A biological pathway linking inflammation and depression: activation of indoleamine 2,3-dioxygenase

This article highlights the evidence linking depression to increased inflammatory drive and explores putative mechanisms for the association by reviewing both preclinical and clinical literature. The enzyme indoleamine 2,3-dioxygenase is induced by proinflammatory cytokines and may form a link between immune functioning and altered neurotransmission, which results in depression. Increased indoleamine 2,3-dioxygenase activity may cause both tryptophan depletion and increased neurotoxic metabolites of the kynurenine pathway, two alterations which have been hypothesized to cause depression. The tryptophan-kynurenine pathway is comprehensively described with a focus on the evidence linking metabolite alterations to depression. The use of immune-activated groups at high risk of depression have been used to explore these hypotheses; we focus on the studies involving chronic hepatitis C patients receiving interferon-alpha, an immune activating cytokine. Findings from this work have led to novel strategies for the future development of antidepressants including inhibition of indoleamine 2,3-dioxygenase, moderating the cytokines which activate it, or addressing other targets in the kynurenine pathway

Annual time-series analysis of aqueous eDNA reveals ecologically relevant dynamics of lake ecosystem biodiversity

The use of environmental DNA (eDNA) in biodiversity assessments offers a step-change in sensitivity, throughput and simultaneous measures of ecosystem diversity and function. There remains, however, a need to examine eDNA persistence in the wild through simultaneous temporal measures of eDNA and biota. Here, we use metabarcoding of two markers of different lengths, derived from an annual time series of aqueous lake eDNA to examine temporal shifts in ecosystem biodiversity and in an ecologically important group of macroinvertebrates (Diptera: Chironomidae). The analyses allow different levels of detection and validation of taxon richness and community composition (β-diversity) through time, with shorter eDNA fragments dominating the eDNA community. Comparisons between eDNA, community DNA, taxonomy and UK species abundance data further show significant relationships between diversity estimates derived across the disparate methodologies. Our results reveal the temporal dynamics of eDNA and validate the utility of eDNA metabarcoding for tracking seasonal diversity at the ecosystem scale

“The more you know, the more you realise it is really challenging to do”: tensions and uncertainties in person-centred support for people with long-term conditions

ACKNOWLEDGEMENTS We thank the health professionals who participated in this research and shared their experiences and insights. We thank Louise Cotterell and Bev Smith (Health Services Research Unit, University of Aberdeen) for administrative and clerical support, Darshan Patel and colleagues at the Health Foundation for wonderfully facilitative research management, and NJC Secretarial for transcribing services. This study was funded by the Health Foundation (grant reference 7209). Health Foundation staff took part in one of the knowledge exchange discussions at the end of the project, but played no role in the analysis or writing of this manuscript, for which the authors take full responsibility.Peer reviewedPublisher PD

Professionalism, golf coaching and a master of science degree

A distinction can be made between 'professionalisation', which is concerned with occupational status and standing, and 'professionalism,' which refers to matters of quality and standards of practice (especially specialized knowledge, ethics and altruism). The purpose of this stimulus article is to present key features of contemporary medical professionalism as a basis for critically reflecting on discourse associated with Tiger Woods' current coach, Sean Foley. It is suggested that that provision of a Master of Science degree in golf teaching/coaching would facilitate the development of 'professionalism' in golf coaches

Extracellular Histones Inhibit Complement Activation through Interacting with Complement Component 4

Abstract Complement activation leads to membrane attack complex formation, which can lyse not only pathogens but also host cells. Histones can be released from the lysed or damaged cells and serve as a major type of damage-associated molecular pattern, but their effects on the complement system are not clear. In this study, we pulled down two major proteins from human serum using histone-conjugated beads: one was C-reactive protein and the other was C4, as identified by mass spectrometry. In surface plasmon resonance analysis, histone H3 and H4 showed stronger binding to C4 than other histones, with KD around 1 nM. The interaction did not affect C4 cleavage to C4a and C4b. Because histones bind to C4b, a component of C3 and C5 convertases, their activities were significantly inhibited in the presence of histones. Although it is not clear whether the inhibition was achieved through blocking C3 and C5 convertase assembly or just through reducing their activity, the outcome was that both classical and mannose-binding lectin pathways were dramatically inhibited. Using a high concentration of C4 protein, histone-suppressed complement activity could not be fully restored, indicating C4 is not the only target of histones in those pathways. In contrast, the alternative pathway was almost spared, but the overall complement activity activated by zymosan was inhibited by histones. Therefore, we believe that histones inhibiting complement activation is a natural feedback mechanism to prevent the excessive injury of host cells.</jats:p

Simulating a Community Mental Health Service During the COVID-19 Pandemic: Effects of Clinician-Clinician Encounters, Clinician-Patient-Family Encounters, Symptom-Triggered Protective Behaviour, and Household Clustering.

Objectives: Face-to-face healthcare, including psychiatric provision, must continue despite reduced interpersonal contact during the COVID-19 (SARS-CoV-2 coronavirus) pandemic. Community-based services might use domiciliary visits, consultations in healthcare settings, or remote consultations. Services might also alter direct contact between clinicians. We examined the effects of appointment types and clinician-clinician encounters upon infection rates. Design: Computer simulation. Methods: We modelled a COVID-19-like disease in a hypothetical community healthcare team, their patients, and patients' household contacts (family). In one condition, clinicians met patients and briefly met family (e.g., home visit or collateral history). In another, patients attended alone (e.g., clinic visit), segregated from each other. In another, face-to-face contact was eliminated (e.g., videoconferencing). We also varied clinician-clinician contact; baseline and ongoing "external" infection rates; whether overt symptoms reduced transmission risk behaviourally (e.g., via personal protective equipment, PPE); and household clustering. Results: Service organisation had minimal effects on whole-population infection under our assumptions but materially affected clinician infection. Appointment type and inter-clinician contact had greater effects at low external infection rates and without a behavioural symptom response. Clustering magnified the effect of appointment type. We discuss infection control and other factors affecting appointment choice and team organisation. Conclusions: Distancing between clinicians can have significant effects on team infection. Loss of clinicians to infection likely has an adverse impact on care, not modelled here. Appointments must account for clinical necessity as well as infection control. Interventions to reduce transmission risk can synergize, arguing for maximal distancing and behavioural measures (e.g., PPE) consistent with safe care

Case report: Malignant teratoma of the uterine corpus

<p>Abstract</p> <p>Background</p> <p>Teratomas are the commonest germ cell tumours and are most frequently found in the testes and ovary. Extragonadal teratomas are rare and mainly occur in midline structures. Uterine teratomas are extremely rare with only a few previous case reports, usually involving mature teratomas of the uterine cervix.</p> <p>Case Presentation</p> <p>We report an 82-year-old lady presenting with post-menopausal bleeding. Initial investigations revealed a benign teratoma of the uterus which was removed. Her symptoms persisted and a recurrent, now malignant, teratoma of the uterine corpus was resected at hysterectomy. Six months after surgery she relapsed with para-aortic lymphadenopathy and was treated with a taxane, etoposide and cisplatin-containing chemotherapy regimen followed by retroperitoneal lymph node dissection.</p> <p>Conclusion</p> <p>In this report we discuss the aetiology, diagnosis and management of uterine teratomas, and review previous case studies.</p

A review of the relationship between proinflammatory cytokines and major depressive disorder.

BACKGROUND: Determining etiological factors and reviewing advances in diagnostic modalities sensitive and specific to Major Depressive Disorder (MDD) is of importance in its evaluation and treatment. The inflammatory hypothesis is one of the most prevalent topics concerning MDD and may provide insight into the pathogenesis of depression, development of biomarkers, and ultimately production of more effective depression therapies. METHOD: We reviewed several studies to evaluate contemporary concepts concerning proinflammatory cytokines and their relationship to various depressive disorders, the use of anti-inflammatory therapies in MDD treatment, and the application of neuroimaging in conjunction with cytokine profiles from both plasma and CSF as possible diagnostic tools. RESULTS: Proinflammatory cytokines in both plasma and CSF have been found to influence the progression and severity of depressive disorders in different populations. Studies have shown elevated serum levels of IL-1, IL-6, TNF-α, CRP, and MCP-1 in depressed patients, but have presented mixed results with IL-8 serum levels, and with IL-6 and MCP-1 CSF levels. Anti-inflammatory treatment of MDD may have adjuvant properties with current depression medications. MRI and NIRS neuroimaging confirm neurological abnormalities in the presence of elevated proinflammatory cytokines in depressed or stressed patients. LIMITATIONS: Heterogeneity of MDD and limited CSF cytokine research complicate the study of MDD pathogenesis. CONCLUSION: There is significant evidence that inflammatory processes influence the development and progression of MDD. Future studies with larger arrays of cytokine profiles aided by neuroimaging may provide more sensitive and specific modes of diagnostics in determining MDD etiology and provide guidance in individual therapies

Simulating a Community Mental Health Service During the COVID-19 Pandemic: Effects of Clinician-Clinician Encounters, Clinician-Patient-Family Encounters, Symptom-Triggered Protective Behaviour, and Household Clustering.

Objectives: Face-to-face healthcare, including psychiatric provision, must continue despite reduced interpersonal contact during the COVID-19 (SARS-CoV-2 coronavirus) pandemic. Community-based services might use domiciliary visits, consultations in healthcare settings, or remote consultations. Services might also alter direct contact between clinicians. We examined the effects of appointment types and clinician-clinician encounters upon infection rates. Design: Computer simulation. Methods: We modelled a COVID-19-like disease in a hypothetical community healthcare team, their patients, and patients' household contacts (family). In one condition, clinicians met patients and briefly met family (e.g., home visit or collateral history). In another, patients attended alone (e.g., clinic visit), segregated from each other. In another, face-to-face contact was eliminated (e.g., videoconferencing). We also varied clinician-clinician contact; baseline and ongoing "external" infection rates; whether overt symptoms reduced transmission risk behaviourally (e.g., via personal protective equipment, PPE); and household clustering. Results: Service organisation had minimal effects on whole-population infection under our assumptions but materially affected clinician infection. Appointment type and inter-clinician contact had greater effects at low external infection rates and without a behavioural symptom response. Clustering magnified the effect of appointment type. We discuss infection control and other factors affecting appointment choice and team organisation. Conclusions: Distancing between clinicians can have significant effects on team infection. Loss of clinicians to infection likely has an adverse impact on care, not modelled here. Appointments must account for clinical necessity as well as infection control. Interventions to reduce transmission risk can synergize, arguing for maximal distancing and behavioural measures (e.g., PPE) consistent with safe care

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial