PLI: a web-based tool for the comparison of protein-ligand interactions observed on PDB structures.

Abstract Motivation: A large fraction of the entries contained in the Protein Data Bank describe proteins in complex with low molecular weight molecules such as physiological compounds or synthetic drugs. In many cases, the same molecule is found in distinct protein-ligand complexes. There is an increasing interest in Medicinal Chemistry in comparing protein binding sites to get insight on interactions that modulate the binding specificity, as this structural information can be correlated with other experimental data of biochemical or physiological nature and may help in rational drug design. Results: The web service protein-ligand interaction presented here provides a tool to analyse and compare the binding pockets of homologous proteins in complex with a selected ligand. The information is deduced from protein-ligand complexes present in the Protein Data Bank and stored in the underlying database. Availability: Freely accessible at http://bioinformatics.istge.it/pli/. Contact: [email protected]

Structural connectivity and brain network analyses in Parkinson's disease: A cross-sectional and longitudinal study.

IntroductionParkinson's disease (PD) is an idiopathic disease of the central nervous system characterized by both motor and non-motor symptoms. It is the second most common neurodegenerative disease. Magnetic resonance imaging (MRI) can reveal underlying brain changes associated with PD.ObjectiveIn this study, structural connectivity and white matter networks were analyzed by diffusion MRI and graph theory in a cohort of patients with PD and a cohort of healthy controls (HC) obtained from the Parkinson's Progression Markers Initiative (PPMI) database in a cross-sectional analysis. Furthermore, we investigated longitudinal changes in the PD cohort over 36 months.ResultCompared with the control group, participants with PD showed lower structural connectivity in several brain areas, including the corpus callosum, fornix, and uncinate fasciculus, which were also confirmed by a large effect-size. Additionally, altered connectivity between baseline and after 36 months was found in different network paths inside the white matter with a medium effect-size. Network analysis showed trends toward lower network density in PD compared with HC at baseline and after 36 months, though not significant after correction. Significant differences were observed in nodal degree and strength in several nodes.ConclusionIn conclusion, altered structural and network metrics in several brain regions, such as corpus callosum, fornix, and cingulum were found in PD, compared to HC. We also report altered connectivity in the PD group after 36 months, reflecting the impact of both PD pathology and aging processes. These results indicate that structural and network metrics might yield insight into network reorganization that occurs in PD

Free water imaging of the cholinergic system in dementia with Lewy bodies and Alzheimer's disease

INTRODUCTION: Degeneration of cortical cholinergic projections from the nucleus basalis of Meynert (NBM) is characteristic of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), whereas involvement of cholinergic projections from the pedunculopontine nucleus (PPN) to the thalamus is less clear. METHODS: We studied both cholinergic projection systems using a free water-corrected diffusion tensor imaging (DTI) model in the following cases: 46 AD, 48 DLB, 35 mild cognitive impairment (MCI) with AD, 38 MCI with Lewy bodies, and 71 controls. RESULTS: Free water in the NBM-cortical pathway was increased in both dementia and MCI groups compared to controls and associated with cognition. Free water along the PPN-thalamus tract was increased only in DLB and related to visual hallucinations. Results were largely replicated in an independent cohort. DISCUSSION: While NBM-cortical projections degenerate early in AD and DLB, the thalamic cholinergic input from the PPN appears to be more selectively affected in DLB and might associate with visual hallucinations. Highlights: Free water in the NBM-cortical cholinergic pathways is increased in AD and DLB. NBM-cortical pathway integrity is related to overall cognitive performance. Free water in the PPN-thalamus cholinergic pathway is only increased in DLB, not AD. PPN-thalamus pathway integrity might be related to visual hallucinations in DLB

Oral ondansetron versus domperidone for acute gastroenteritis in pediatric emergency departments: Multicenter double blind randomized controlled trial

The use of antiemetics for vomiting in acute gastroenteritis in children is still a matter of debate. We conducted a double-blind randomized trial to evaluate whether a single oral dose of ondansetron vs domperidone or placebo improves outcomes in children with gastroenteritis. After failure of initial oral rehydration administration, children aged 1-6 years admitted for gastroenteritis to the pediatric emergency departments of 15 hospitals in Italy were randomized to receive one oral dose of ondansetron (0.15 mg/kg) or domperidone (0.5 mg/kg) or placebo. The primary outcome was the percentage of children receiving nasogastric or intravenous rehydration. A p value of 0.014 was used to indicate statistical significance (and 98.6% CI were calculated) as a result of having carried out two interim analyses. 1,313 children were eligible for the first attempt with oral rehydration solution, which was successful for 832 (63.4%); 356 underwent randomization (the parents of 125 children did not give consent): 118 to placebo, 119 to domperidone, and 119 to ondansetron. Fourteen (11.8%) needed intravenous rehydration in the ondansetron group vs 30 (25.2%) and 34 (28.8%) in the domperidone and placebo groups, respectively. Ondansetron reduced the risk of intravenous rehydration by over 50%, both vs placebo (RR 0.41, 98.6% CI 0.20-0.83) and domperidone (RR 0.47, 98.6% CI 0.23-0.97). No differences for adverse events were seen among groups. In a context of emergency care, 6 out of 10 children aged 1-6 years with vomiting due to gastroenteritis and without severe dehydration can be managed effectively with administration of oral rehydration solution alone. In children who fail oral rehydration, a single oral dose of ondansetron reduces the need for intravenous rehydration and the percentage of children who continue to vomit, thereby facilitating the success of oral rehydration. Domperidone was not effective for the symptomatic treatment of vomiting during acute gastroenteritis

Free-water diffusion tensor imaging improves the accuracy and sensitivity of white matter analysis in Alzheimer’s disease

Magnetic resonance imaging (MRI) based diffusion tensor imaging (DTI) can assess white matter (WM) integrity through several metrics, such as fractional anisotropy (FA), axial/radial diffusivities (AxD/RD), and mode of anisotropy (MA). Standard DTI is susceptible to the effects of extracellular free water (FW), which can be removed using an advanced free-water DTI (FW-DTI) model. The purpose of this study was to compare standard and FW-DTI metrics in the context of Alzheimer’s disease (AD). Data were obtained from the Open Access Series of Imaging Studies (OASIS-3) database and included both healthy controls (HC) and mild-to-moderate AD. With both standard and FW-DTI, decreased FA was found in AD, mainly in the corpus callosum and fornix, consistent with neurodegenerative mechanisms. Widespread higher AxD and RD were observed with standard DTI; however, the FW index, indicative of AD-associated neurodegeneration, was significantly elevated in these regions in AD, highlighting the potential impact of free water contributions on standard DTI in neurodegenerative pathologies. Using FW-DTI, improved consistency was observed in FA, AxD, and RD, and the complementary FW index was higher in the AD group as expected. With both standard and FW-DTI, higher values of MA coupled with higher values of FA in AD were found in the anterior thalamic radiation and cortico-spinal tract, most likely arising from a loss of crossing fibers. In conclusion, FW-DTI better reflects the underlying pathology of AD and improves the accuracy of DTI metrics related to WM integrity in Alzheimer’s disease

Dynamic Contrast-Enhanced MRI in the Study of Brain Tumors. Comparison Between the Extended Tofts-Kety Model and a Phenomenological Universalities (PUN) Algorithm

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a well-established technique for studying blood\ue2\u80\u93brain barrier (BBB) permeability that allows measurements to be made for a wide range of brain pathologies, including multiple sclerosis and brain tumors (BT). This latter application is particularly interesting, because high-grade gliomas are characterized by increased microvascular permeability and a loss of BBB function due to the structural abnormalities of the endothelial layer. In this study, we compared the extended Tofts-Kety (ETK) model and an extended derivate class from phenomenological universalities called EU1 in 30 adult patients with different BT grades. A total of 75 regions of interest were manually drawn on the MRI and subsequently analyzed using the ETK and EU1 algorithms. Significant linear correlations were found among the parameters obtained by these two algorithms. The means of R2 obtained using ETK and EU1 models for high-grade tumors were 0.81 and 0.91, while those for low-grade tumors were 0.82 and 0.85, respectively; therefore, these two models are equivalent. In conclusion, we can confirm that the application of the EU1 model to the DCE-MRI experimental data might be a useful alternative to pharmacokinetic models in the study of BT, because the analytic results can be generated more quickly and easily than with the ETK model

Systematic assessment of the impact of DTI methodology on fractional anisotropy measures in Alzheimer’s disease

White matter microstructural changes in Alzheimer’s disease (AD) are often assessed using fractional anisotropy (FA) obtained from diffusion tensor imaging (DTI). FA depends on the acquisition and analysis methods, including the fitting algorithm. In this study, we compared FA maps from different acquisitions and fitting algorithms in AD, mild cognitive impairment (MCI), and healthy controls (HCs) using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Three acquisitions from two vendors were compared (Siemens 30, GE 48, and Siemens 54 directions). DTI data were fit using nine fitting algorithms (four linear least squares (LLS), two weighted LLS (WLLS), and three non-linear LLS (NLLS) from four software tools (FSL, DSI-Studio, CAMINO, and AFNI). Different cluster volumes and effect-sizes were observed across acquisitions and fits, but higher consistency was observed as the number of diffusion directions increased. Significant differences were observed between HC and AD groups for all acquisitions, while significant differences between HC and MCI groups were only observed for GE48 and SI54. Using the intraclass correlation coefficient, AFNI-LLS and CAMINO-RESTORE were the least consistent with the other algorithms. By combining data across all three acquisitions and nine fits, differences between AD and HC/MCI groups were observed in the fornix and corpus callosum, indicating FA differences in these regions may be robust DTI-based biomarkers. This study demonstrates that comparisons of FA across aging populations could be confounded by variability in acquisitions and fit methodologies and that identifying the most robust DTI methodology is critical to provide more reliable DTI-based neuroimaging biomarkers for assessing microstructural changes in AD

Analysis of Brain Structural Connectivity Networks and White Matter Integrity in Patients With Mild Cognitive Impairment.

White matter integrity and structural connectivity may be altered in mild cognitive impairment (MCI), and these changes may closely reflect decline in specific cognitive domains. Multi-shell diffusion data in healthy control (HC

Analysis of Brain Structural Connectivity Networks and White Matter Integrity in Patients With Mild Cognitive Impairment

White matter integrity and structural connectivity may be altered in mild cognitive impairment (MCI), and these changes may closely reflect decline in specific cognitive domains. Multi-shell diffusion data in healthy control (HC, n = 31) and mild cognitive impairment (MCI, n = 19) cohorts were downloaded from the ADNI3 database. The data were analyzed using an advanced approach to assess both white matter microstructural integrity and structural connectivity. Compared with HC, lower intracellular compartment (IC) and higher isotropic (ISO) values were found in MCI. Additionally, significant correlations were found between IC and Montreal Cognitive Assessment (MoCA) scores in the MCI cohort. Network analysis detected structural connectivity differences between the two groups, with lower connectivity in MCI. Additionally, significant differences between HC and MCI were observed for global network efficiency. Our results demonstrate the potential of advanced diffusion MRI biomarkers for understanding brain changes in MCI

White Matter Microstructural Differences between Essential Tremor and Parkinson Disease, Evaluated Using Advanced Diffusion MRI Biomarkers

Background: Essential tremor (ET) is a common slowly-progressive neurologic disorder. It is predominantly characterized by kinetic tremors involving bilateral upper limbs. Although ET shares motor similarities with Parkinson disease (PD), there is no known relationship between ET and PD. Methods: We studied white matter differences between 17 ET and 68 PD patients using standard diffusion tensor imaging and fixel-based analysis (FBA). Diffusion magnetic resonance imaging data were acquired from two scanners (General Electric (GE) and Philips) with different numbers of diffusion directions. Fractional anisotropy maps were generated by the Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL), and FBA was performed using MRtrix3 to obtain fiber density, fiber bundle, and fiber density bundle cross-section. Results: Compared with PD, significantly lower values of fiber density, fiber bundle, and fiber density bundle cross-section were found in the corpus callosum and left tapetum of the ET group. Additionally, significantly lower functional anisotropy values were found in the ET compared to the PD group, principally in the corpus callosum, corona radiata, and cingulum. In conclusion, differences in white matter integrity between ET and PD were observed by both FBA-based metrics and diffusion tensor imaging. Conclusions: Advanced diffusion-based metrics may provide a better understanding of the white matter microstructural characteristics in disparate motor-associated diseases with different underlying phenotypes, such as ET and PD