Dose-dependent reduction in body weight with LIK066 (licogliflozin) treatment in Japanese patients with obesity.

AIMS: LIK066 (licogliflozin) is a dual sodium glucose co-transporter 1/2 inhibitor with potential benefits in weight loss. This study evaluated the efficacy, tolerability and safety of licogliflozin in Japanese adults with obesity. MATERIALS AND METHODS: This study was a randomized, double-blind, placebo-controlled, dose-finding study to evaluate the effect of licogliflozin (2.5, 10, 25 and 50 mg once daily) in 126 Japanese patients with obesity. The primary objective was to examine the dose-response relationship of licogliflozin treatment in body weight reduction relative to placebo at 12 weeks. The secondary objectives included assessment of responder rates, change in parameters related to complications, visceral and subcutaneous fat area, and safety during 12 weeks of treatment. RESULTS: The placebo-subtracted least square mean percentage change in body weight from baseline at week 12 was -1.99 (95% confidence interval -2.92, -0.21), -3.00 (-4.15, -1.70), -3.54 (-4.54, -2.26) and - 3.91% (-5.01, -2.77) in licogliflozin 2.5, 10, 25 and 50 mg once-daily dose groups, respectively. The proportion of responders with ≥3% reduction in body weight in the licogliflozin 2.5, 10, 25 and 50 mg once-daily dose groups were 15.8%, 55.6%, 50.0% and 56.7%, respectively, versus placebo [7.1%; P ≤0.002 for all except the 2.5 mg once-daily group (P = 0.39)]. Dose-dependent reductions were observed significantly in haemoglobin A1c, uric acid, fasting plasma glucose and potentially in the waist circumference, diastolic blood pressure and visceral fat area. CONCLUSION: Dual inhibition of SGLT1/2 with licogliflozin treatment induced a dose-dependent reduction in body weight in Japanese patients with obesity. Treatment with licogliflozin was safe and well tolerated in this study. The study is registered with ClinicalTrials.gov (NCT03320941).

Temporal characteristics of facial ensemble in individuals with autism spectrum disorder: examination from arousal and attentional allocation.

Introduction: Individuals with Autism Spectrum Disorder (ASD) show atypical recognition of facial emotions, which has been suggested to stem from arousal and attention allocation. Recent studies have focused on the ability to perceive an average expression from multiple spatially different expressions. This study investigated the effect of autistic traits on temporal ensemble, that is, the perception of the average expression from multiple changing expressions. Methods: We conducted a simplified temporal-ensemble task and analyzed behavioral responses, pupil size, and viewing times for eyes of a face. Participants with and without diagnosis of ASD viewed serial presentations of facial expressions that randomly switched between emotional and neutral. The temporal ratio of the emotional expressions was manipulated. The participants estimated the intensity of the facial emotions for the overall presentation. Results: We obtained three major results: (a) many participants with ASD were less susceptible to the ratio of anger expression for temporal ensembles, (b) they produced significantly greater pupil size for angry expressions (within-participants comparison) and smaller pupil size for sad expressions (between-groups comparison), and (c) pupil size and viewing time to eyes were not correlated with the temporal ensemble. Discussion: These results suggest atypical temporal integration of anger expression and arousal characteristics in individuals with ASD; however, the atypical integration is not fully explained by arousal or attentional allocation.

Analysis of the alpha activity envelope in electroencephalography in relation to the ratio of excitatory to inhibitory neural activity.

Alpha waves, one of the major components of resting and awake cortical activity in human electroencephalography (EEG), are known to show waxing and waning, but this phenomenon has rarely been analyzed. In the present study, we analyzed this phenomenon from the viewpoint of excitation and inhibition. The alpha wave envelope was subjected to secondary differentiation. This gave the positive (acceleration positive, Ap) and negative (acceleration negative, An) values of acceleration and their ratio (Ap-An ratio) at each sampling point of the envelope signals for 60 seconds. This analysis was performed on 36 participants with Alzheimer's disease (AD), 23 with frontotemporal dementia (FTD) and 29 age-matched healthy participants (NC) whose data were provided as open datasets. The mean values of the Ap-An ratio for 60 seconds at each EEG electrode were compared between the NC and AD/FTD groups. The AD (1.41 ±0.01 (SD)) and FTD (1.40 ±0.02) groups showed a larger Ap-An ratio than the NC group (1.38 ±0.02, p<0.05). A significant correlation between the envelope amplitude of alpha activity and the Ap-An ratio was observed at most electrodes in the NC group (Pearson's correlation coefficient, r = -0.92 ±0.15, mean for all electrodes), whereas the correlation was disrupted in AD (-0.09 ±0.21, p<0.05) and disrupted in the frontal region in the FTD group. The present method analyzed the envelope of alpha waves from a new perspective, that of excitation and inhibition, and it could detect properties of the EEG, Ap-An ratio, that have not been revealed by existing methods. The present study proposed a new method to analyze the alpha activity envelope in electroencephalography, which could be related to excitatory and inhibitory neural activity.

Weakened Bayesian Calibration for Tactile Temporal Order Judgment in Individuals with Higher Autistic Traits.

Previous psychophysical studies reported a positive aftereffect in tactile temporal order judgments, which can be explained by the Bayesian estimation model ('Bayesian calibration'). We investigated the relationship between Bayesian calibration and autistic traits in participants with typical development (TD) and autism spectrum disorder (ASD). Bayesian calibration was weakened in TD participants with high autistic traits, consistent with the 'hypo-priors' hypothesis for autistic perceptions. The results from the ASD group were generally observed as a continuation of those from the TD groups. Meanwhile, two ASD participants showed irregularly large positive or negative aftereffects. We discussed the mechanisms behind the general results among TD and ASD participants and two particular results among ASD participants based on the Bayesian estimation model.

Enhanced use of gaze cue in a face-following task after brief trial experience in individuals with autism spectrum disorder.

Eye movements toward sequentially presented face images with or without gaze cues were recorded to investigate whether those with ASD, in comparison to their typically developing (TD) peers, could prospectively perform the task according to gaze cues. Line-drawn face images were sequentially presented for one second each on a laptop PC display, and the face images shifted from side-to-side and up-and-down. In the gaze cue condition, the gaze of the face image was directed to the position where the next face would be presented. Although the participants with ASD looked less at the eye area of the face image than their TD peers, they could perform comparable smooth gaze shift to the gaze cue of the face image in the gaze cue condition. This appropriate gaze shift in the ASD group was more evident in the second half of trials in than in the first half, as revealed by the mean proportion of fixation time in the eye area to valid gaze data in the early phase (during face image presentation) and the time to first fixation on the eye area. These results suggest that individuals with ASD may benefit from the short-period trial experiment by enhancing the usage of gaze cue.

Cutaneous and stick rabbit illusions in individuals with autism spectrum disorder.

Prediction is the process by which future events are anticipated based on past events; in contrast, postdiction is the retrospective interpretation of past events based on latter, more recent events. The prediction and postdiction are suggested to be similar based on theoretical models. Previous studies suggest that prediction is impaired in individuals with autism spectrum disorder (ASD). However, it is unclear whether postdiction is also impaired in individuals with ASD. In this study, we evaluated postdiction in individuals with ASD using the cutaneous and stick rabbit illusion paradigms in which the perceived location of a touch shifts postdictively in response to a subsequent touch stimulus. We observed significant cutaneous and stick rabbit illusion in both typically developing (TD) and ASD groups; therefore, postdiction was functional in individuals with ASD. Our present results suggest that postdiction involves a different neuronal process than prediction. We also observed that the ASD group exhibited significantly larger individual difference compared with the TD group in the stick rabbit illusion, which is considered to reflect extension of body schema to external objects. We discuss implications of the individual difference among the ASD participants in the context of sports requiring interactions between the body and external objects.

Action performance in children with autism spectrum disorder at preschool age: a pilot study.

Objectives: Motor deficits related to imitation have been observed in autism spectrum disorder (ASD) patients. This pilot investigation focused on motor performances, including daily tool-use actions, performing an action in the absence of the tool, and imitating (copying tool-use action presented visually), in eight children with ASD and eight children with typical development (TD), with all of pre-school age (4-6 years). Methods: Motor performances were compared between the children with ASD and TD. Differences between an actual tool-use action and performing a tool-use action without the tool according to verbal instruction were also assessed between the groups. Results: Children with ASD showed impairments in imitating, but their actual tool-use actions and tool-use actions without tools following verbal instruction were not different from those of TD children. The spatial error rate in the tasks was higher in children with ASD. Conclusions: The present study indicates that disturbance in imitating actions appears by the age of 4-6 years in children with ASD, possibly as a characteristic symptom affecting motor performance at pre-school age. Generalized apraxia might follow by the age of 8 years or older.

Higher Tactile Temporal Resolution as a Basis of Hypersensitivity in Individuals with Autism Spectrum Disorder.

Many individuals with autism spectrum disorder (ASD) have symptoms of sensory hypersensitivity. Several studies have shown high individual variations in temporal processing of tactile stimuli. We hypothesized that these individual differences are linked to differences in hyper-reactivity among individuals with ASD. Participants performed two tasks as to vibrotactile stimuli: One is a temporal order judgement task, and another is a detection task. We found that individuals with ASD with higher temporal resolution tended to have more severe hypersensitivity symptoms. In contrast, the tactile detection threshold/sensitivity were related to the severities of stereotyped behaviour and restricted interests, rather than to hypersensitivity. Our findings demonstrate that higher temporal resolution to sensory stimuli may contribute to sensory hypersensitivity in individuals with ASD.

Older Adolescents and Young Adults With Autism Spectrum Disorder Have Difficulty Chaining Motor Acts When Performing Prehension Movements Compared to Typically Developing Peers.

It is known that motor actions performed by individuals with autism spectrum disorders (ASD) are clumsy and a previous study revealed that children with ASD of around 8 years old showed less smooth movement and dysfunction of appropriate usage of online vision for grip aperture control. The present study investigates whether and how the kinematic properties of reach-to-grasp movements in older adolescents and adults with ASD [mean (±SD) age: 18.3 ± 2.1] differ from those in typically developing (TD) peers [mean (±SD) age: 19.1 ± 2.2]. Revealing the kinematic properties of reach-to-grasp movements in older adolescents and adults with ASD is indispensable in determining the developmental trajectory of this motor behavior in individuals with ASD. While wearing liquid crystal shutter goggles, participants reached for and grasped a cylinder with a diameter of either 4 or 6 cm. Two visual conditions were tested: a full vision (FV) condition (the goggles remained transparent during the movement) and a no vision (NV) condition (the goggles were closed immediately after the movement was initiated). These two visual conditions were either alternated with each trial in a single experimental session (alternated condition) or blocked within the session (blocked condition). We found that the reaching movement smoothness calculated as a normalized jerk score (i.e., index of skilled, coordinated human movements) of ASD participants did not differ significantly from that of TD peers although ASD participants showed smoother reaching in the alternated condition than in the blocked condition. The influence of online vision and its visual condition schedule on grip aperture during the in-flight phase was remarkably similar between the ASD and TD groups. Furthermore, we found that ASD group experienced a significant longer transition period from grasping end (i.e., stable holding when touching the surface of the object) to uplift initiation than the TD group. The results suggest that (1) deficits in movement smoothness and the use of online vision for motor control are rectified by the time individuals with ASD reach late adolescence and (2) older adolescents and adults with ASD still have difficulties chaining motor acts.

Efficacy and safety of a single-pill combination of vildagliptin and metformin in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled trial.

INTRODUCTION: The use of dipeptidyl peptidase-4 inhibitors in combination with metformin is increasing in Japanese patients with type 2 diabetes mellitus (T2DM), but no single-pill combination (SPC) is currently available in Japan. The objective of this study was to assess the efficacy and safety of vildagliptin/metformin SPC in Japanese patients with T2DM inadequately controlled with vildagliptin monotherapy. METHODS: This was a 14-week, randomized, double-blind, parallel-group, placebo-controlled trial. 171 patients with T2DM inadequately controlled [HbA1c (glycosylated hemoglobin) 7.0-10.0%] with vildagliptin 50 mg twice daily (bid) were randomized (2:1) to receive either a vildagliptin/metformin SPC (n = 115) or matching vildagliptin/placebo SPC (n = 56). RESULTS: Baseline demographics and background characteristics were generally comparable between the treatment groups. The change in HbA1c [mean ± standard error (SE)] was -0.8 ± 0.1% in the vildagliptin/metformin SPC (baseline HbA1c, 7.9 ± 0.1%) group and 0.1 ± 0.1% in the vildagliptin/placebo SPC (baseline HbA1c, 8.0 ± 0.1%) group, with a between-treatment difference of -1.0 ± 0.1% (P <0.001) in favor of the vildagliptin/metformin SPC group. The proportion of patients achieving target HbA1c <7.0% was significantly higher with vildagliptin/metformin SPC compared with vildagliptin/placebo SPC (45.8% vs. 13.5%, P <0.001). The overall incidences of adverse events (AEs) were 43.5% in the vildagliptin/metformin SPC and 67.9% in the vildagliptin/placebo SPC group. The incidences of serious AEs were low in both the treatment groups (0.9% vs. 3.6%, respectively). Body weight remained constant throughout the study in both the treatment groups. There were no deaths or hypoglycemic events during the study. CONCLUSIONS: Switching Japanese patients with T2DM requiring treatment intensification, from vildagliptin monotherapy to a vildagliptin/metformin SPC (50/250 or 50/500 mg) was efficacious and safe, eliciting significant reduction in HbA1c without increased risk of hypoglycemia and weight gain.

Disappearance of glibenclamide-induced hypoglycemia in Wistar-Kyoto rats.

The aim of the present study is to investigate difference in sensitivity to glibenclamide, a sulfonylurea oral antidiabetic agent, among Wistar rats, Spontaneously Hypertensive rats (SHR/Izm) and Wistar-Kyoto rats (WKY/Izm). We examined the effect of glibenclamide on blood levels of glucose and insulin in these rat strains. Under anesthesia with pentobarbital sodium (50 mg/kg, i.p.), blood samples were collected before and 5-120 min after administration of glibenclamide (10 mg/kg, i.p.). Blood levels of glucose and insulin in each sample were measured by glucose oxidase method and radioimmunoassay, respectively. In 8 week-old rats of all strains tested, blood levels of glucose were decreased by glibenclamide. In 12-20-week-old rats, although blood levels of glucose in Wistar and SHR/Izm were decreased after glibenclamide administration, those of WKY/Izm were not decreased. In rats of this age, time-course and extent of increases in blood insulin levels observed after administration of glibenclamide in WKY/Izm was almost the same as that of SHR/Izm, however, smaller than that of Wistar. Both insulin secretions induced via inactivation of ATP-sensitive K+ channel and sensitivity of pancreatic beta-cells to insulin seems to be decreased in WKY/Izm after 12 weeks of age. This phenomenon may explain the mechanism of glucose intolerance previously reported in WKY/Izm.