Adequate Patient Characterization in COPD: Reasons to Go Beyond GOLD Classification

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) serves as a guide to treat and manage different severity classes of patients with COPD. It was suggested that the five categories of FEV1 % predicted (GOLD 0–4), can be applied for selecting different therapeutic approaches. However, validation of these selective properties is very poor. To determine the relevance of the GOLD staging system for estimating the severity of clinical problems, GOLD 2 (n=70) and GOLD 3 (n=65) patients were drawn from a prospective cohort of patients with COPD and evaluated crosssectionally by a newly developed Nijmegen Integral Assessment Framework (NIAF). The NIAF is a detailed assessment of a wide range of aspects of health status (HS). Significant, though small, differences were found in Static Lung Volumes, Exercise Capacity, Subjective Pulmonary Complaints, Subjective Impairment, and Health-Related QoL, besides Airflow of course. Moreover, overlap between scores of these five HS sub-domains was substantial, indicating small clinical relevance for discernment. No significant differences were found in nine other aspects of HS. It is concluded that GOLD stages do not discriminate in any aspect of HS other than airflow obstruction, and therefore do not help the clinician in deciding which treatment modalities are appropriate

Munc18-1: sequential interactions with the fusion machinery stimulate vesicle docking and priming

Exocytosis of secretory or synaptic vesicles is executed by a mechanism including the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins. Munc18-1 is a part of this fusion machinery, but its role is controversial because it is indispensable for fusion but also inhibits the assembly of purified SNAREs in vitro. This inhibition reflects the binding of Munc18-1 to a closed conformation of the target-SNARE syntaxin1. The controversy would be solved if binding to closed syntaxin1 were shown to be stimulatory for vesicle fusion and/or additional essential interactions were identified between Munc18-1 and the fusion machinery. Here, we provide evidence for both notions by dissecting sequential steps of the exocytotic cascade while expressing Munc18 variants in the Munc18-1 null background. In Munc18-1 null chromaffin cells, vesicle docking is abolished and syntaxin levels are reduced. A mutation that diminished Munc18 binding to syntaxin1 in vitro attenuated the vesicle-docking step but rescued vesicle priming in excess of docking. Conversely, expressing the Munc18-2 isoform, which also displays binding to closed syntaxin1, rescued vesicle docking identical with Munc18-1 but impaired more downstream vesicle priming steps. All Munc18 variants restored syntaxin1 levels at least to wild-type levels, showing that the docking phenotype is not caused by syntaxin1 reduction. None of the Munc18 variants affected vesicle fusion kinetics or fusion pore duration. In conclusion, binding of Munc18-1 to closed syntaxin1 stimulates vesicle docking and a distinct interaction mode regulates the consecutive priming step. Copyright © 2007 Society for Neuroscience

Munc18-1 promotes larger dense-core vesicle docking.

AbstractSecretory vesicles dock at the plasma membrane before Ca2+ triggers their exocytosis. Exocytosis requires the assembly of SNARE complexes formed by the vesicle protein Synaptobrevin and the membrane proteins Syntaxin-1 and SNAP-25. We analyzed the role of Munc18-1, a cytosolic binding partner of Syntaxin-1, in large dense-core vesicle (LDCV) secretion. Calcium-dependent LDCV exocytosis was reduced 10-fold in mouse chromaffin cells lacking Munc18-1, but the kinetic properties of the remaining release, including single fusion events, were not different from controls. Concomitantly, mutant cells displayed a 10-fold reduction in morphologically docked LDCVs. Moreover, acute overexpression of Munc18-1 in bovine chromaffin cells increased the amount of releasable vesicles and accelerated vesicle supply. We conclude that Munc18-1 functions upstream of SNARE complex formation and promotes LDCV docking

Psychotropic medication use and cognition in institutionalized older adults with mild to moderate dementia

Background: Most studies examining psychotropic medication use on cognition in older persons with dementia include measures of global cognitive function. The present study examined the relationship between different types of psychotropic medication and specific cognitive functions in older people with dementia. Methods: Two hundred and six institutionalized older adults with dementia (180 women, mean age 85 years) were administered neuropsychological tests. Psychotropic medication use was extracted from their medical status and categorized as: sedatives, antidepressants and antipsychotics. Results: Analysis of covariance revealed that psychotropic consumers, and particularly those who used antipsychotics, performed worse on neuropsychological tests of executive/attentional functioning than non-consumers. There were no differences between consumers of other classes of psychotropic drugs and non-consumers. The number of psychotropic drugs used was inversely related to executive/attentional functioning. Conclusions: These findings show that in institutionalized older adults with dementia, specific impairment of cognitive function, i.e. executive/attentional impairments, are associated with antipsychotic medication use. Future longitudinal studies are recommended. © 2009 International Psychogeriatric Association

Functional outcome is tied to dynamic brain states after mild to moderate traumatic brain injury

The current study set out to investigate the dynamic functional connectome in relation to long-term recovery after mild to moderate traumatic brain injury (TBI). Longitudinal resting-state functional MRI data were collected (at 1 and 3 months postinjury) from a prospectively enrolled cohort consisting of 68 patients with TBI (92% mild TBI) and 20 healthy subjects. Patients underwent a neuropsychological assessment at 3 months postinjury. Outcome was measured using the Glasgow Outcome Scale Extended (GOS-E) at 6 months postinjury. The 57 patients who completed the GOS-E were classified as recovered completely (GOS-E = 8; n = 37) or incompletely (GOS-E < 8; n = 20). Neuropsychological test scores were similar for all groups. Patients with incomplete recovery spent less time in a segregated brain state compared to recovered patients during the second visit. Also, these patients moved less frequently from one meta-state to another as compared to healthy controls and recovered patients. Furthermore, incomplete recovery was associated with disruptions in cyclic state transition patterns, called attractors, during both visits. This study demonstrates that poor long-term functional recovery is associated with alterations in dynamics between brain networks, which becomes more marked as a function of time. These results could be related to psychological processes rather than injury-effects, which is an interesting area for further work. Another natural progression of the current study is to examine whether these dynamic measures can be used to monitor treatment effects

Between the hammer and the anvil? The anti-money laundering-complex and its interactions with the compliance industry

International audienc

The Collaboration on Attachment Transmission Synthesis (CATS): A Move to the Level of Individual-Participant-Data Meta-Analysis.

Generations of researchers have tested and used attachment theory to understand children's development. To bring coherence to the expansive set of findings from small-sample studies, the field early on adopted meta-analysis. Nevertheless, gaps in understanding intergenerational transmission of individual differences in attachment continue to exist. We discuss how attachment research has been addressing these challenges by collaborating in formulating questions and pooling data and resources for individual-participant-data meta-analyses. The collaborative model means that sharing hard-won and valuable data goes hand in hand with directly and intensively interacting with a large community of researchers in the initiation phase of research, deliberating on and critically reviewing new hypotheses, and providing access to a large, carefully curated pool of data for testing these hypotheses. Challenges in pooling data are also discussed.Wellcom

The first 20,000 strange situation procedures: A meta-analytic review

The Strange Situation Procedure (SSP) was developed five decades ago to assess infant–parent attachment relationships. Although the procedure itself has remained relatively constant in over 285 studies (20,720 dyads) conducted to date, there have been vast sociological changes during this time, and research foci shifts to studying diverse populations. Since its inception, the SSP has also been adopted in over 20 countries. In this meta-analysis, we collate this large body of work, with the objectives of producing reliable estimates of the distribution of the four SSP attachment classifications, assessing temporal trends and geographical differences, and determining if and when distributions are different across various populations. Results revealed that the global distribution of SSP attachment was 51.6% secure, 14.7% avoidant, 10.2% resistant, and 23.5% disorganized. There were no differences in the distribution among mothers and fathers, and no child age or sex differences. We found a temporal trend in which there was less avoidant attachment over time and there were attachment distribution differences between samples from North America versus other regions of the world, particularly Asia, Middle East/Israel and South America. We found higher rates of avoidant and disorganized attachment in populations with sociodemographic risks and higher rates of disorganized attachment in samples where parents had psychopathology and when the child experienced maltreatment or was adopted from foster or institutional care. The implications of these findings for future research and practice are discussed. (PsycInfo Database Record (c) 2023 APA, all rights reserved

A novel method for the genome-wide high resolution analysis of DNA damage

DNA damage occurs via endogenous and exogenous genotoxic agents and compromises a genome’s integrity. Knowing where damage occurs within a genome is crucial to understanding the repair mechanisms which protect this integrity. This paper describes a new development based on microarray technology which uses ultraviolet light induced DNA damage as a paradigm to determine the position and frequency of DNA damage and its subsequent repair throughout the entire yeast genome

Contribution of Cystine-Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine–glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine–glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex, an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial t-maze task, and this effect was also reversed by N-acetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystine–glutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine–glutamate exchange and group II mGluR activation. Finally, protein levels from postmortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine–glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine–glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP