{ "items": [ "\n\n
BACKGROUND: Paranoia-incorrectly thinking that others are deliberating trying to harm you-causes distress, undermines social interactions and leads to withdrawal. It presents across multiple psychiatric diagnoses. OBJECTIVE: The primary aim was to determine the extent that cognitive and social processes may explain paranoia. The secondary aim was to identify explanatory factors that distinguished paranoia and social anxiety. METHODS: 10\u2009382 UK adults, quota sampled to match the population for age, gender, ethnicity, income and region, participated in a non-probability survey. All participants completed a paranoia measure and assessments of cognitive and social processes. Structural equation modelling was conducted. FINDINGS: 2586 (24.9%) participants described being mistrustful of other people. 1756 (16.9%) participants wanted help to trust more. 66.7% of variance in paranoia was explained by a model comprising (in descending order of importance): within-situation defence behaviours, negative images, negative self-beliefs, discrimination, dissociation, aberrant salience, anxiety sensitivity, agoraphobic distress, worry, less social support, agoraphobic avoidance, less analytical reasoning and alcohol use. All explanatory factors were associated with paranoia and social anxiety. Ten factors were more closely associated with paranoia than social anxiety, including discrimination, hallucinations, negative images, aberrant salience and alcohol use. Nine factors were more closely associated with social anxiety, including less positive self-belief, an external locus of control, worry and less analytical reasoning. CONCLUSIONS: Multiple causes are likely to be involved in paranoia. Cognitive and social processes may explain a high degree of paranoia. CLINICAL IMPLICATIONS: Multiple clear targets for intervention to reduce paranoia are identified.
\n \n\n \n \nSignal sequences are short peptides at the N terminus of proteins destined for the secretion pathway. Typically, after cleavage by peptidases, signal peptides are degraded by intra-membrane proteases. In some cases, however, signal peptides can be processed further and released into the endoplasmic reticulum, secretion pathways, or cytoplasm. The consequences of these processes remain unclear, in particular considering that dysregulated signal peptides could potentially aggregate and induce cytotoxicity. To investigate this problem, we study the signal peptide of the amyloid precursor protein (APP), which originates the Alzheimer's \u03b2-amyloid (A\u03b2) peptide. Our results show that this signal peptide (residues 1\u201317 of APP [APP1\u201317SP]) can form amyloid-like cytotoxic aggregates. We further demonstrate that APP1\u201317SP seeds promote aggregation of A\u03b2, which raises the intriguing possibility of an interplay between APP1\u201317SP and A\u03b2 aggregation in disease processes.
\n \n\n \n \nThe ongoing SARS-CoV-2 pandemic was initially managed by non-pharmaceutical interventions such as diagnostic testing, isolation of positive cases, physical distancing and lockdowns. The advent of vaccines has provided crucial protection against SARS-CoV-2. Neutralising antibody (nAb) responses are a key correlate of protection, and therefore measuring nAb responses is essential for monitoring vaccine efficacy. Fingerstick dried blood spots (DBS) are ideal for use in large-scale sero-surveillance because they are inexpensive, offer the option of self-collection and can be transported and stored at ambient temperatures. Such advantages also make DBS appealing to use in resource-limited settings and in potential future pandemics. In this study, nAb responses in sera, venous blood and fingerstick blood stored on filter paper were measured. Samples were collected from SARS-CoV-2 acutely infected individuals, SARS-CoV-2 convalescent individuals and SARS-CoV-2 vaccinated individuals. Good agreement was observed between the nAb responses measured in eluted DBS and paired sera. Stability of nAb responses was also observed in sera stored on filter paper at room temperature for 28\u00a0days. Overall, this study provides support for the use of filter paper as a viable sample collection method to study nAb responses.
\n \n\n \n \nBACKGROUND: Abrupt cessation of therapy with a selective serotonin reuptake inhibitor (SSRI) is associated with a discontinuation syndrome, typified by numerous disabling symptoms, including anxiety. Surprisingly, little is known of the behavioural effect of SSRI discontinuation in animals. AIM: Here, the effect of SSRI discontinuation on anxiety-like behaviour was systematically investigated in mice. METHODS: Experiments were based on a three-arm experimental design comprising saline, continued SSRI and discontinued SSRI. Mice were assessed 2\u2009days after SSRI discontinuation over a 5-day period using the elevated plus maze (EPM) and other anxiety tests. RESULTS: An exploratory experiment found cessation of paroxetine (12\u2009days) was associated with decreased open-arm exploration and reduced total distance travelled, in male but not female mice. Follow-up studies confirmed a discontinuation effect on the EPM in male mice after paroxetine (12\u2009days) and also citalopram (12\u2009days). Mice receiving continued paroxetine (but not citalopram) also showed decreased open-arm exploration but this was dissociable from the effects of discontinuation. The discontinuation response to paroxetine did not strengthen after 28\u2009days of treatment but was absent after 7\u2009days of treatment. A discontinuation response was not discernible in other anxiety and fear-learning tests applied 3-5\u2009days after treatment cessation. Finally, discontinuation effects on the EPM were typically associated with decreased locomotion on the test. However, separate locomotor testing implicated anxiety-provoked behavioural inhibition rather than a general reduction in motor activity. CONCLUSION: Overall, this study provides evidence for a short-lasting behavioural discontinuation response to cessation of SSRI treatment in mice.
\n \n\n \n \nABSTRACTPsychosis in disorders like schizophrenia is commonly associated with aberrant salience and elevated striatal dopamine. However, the underlying cause(s) of this hyper-dopaminergic state remain elusive. Various lines of evidence point to glutamatergic dysfunction and impairments in synaptic plasticity in the aetiology of schizophrenia, including deficits associated with the GluA1 AMPAR subunit. GluA1 knockout (Gria1-/-) mice provide a model of impaired synaptic plasticity in schizophrenia and exhibit a selective deficit in a form of short-term memory which underlies short-term habituation. As such, these mice are unable to reduce attention to recently presented stimuli. In this study we used fast-scan cyclic voltammetry to measure phasic dopamine responses in the nucleus accumbens ofGria1-/-mice to determine whether this behavioral phenotype might be a key driver of a hyper-dopaminergic state. There was no effect of GluA1 deletion on electrically-evoked dopamine responses in anaesthetized mice, demonstrating normal endogenous release properties of dopamine neurons inGria1-/-mice. Furthermore, dopamine signals were initially similar inGria1-/-mice compared to controls in response to both sucrose rewards and neutral light stimuli. They were also equally sensitive to changes in the magnitude of delivered rewards. In contrast, however, these stimulus-evoked dopamine signals failed to habituate with repeated presentations inGria1-/-mice, resulting in a task-relevant, hyper-dopaminergic phenotype. Thus, here we show that GluA1 dysfunction, resulting in impaired short-term habituation, is a key driver of enhanced striatal dopamine responses, which may be an important contributor to aberrant salience and psychosis in psychiatric disorders like schizophrenia.
\n \n\n \n \nPharmacological studies established a role for AMPARs in the mammalian forebrain in spatial memory performance. Here we generated global GluA1/3 double knockout mice (Gria1/3-/-) and conditional knockouts lacking GluA1 and GluA3 AMPAR subunits specifically from principal cells across the forebrain (Gria1/3\u0394Fb). In both models, loss of GluA1 and GluA3 resulted in reduced hippocampal GluA2 and increased levels of the NMDAR subunit GluN2A. Electrically-evoked AMPAR-mediated EPSPs were greatly diminished, and there was an absence of tetanus-induced LTP. Gria1/3-/- mice showed premature mortality. Gria1/3\u0394Fb mice were viable, and their memory performance could be analyzed. In the Morris water maze (MWM), Gria1/3\u0394Fb mice showed profound long-term memory deficits, in marked contrast to the normal MWM learning previously seen in single Gria1-/- and Gria3-/- knockout mice. Our results suggest a redundancy of function within the pool of available ionotropic glutamate receptors for long-term spatial memory performance.
\n \n\n \n \nRATIONALE: Non-invasive home cage monitoring is emerging as a valuable tool to assess the effects of experimental interventions on mouse behaviour. A field in which these techniques may prove useful is the study of repeated selective serotonin reuptake inhibitor (SSRI) treatment and discontinuation. SSRI discontinuation syndrome is an under-researched condition that includes the emergence of sleep disturbances following treatment cessation. OBJECTIVES: We used passive infrared (PIR) monitoring to investigate changes in activity, sleep, and circadian rhythms during repeated treatment with the SSRI paroxetine and its discontinuation in mice. METHODS: Male mice received paroxetine (10\u00a0mg/kg/day, s.c.) for 12\u00a0days, then were swapped to saline injections for a 13\u00a0day discontinuation period and compared to mice that received saline injections throughout. Mice were continuously tracked using the Continuous Open Mouse Phenotyping of Activity and Sleep Status (COMPASS) system. RESULTS: Repeated paroxetine treatment reduced activity and increased behaviourally-defined sleep in the dark phase. These effects recovered to saline-control levels within 24\u00a0h of paroxetine cessation, yet there was also evidence of a lengthening of sleep bouts in the dark phase for up to a week following discontinuation. CONCLUSIONS: This study provides the first example of how continuous non-invasive home cage monitoring can be used to detect objective behavioural changes in activity and sleep during and after drug treatment in mice. These data suggest that effects of paroxetine administration reversed soon after its discontinuation but identified an emergent change in sleep bout duration, which could be used as a biomarker in future preclinical studies to prevent or minimise SSRI discontinuation symptoms.
\n \n\n \n \nPurpose: To explore the utility of phosphorus magnetic resonance spectroscopy (31P MRS) in identifying anthracycline-induced cardiac toxicity in patients with breast cancer. Methods: Twenty patients with newly diagnosed breast cancer receiving anthracycline-based chemotherapy had cardiac magnetic resonance assessment of left ventricular ejection fraction (LVEF) and 31P MRS to determine myocardial Phosphocreatine/Adenosine Triphosphate Ratio (PCr/ATP) at three time points: pre-, mid-, and end-chemotherapy. Plasma high sensitivity cardiac troponin-I (cTn-I) tests and electrocardiograms were also performed at these same time points. Results: Phosphocreatine/Adenosine Triphosphate did not change significantly between pre- and mid-chemo (2.16 \u00b1 0.46 vs. 2.00 \u00b1 0.56, p = 0.80) and pre- and end-chemo (2.16 \u00b1 0.46 vs. 2.17 \u00b1 0.86, p = 0.99). Mean LVEF reduced significantly by 5.1% between pre- and end-chemo (61.4 \u00b1 4.4 vs. 56.3 \u00b1 8.1 %, p = 0.02). Change in PCr/ATP ratios from pre- to end-chemo correlated inversely with changes in LVEF over the same period (r = -0.65, p = 0.006). Plasma cTn-I increased progressively during chemotherapy from pre- to mid-chemo (1.35 \u00b1 0.81 to 4.40 \u00b1 2.64 ng/L; p = 0.01) and from mid- to end-chemo (4.40 \u00b1 2.64 to 18.33 \u00b1 13.23 ng/L; p = 0.001). Conclusions: In this small cohort pilot study, we did not observe a clear change in mean PCr/ATP values during chemotherapy despite evidence of increased plasma cardiac biomarkers and reduced LVEF. Future similar studies should be adequately powered to take account of patient drop-out and variable changes in PCr/ATP and could include T1 and T2 mapping.
\n \n\n \n \nBACKGROUND AND OBJECTIVES: Directional deep brain stimulation (DBS) electrodes are increasingly used, but conventional computed tomography (CT) is unable to directly image segmented contacts owing to physics-based resolution constraints. Postoperative electrode segment orientation assessment is necessary because of the possibility of significant deviation during or immediately after insertion. Photon-counting detector (PCD) CT is a relatively novel technology that enables high resolution imaging while addressing several limitations intrinsic to CT. We show how PCD CT can enable clear in\u00a0vivo imaging of DBS electrodes, including segmented contacts and markers for all major lead manufacturers. MATERIALS AND METHODS: We describe postoperative imaging and reconstruction protocols we have developed to enable optimal lead visualization. PCD CT images were obtained of directional leads from the three major manufacturers and fused with preoperative 3T magnetic resonance imaging (MRI). Radiation dosimetry also was evaluated and compared with conventional imaging controls. Orientation estimates from directly imaged leads were compared with validated software-based reconstructions (derived from standard CT imaging artifact analysis) to quantify congruence in alignment and directional orientation. RESULTS: High-fidelity images were obtained for 15 patients, clearly indicating the segmented contacts and directional markers both on CT alone and when fused to MRI. Our routine imaging protocol is described. Ionizing radiation doses were significantly lower than with conventional CT. For most leads, the directly imaged lead orientations and depths corresponded closely to those predicted by CT artifact-based reconstructions. However, unlike direct imaging, the software reconstructions were susceptible to 180\u00b0 error in orientation assessment. CONCLUSIONS: High-resolution photon-counting CT can very clearly image segmented DBS electrode contacts and directional markers and unambiguously determine lead orientation, with lower radiation than in conventional imaging. This obviates the need for further imaging and may facilitate anatomically tailored directional programming.
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