An experimental paradigm for triggering a depressive syndrome.

Research investigating whether depression is an adaptation or a disorder has been hindered by the lack of an experimental paradigm that can test causal relationships. Moreover, studies attempting to induce the syndrome often fail to capture the suite of feelings, thoughts, and behaviors that characterize depression. An experimental paradigm for triggering depressive symptoms can improve our etiological understanding of the syndrome. The present study attempts to induce core symptoms of depression, particularly those related to rumination, in a healthy, nonclinical sample through a controlled social experiment. These symptoms are sad or depressed mood, anhedonia, feelings of worthlessness or guilt, and difficulty concentrating. One hundred and thirty-four undergraduate students were randomly assigned to either an exclusion (E) or control (C) group. Participants in the exclusion group were exposed to a modified Cyberball paradigm, designed to make them feel socially excluded, followed by a dual-interference task to assess whether their exclusion interfered with their working memory. Excluded participants: (a) self-reported a significant increase in sadness and decrease in happiness, but not anxiety or calmness; (b) scored significantly higher in four of five variables related to depressive rumination; and (c) performed significantly worse on a dual-interference task, suggesting an impaired ability to concentrate. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Long COVID in long-term care: a rapid realist review.

OBJECTIVES: The goals of this rapid realist review were to ask: (a) what are the key mechanisms that drive successful interventions for long COVID in long-term care (LTC) and (b) what are the critical contexts that determine whether the mechanisms produce the intended outcomes? DESIGN: Rapid realist review. DATA SOURCES: Medline, CINAHL, Embase, PsycINFO and Web of Science for peer-reviewed literature and Google for grey literature were searched up to 23 February 2023. ELIGIBILITY CRITERIA: We included sources focused on interventions, persons in LTC, long COVID or post-acute phase at least 4 weeks following initial COVID-19 infection and ones that had a connection with source materials. DATA EXTRACTION AND SYNTHESIS: Three independent reviewers searched, screened and coded studies. Two independent moderators resolved conflicts. A data extraction tool organised relevant data into context-mechanism-outcome configurations using realist methodology. Twenty-one sources provided 51 intervention data excerpts used to develop our programme theory. Synthesised findings were presented to a reference group and expert panel for confirmatory purposes. RESULTS: Fifteen peer-reviewed articles and six grey literature sources were eligible for inclusion. Eleven context-mechanism-outcome configurations identify those contextual factors and underlying mechanisms associated with desired outcomes, such as clinical care processes and policies that ensure timely access to requisite resources for quality care delivery, and resident-centred assessments and care planning to address resident preferences and needs. The underlying mechanisms associated with enhanced outcomes for LTC long COVID survivors were: awareness, accountability, vigilance and empathetic listening. CONCLUSIONS: Although the LTC sector struggles with organisational capacity issues, they should be aware that comprehensively assessing and monitoring COVID-19 survivors and providing timely interventions to those with long COVID is imperative. This is due to the greater care needs of residents with long COVID, and coordinated efficient care is required to optimise their quality of life.

Diagnosis and practical management of digoxin toxicity: a narrative review and consensus.

There are currently no universally accepted guidelines for the management of digoxin toxicity. In the absence of clinical practice guidelines, a set of consensus recommendations for management of digoxin toxicity in the clinical setting were developed through a modified Delphi approach. The recommendations highlight the importance of early recognition of signs of potentially life-threatening toxicity that requires immediate treatment with digoxin-specific antibodies. The consensus identifies a straightforward approach to dosing immune antibody fragments according to the presence or absence of signs of life-threatening toxicity. Supportive measures and management of specific signs of toxicity are also covered.

An assessment of the effects of neurokinin1 receptor antagonism against nausea and vomiting: Relative efficacy, sites of action and lessons for future drug development.

A broad-spectrum anti-vomiting effect of neurokinin1 receptor antagonists (NK1 RA), shown in pre-clinical animal studies, has been supported by a more limited range of clinical studies in different indications. However, this review suggests that compared with vomiting, the self-reported sensation of nausea is less affected or possibly unaffected (depending on the stimulus) by NK1 receptor antagonism, a common finding for anti-emetics. The stimulus-independent effects of NK1 RAs against vomiting are explicable by actions within the central pattern generator (ventral brainstem) and the nucleus tractus solitarius (NTS; dorsal brainstem), with additional effects on vagal afferent activity for certain stimuli (e.g., highly emetogenic chemotherapy). The central pattern generator and NTS neurones are multifunctional so the notable lack of obvious effects of NK1 RAs on other reflexes mediated by the same neurones suggests that their anti-vomiting action is dependent on the activation state of the pathway leading to vomiting. Nausea requires activation of cerebral pathways by projection of information from the NTS. Although NK1 receptors are present in cerebral nuclei implicated in nausea, and imaging studies show very high receptor occupancy at clinically used doses, the variable or limited ability of NK1 RAs to inhibit nausea emphasizes: (i) our inadequate understanding of the mechanisms of nausea; and (ii) that classification of a drug as an anti-emetic may give a false impression of efficacy against nausea vs. vomiting. We discuss the potential mechanisms for the differential efficacy of NK1 RA and the implications for future development of drugs that can effectively treat nausea, an area of unmet clinical need.

Review article: An analysis of the pharmacological rationale for selecting drugs to inhibit vomiting or increase gastric emptying during treatment of gastroparesis.

BACKGROUND: Drugs which can inhibit nausea/vomiting and/or increase gastric emptying are used to treat gastroparesis, mostly 'off-label'. Within each category, they act at different targets and modulate different physiological mechanisms. AIMS: Address the questions: In gastroparesis, why should blocking one pathway causing vomiting, be more appropriate than another? Why might increasing gastric emptying via one mechanism be more appropriate than another? METHODS: Drugs used clinically were identified via consensus opinions and reviews, excluding the poorly characterised. Their pharmacology was defined, mapped to mechanisms influencing vomiting and gastric emptying, and rationale developed for therapeutic use. RESULTS: Vomiting: Rationale for 5-HT3 , D2 , H1 or muscarinic antagonists, and mirtazapine, amitriptyline, nortriptyline, are poor. Arguments for inhibiting central consequences of vagal afferent transmission by NK1 antagonism are complicated by doubts over effects on nausea. Gastric emptying: Confusion emerges because of side-effects of drugs increasing gastric emptying: Metoclopramide (5-HT4 agonist, D2 and 5-HT3 antagonist; also blocks some emetic stimuli and causes tardive dyskinesia) and Erythromycin (high-efficacy motilin agonist, requiring low doses to minimise side-effects). Limited trials with selective 5-HT4 agonists indicate variable efficacy. CONCLUSIONS: Several drug classes inhibiting vomiting have no scientific rationale. NK1 antagonism has rationale but complicated by limited efficacy against nausea. Studies must resolve variable efficacy of selective 5-HT4 agonists and apparent superiority over motilin agonists. Overall, lack of robust activity indicates a need for novel approaches targeting nausea (e.g., modulating gastric pacemaker or vagal activity, use of receptor agonists or new targets such as GDF15) and objective assessments of nausea.

Anti-emetic effects of thalidomide: Evidence, mechanism of action, and future directions.

The rationale for using thalidomide (THD) as a treatment for nausea and vomiting during pregnancy in the late 1950s appears to have been based on its sedative or hypnotic properties. In contrast to contemporaneous studies on the anti-emetic activity of phenothiazines, we were unable to identify publications reporting preclinical or clinical evaluation of THD as an anti-emetic. Our survey of the literature revealed a clinical study in 1965 showing THD reduced vomiting in cancer chemotherapy which was substantiated by similar studies from 2000, particularly showing efficacy in the delayed phase of chemotherapy-induced nausea and vomiting. To identify the mechanism(s) potentially involved in thalidomide's anti-emetic activity we reviewed its pharmacology in the light of nausea and vomiting mechanisms and their pharmacology with a particular emphasis on chemotherapy and pregnancy. The process identified the following potential mechanisms: reduced secretion of Growth Differentiation Factor 15, suppression of inflammation/prostaglandin production, downregulation of cytotoxic drug induced upregulation of iNOS, and modulation of BK (KCa1.1) channels and GABAA/glutamate transmission at critical points in the emetic pathways (nucleus tractus solitarius, area postrema). We propose ways to investigate these hypothesized mechanisms and discuss the associated challenges (e.g., objective quantification of nausea) in addition to some of the more general aspects of developing novel drugs to treat nausea and vomiting.

All the brain's a stage for serotonin: the forgotten story of serotonin diffusion across cell membranes.

In the conventional model of serotonin neurotransmission, serotonin released by neurons in the midbrain raphe nuclei exerts its actions on forebrain neurons by interacting with a large family of post-synaptic receptors. The actions of serotonin are terminated by active transport of serotonin back into the releasing neuron, which is mediated by the serotonin reuptake transporter (SERT). Because SERT is expressed pre-synaptically and is widely thought to be the only serotonin transporter in the forebrain, the conventional model does not include serotonin transport into post-synaptic neurons. However, a large body of evidence accumulating since the 1970s has shown that serotonin, despite having a positive charge, can cross cell membranes through a diffusion-like process. Multiple low-affinity, high-capacity, sodium-independent transporters, widely expressed in the brain, allow the carrier-mediated diffusion of serotonin into forebrain neurons. The amount of serotonin crossing cell membranes through this mechanism under physiological conditions is considerable. Most prominent textbooks fail to include this alternative method of serotonin uptake in the brain, and even most neuroscientists are unaware of it. This failure has limited our understanding of a key regulator of serotonergic neurotransmission, impeded research on the potential intracellular actions of serotonin in post-synaptic neurons and glial cells, and may have impeded our understanding of the mechanism by which antidepressant medications reduce depressive symptoms.

Synergistic augmentation of rhythmic myogenic contractions of human stomach by arginine vasopressin and adrenaline: Implications for the induction of nausea.

BACKGROUND AND PURPOSE: Nausea is associated with the hormonal secretion of vasopressin and adrenaline, although their actions in inducing nausea is poorly understood. Here, we have investigated their actions on human stomach muscle. EXPERIMENTAL APPROACH: Muscle strips were suspended in tissue baths and neuronal-/non-neuronally-mediated contractions were measured. Custom software analysed eight motility parameters defining spontaneous phasic non-neuronally mediated contractions. Receptor distributions were assessed by qPCR and immunofluorescence. KEY RESULTS: V1A receptors and α1 -adrenoceptors were located on muscle as well as interstitial cells of Cajal (ICCs). Myogenic contractions of human proximal and distal stomach (respectively, 2.6 ± 0.1 and 2.7 ± 0.0 per minute; n = 44) were larger in the distal area (1.1 ± 0.1 and 5.0 ± 0.1 mN), developing relatively slowly (proximal) or rapidly (distal). Vasopressin caused tonic (proximal) or short-lived (distal) increases in muscle tone and increased myogenic contraction amplitude, frequency and rate (acting at V1A receptors; thresholds 10-11 -10-10  M); by contrast, cholinergically mediated contractions were unaffected. Oxytocin acted similarly to vasopressin but less potently, at OT receptors). Adrenaline increased (10-10 -10-5  M; α1 -adrenoceptors) and decreased (≥10-6  M; ß-adrenoceptors) muscle tone and enhanced/reduced myogenic contractions. Cholinergically mediated contractions were reduced (α2 -adrenoceptors). Combined, vasopressin (10-9  M) and adrenaline (10-8  M) increased muscle tone and phasic myogenic activity in a synergistic manner. CONCLUSIONS AND IMPLICATIONS: Vasopressin and adrenaline increased human gastric tone and myogenic contraction amplitude, rate of contraction and frequency. In combination, their actions were further increased in a synergistic manner. Such activity may promote nausea.

Methodological considerations in studying digestive system physiology in octopus: limitations, lacunae and lessons learnt.

Current understanding of cephalopod digestive tract physiology is based on relatively "old" literature and a "mosaic of data" from multiple species. To provide a background to the discussion of methodologies for investigating physiology we first review the anatomy of the cephalopod digestive tract with a focus on Octopus vulgaris, highlighting structure-function relationships and species differences with potential functional consequences (e.g., absence of a crop in cuttlefish and squid; presence of a caecal sac in squid). We caution about extrapolation of data on the digestive system physiology from one cephalopod species to another because of the anatomical differences. The contribution of anatomical and histological techniques (e.g., digestive enzyme histochemistry and neurotransmitter immunohistochemistry) to understanding physiological processes is discussed. For each major digestive tract function we briefly review current knowledge, and then discuss techniques and their limitations for the following parameters: 1) Measuring motility in vitro (e.g., spatiotemporal mapping, tension and pressure), in vivo (labelled food, high resolution ultrasound) and aspects of pharmacology; 2) Measuring food ingestion and the time course of digestion with an emphasis on understanding enzyme function in each gut region with respect to time; 3) Assessing transepithelial transport of nutrients; 4) Measuring the energetic cost of food processing, impact of environmental temperature and metabolic rate (flow-through/intermittent respirometry); 4) Investigating neural (brain, gastric ganglion, enteric) and endocrine control processes with an emphasis on application of molecular techniques to identify receptors and their ligands. A number of major knowledge lacunae are identified where available techniques need to be applied to cephalopods, these include: 1) What is the physiological function of the caecal leaflets and intestinal typhlosoles in octopus? 2) What role does the transepithelial transport in the caecum and intestine play in ion, water and nutrient transport? 3) What information is signalled from the digestive tract to the brain regarding the food ingested and the progress of digestion? It is hoped that by combining discussion of the physiology of the cephalopod digestive system with an overview of techniques and identification of key knowledge gaps that this will encourage a more systematic approach to research in this area.

A multi-parameter approach to measurement of spontaneous myogenic contractions in human stomach: Utilization to assess potential modulators of myogenic contractions.

Electrical slow waves, generated by interstitial cells of Cajal (ICC), cause spontaneous contractions of human stomach. Software was developed to measure muscle tone and eleven different parameters defining these contractions in human stomach, displaying data as radar plots. A pilot study assessed the effects of potential modulators, selected from among compounds known to influence ICC activity; n = 4-7 each concentration tested/compound. Human distal stomach (corpus-antrum) muscle strips were suspended in tissue baths for measuring myogenic (non-neuronal) contractions in the presence of tetrodotoxin (10-6 M). Initial characterization: Contractions (amplitude 4 ± 0.4mN, frequency 3 ± 0.1 min-1, n = 49) were unchanged by ꭃ-conotoxin GVIA (10-7 M) or indomethacin (10-6 M) but abolished by nifedipine (10-4 M). Carbachol (10-7 M) increased contraction rate and amplitude; 10-6-10-5 M increased tone and caused large, irregular contractions. [Ca2+]imodulators: Ryanodine (10-5-10-4 M) increased muscle tone accompanied by inhibition of myogenic contractions. Xestospongin-C (10-6 M; IP3 channel inhibitor) had no effects. SERCA pump inhibitors, 2-APB and cycloplazonic acid (10-5-10-4 M) increased tone and myogenic contraction amplitude before abolishing contractions; thapsigargin was weakly active. CaCC blockers: MONNA and CaCCinh-A01 had little-or-no effects on tone but reduced myogenic contractions; MONNA (10-4 M) was more effective, reducing amplitude (77.8 ± 15.2%) and frequency. CaV3.1/3.2/3.3 channel block: Mibefradil reduced tone and myogenic contraction amplitude (pIC50 4.8 ± 0.9). Inward-rectifying K+-channel inhibitor: E-4031 (10-4 M) increased contraction duration (17.4 ± 5.8%). Conclusions: (1) Measurement of multiple parameters of myogenic contractions identified subtle differences between compounds, (2) only E-4031 and CaCC blockers influenced myogenic contractions, not muscle tone, (3) studies are needed with compounds with known and/or improved selectivity/potency for human targets affecting ICC functions.

Evidence for tetrodotoxin-resistant spontaneous myogenic contractions of mouse isolated stomach that are dependent on acetylcholine.

BACKGROUND AND PURPOSE: Gastric pacemaker cells, interstitial cells of Cajal (ICC), are believed to initiate myogenic (non-neuronal) contractions. These become damaged in gastroparesis, associated with dysrhythmic electrical activity and nausea. We utilised mouse isolated stomach to model myogenic contractions and investigate their origin and actions of interstitial cells of Cajal modulators. EXPERIMENTAL APPROACH: Intraluminal pressure was recorded following distension with a physiological volume; tone, contraction amplitude and frequency were quantified. Compounds were bath applied. KEY RESULTS: The stomach exhibited regular large amplitude contractions (median amplitude 9.0 [4.7-14.8] cmH2 O, frequency 2.9 [2.5-3.4] c.p.m; n = 20), appearing to progress aborally. Tetrodotoxin (TTX, 10-6 M) had no effect on tone, frequency or amplitude but blocked responses to nerve stimulation. ω-conotoxin GVIA (10-7 M) ± TTX was without effect on baseline motility. In the presence of TTX, (1) atropine (10-10 -10-6 M) reduced contraction amplitude and frequency in a concentration-related manner (pIC50 7.5 ± 0.3 M for amplitude), (2) CaCC channel (previously ANO1) inhibitors MONNA and CaCCinh-A01 reduced contraction amplitude (significant at 10-5 , 10-4 M respectively) and frequency (significant at 10-5 M), and (3), neostigmine (10-5 M) evoked a large, variable, increase in contraction amplitude, reduced by atropine (10-8 -10-6 M) but unaffected (exploratory study) by the H1 receptor antagonist mepyramine (10-6 M). CONCLUSIONS AND IMPLICATIONS: The distended mouse stomach exhibited myogenic contractions, resistant to blockade of neural activity by TTX. In the presence of TTX, these contractions were prevented or reduced by compounds blocking interstitial cells of Cajal activity or by atropine and enhanced by neostigmine (antagonised by atropine), suggesting involvement of non-neuronal ACh in their regulation.

Single Incision Robotic Cystectomy and Hybrid Orthotopic Neobladder Reconstruction: A Step by Step Description.

OBJECTIVE: To describe a new technique for single incision robotic cystectomy and Studer-type ileal neobladder using the single-port (SP) da Vinci SP robotic platform. METHODS: In April 2021, a 71 year-old patient underwent a single incision robotic cystectomy and orthotopic Studer-type ileal neobladder using the single-port da Vinci SP robotic platform for cT2, cN0 urothelial carcinoma of the bladder. He was not a candidate for neoadjuvant cisplatin-based combination chemotherapy and declined participation in a clinical trial. RESULTS: Total operative time was 554 minutes and estimated blood loss was 250 cc. He was discharged on postoperative day six without developing any Clavien complications. He underwent adjuvant chemotherapy for node-positive disease and follow-up through June 2021 was notable for the absence of any significant complications or readmissions. We provide a comprehensive discussion of the required instrumentation, a description of the technique with illustrations, and discuss the advantages and disadvantages of this technology as it pertains to cystectomy and urinary diversion. CONCLUSION: We make no claim regarding the superiority of this technique over others, only that it is technically feasible and that the approach holds promise.

Cognitive Behavior Therapy for Depression From an Evolutionary Perspective.

Evolutionary medicine attempts to solve a problem with which traditional medicine has struggled historically; how do we distinguish between diseased states and "healthy" responses to disease states? Fever and diarrhea represent classic examples of evolved adaptations that increase the likelihood of survival in response to the presence of pathogens in the body. Whereas, the severe mental disorders like psychotic mania or the schizophrenias may involve true "disease" states best treated pharmacologically, most non-psychotic "disorders" that revolve around negative affects like depression or anxiety are likely adaptations that evolved to serve a function that increased inclusive fitness in our ancestral past. What this likely means is that the proximal mechanisms underlying the non-psychotic "disorders" are "species typical" and neither diseases nor disorders. Rather, they are coordinated "whole body" responses that prepare the individual to respond in a maximally functional fashion to the variety of different challenges that our ancestors faced. A case can be made that depression evolved to facilitate a deliberate cognitive style (rumination) in response to complex (often social) problems. What this further suggests is that those interventions that best facilitate the functions that those adaptations evolved to serve (such as rumination) are likely to be preferred over those like medications that simply anesthetize the distress. We consider the mechanisms that evolved to generate depression and the processes utilized in cognitive behavior therapy to facilitate those functions from an adaptationist evolutionary perspective.

Evolutionary theory and the treatment of depression: It is all about the squids and the sea bass.

According to the analytical rumination hypothesis, depression is an evolved adaptation (like pain or anxiety) that served in our ancestral past to keep people focused on complex interpersonal problems until they could arrive at a resolution (spontaneous remission). If this is true, then those clinical treatments that most facilitate the functions that depression evolved to serve are likely to be more advantageous in the long run than others that simply relieve distress. For example, antidepressant medications may be efficacious in the treatment of depression but only work for so long as they are taken. They may also have an iatrogenic effect that prolongs the duration of the underlying episode. Cognitive and behavioral interventions are as efficacious as medications in terms of reducing acute distress and also appear to have an enduring effect that protects against the return of subsequent symptoms. However, the bulk of the evidence for this effect comes from comparisons to prior medication treatment and it remains unclear whether these psychosocial interventions are truly preventative, or antidepressant medications iatrogenic. A study is described that could resolve this issue and test evolutionary theory with respect to the purported role of rumination in bringing about spontaneous remission.

Individual Differences in Response to Antidepressants: A Meta-analysis of Placebo-Controlled Randomized Clinical Trials.

Importance: Antidepressants are commonly used to treat major depressive disorder (MDD). Antidepressant outcomes can vary based on individual differences; however, it is unclear whether specific factors determine this variability or whether it is at random. Objective: To investigate the assumption of systematic variability in symptomatic response to antidepressants and to assess whether variability is associated with MDD severity, antidepressant class, or study publication year. Data Sources: Data used were updated from a network meta-analysis of treatment with licensed antidepressants in adults with MDD. The Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, and PsycInfo were searched from inception to March 21, 2019. Additional sources were international trial registries and sponsors, drug companies and regulatory agencies' websites, and reference lists of published articles. Data were analyzed between June 8, 2020, and June 13, 2020. Study Selection: Analysis was restricted to double-blind, randomized placebo-controlled trials with depression scores available at the study's end point. Data Extraction and Synthesis: Baseline means, number of participants, end point means and SDs of total depression scores, antidepressant type, and publication year were extracted. Main Outcomes and Measures: Log SDs (bln σ̂) were derived for treatment groups (ie, antidepressant and placebo). A random-slope mixed-effects model was conducted to estimate the difference in bln σ̂ between treatment groups while controlling for end point mean. Secondary models determined whether differences in variability between groups were associated with baseline MDD severity; antidepressant class (selective serotonin reuptake inhibitors and other related drugs; serotonin and norepinephrine reuptake inhibitors; norepinephrine-dopamine reuptake inhibitors; noradrenergic agents; or other antidepressants); and publication year. Results: In the 91 eligible trials (18 965 participants), variability in response did not differ significantly between antidepressants and placebo (bln σ̂, 1.02; 95% CI, 0.99-1.05; P = .19). This finding is consistent with a range of treatment effect SDs (up to 16.10), depending on the association between the antidepressant and placebo effects. Variability was not associated with baseline MDD severity or publication year. Responses to noradrenergic agents were 11% more variable than responses to selective serotonin reuptake inhibitors (bln σ̂, 1.11; 95% CI, 1.01-1.21; P = .02). Conclusions and Relevance: Although this study cannot rule out the possibility of treatment effect heterogeneity, it does not provide empirical support for personalizing antidepressant treatment based solely on total depression scores. Future studies should explore whether individual symptom scores or biomarkers are associated with variability in response to antidepressants.

COVID-19, nausea, and vomiting.

Exclusion of nausea (N) and vomiting (V) from detailed consideration as symptoms of COVID-19 is surprising as N can be an early presenting symptom. We examined the incidence of NV during infection before defining potential mechanisms. We estimate that the overall incidence of nausea (median 10.5%), although variable, is comparable with diarrhea. Poor definition of N, confusion with appetite loss, and reporting of N and/or V as a single entity may contribute to reporting variability and likely underestimation. We propose that emetic mechanisms are activated by mediators released from the intestinal epithelium by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) modulate vagal afferents projecting to the brainstem and after entry into the blood, activate the area postrema (AP) also implicated in anorexia. The receptor for spike protein of SARS-CoV-2, angiotensin 2 converting enzyme (ACE2), and transmembrane protease serine (for viral entry) is expressed in upper gastrointestinal (GI) enterocytes, ACE2 is expressed on enteroendocrine cells (EECs), and SARS-CoV-2 infects enterocytes but not EECs (studies needed with native EECs). The resultant virus-induced release of epithelial mediators due to exocytosis, inflammation, and apoptosis provides the peripheral and central emetic drives. Additionally, data from SARS-CoV-2 show an increase in plasma angiotensin II (consequent on SARS-CoV-2/ACE2 interaction), a centrally (AP) acting emetic, providing a further potential mechanism in COVID-19. Viral invasion of the dorsal brainstem is also a possibility but more likely in delayed onset symptoms. Overall, greater attention must be given to nausea as an early symptom of COVID-19 and for the insights provided into the GI effects of SARS-CoV-2.

Copeptin, a surrogate marker of arginine8 vasopressin, has no ability to modulate human and mouse gastric motility.

Copeptin, a glycosylated peptide fragment derived from the C-terminal region of the precursor of arginine8 vasopressin (AVP), is co-secreted with AVP in equimolar amounts. Elevated plasma AVP modulates gastric motility so we investigated whether copeptin had a similar effect. Copeptin (10-9-10-7M), and AVP (10-12-10-5M), were evaluated for their ability to modulate spontaneous and electrically-evoked (EFS) contractions of human proximal and distal gastric circular muscle in vitro. Similar experiments were performed on the mouse stomach and we re-examined the published effect of copeptin on the mouse aorta. In the presence of tetrodotoxin (10-6M), atropine (10-6M) and L-NAME (3 × 10-4M), human proximal and distal stomach muscle contracted spontaneously and rhythmically as did mouse distal stomach. Copeptin (10-9-10-7M), had no effect on baseline muscle tone or myogenic spontaneous contractions of either human or mouse stomach. However, AVP concentration-dependently increased tone, amplitude and frequency of contractions in both regions of human stomach with similar potency (pEC50 9.0-9.5; n = 4) and threshold concentration (10-11-10-10M). AVP was similarly active in the mouse stomach. EFS-evoked cholinergic contractions (human and mouse) were unaffected by both peptides EFS-evoked relaxations of mouse stomach were unaffected by copeptin. In sub-maximally contracted mouse aorta the elevated tone was unaffected by copeptin (10-7M) (cf. previously published study) but was reduced by carbachol (10-6M) and sodium nitroprusside (10-3M). We conclude that in contrast to AVP, copeptin over a concentration range reported in the plasma has no direct ability to modulate the motility of the human and mouse stomach.

Disordered doctors or rational rats? Testing adaptationist and disorder hypotheses for melancholic depression and their relevance for clinical psychology.

Most clinicians view depression as a painful disorder in which motivation to pursue adaptive goals is lacking and cognition is impaired. An alternative hypothesis-grounded in a common evolutionary approach-suggests that depression is inherently motivational and evolved to motivate avoidant learning of harmful situations. Testing these hypotheses requires a clear definition of "disorder". Wakefield's harmful dysfunction evolution-based definition proposes that all unambiguous cases of disorder involve a malfunctioning adaptation. These hypotheses-functional adaptation and malfunctioning adaptation-are mutually exclusive and require a common research strategy. One must identify and map out the relevant adaptation-characterized by a high degree of non-random organization and coordination for promoting a function-which will eventually result in a conceptual blueprint of where and how the adaptation can malfunction. Using inescapable shock in rats and physicians' emotional responses to medical errors to provide context, we show how the symptoms of melancholic depression exhibit signs of adaptation for motivating a time-consuming, attentionally-demanding, energetically-expensive avoidant learning style after experiencing a harmful event. We discuss how this adaptationist approach may provide insight into spontaneous remission and the effects of psychotherapies and antidepressant medications.