at different scales of approximation. Here, we introduce a methodology to generate a structured volumetric mesh of icosahedral viral capsids (CapsidMesh) based on the atomic positions of their constituents. Material properties of the capsid proteins can be set on every mesh element individually. Hence, we have control over all levels of protein structure (atoms, amino acids, subunits, oligomers, and capsid). The CapsidMesh models are suitable for numerical simulations and analysis of a physical process using a third-party package. In particular, we used our methodology to generate a CapsidMesh of several capsids previously characterized by atomic force microscopy experiments and then simulated the mechanical nanoindentation through the finite element method. By fitting to the experimental linear elastic response, we estimated the elastic modulus and mechanical stresses produced on the capsids. Our results show that the atomic detail of the CapsidMesh is sufficient to reproduce anisotropic properties of the particle.

Author Correction: Exploring the alpha desynchronization hypothesis in resting state networks with intracranial electroencephalography and wiring cost estimates.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Exploring the alpha desynchronization hypothesis in resting state networks with intracranial electroencephalography and wiring cost estimates.

This paper addresses a fundamental question, are eyes closed and eyes open resting states equivalent baseline conditions, or do they have consistently different electrophysiological signatures? We compare the functional connectivity patterns in an eyes closed resting state with an eyes open resting state to investigate the alpha desynchronization hypothesis. The change in functional connectivity from eyes closed to eyes open, is here, for the first time, studied with intracranial recordings. We perform network connectivity analysis in iEEG and we find that phase-based connectivity is sensitive to the transition from eyes closed to eyes open only in interhemispheral and frontal electrodes. Power based connectivity, on the other hand, consistently discriminates between the two conditions in temporal and interhemispheral electrodes. Additionally, we provide a calculation for the wiring cost, defined in terms of the connectivity between electrodes weighted by distance. We find that the wiring cost variation from eyes closed to eyes open is sensitive to the eyes closed and eyes open conditions. We extend the standard network-based approach using the filtration method from algebraic topology which does not rely on the threshold selection problem. Both the wiring cost measure defined here and this novel methodology provide a new avenue for understanding the electrophysiology of resting state.

Closed-Loop Neurostimulators: A Survey and A Seizure-Predicting Design Example for Intractable Epilepsy Treatment.

First, existing commercially available open-loop and closed-loop implantable neurostimulators are reviewed and compared in terms of their targeted application, physical size, system-level features, and performance as a medical device. Next, signal processing algorithms as the primary strength point of the closed-loop neurostimulators are reviewed, and various design and implementation requirements and trade-offs are discussed in details along with quantitative examples. The review results in a set of guidelines for algorithm selection and evaluation. Second, the implementation of an inductively-powered seizure-predicting microsystem for monitoring and treatment of intractable epilepsy is presented. The miniaturized system is comprised of two miniboards and a power receiver coil. The first board hosts a 24-channel neurostimulator system on chip fabricated in a [Formula: see text] CMOS technology and performs neural recording, on-chip digital signal processing, and electrical stimulation. The second board communicates recorded brain signals as well as signal processing results wirelessly. The multilayer flexible coil receives inductively-transmitted power. The system is sized at 2 × 2 × 0.7 [Formula: see text] and weighs 6 g. The approach is validated in the control of chronic seizures in vivo in freely moving rats.

Low-Frequency Noise and Offset Rejection in DC-Coupled Neural Amplifiers: A Review and Digitally-Assisted Design Tutorial.

We review integrated circuits for low-frequency noise and offset rejection as a motivation for the presented digitally-assisted neural amplifier design methodology. Conventional AC-coupled neural amplifiers inherently reject input DC offset but have key limitations in area, linearity, DC drift, and spectral accuracy. Their chopper stabilization reduces low-frequency intrinsic noise at the cost of degraded area, input impedance and design complexity. DC-coupled implementations with digital high-pass filtering yield improved area, linearity, drift, and spectral accuracy and are inherently suitable for simple chopper stabilization. As a design example, a 56-channel 0.13 [Formula: see text] CMOS intracranial EEG interface is presented. DC offset of up to ±50 mV is rejected by a digital low-pass filter and a 16-bit delta-sigma DAC feeding back into the folding node of a folded-cascode LNA with CMRR of 65 dB. A bank of seven column-parallel fully differential SAR ADCs with ENOB of 6.6 are shared among 56 channels resulting in 0.018 [Formula: see text] effective channel area. Compensation-free direct input chopping yields integrated input-referred noise of 4.2 µVrms over the bandwidth of 1 Hz to 1 kHz. The 8.7 [Formula: see text] chip dissipating 1.07 mW has been validated in vivo in online intracranial EEG monitoring in freely moving rats.

Consenso para las prácticas de alimentación complementaria en lactantes sanos / Guidelines for complementary feeding in healthy infants

Resumen: La nutrición adecuada durante los primeros dos años de vida es fundamental para el desarrollo pleno del potencial de cada ser humano; actualmente se reconoce que este periodo es una ventana crítica para la promoción de un crecimiento y desarrollo óptimos y un buen estado de salud. Por tanto, cumplir con una alimentación adecuada en esta etapa de la vida tiene impacto sobre la salud, estado de nutrición, crecimiento y desarrollo de los niños; no sólo en el corto plazo, sino en el mediano y largo plazo. El presente trabajo ofrece recomendaciones de alimentación complementaria (AC) que se presentan en forma de preguntas o enunciados que consideran temas importantes para quienes atienden niños durante esta etapa de la vida; por ejemplo: inicio de la alimentación complementaria a los 4 o 6 meses de edad; exposición a alimentos potencialmente alergénicos; introducción de bebidas azucaradas; uso de edulcorantes artificiales y productos light; secuencia de introducción de alimentos; modificaciones de consistencia de alimentos de acuerdo a la maduración neurológica; número de días para probar aceptación y tolerancia a los alimentos nuevos; cantidades por cada tiempo de comida; prácticas inadecuadas de alimentación complementaria; mitos y realidades de la alimentación complementaria; hitos del desarrollo; práctica del "Baby Led Weaning" y práctica de vegetarianismo.

Abstract: A proper nutrition during the first two years of life is critical to reach the full potential of every human being; now, this period is recognized as a critical window for promoting optimal growth, development, and good health. Therefore, adequate feeding at this stage of life has an impact on health, nutritional status, growth and development of children; not only in the short term, but in the medium and long term. This paper provides recommendations on complementary feeding (CF) presented as questions or statements that are important for those who take care for children during this stage of life. For example: When to start complementary feedings: 4 or 6 months of age?; Exposure to potentially allergenic foods; Introduction of sweetened beverages; Use of artificial sweeteners and light products; Food introduction sequence; Food consistency changes according to neurological maturation; Number of days to test acceptance and tolerance to new foods; Amounts for each meal; Inadequate complementary feeding practices; Myths and realities of complementary feeding; Developmental milestones; Practice of "Baby Led Weaning" and practice of vegetarianism.

Low-Radiation Cellular Inductive Powering of Rodent Wireless Brain Interfaces: Methodology and Design Guide.

This paper presents a general methodology of inductive power delivery in wireless chronic rodent electrophysiology applications. The focus is on such systems design considerations under the following key constraints: maximum power delivery under the allowable specific absorption rate (SAR), low cost and spatial scalability. The methodology includes inductive coil design considerations within a low-frequency ferrite-core-free power transfer link which includes a scalable coil-array power transmitter floor and a single-coil implanted or worn power receiver. A specific design example is presented that includes the concept of low-SAR cellular single-transmitter-coil powering through dynamic tracking of a magnet-less receiver spatial location. The transmitter coil instantaneous supply current is monitored using a small number of low-cost electronic components. A drop in its value indicates the proximity of the receiver due to the reflected impedance of the latter. Only the transmitter coil nearest to the receiver is activated. Operating at the low frequency of 1.5 MHz, the inductive powering floor delivers a maximum of 15.9 W below the IEEE C95 SAR limit, which is over three times greater than that in other recently reported designs. The power transfer efficiency of 39% and 13% at the nominal and maximum distances of 8 cm and 11 cm, respectively, is maintained.

Seizure Suppression Efficacy of Closed-Loop Versus Open-Loop Deep Brain Stimulation in a Rodent Model of Epilepsy.

We assess and compare the effects of both closed-loop and open-loop neurostimulation of the rat hippocampus by means of a custom low-power programmable therapeutic neurostimulation device on the suppression of spontaneous seizures in a rodent model of epilepsy. Chronic seizures were induced by intraperitoneal kainic acid injection. Two bipolar electrodes were implanted into the CA1 regions of both hippocampi. The electrodes were connected to the custom-built programmable therapeutic neurostimulation device that can trigger an electrical stimulation either in a periodic manner or upon detection of the intracerebral electroencephalographic (icEEE) seizure onset. This device includes a microchip consisting of a 256-channel icEEG recording system and a 64-channel stimulator, and a programmable seizure detector implemented in a field-programmable gate array (FPGA). The neurostimulator was used to evaluate seizure suppression efficacy in ten epileptic rats for a total of 240 subject-days (5760 subject-hours). For this purpose, all rats were randomly divided into two groups: the no-stimulation group and the stimulation group. The no-stimulation group did not receive stimulation. The stimulation group received, first, closed-loop stimulation and, next, open-loop stimulation. The no-stimulation and stimulation groups had a similar seizure frequency baseline, averaging five seizures per day. Closed-loop stimulation reduced seizure frequency by 90% and open-loop stimulation reduced seizure frequency by 17%, both in the stimulation group as compared to the no-stimulation group.

[Guidelines for complementary feeding in healthy infants]. / Consenso para las prácticas de alimentación complementaria en lactantes sanos.

A proper nutrition during the first two years of life is critical to reach the full potential of every human being; now, this period is recognized as a critical window for promoting optimal growth, development, and good health. Therefore, adequate feeding at this stage of life has an impact on health, nutritional status, growth and development of children; not only in the short term, but in the medium and long term. This paper provides recommendations on complementary feeding (CF) presented as questions or statements that are important for those who take care for children during this stage of life. For example: When to start complementary feedings: 4 or 6 months of age?; Exposure to potentially allergenic foods; Introduction of sweetened beverages; Use of artificial sweeteners and light products; Food introduction sequence; Food consistency changes according to neurological maturation; Number of days to test acceptance and tolerance to new foods; Amounts for each meal; Inadequate complementary feeding practices; Myths and realities of complementary feeding; Developmental milestones; Practice of "Baby Led Weaning" and practice of vegetarianism.

320-channel active probe for high-resolution neuromonitoring and responsive neurostimulation.

We present a 320-channel active probe for high-spatial-resolution neuromonitoring and responsive neurostimulation. The probe comprises an integrated circuit (IC) cell array bonded to the back side of a pitch-matched microelectrode array. The IC enables up to 256-site neural recording and 64-site neural stimulation at the spatial resolution of 400 µ m and 200 µ m, respectively. It is suitable for direct integration with electrode arrays with the shank pitch of integer multiples of 200 µm. In the presented configuration, the IC is bonded with a 8 × 8 400 µ m-pitch Utah electrode array (UEA) and up to additional 192 recording channels are used for peripheral neuromonitoring. The 0.35 µ m CMOS circuit array has a total die size of 3.5 mm × 3.65 mm. Each stimulator channel employs a current memory for simultaneous multi-site neurostimulation, outputs 20 µA-250 µA square or arbitrary waveform current, occupies 0.02 mm (2), and dissipates 2.76 µ W quiescent power. Each fully differential recording channel has two stages of amplification and filtering and an 8-bit single-slope ADC, occupies 0.035 mm (2) , and consumes 51.9 µ W. The neural probe has been experimentally validated in epileptic seizure propagation studies in a mouse hippocampal slice in vitro and in responsive neurostimulation for seizure suppression in an acute epilepsy rat model in vivo .

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Eye movement measurement in diagnostic assessment of disorders of consciousness.

We review the literature to appraise the evidence supporting or disputing the use of eye movement measurement in disorders of consciousness (DOC) with low levels of arousal or awareness, such as minimally conscious state (MCS), vegetative state (VS), and coma for diagnostic and prognostic purposes. We will focus on the effectiveness of each technique in the diagnostic classification of these patients and the gradual trend in research from manual to computerized tracking methods. New tools have become available at clinicians' disposal to assess eye movements with high spatial and temporal fidelity. The close relationship between eye movement generation and organic dysfunction in the brain allows these tools to be applied to the assessment of severe DOC as a unique supplementary toolset. We posit that eye tracking can improve clinical diagnostic precision for DOC, a key component of assessment that often dictates the course of clinical care in DOC patients. We see the emergence of long-term eye-tracking studies with seamless integration of technology in the future to improve the performance of clinical assessment in DOC.

Power law scaling in synchronization of brain signals depends on cognitive load.

As it has several features that optimize information processing, it has been proposed that criticality governs the dynamics of nervous system activity. Indications of such dynamics have been reported for a variety of in vitro and in vivo recordings, ranging from in vitro slice electrophysiology to human functional magnetic resonance imaging. However, there still remains considerable debate as to whether the brain actually operates close to criticality or in another governing state such as stochastic or oscillatory dynamics. A tool used to investigate the criticality of nervous system data is the inspection of power-law distributions. Although the findings are controversial, such power-law scaling has been found in different types of recordings. Here, we studied whether there is a power law scaling in the distribution of the phase synchronization derived from magnetoencephalographic recordings during executive function tasks performed by children with and without autism. Characterizing the brain dynamics that is different between autistic and non-autistic individuals is important in order to find differences that could either aid diagnosis or provide insights as to possible therapeutic interventions in autism. We report in this study that power law scaling in the distributions of a phase synchrony index is not very common and its frequency of occurrence is similar in the control and the autism group. In addition, power law scaling tends to diminish with increased cognitive load (difficulty or engagement in the task). There were indications of changes in the probability distribution functions for the phase synchrony that were associated with a transition from power law scaling to lack of power law (or vice versa), which suggests the presence of phenomenological bifurcations in brain dynamics associated with cognitive load. Hence, brain dynamics may fluctuate between criticality and other regimes depending upon context and behaviors.