Search

Aims: Phosphodiesterase 2 (PDE2) regulates intracellular cyclic adenosine monophosphate and guanosine monophosphate (cAMP/cGMP) levels, which contribute to processes crucial for learning and memory. BI 474121, a potent and selective PDE2 inhibitor, is in development for treating cognitive impairment associated with schizophrenia. Methods: The effects of BI 474121 on cGMP concentrations were first assessed in rat cerebrospinal fluid (CSF) to demonstrate central nervous system (CNS) and functional target engagement. Next, a Phase I study in healthy participants assessed the pharmacokinetics of BI 474121 in CSF vs. plasma, the pharmacodynamics of BI 474121 by measuring cGMP concentrations in the CSF, and the safety of BI 474121. Results: In rats, BI 474121 was associated with a dose‐dependent increase (71% at the highest dose tested [3.0 mg kg−1]) in cGMP levels in the CSF relative to vehicle (P < 0.001). In healthy participants, the maximum‐measured concentration CSF‐to‐plasma ratio for BI 474121 exposure was similar following single oral doses of BI 474121 2.5, 10, 20 and 40 mg (dose‐adjusted geometric mean: 8.96% overall). BI 474121 2.5–40 mg administration in healthy participants also increased cGMP levels in CSF (maximum exposure‐related change from baseline ratio, BI 474121: 1.44–2.20 vs. placebo: 1.26). The most common treatment‐emergent adverse event (AE) was mild‐to‐moderate post‐lumbar puncture syndrome, which resolved with standard treatment. No AEs of special interest were observed. Conclusions: BI 474121 crosses the blood–brain barrier to inhibit PDE2, supporting cGMP as a translational marker to monitor CNS target engagement. These findings promote further clinical development of BI 474121. ClinicalTrials.gov number (NCT04672954). [ABSTRACT FROM AUTHOR]

Background: Noradrenergic signaling declines in Parkinson's disease (PD) following locus coeruleus neurodegeneration. Epidemiologic studies demonstrate that β-acting drugs slow PD progression. Objective: The primary objective was to compare the safety and effects of 3 β-adrenoceptor (β-AR) acting drugs on central nervous system (CNS) function after a single dose in healthy volunteers (HVs) and evaluate the effects of multiple doses of β-AR acting drugs in HVs and PD-patients. Methods: In Part A, HVs received single doses of 32 mg salbutamol, 160μg clenbuterol, 60 mg pindolol and placebo administered in a randomized, 4-way cross-over study. In Part B (randomized cross-over) and Part C (parallel, 2:1 randomized), placebo and/or clenbuterol (20μg on Day 1, 40μg on Day 2, 80μg on Days 3–7) were administered. CNS functions were assessed using the NeuroCart test battery, including pupillometry, adaptive tracking and recall tests. Results: Twenty-seven HVs and 12 PD-patients completed the study. Clenbuterol improved and pindolol reduced the adaptive tracking and immediate verbal recall performance. Clenbuterol and salbutamol increased and pindolol decreased pupil-to-iris ratios. Clenbuterol was selected for Parts B and C. In Part B, clenbuterol significantly increased performance in adaptive tracking with a tendency toward improved performance in immediate and delayed verbal recall. In Part C trends toward improved performance in immediate and delayed verbal recall were observed in PD-patients. Typical cardiovascular peripheral β2-AR effects were observed with clenbuterol. Conclusions: This study demonstrates the pro-cognitive effects of clenbuterol in HVs with similar trends in PD-patients. The mechanism of action is likely activation of β2-ARs in the CNS. Plain Language Summary: Aims and Purpose of the Research: This research aimed to explore how three different drugs affect brain function. These drugs are salbutamol, clenbuterol, and pindolol and work in the brain by stimulating specific brain cells that can improve aspects like memory and coordination. The main question was to see how safe these drugs were and how they impact the brain function after one dose in healthy people, and after multiple doses in both healthy people and those with Parkinson's disease. Background of the Research: Parkinson's disease is a condition where brain cells start to die, which affects different areas of the brain, including movement function, as well as memory and attention. This research matters because finding drugs that affect the brain function could improve the lives of people with Parkinson's disease. Methods and Research Design: The study was conducted in three parts. In the first part, healthy volunteers took one dose of each of the three drugs— salbutamol, clenbuterol, and pindolol— as well as a placebo (a harmless pill that has no effect). The researchers tested the participants' brain functions using various tasks including memory tests and eye response measurements. In the second and third part, healthy people and people with Parkinson's disease took the drug that performed best in healthy volunteers for seven days. Results and Importance: In the first part, a single dose of clenbuterol was safe and improved memory and attentions tasks in healthy people, and therefore was chosen for further testing in the second and third part. In these parts, multiple doses of clenbuterol were safe and helped improve memory and attention tasks in healthy people, with similar positive trends seen in people with Parkinson's disease. The study suggests that clenbuterol might help improve brain function by activating specific receptors in the brain. These results are important because they suggest that clenbuterol could be a potential treatment to help improve brain function in people with Parkinson's disease. However, more research is needed to fully understand its effects and to confirm these findings. [ABSTRACT FROM AUTHOR]

Apomorphine, used to treat OFF episodes in patients with Parkinson's disease (PD), is typically administered via subcutaneous injections. Administration of an oromucosal solution could offer a non‐invasive and user‐friendly alternative. This two‐part clinical study evaluated the safety, tolerability, pharmacokinetics (PK), and dose proportionality of a novel apomorphine hydrochloride oromucosal solution, as well as its relative bioavailability to subcutaneous apomorphine injection and apomorphine sublingual film. In part A of the study, 12 patients with PD received 2 mg oromucosal apomorphine (4% weight/volume) and 2 mg subcutaneous apomorphine in a randomized order, followed by 4 and 8 mg oromucosal apomorphine. In part B of the study, 13 patients with PD received 7 mg oromucosal apomorphine (7% weight/volume) and 30 mg sublingual apomorphine in a randomized order, followed by 14 mg oromucosal apomorphine. Washout between dose administrations in both study parts was at least 2 days. Safety, tolerability, and PK were assessed pre‐ and post‐dose. Both study parts showed that oromucosal apomorphine was generally well‐tolerated. Observed side effects were typical for apomorphine administration and included asymptomatic orthostatic hypotension, yawning, fatigue, and somnolence. Oromucosal apomorphine exposure increased with dose, although less than dose proportional. The mean (SD) maximum exposure reached with 14 mg oromucosal apomorphine was 753.0 (298.6) ng*min/mL (area under the plasma concentration–time curve from zero to infinity) and 8.0 (3.3) ng/mL (maximum plasma concentration). This was comparable to exposure reached after 2 mg subcutaneous apomorphine and approximately half of the exposure observed with 30 mg sublingual apomorphine. In summary, clinically relevant plasma concentrations could be reached in PD patients without tolerability issues. [ABSTRACT FROM AUTHOR]

The characteristics of pneumococcal carriage vary between infants and adults. Host immune factors have been shown to contribute to these age-specific differences, but the role of pathogen sequence variation is currently less well-known. Identification of age-associated pathogen genetic factors could leadto improved vaccine formulations. We therefore performed genome sequencing in a large carriage cohort of children and adults and combined this with data from an existing age-stratified carriage study. We compiled a dictionary of pathogen genetic variation, including serotype, strain, sequence elements, single-nucleotide polymorphisms (SNPs), and clusters of orthologous genes (COGs) for each cohort - all of which were used in a genome-wide association with host age. Age-dependent colonization showed weak evidence of being heritable in the first cohort (h² = 0.10, 95% CI 0.00-0.69) and stronger evidence in the second cohort (h² = 0.56, 95% CI 0.23-0.87). We found that serotypes and genetic background (strain) explained a proportion of the heritability in the first cohort (h²serotype = 0.07, 95% CI 0.04-0.14 and h²GPSC = 0.06, 95% CI 0.03-0.13) and the second cohort (h²serotype = 0.11, 95% CI 0.05-0.21 and h²GPSC = 0.20, 95% CI 0.12-0.31). In a meta-analysis of these cohorts, we found one candidate association (p=1.2 × 10-9) upstream of an accessory Sec-dependent serine-rich glycoprotein adhesin. Overall, while we did find a small effect of pathogen genome variation on pneumococcal carriage between child and adult hosts, this was variable between populations and does not appear to be caused by strong effects of individual genes. This supports proposals for adaptive future vaccination strategies that are primarily targeted at dominant circulating serotypes and tailored to the composition of the pathogen populations. [ABSTRACT FROM AUTHOR]

The importance of intuitionistic temporal logics in Computer Science and Artificial Intelligence has become increasingly clear in the last few years. From the proof-theory point of view, intuitionistic temporal logics have made it possible to extend functional programming languages with new features via type theory, while from the semantics perspective, several logics for reasoning about dynamical systems and several semantics for logic programming have their roots in this framework. We consider several axiomatic systems for intuitionistic linear temporal logic and show that each of these systems is sound for a class of structures based either on Kripke frames or on dynamic topological systems. We provide two distinct interpretations of "henceforth", both of which are natural intuitionistic variants of the classical one. We completely establish the order relation between the semantically defined logics based on both interpretations of "henceforth" and, using our soundness results, show that the axiomatically defined logics enjoy the same order relations. [ABSTRACT FROM AUTHOR]

Compared detailed (favoring field dependence and induction) and nondetailed (favoring field dependence and deduction) assignments on biology achievement of grade 10 male students (N=95) over a seven-month period. Detailed assignments, employing pictorial and verbal block diagrams and high structure, significantly enhanced learning among some students. (JN)

In the topological semantics, quantified intuitionistic logic, QH, is known to be strongly complete not only for the class of all topological spaces but also for some particular topological spaces — for example, for the irrational line, P, and for the rational line, Q, in each case with a constant countable domain for the quantifiers. Each of P and Q is a separable zero-dimensional dense-in-itself metrizable space. The main result of the current article generalizes these known results: QH is strongly complete for any zero-dimensional dense-in-itself metrizable space with a constant domain of cardinality ≤ the space's weight; consequently, QH is strongly complete for any separable zero-dimensional dense-in-itself metrizable space with a constant countable domain. We also prove a result that follows from earlier work of Moerdijk: if we allow varying domains for the quantifiers, then QH is strongly complete for any dense-in-itself metrizable space with countable domains. [ABSTRACT FROM AUTHOR]

We add propositional quantifiers to the propositional modal logic S4 and to the propositional intuitionistic logic H, introducing axiom schemes that are the natural analogs to axiom schemes typically used for first-order quantifiers in classical and intuitionistic logic. We show that the resulting logics are sound and complete for a topological semantics extending, in a natural way, the topological semantics for S4 and for H. [ABSTRACT FROM AUTHOR]

Introduction: Lobar and non-lobar non-traumatic intracerebral hemorrhage (ICH) are presumably caused by different types of small vessel diseases. The aim of this study was to assess risk factors for ICH according to location. Methods: In two large prospective studies, SMART (n = 9088) and ESPRIT (n = 2625), including patients with manifest cardiovascular, cerebrovascular or peripheral artery disease or with vascular risk factors, we investigated potential risk factors for ICH during follow-up according to lobar or non-lobar location by Cox proportional hazards analyses. Results: During 65,156 patient years of follow up 19 patients had lobar ICH (incidence rate 29, 95% CI 19–42 per 100,000 person-years) and 24 non-lobar ICH (incidence rate 37, 95% CI 26–51 per 100,000 person-years). Age significantly increased the risk of lobar ICH (HR per 10 years increase 1.90; 95% CI 1.17–3.10) in the multivariable analysis, but not of non-lobar hemorrhage. Anticoagulant medication (HR 3.49; 95% CI 1.20–10.2) and male sex (HR 3.79; 95% CI 1.13–12.8) increased the risk of non-lobar but not lobar ICH. Conclusion: This study shows an elevated risk of future ICH in patients with manifestations of, or risk factors for, cardiovascular, cerebrovascular or peripheral artery disease. Our data suggest that risk factors for ICH vary according to location, supporting the hypothesis of a differential pathophysiology of lobar and non-lobar ICH. [ABSTRACT FROM AUTHOR]

Shehtman introduced bimodal logics of the products of Kripke frames, thereby introducing frame products of unimodal logics. Van Benthem, Bezhanishvili, ten Cate and Sarenac generalize this idea to the bimodal logics of the products of topological spaces, thereby introducing topological products of unimodal logics. In particular, they show that the topological product of S4 and S4 is S4 $${\bigoplus}$$ S4, i.e., the fusion of S4 and S4: this logic is strictly weaker than the frame product S4 × S4. Indeed, van Benthem et al. show that S4 $${\bigoplus}$$ S4 is the bimodal logic of the particular product space [InlineEquation not available: see fulltext.], leaving open the question of whether S4 $${\bigoplus}$$ S4 is also complete for the product space [InlineEquation not available: see fulltext.]. We answer this question in the negative. [ABSTRACT FROM AUTHOR]

In the topological semantics for propositional modal logic, S4 is known to be complete for the class of all topological spaces, for the rational line, for Cantor space, and for the real line. In the topological semantics for quantified modal logic, QS4 is known to be complete for the class of all topological spaces, and for the family of subspaces of the irrational line. The main result of the current paper is that QS4 is complete, indeed strongly complete, for the rational line. [ABSTRACT FROM PUBLISHER]

In the topological semantics for modal logic, S4 is well-known to be complete for the rational line, for the real line, and for Cantor space: these are special cases of S4’s completeness for any dense-in-itself metric space. The construction used to prove completeness can be slightly amended to show that S4 is not only complete, but also strongly complete, for the rational line. But no similarly easy amendment is available for the real line or for Cantor space and the question of strong completeness for these spaces has remained open, together with the more general question of strong completeness for any dense-in-itself metric space. In this paper, we prove that S4 is strongly complete for any dense-in-itself metric space. [ABSTRACT FROM AUTHOR]