Altered visual and haptic verticality perception in posterior cortical atrophy and Alzheimer's disease

There is increasing theoretical and empirical support for the brain combining multisensory information to determine the direction of gravity and hence uprightness. A fundamental part of the process is the spatial transformation of sensory signals between reference frames: eye-centred, head-centred, body-centred, etc. The question ‘Am I the right way up?’ posed by a patient with posterior cortical atrophy (PCA) suggests disturbances in upright perception, subsequently investigated in PCA and typical Alzheimer's disease (tAD) based on what looks or feels upright. Participants repeatedly aligned to vertical a rod presented either visually (visual-vertical) or haptically (haptic-vertical). Visual-vertical involved orienting a projected rod presented without or with a visual orientation cue (circle, tilted square (±18°)). Haptic-vertical involved orientating a grasped rod with eyes closed using a combination of side (left, right) and hand (unimanual, bimanual) configurations. Intraindividual uncertainty and bias defined verticality perception. Uncertainty was consistently greater in both patient groups than in control groups, and greater in PCA than tAD. Bias in the frontal plane was strongly directionally affected by visual cue tilt (visual-vertical) and grip side (haptic-vertical). A model was developed that assumed verticality information from multiple sources is combined in a statistically optimal way to produce observed uncertainties and biases. Model results suggest the mechanism that spatially transforms graviceptive information between body parts is disturbed in both patient groups. Despite visual dysfunction being typically considered the primary feature of PCA, disturbances were greater in PCA than tAD particularly for haptic-vertical, and are considered in light of posterior parietal vulnerability

Altered visual and haptic verticality perception in posterior cortical atrophy and Alzheimer's disease

Abstract: There is increasing theoretical and empirical support for the brain combining multisensory information to determine the direction of gravity and hence uprightness. A fundamental part of the process is the spatial transformation of sensory signals between reference frames: eye-centred, head-centred, body-centred, etc. The question ‘Am I the right way up?’ posed by a patient with posterior cortical atrophy (PCA) suggests disturbances in upright perception, subsequently investigated in PCA and typical Alzheimer's disease (tAD) based on what looks or feels upright. Participants repeatedly aligned to vertical a rod presented either visually (visual-vertical) or haptically (haptic-vertical). Visual-vertical involved orienting a projected rod presented without or with a visual orientation cue (circle, tilted square (±18°)). Haptic-vertical involved orientating a grasped rod with eyes closed using a combination of side (left, right) and hand (unimanual, bimanual) configurations. Intraindividual uncertainty and bias defined verticality perception. Uncertainty was consistently greater in both patient groups than in control groups, and greater in PCA than tAD. Bias in the frontal plane was strongly directionally affected by visual cue tilt (visual-vertical) and grip side (haptic-vertical). A model was developed that assumed verticality information from multiple sources is combined in a statistically optimal way to produce observed uncertainties and biases. Model results suggest the mechanism that spatially transforms graviceptive information between body parts is disturbed in both patient groups. Despite visual dysfunction being typically considered the primary feature of PCA, disturbances were greater in PCA than tAD particularly for haptic-vertical, and are considered in light of posterior parietal vulnerability. (Figure presented.). Key points: The perception of upright requires accurate and precise estimates of orientation based on multiple noisy sensory signals. The question ‘Am I the right way up?’ posed by a patient with posterior cortical atrophy (PCA; purported ‘visual variant Alzheimer's’) suggests disturbances in the perception of upright. What looks or feels upright in PCA and typical Alzheimer's disease (tAD) was investigated by asking participants to repeatedly align to vertical a rod presented visually (visual-vertical) or haptically (haptic-vertical). PCA and tAD groups exhibited not only greater perceptual uncertainty than controls, but also exaggerated bias induced by tilted visual orientation cues (visual-vertical) and grip side (haptic-vertical). When modelled, these abnormalities, which were particularly evident in PCA haptic-vertical performance, were compatible with disruption of a mechanism that spatially transforms verticality information between body parts. The findings suggest an important role of posterior parietal cortex in verticality perception, and have implications for understanding spatial disorientation in dementia. © 2021 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society

ReadClear: An Assistive Reading Tool for People Living with Posterior Cortical Atrophy

BACKGROUND: Progressive reading impairment is an early and debilitating symptom of posterior cortical atrophy (PCA) arising from the progressive deterioration of visual processing skills. OBJECTIVE: The goal of this study was to test the effectiveness of a purpose-built reading app (ReadClear) co-produced with people living with PCA and designed to reduce the reading difficulties experienced by this population (e.g., getting lost in the page and missing words when reading). METHODS: Twenty subjects with PCA were included in a cross-over design home-based study aimed at determining whether ReadClear could 1) enhance the subjective reading experience (reading pleasantness) and 2) improve reading accuracy (reducing the number of reading errors) compared with a sham condition (a standard e-reader). RESULTS: Reading using ReadClear provided a better subjective reading experience than sham (p = 0.018, d = 0.5) and significantly reduced the percentage of reading errors (p <  0.0001, r = 0.82), particularly errors due to omissions (p = 0.01, r = 0.50), repeated words (p = 0.002, r = 0.69), and regressions in the text (p = 0.003, r = 0.69). We found that different kinds of reading errors were related to specific neuropsychological profiles. CONCLUSION: ReadClear can assist reading in people living with PCA by reducing the number of reading errors and improving the subjective reading experience of users

Chemical Doping of the Organic Semiconductor C8-BTBT-C8 Using an Aqueous Iodine Solution for Device Mobility Enhancement

The performance of organic field-effect transistors is still severely limited by factors such as contact resistance and charge trapping. Chemical doping is considered to be a promising key enabler for improving device performance, although there is a limited number of established doping protocols as well as a lack of understanding of the doping mechanisms. Here, a very simple doping methodology based on exposing an organic semiconductor thin film to an aqueous iodine solution is reported. The doped devices exhibit enhanced device mobility, which becomes channel-length independent, a decreased threshold voltage and a reduction in the density of interfacial traps. The device OFF current is not altered, which is in agreement with the spectroscopic data that points out that no charge transfer processes are occurring. Kelvin probe force microscopy characterization of the devices under operando conditions unambiguously proves that an important reduction of the contact resistance takes place after their exposition to the iodine solution, reaching almost ohmic contact

Effects of lighting variability on locomotion in posterior cortical atrophy

INTRODUCTION: Clinical reports describe patients with Alzheimer's disease (AD) exhibiting atypical adaptive walking responses to the visual environment; however, there is limited empirical investigation of such behaviors or factors modulating their expression. We aim to evaluate effects of lighting‐based interventions and clinical presentation (visual‐ vs memory‐led) on walking function in participants with posterior cortical atrophy (PCA) and typical AD (tAD). METHODS: Participants with PCA (n = 10), tAD (n = 9), and healthy controls (n = 12) walked to visible target destinations under different lighting conditions within two pilot repeated‐measures design investigations (Experiment 1: 32 trials per participant; Experiment 2: 36 trials per participant). Participants walked to destinations with the floorpath interrupted by shadows varying in spatial extent (Experiment 1: no, medium, high shadow) or with different localized parts of the environment illuminated (Experiment 2: target, middle, or distractor illuminated). The primary study outcome for both experimental tasks was completion time; secondary kinematic outcomes were proportions of steps identified as outliers (Experiment 1) and walking path directness (Experiment 2). RESULTS: In Experiment 1, PCA participants overall demonstrated modest reductions in time taken to reach destinations when walking to destinations uninterrupted by shadows compared to high shadow conditions (7.1% reduction [95% confidence interval 2.5, 11.5; P = .003]). Experiment 2 found no evidence of differences in task performance for different localized lighting conditions in PCA participants overall. Neither experiment found evidence of differences in task performance between conditions in tAD or control participants overall. Completion time in both patient groups was longer relative to controls, and longer in PCA relative to tAD groups. DISCUSSION: Findings represent a quantitative characterization of a clinical phenomenon involving patients misperceiving shadows, implicating dementia‐related cortico‐visual impairments. Results contribute to evidence‐based design guidelines for dementia‐friendly environments

A rapid in vivo screen for pancreatic ductal adenocarcinoma therapeutics

Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related deaths in the United States, and is projected to be second by 2025. It has the worst survival rate among all major cancers. Two pressing needs for extending life expectancy of affected individuals are the development of new approaches to identify improved therapeutics, addressed herein, and the identification of early markers. PDA advances through a complex series of intercellular and physiological interactions that drive cancer progression in response to organ stress, organ failure, malnutrition, and infiltrating immune and stromal cells. Candidate drugs identified in organ culture or cell-based screens must be validated in preclinical models such as KIC (p48Cre;LSL-KrasG12D;Cdkn2af/f) mice, a genetically engineered model of PDA in which large aggressive tumors develop by 4 weeks of age. We report a rapid, systematic and robust in vivo screen for effective drug combinations to treat Kras-dependent PDA. Kras mutations occur early in tumor progression in over 90% of human PDA cases. Protein kinase and G-protein coupled receptor (GPCR) signaling activates Kras. Regulators of G-protein signaling (RGS) proteins are coincidence detectors that can be induced by multiple inputs to feedback-regulate GPCR signaling. We crossed Rgs16::GFP bacterial artificial chromosome (BAC) transgenic mice withKIC mice and show that the Rgs16::GFP transgene is a KrasG12D-dependent marker of all stages of PDA, and increases proportionally to tumor burden in KIC mice. RNA sequencing (RNA-Seq) analysis of cultured primary PDA cells reveals characteristics of embryonic progenitors of pancreatic ducts and endocrine cells, and extraordinarily high expression of the receptor tyrosine kinase Axl, an emerging cancer drug target. In proof-of-principle drug screens, we find that weanling KIC mice with PDA treated for 2 weeks with gemcitabine (with or without Abraxane) plus inhibitors of Axl signaling (warfarin and BGB324) have fewer tumor initiation sites and reduced tumor size compared with the standard-of-care treatment. Rgs16::GFP is therefore an in vivo reporter of PDA progression and sensitivity to new chemotherapeutic drug regimens such as Axl-targeted agents. This screening strategy can potentially be applied to identify improved therapeutics for other cancers

Micro and nano-patterning of single-crystal diamond by swift heavy ion irradiation

This paper presents experimental data and analysis of the structural damage caused by swift-heavy ion irradiation of single-crystal diamond. The patterned buried structural damage is shown to generate, via swelling, a mirror- pattern on the sample surface, which remains largely damage-free. While extensive results are available for light ion implantations, this effect is reported here for the first time in the heavy ion regime,where a completely different range of input parameters (in terms of ion species, energy, stopping power, etc.) is available for customized irradiation. The chosen ion species are Au and Br, in the energy range 10–40 MeV. The observed patterns, as characterized by profilometry and atomic force microscopy, are reported in a series ofmodel experiments,which show swelling patterns ranging from a few nm to above 200 nm. Moreover, a systematic phenomenological modeling is presented, inwhich surface swelling measurements are correlated to buried crystal damage. A comparison ismade with data for light ion implantations, showing good compatibilitywith the proposedmodels. The modeling presented in thiswork can be useful for the design and realization of micropatterned surfaces in single crystal diamond, allowing generating highly customized structures by combining appropriately chosen irradiation parameters and masks

Next-generation sequencing reveals deep intronic cryptic ABCC8 and HADH splicing founder mutations causing hyperinsulinism by pseudoexon activation

Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc.Next-generation sequencing (NGS) enables analysis of the human genome on a scale previously unachievable by Sanger sequencing. Exome sequencing of the coding regions and conserved splice sites has been very successful in the identification of disease-causing mutations, and targeting of these regions has extended clinical diagnostic testing from analysis of fewer than ten genes per phenotype to more than 100. Noncoding mutations have been less extensively studied despite evidence from mRNA analysis for the existence of deep intronic mutations in >20 genes. We investigated individuals with hyperinsulinaemic hypoglycaemia and biochemical or genetic evidence to suggest noncoding mutations by using NGS to analyze the entire genomic regions of ABCC8 (117 kb) and HADH (94 kb) from overlapping ~10 kb PCR amplicons. Two deep intronic mutations, c.1333-1013A>G in ABCC8 and c.636+471G>T HADH, were identified. Both are predicted to create a cryptic splice donor site and an out-of-frame pseudoexon. Sequence analysis of mRNA from affected individuals' fibroblasts or lymphoblastoid cells confirmed mutant transcripts with pseudoexon inclusion and premature termination codons. Testing of additional individuals showed that these are founder mutations in the Irish and Turkish populations, accounting for 14% of focal hyperinsulinism cases and 32% of subjects with HADH mutations in our cohort. The identification of deep intronic mutations has previously focused on the detection of aberrant mRNA transcripts in a subset of disorders for which RNA is readily obtained from the target tissue or ectopically expressed at sufficient levels. Our approach of using NGS to analyze the entire genomic DNA sequence is applicable to any disease

Characteristics of patients operated for primary hyperparathyroidism at university hospitals in Türkiye: Differences among Türkiye's geographical regions

Purpose: The aim of this study was to define the clinical and laboratory characteristics of patients operated on for primary hyperpatathyroidism (PHPT) at university hospitals in Türkiye, and to investigate the differences in the clinical presentations of the disease between different geographical regions. Methods: Patients operated on for PHPT in the university hospitals of Türkiye were included in the study. The demographic, clinical, and laboratory findings and the operational data of the patients were investigated according to the whole country and to different geographical regions. Comparisons were performed according to whole country and regions. Results: A total of 1,162 cases were included in the study from different regions and 20 university hospitals. The mean age of patients was 52.4 ± 0.38 (mean ± standard error) in the general population of Türkiye. The rates of hypertension, urolithiasis, bone disease and 25-hydroxyvitamin D insufficiency were 35%, 18.6%, 67.6%, and 63%, respectively. The median parathormone (PTH), serum total calcium (Ca+2) and phosphorus value were 220 pg/mL (range, 70-2,500 pg/mL), 11.2 mg/dL (range, 9.5-11.2 mg/dL), and 2.4 mg/dL (range, 1-4.7 mg/dL), respectively. The median size of the adenomas resected was 16 mm (range, 4-70 mm). Significant differences were observed in the clinical and laboratory findings of the patients operated on due to PHPT between different geographical regions of Türkiye (P &lt; 0.05). Conclusion: The clinical and laboratory characteristics of the patients with PHPT in different geographical regions of Türkiye differ. Furthermore, the general findings of the cases in Türkiye give us a hint that the severity of the disease here is somewhere between Eastern and Western countries. Copyright © 2016, the Korean Surgical Society