Use of functional imaging across clinical phases in CNS drug development

The use of novel brain biomarkers using nuclear magnetic resonance imaging holds potential of making central nervous system (CNS) drug development more efficient. By evaluating changes in brain function in the disease state or drug effects on brain function, the technology opens up the possibility of obtaining objective data on drug effects in the living awake brain. By providing objective data, imaging may improve the probability of success of identifying useful drugs to treat CNS diseases across all clinical phases (I–IV) of drug development. The evolution of functional imaging and the promise it holds to contribute to drug development will require the development of standards (including good imaging practice), but, if well integrated into drug development, functional imaging can define markers of CNS penetration, drug dosing and target engagement (even for drugs that are not amenable to positron emission tomography imaging) in phase I; differentiate objective measures of efficacy and side effects and responders vs non-responders in phase II, evaluate differences between placebo and drug in phase III trials and provide insights into disease modification in phase IV trials

Nonergodic behavior of the clean Bose-Hubbard chain

We study ergodicity breaking in the clean Bose-Hubbard chain for small hopping strength. We see the existence of a non-ergodic regime by means of indicators as the half-chain entanglement entropy of the eigenstates, the average level spacing ratio, {the properties of the eigenstate-expectation distribution of the correlation and the scaling of the Inverse Participation Ratio averages.} We find that this ergodicity breaking {is different from many-body localization} because the average half-chain entanglement entropy of the eigenstates obeys volume law. This ergodicity breaking appears unrelated to the spectrum being organized in quasidegenerate multiplets at small hopping and finite system sizes, so in principle it can survive also for larger system sizes. We find that some imbalance oscillations in time which could mark the existence of a glassy behaviour in space are well described by the dynamics of a single symmetry-breaking doublet and {quantitatively} captured by a perturbative effective XXZ model. We show that the amplitude of these oscillations vanishes in the large-size limit. {Our findings are numerically obtained for systems with $L < 12$. Extrapolations of our scalings to larger system sizes should be taken with care, as discussed in the paper.Comment: 18 pages, 13 figures, extensively revised version published in Physical Review B, Eq. (21) in the correct for

The Relationship Antecedents of Smoking (RAS) Scale: A new scale to assess couple-focused triggers to smoke.

The purpose of this pilot study is to assess the reliability and construct validity of a measure of relationship-focused antecedents for smoking (RAS). The scale includes both positively-valenced items (e.g.. “I feel like smoking when I am relaxing with my partner”) and negatively-valenced items (e.g., “I feel like smoking when my partner criticizes me”). Participants included 123 individuals who smoke cigarettes with co-habitating smoking (n=63) or non-smoking (n=60) romantic partners. Participants completed the RAS and a series of measures associated with smoking outcomes. Principal component analysis with varimax rotation resulted in a 2-component solution. The RAS showed excellent internal consistency for the total scale (α=.96) and for the positive (α=.88) and negative (α=.97) subscales. Higher positive subscale scores were associated with lower motivation to quit while higher negative scores were associated with lower relationship satisfaction and dyadic efficacy to quit. Higher scores on both subscales were related to higher social motives, dependence motives, and social outcome expectances. Participants with smoking partners reported higher positive subscale scores and lower negative subscale scores. The RAS may be helpful in the design of smoking cessation interventions for couples

Spin-polarized oxygen hole states in cation deficient La(1-x)CaxMnO(3+delta)

When holes are doped into a Mott-Hubbard type insulator, like lightly doped manganites of the La(1-x)CaxMnO3 family, the cooperative Jahn-Teller distortions and the appearance of orbital ordering require an arrangement of Mn(3+)/Mn(4+) for the establishment of the insulating canted antiferromagnetic (for x<=0.1), or of the insulating ferromagnetic (for 0.1<x<= 0.2) ground state. In the present work we provide NMR evidence about a novel and at the same time puzzling effect in La(1-x)CaxMnO(3+delta) systems with cation deficience. We show that in the low Ca-doping regime, these systems exhibit a very strong hyperfine field at certain La nuclear sites, which is not present in the stoichiometric compounds. Comparison of our NMR results with recent x-ray absorption data at the Mn K edge, suggests the formation of a spin-polarized hole arrangement on the 2p oxygen orbitals as the origin of this effect.Comment: 10 pages, 4 Figures, submitted to PR

Definition of Naturally Processed Peptides Reveals Convergent Presentation of Autoantigenic Topoisomerase I Epitopes in Scleroderma.

ObjectiveAutoimmune responses to DNA topoisomerase I (topo I) are found in a subset of scleroderma patients who are at high risk for interstitial lung disease (ILD) and mortality. Anti-topo I antibodies (ATAs) are associated with specific HLA-DRB1 alleles, and the frequency of HLA-DR-restricted topo I-specific CD4+ T cells is associated with the presence, severity, and progression of ILD. Although this strongly implicates the presentation of topo I peptides by HLA-DR in scleroderma pathogenesis, the processing and presentation of topo I has not been studied.MethodsWe developed a natural antigen processing assay (NAPA) to identify putative CD4+ T cell epitopes of topo I presented by monocyte-derived dendritic cells (mo-DCs) from 6 ATA-positive patients with scleroderma. Mo-DCs were pulsed with topo I protein, HLA-DR-peptide complexes were isolated, and eluted peptides were analyzed by mass spectrometry. We then examined the ability of these naturally presented peptides to induce CD4+ T cell activation in 11 ATA-positive and 11 ATA-negative scleroderma patients.ResultsWe found that a common set of 10 topo I epitopes was presented by Mo-DCs from scleroderma patients with diverse HLA-DR variants. Sequence analysis revealed shared peptide-binding motifs within the HLA-DRβ chains of ATA-positive patients and a subset of topo I epitopes with distinct sets of anchor residues capable of binding to multiple different HLA-DR variants. The NAPA-derived epitopes elicited robust CD4+ T cell responses in 73% of ATA-positive patients (8 of 11), and the number of epitopes recognized correlated with ILD severity (P = 0.025).ConclusionThese findings mechanistically implicate the presentation of a convergent set of topo I epitopes in the development of scleroderma

Neuroimaging revolutionizes therapeutic approaches to chronic pain

An understanding of how the brain changes in chronic pain or responds to pharmacological or other therapeutic interventions has been significantly changed as a result of developments in neuroimaging of the CNS. These developments have occurred in 3 domains : (1) Anatomical Imaging which has demonstrated changes in brain volume in chronic pain; (2) Functional Imaging (fMRI) that has demonstrated an altered state in the brain in chronic pain conditions including back pain, neuropathic pain, and complex regional pain syndromes. In addition the response of the brain to drugs has provided new insights into how these may modify normal and abnormal circuits (phMRI or pharmacological MRI); (3) Chemical Imaging (Magnetic Resonance Spectroscopy or MRS) has helped our understanding of measures of chemical changes in chronic pain. Taken together these three domains have already changed the way in which we think of pain – it should now be considered an altered brain state in which there may be altered functional connections or systems and a state that has components of degenerative aspects of the CNS

A review on slurry bioreactors for bioremediation of soils and sediments

The aim of this work is to present a critical review on slurry bioreactors (SB) and their application to bioremediation of soils and sediments polluted with recalcitrant and toxic compounds. The scope of the review encompasses the following subjects: (i) process fundamentals of SB and analysis of advantages and disadvantages; (ii) the most recent applications of SB to laboratory scale and commercial scale soil bioremediation, with a focus on pesticides, explosives, polynuclear aromatic hydrocarbons, and chlorinated organic pollutants; (iii) trends on the use of surfactants to improve availability of contaminants and supplementation with degradable carbon sources to enhance cometabolism of pollutants; (iv) recent findings on the utilization of electron acceptors other than oxygen; (v) bioaugmentation and advances made on characterization of microbial communities of SB; (vi) developments on ecotoxicity assays aimed at evaluating bioremediation efficiency of the process

Case Report: REL-1017 Reduces Abnormal Clinician Administered Dissociative States Scale Scores in Patients with Major Depressive Disorder

BACKGROUND: Dissociative symptoms may be found in a subset of patients with major depressive disorders (MDD). The Clinician-Administered Dissociative States Scale (CADSS) is a 23-item scale for the measurement of present-state dissociative symptoms with good inter-rater reliability and construct validity that can discriminate patients with dissociative disorders. The total CADSS score is derived by adding the score for each of the 23 items. A score of 4 or more on the CADSS is considered abnormal and clinically meaningful. Uncompetitive N-methyl-d-aspartic acid receptor (NMDAR) channel blockers have been proposed as a treatment for post-traumatic stress disorder (PTSD). REL-1017 is a novel, low potency, NMDAR channel blocker currently in Phase 3 studies for MDD. METHODS: This retrospective case series describes a subset of patients from a double-blind, randomized, placebo-controlled, in-patient 7-day, phase 2 trial of oral, once daily, 25&nbsp;mg (75&nbsp;mg loading dose on day 1, first dose) and 50&nbsp;mg REL-1017 (100&nbsp;mg loading dose on day 1, first dose) as an adjunctive treatment for MDD. This subset of patients was selected based on abnormal CADSS score at baseline, pre-treatment with the study drug. As part of REL-1017 safety evaluation, the CADSS was administered at four timepoints to all study patients: (a) 30 to 60&nbsp;minutes pre-treatment at baseline on day 1; (b) 2&nbsp;hours post-treatment on day 1 (after the first dose of study drug); (c) 2&nbsp;hours post-treatment on day 7 (after the last dose); and (d) prior to discharge on day 9 (2&nbsp;days after the last dose). RESULTS: Among the 62 randomized patients, four patients had a CADSS score of at least 4 on day 1 before study drug administration (2 patients in the 25&nbsp;mg arm [CADSS score 22 and 4]; 1 patient in the 50&nbsp;mg arm [CADSS score 35]; 1 patient in the placebo arm [CADSS score 6]). Among these 4 patients, starting on day 1, 2&nbsp;hours post-treatment, the 2 subjects in the 25&nbsp;mg subgroup (75&nbsp;mg loading dose) and 1 subject in the 50&nbsp;mg subgroup (100&nbsp;mg loading dose) showed a clinically meaningful decrease in their CADSS score, while the single patient in the placebo group showed no change. CADSS scores on Day 1 pre-treatment, day 1 post-treatment, day 7 post last treatment, and on day 9 prior to discharge were 22-2-6-0; 4-0-0-0; 35-14-9-0, and 6-6-n/a-n/a, for the two patients in the 25&nbsp;mg REL-1017 subgroup, the single patient in the 50&nbsp;mg REL-1017 subgroup, and the single patient in the placebo group, respectively. CONCLUSIONS: These retrospective case report data potentially signal that REL-1017 may determine rapid and sustained improvement in patients with MDD and concurrent clinically meaningful dissociative symptoms assessed by a CADSS score of 4 or above. Ongoing phase 3 trials with REL-1017 are expected to enroll a total of 1200 outpatients with MDD. These studies will potentially generate additional data that may support the initiation of controlled studies with REL-1017 for the treatment of PTSD. FUNDING: Relmada Therapeutics