Decreased circulating IPA levels identify subjects with metabolic comorbidities: A multi-omics study.

In recent years several experimental observations demonstrated that the gut microbiome plays a role in regulating positively or negatively metabolic homeostasis. Indole-3-propionic acid (IPA), a Tryptophan catabolic product mainly produced by C. Sporogenes, has been recently shown to exert either favorable or unfavorable effects in the context of metabolic and cardiovascular diseases. We performed a study to delineate clinical and multiomics characteristics of human subjects characterized by low and high IPA levels. Subjects with low IPA blood levels showed insulin resistance, overweight, low-grade inflammation, and features of metabolic syndrome compared to those with high IPA. Metabolomics analysis revealed that IPA was negatively correlated with leucine, isoleucine, and valine metabolism. Transcriptomics analysis in colon tissue revealed the enrichment of several signaling, regulatory, and metabolic processes. Metagenomics revealed several OTU of ruminococcus, alistipes, blautia, butyrivibrio and akkermansia were significantly enriched in highIPA group while in lowIPA group Escherichia-Shigella, megasphera, and Desulfovibrio genus were more abundant. Next, we tested the hypothesis that treatment with IPA in a mouse model may recapitulate the observations of human subjects, at least in part. We found that a short treatment with IPA (4 days at 20/mg/kg) improved glucose tolerance and Akt phosphorylation in the skeletal muscle level, while regulating blood BCAA levels and gene expression in colon tissue, all consistent with results observed in human subjects stratified for IPA levels. Our results suggest that treatment with IPA may be considered a potential strategy to improve insulin resistance in subjects with dysbiosis.

Preventive exercise attenuates IL-2-driven mood disorders in multiple sclerosis.

BACKGROUND: Elevated levels of specific proinflammatory molecules in the cerebrospinal fluid (CSF) have been associated with disability progression, enhanced neurodegeneration and higher incidence of mood disorders in people with multiple sclerosis (MS). Studies in animal models of MS suggest that preventive exercise may play an immunomodulatory activity, with beneficial effects on both motor deficits and behavioral alterations. Here we explored the impact of lifestyle physical activity on clinical presentation and associated central inflammation in a large group of newly diagnosed patients with MS. Furthermore, we addressed the causal link between exercise-mediated immunomodulation and mood symptoms in the animal setting. METHODS: A cross-sectional study was conducted on 235 relapsing-remitting MS patients at the time of the diagnosis. Patients were divided into 3 groups ("sedentary", "lifestyle physical activity" and "exercise") according to the level of physical activity in the six months preceding the evaluation. Patients underwent clinical, neuropsychological and psychiatric evaluation, magnetic resonance imaging and lumbar puncture for diagnostic purposes. The CSF levels of proinflammatory and anti-inflammatory cytokines were analyzed and compared with a group of 80 individuals with non-inflammatory and non-degenerative diseases. Behavioral and electrophysiological studies were carried out in control mice receiving intracerebral injection of IL-2 or vehicle. Behavior was also assessed in mice with experimental autoimmune encephalomyelitis (EAE), animal model of MS, reared in standard (sedentary group) or running wheel-equipped (exercise group) cages. RESULTS: In exercising MS patients, depression and anxiety were reduced compared to sedentary patients. The CSF levels of the interleukin-2 and 6 (IL-2, IL-6) were increased in MS patients compared with control individuals. In MS subjects exercise was associated with normalized CSF levels of IL-2. In EAE mice exercise started before disease onset reduced both behavioral alterations and striatal IL-2 expression. Notably, a causal role of IL-2 in mood disorders was shown. IL-2 administration in control healthy mice induced anxious- and depressive-like behaviors and impaired type-1 cannabinoid (CB1) receptor-mediated neurotransmission at GABAergic synapses, mimicking EAE-induced synaptic dysfunction. CONCLUSIONS: Our results indicate an immunomodulatory effect of exercise in MS patients, associated with reduced CSF expression of IL-2, which might result in reduced mood disorders. These data suggest that exercise in the early stages may act as a disease-modifying therapy in MS although further longitudinal studies are needed to clarify this issue.

Visual pursuit biases tactile velocity perception.

During a smooth pursuit eye movement of a target stimulus, a briefly flashed stationary background appears to move in the opposite direction as the eye's motion-an effect known as the Filehne illusion. Similar illusions occur in audition, in the vestibular system, and in touch. Recently, we found that the movement of a surface perceived from tactile slip was biased if this surface was sensed with the moving hand. The analogy between these two illusions suggests similar mechanisms of motion processing between the vision and touch. In the present study, we further assessed the interplay between these two sensory channels by investigating a novel paradigm that associated an eye pursuit of a visual target with a tactile motion over the skin of the fingertip. We showed that smooth pursuit eye movements can bias the perceived direction of motion in touch. Similarly to the classical report from the Filehne illusion in vision, a static tactile surface was perceived as moving rightward with a leftward eye pursuit movement, and vice versa. However, this time the direction of surface motion was perceived from touch. The biasing effects of eye pursuit on tactile motion were modulated by the reliability of the tactile and visual stimuli, consistently with a Bayesian model of motion perception. Overall, these results support a modality- and effector-independent process with common representations for motion perception.NEW & NOTEWORTHY The study showed that smooth pursuit eye movement produces a bias in tactile motion perception. This phenomenon is modulated by the reliability of the tactile estimate and by the presence of a visual background, in line with the predictions of the Bayesian framework of motion perception. Overall, these results support the hypothesis of shared representations for motion perception.

The interaction between motion and texture in the sense of touch.

Besides providing information on elementary properties of objects, like texture, roughness, and softness, the sense of touch is also important in building a representation of object movement and the movement of our hands. Neural and behavioral studies shed light on the mechanisms and limits of our sense of touch in the perception of texture and motion, and of its role in the control of movement of our hands. The interplay between the geometrical and mechanical properties of the touched objects, such as shape and texture, the movement of the hand exploring the object, and the motion felt by touch, will be discussed in this article. Interestingly, the interaction between motion and textures can generate perceptual illusions in touch. For example, the orientation and the spacing of the texture elements on a static surface induces the illusion of surface motion when we move our hand on it or can elicit the perception of a curved trajectory during sliding, straight hand movements. In this work we present a multiperspective view that encompasses both the perceptual and the motor aspects, as well as the response of peripheral and central nerve structures, to analyze and better understand the complex mechanisms underpinning the tactile representation of texture and motion. Such a better understanding of the spatiotemporal features of the tactile stimulus can reveal novel transdisciplinary applications in neuroscience and haptics.

Illusory changes in the perceived speed of motion derived from proprioception and touch.

In vision, the perceived velocity of a moving stimulus differs depending on whether we pursue it with the eyes or not: A stimulus moving across the retina with the eyes stationary is perceived as being faster compared with a stimulus of the same physical speed that the observer pursues with the eyes, while its retinal motion is zero. This effect is known as the Aubert-Fleischl phenomenon. Here, we describe an analog phenomenon in touch. We asked participants to estimate the speed of a moving stimulus either from tactile motion only (i.e., motion across the skin), while keeping the hand world stationary, or from kinesthesia only by tracking the stimulus with a guided arm movement, such that the tactile motion on the finger was zero (i.e., only finger motion but no movement across the skin). Participants overestimated the velocity of the stimulus determined from tactile motion compared with kinesthesia in analogy with the visual Aubert-Fleischl phenomenon. In two follow-up experiments, we manipulated the stimulus noise by changing the texture of the touched surface. Similarly to the visual phenomenon, this significantly affected the strength of the illusion. This study supports the hypothesis of shared computations for motion processing between vision and touch.NEW & NOTEWORTHY In vision, the perceived velocity of a moving stimulus is different depending on whether we pursue it with the eyes or not, an effect known as the Aubert-Fleischl phenomenon. We describe an analog phenomenon in touch. We asked participants to estimate the speed of a moving stimulus either from tactile motion or by pursuing it with the hand. Participants overestimated the stimulus velocity measured from tactile motion compared with kinesthesia, in analogy with the visual Aubert-Fleischl phenomenon.

Motion direction, luminance contrast, and speed perception: An unexpected meeting.

Motion direction and luminance contrast are two central features in the representation of visual motion in humans. In five psychophysical experiments, we showed that these two features affect the perceived speed of a visual stimulus. Our data showed a surprising interaction between contrast and direction. Participants perceived downward moving stimuli as faster than upward or rightward stimuli, but only at high contrast. Likewise, luminance contrast produced an underestimation of motion speed, but mostly when the stimuli moved downward. We explained these novel phenomena by means of a theoretical model, accounting for prior knowledge of motion dynamics.

Correction: Application of the Intermediate-Stage Subclassification to Patients With Untreated Hepatocellular Carcinoma.

In the Italian Liver Cancer (ITA.LI.CA) Group, contributor name Alberta Capelli is misspelled and should be corrected to Alberta Cappelli.

Multidigit force control during unconstrained grasping in response to object perturbations.

Because of the complex anatomy of the human hand, in the absence of external constraints, a large number of postures and force combinations can be used to attain a stable grasp. Motor synergies provide a viable strategy to solve this problem of motor redundancy. In this study, we exploited the technical advantages of an innovative sensorized object to study unconstrained hand grasping within the theoretical framework of motor synergies. Participants were required to grasp, lift, and hold the sensorized object. During the holding phase, we repetitively applied external disturbance forces and torques and recorded the spatiotemporal distribution of grip forces produced by each digit. We found that the time to reach the maximum grip force during each perturbation was roughly equal across fingers, consistent with a synchronous, synergistic stiffening across digits. We further evaluated this hypothesis by comparing the force distribution of human grasping vs. robotic grasping, where the control strategy was set by the experimenter. We controlled the global hand stiffness of the robotic hand and found that this control algorithm produced a force pattern qualitatively similar to human grasping performance. Our results suggest that the nervous system uses a default whole hand synergistic control to maintain a stable grasp regardless of the number of digits involved in the task, their position on the objects, and the type and frequency of external perturbations.NEW & NOTEWORTHY We studied hand grasping using a sensorized object allowing unconstrained finger placement. During object perturbation, the time to reach the peak force was roughly equal across fingers, consistently with a synergistic stiffening across fingers. Force distribution of a robotic grasping hand, where the control algorithm is based on global hand stiffness, was qualitatively similar to human grasping. This suggests that the central nervous system uses a default whole hand synergistic control to maintain a stable grasp.

Intercepting virtual balls approaching under different gravity conditions: evidence for spatial prediction.

To accurately time motor responses when intercepting falling balls we rely on an internal model of gravity. However, whether and how such a model is also used to estimate the spatial location of interception is still an open question. Here we addressed this issue by asking 25 participants to intercept balls projected from a fixed location 6 m in front of them and approaching along trajectories with different arrival locations, flight durations, and gravity accelerations (0g and 1g). The trajectories were displayed in an immersive virtual reality system with a wide field of view. Participants intercepted approaching balls with a racket, and they were free to choose the time and place of interception. We found that participants often achieved a better performance with 1g than 0g balls. Moreover, the interception points were distributed along the direction of a 1g path for both 1g and 0g balls. In the latter case, interceptions tended to cluster on the upper half of the racket, indicating that participants aimed at a lower position than the actual 0g path. These results suggest that an internal model of gravity was probably used in predicting the interception locations. However, we found that the difference in performance between 1g and 0g balls was modulated by flight duration, the difference being larger for faster balls. In addition, the number of peaks in the hand speed profiles increased with flight duration, suggesting that visual information was used to adjust the motor response, correcting the prediction to some extent.NEW & NOTEWORTHY Here we show that an internal model of gravity plays a key role in predicting where to intercept a fast-moving target. Participants also assumed an accelerated motion when intercepting balls approaching in a virtual environment at constant velocity. We also show that the role of visual information in guiding interceptive movement increases when more time is available.

Erratum: Positive PET in a Patient With Esophageal Leiomyoma.

This corrects the article DOI: 10.1038/ajg.2016.205.

Application of the Intermediate-Stage Subclassification to Patients With Untreated Hepatocellular Carcinoma.

OBJECTIVES: The Barcelona Clinic Liver Cancer (BCLC) intermediate stage (BCLC B) includes a heterogeneous population of patients with hepatocellular carcinoma (HCC). Recently, in order to facilitate treatment decisions, a panel of experts proposed to subclassify BCLC B patients. In this study, we aimed to assess the prognostic capability of the BCLC B stage reclassification in a large cohort of patients with untreated HCC managed by the Italian Liver Cancer Group. METHODS: We assessed the prognosis of 269 untreated HCC patients observed in the period 1987-2012 who were reclassified according to the proposed subclassification of the BCLC B stage from stage B1 to stage B4. We evaluated and compared the survival of the various substages. RESULTS: Median survival progressively decreased from stage B1 (n=65, 24.2%: 25 months) through stages B2 (n=105, 39.0%: 16 months) and B3 (n=22, 8.2%: 9 months), to stage B4 (n=77, 28.6%: 5 months; P<0.0001). Moreover, we observed a significantly different survival between contiguous stages (B1 vs. B2, P=0.0002; B2 vs. B3, P<0.0001; B3 vs. B4, P=0.0219). In multivariate analysis, the BCLC B subclassification (P<0.0001), MELD score (P=0.0013), and platelet count (P=0.0252) were independent predictors of survival. CONCLUSIONS: The subclassification of the intermediate-stage HCC predicts the prognosis of patients with untreated HCC. The prognostic figures identified in this study may be used as a benchmark to assess the efficacy of therapeutic intervention in the various BCLC B substages, whereas it remains to be established whether incorporation of the MELD score might improve the prognosis of treated patients.

The role of vibration in tactile speed perception.

The relative motion between the surface of an object and our fingers produces patterns of skin deformation such as stretch, indentation, and vibrations. In this study, we hypothesized that motion-induced vibrations are combined with other tactile cues for the discrimination of tactile speed. Specifically, we hypothesized that vibrations provide a critical cue to tactile speed on surfaces lacking individually detectable features like dots or ridges. Thus masking vibrations unrelated to slip motion should impair the discriminability of tactile speed, and the effect should be surface-dependent. To test this hypothesis, we measured the precision of participants in discriminating the speed of moving surfaces having either a fine or a ridged texture, while adding masking vibratory noise in the working range of the fast-adapting mechanoreceptive afferents. Vibratory noise significantly reduced the precision of speed discrimination, and the effect was much stronger on the fine-textured than on the ridged surface. On both surfaces, masking vibrations at intermediate frequencies of 64 Hz (65-µm peak-to-peak amplitude) and 128 Hz (10 µm) had the strongest effect, followed by high-frequency vibrations of 256 Hz (1 µm) and low-frequency vibrations of 32 Hz (50 and 25 µm). These results are consistent with our hypothesis that slip-induced vibrations concur to the discrimination of tactile speed.

Measurement of oro-caecal transit time by magnetic resonance imaging.

OBJECTIVES: To assess prospectively the agreement of orocaecal transit time (OCTT) measurements by lactulose hydrogen breath test (LHBT) and magnetic resonance imaging (MRI) in healthy subjects. METHODS: Volunteers underwent abdominal 1.5-T MRI using axial and coronal single-shot fast-spin-echo T2-weighted sequences, having fasted and after lactulose ingestion (10 g/125 mL). Imaging and H2 excretion gas-chromatography were performed concurrently every 15 min up to 180 min. MR images were analyzed using semiautomatic segmentation to calculate small bowel gas volume (SBGV) and visually to detect bolus arrival in the caecum. Agreement between MRI- and LHBT-OCTT was assessed. RESULTS: Twenty-eight subjects (17 men/11 women; mean age ± standard deviation 30 ± 8 years) were evaluated. Two H2 non-producers on LHBT were excluded. OCTT measured by MRI and LHBT was concordant in 18/26 (69 %) subjects (excellent agreement, k = 0.924). Median SBGV was 49.0 mL (interquartile interval 44.1 - 51.6 mL). In 8/26 (31 %) subjects, MRI showed that the lactulose bolus was in the terminal ileum and not the caecum when H2E increased on LHBT. Median OCTT measured by MRI was significantly longer than OCTT measured by LHBT [135 min (120 - 150 min) vs. 127.5 min (105 - 150 min); p = 0.008]. Above baseline levels, correlation between [H2] and SBGV was significant (r = 0.964; p < 0.001). CONCLUSIONS: MRI provides valid measurements of OCTT and gas production in the small bowel. KEY POINTS: • MRI is a valid technique to measure OCTT. • Excellent agreement between MRI and LHBT was found. • Measuring gas production using MRI may provide evidence of small bowel fermentation.

The relativity of reaching: Motion of the touched surface alters the trajectory of hand movements.

For dexterous control of the hand, humans integrate sensory information and prior knowledge regarding their bodies and the world. We studied the role of touch in hand motor control by challenging a fundamental prior assumption-that self-motion of inanimate objects is unlikely upon contact. In a reaching task, participants slid their fingertips across a robotic interface, with their hand hidden from sight. Unbeknownst to the participants, the robotic interface remained static, followed hand movement, or moved in opposition to it. We considered two hypotheses. Either participants were able to account for surface motion or, if the stationarity assumption held, they would integrate the biased tactile cues and proprioception. Motor errors consistent with the latter hypothesis were observed. The role of visual feedback, tactile sensitivity, and friction was also investigated. Our study carries profound implications for human-machine collaboration in a world where objects may no longer conform to the stationarity assumption.

A comparison between lactose breath test and quick test on duodenal biopsies for diagnosing lactase deficiency in patients with self-reported lactose intolerance.

BACKGROUND: A lactose breath test (LBT) is usually used to diagnose lactase deficiency, and a lactose quick test (LQT) has been proposed as a new test on duodenal biopsies to detect this disorder. GOALS: We aimed to assess the diagnostic accuracy of LBT and LQT and their ability to predict the clinical response to a lactose-free diet in patients with self-reported lactose intolerance. STUDY: Fifty-five patients (age 47 ± 14 y; M/F 15/36) underwent upper gastrointestinal endoscopy and 25g-LBT. Two duodenal biopsies were taken to determine lactase deficiency (normal, mild, or severe) by LQT and to rule out other causes of secondary lactose malabsorption. Patients with a positive LBT and normal LQT also underwent a glucose breath test to exclude small intestinal bacterial overgrowth as a cause of the former result. The severity of gastrointestinal symptoms was measured with a GSS questionnaire, under basal condition and 1 month after a lactose-free diet. RESULTS: Lactose malabsorption was detected in 31/51 patients with LBT and in 37/51 patients with LQT (P = NS). Celiac disease was found in 2 patients. Two LBT+ patients showed a positive glucose breath test for small intestinal bacterial overgrowth. Eight patients had a mild hypolactasia by LQT and a negative LBT, but they had a significant improvement of symptoms after diet. LQT and LBT were concordant in 83% of cases and predicted the response to a lactose-free diet in 98% and 81% of the cases, respectively (P = 0.03). CONCLUSIONS: LQT is as sensitive as LBT in detecting lactase deficiency; however, it seems to be more accurate than LBT in predicting the clinical response to a lactose-free diet.

On the Correlation Between Tactile Stimulation and Pleasantness.

Several studies in the affective haptics research field showed the potential of using haptic technology to convey emotions in remote communications. In this context, it is of interest to simplify the haptic feedback without altering the informative content of the stimulus, with a two-fold advantage. On one side, it would allow the development of affective haptic devices whose technological complexity is limited, hence more compatible with wearability and portability requirements. On the other side, having a simplified set of stimuli would decrease the amount of data to be transmitted, thus improving the overall quality of remote haptic interactions. In this work, we investigated the correlation between the parameters regulating a caress-like stimulation and the perceived pleasantness. This was done by means of two experiments, in which we asked subjects to adjust the temperature and the motion velocity of a set of stimuli in order to find the most pleasant combination. Results indicated that subjects preferred different values of temperature and velocity of the stimulus depending on the proposed tactile stimulation. A small difference in the pleasantness ratings was observed between caresses provided with linear movements and those given as discrete sequences of taps. In particular, participants preferred linear movements set at 34.5 °C and 3.4 cms-1. As regards caress-like stimuli provided with discrete sequences of taps, the preferred temperature and velocity were 33.2 °C and 2.9 cms-1, respectively. The presence of vibration had a little effect on the perceived pleasantness.

Bayesian hierarchical models and prior elicitation for fitting psychometric functions.

Our previous articles demonstrated how to analyze psychophysical data from a group of participants using generalized linear mixed models (GLMM) and two-level methods. The aim of this article is to revisit hierarchical models in a Bayesian framework. Bayesian models have been previously discussed for the analysis of psychometric functions although this approach is still seldom applied. The main advantage of using Bayesian models is that if the prior is informative, the uncertainty of the parameters is reduced through the combination of prior knowledge and the experimental data. Here, we evaluate uncertainties between and within participants through posterior distributions. To demonstrate the Bayesian approach, we re-analyzed data from two of our previous studies on the tactile discrimination of speed. We considered different methods to include a priori knowledge in the prior distribution, not only from the literature but also from previous experiments. A special type of Bayesian model, the power prior distribution, allowed us to modulate the weight of the prior, constructed from a first set of data, and use it to fit a second one. Bayesian models estimated the probability distributions of the parameters of interest that convey information about the effects of the experimental variables, their uncertainty, and the reliability of individual participants. We implemented these models using the software Just Another Gibbs Sampler (JAGS) that we interfaced with R with the package rjags. The Bayesian hierarchical model will provide a promising and powerful method for the analysis of psychometric functions in psychophysical experiments.

Modulating the Perceived Softness of Real Objects Through Wearable Feel-Through Haptics.

In vision, Augmented Reality (AR) allows the superposition of digital content on real-world visual information, relying on the well-established See-through paradigm. In the haptic domain, a putative Feel-through wearable device should allow to modify the tactile sensation without masking the actual cutaneous perception of the physical objects. To the best of our knowledge, a similar technology is still far to be effectively implemented. In this work, we present an approach that allows, for the first time, to modulate the perceived softness of real objects using a Feel-through wearable that uses a thin fabric as interaction surface. During the interaction with real objects, the device can modulate the growth of the contact area over the fingerpad without affecting the force experienced by the user, thus modulating the perceived softness. To this aim, the lifting mechanism of our system warps the fabric around the fingerpad in a way proportional to the force exerted on the specimen under exploration. At the same time, the stretching state of the fabric is controlled to keep a loose contact with the fingerpad. We demonstrated that different softness perceptions for the same specimens can be elicited, by suitably controlling the lifting mechanism of the system.

Altering Time Perception in Virtual Reality Through Multimodal Visual-Tactile Kappa Effect.

The perception of time is highly subjective and intertwined with space perception. In a well-known perceptual illusion, called Kappa effect, the distance between consecutive stimuli is modified to induce time distortions in the perceived inter-stimulus interval that are proportional to the distance between the stimuli. However, to the best of our knowledge, this effect has not been characterized and exploited in virtual reality (VR) within a multisensory elicitation framework. This paper investigates the Kappa effect elicited by concurrent visual-tactile stimuli delivered to the forearm, through a multimodal VR interface. This paper compares the outcomes of an experiment in VR with the results of the same experiment performed in the "physical world", where a multimodal interface was applied to participants' forearm to deliver controlled visual-tactile stimuli. Our results suggest that a multimodal Kappa effect can be elicited both in VR and in the physical world relying on concurrent visual-tactile stimulation. Moreover, our results confirm the existence of a relation between the ability of participants in discriminating the duration of time intervals and the magnitude of the experienced Kappa effect. These outcomes can be exploited to modulate the subjective perception of time in VR, paving the path toward more personalised human-computer interaction.

A hierarchical sensorimotor control framework for human-in-the-loop robotic hands.

Human manual dexterity relies critically on touch. Robotic and prosthetic hands are much less dexterous and make little use of the many tactile sensors available. We propose a framework modeled on the hierarchical sensorimotor controllers of the nervous system to link sensing to action in human-in-the-loop, haptically enabled, artificial hands.