Kappa and lambda immunohistochemistry and in situ hybridization in the evaluation of atypical cutaneous lymphoid infiltrates

BackgroundAtypical cutaneous lymphoid infiltrates are challenging lesions in dermatopathology. We present a summary of the literature regarding kappa and lambda immunohistochemistry (IHC) and in situ hybridization (ISH) in the evaluation of atypical cutaneous or mucosal lymphoid infiltrates.MethodsRelevant articles from 1967 to 2018 in the English language were identified and summarized. In the absence of larger studies, case series of n ≥ 3 were included.ResultsSixty‐three articles assessing kappa and lambda IHC and/or ISH were identified. Most focused on marginal zone lymphomas. Other lymphomas included follicle center lymphoma, diffuse large B‐cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, lymphoplasmacytic lymphoma, plasmablastic lymphoma, multiple myeloma, monoclonal gammopathy of undetermined significance, and polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS). Non‐neoplastic lesions included reactive lymphoid hyperplasia, cutaneous plasmacytosis, connective tissue disease, IgG4‐related disease, acrodermatitis chronic atrophicans, Zoon balanitis, dermatitides, and infiltrates around epithelial dysplasias/neoplasias.ConclusionKappa and lambda IHC and ISH are useful tools in the evaluation of cutaneous B‐cell lymphomas and plasma cell neoplasms. The literature supports that the detection of light‐chain restriction by IHC and ISH is one of the most useful findings in the differential diagnosis of reactive lymphoid hyperplasia vs B‐cell lymphoma with plasmacytic differentiation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163451/2/cup13858.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163451/1/cup13858_am.pd

The association between histamine 2 receptor antagonist use and Clostridium difficile infection: a systematic review and meta-analysis.

Background Clostridium difficile infection (CDI) is a major health problem. Epidemiological evidence suggests that there is an association between acid suppression therapy and development of CDI. Purpose We sought to systematically review the literature that examined the association between histamine 2 receptor antagonists (H2RAs) and CDI. Data source We searched Medline, Current Contents, Embase, ISI Web of Science and Elsevier Scopus from 1990 to 2012 for all analytical studies that examined the association between H2RAs and CDI. Study selection Two authors independently reviewed the studies for eligibility. Data extraction Data about studies characteristics, adjusted effect estimates and quality were extracted. Data synthesis Thirty-five observations from 33 eligible studies that included 201834 participants were analyzed. Studies were performed in 6 countries and nine of them were multicenter. Most studies did not specify the type or duration of H2RAs therapy. The pooled effect estimate was 1.44, 95% CI (1.22–1.7), I2 = 70.5%. This association was consistent across different subgroups (by study design and country) and there was no evidence of publication bias. The pooled effect estimate for high quality studies was 1.39 (1.15–1.68), I2 = 72.3%. Meta-regression analysis of 10 study-level variables did not identify sources of heterogeneity. In a speculative analysis, the number needed to harm (NNH) with H2RAs at 14 days after hospital admission in patients receiving antibiotics or not was 58, 95% CI (37, 115) and 425, 95% CI (267, 848), respectively. For the general population, the NNH at 1 year was 4549, 95% CI (2860, 9097). Conclusion In this rigorous systematic review and meta-analysis, we observed an association between H2RAs and CDI. The absolute risk of CDI associated with H2RAs is highest in hospitalized patients receiving antibiotics

Biosynthesis of bioactive diterpenoids in the medicinal plant Vitex agnus‐castus

Vitex agnus‐castus L. (Lamiaceae) is a medicinal plant historically used throughout the Mediterranean region to treat menstrual cycle disorders, and is still used today as a clinically effective treatment for premenstrual syndrome. The pharmaceutical activity of the plant extract is linked to its ability to lower prolactin levels. This feature has been attributed to the presence of dopaminergic diterpenoids that can bind to dopamine receptors in the pituitary gland. Phytochemical analyses of V. agnus‐castus show that it contains an enormous array of structurally related diterpenoids and, as such, holds potential as a rich source of new dopaminergic drugs. The present work investigated the localisation and biosynthesis of diterpenoids in V. agnus‐castus . With the assistance of matrix‐assisted laser desorption ionisation‐mass spectrometry imaging (MALDI‐MSI), diterpenoids were localised to trichomes on the surface of fruit and leaves. Analysis of a trichome‐specific transcriptome database, coupled with expression studies, identified seven candidate genes involved in diterpenoid biosynthesis: three class II diterpene synthases (diTPSs); three class I diTPSs; and a cytochrome P450 (CYP). Combinatorial assays of the diTPSs resulted in the formation of a range of different diterpenes that can account for several of the backbones of bioactive diterpenoids observed in V. agnus‐castus . The identified CYP, Vac CYP76BK1, was found to catalyse 16‐hydroxylation of the diol‐diterpene, peregrinol, to labd‐13Z ‐ene‐9,15,16‐triol when expressed in Saccharomyces cerevisiae . Notably, this product is a potential intermediate in the biosynthetic pathway towards bioactive furan‐ and lactone‐containing diterpenoids that are present in this species

Alpha-tocotrienol is the most abundant tocotrienol isomer circulated in plasma and lipoproteins after postprandial tocotrienol-rich vitamin E supplementation

<p>Abstract</p> <p>Background</p> <p>Tocotrienols (T3) and tocopherols (T), both members of the natural vitamin E family have unique biological functions in humans. T3 are detected in circulating human plasma and lipoproteins, although at concentrations significantly lower than α-tocopherol (α-T). T3, especially α-T3 is known to be neuropotective at nanomolar concentrations and this study evaluated the postprandial fate of T3 and α-T in plasma and lipoproteins.</p> <p>Methods</p> <p>Ten healthy volunteers (5 males and 5 females) were administered a single dose of vitamin E [526 mg palm tocotrienol-rich fraction (TRF) or 537 mg α-T] after 7-d pre-conditioning on a T3-free diet. Blood was sampled at baseline (fasted) and 2, 4, 5, 6, 8, and 24 h after supplementation. Concentrations of T and T3 isomers in plasma, triacylglycerol-rich particles (TRP), LDL, and HDL were measured at each postprandial interval.</p> <p>Results</p> <p>After TRF supplementation, plasma α-T3 and γ-T3 peaked at 5 h (α-T3: 4.74 ± 1.69 μM; γ-T3: 2.73 ± 1.27 μM). δ-T3 peaked earlier at 4 h (0.53 ± 0.25 μM). In contrast, α-T peaked at 6 h (30.13 ± 2.91 μM) and 8 h (37.80 ± 3.59 μM) following supplementation with TRF and α-T, respectively. α-T was the major vitamin E isomer detected in plasma, TRP, LDL, and HDL even after supplementation with TRF (composed of 70% T3). No T3 were detected during fasted states. T3 are detected postprandially only after TRF supplementation and concentrations were significantly lower than α-T.</p> <p>Conclusions</p> <p>Bio-discrimination between vitamin E isomers in humans reduces the rate of T3 absorption and affects their incorporation into lipoproteins. Although low absorption of T3 into circulation may impact some of their physiological functions in humans, T3 have biological functions well below concentration noted in this study.</p

Machine learning–driven multiscale modeling reveals lipid-dependent dynamics of RAS signaling proteins

RAS is a signaling protein associated with the cell membrane that is mutated in up to 30% of human cancers. RAS signaling has been proposed to be regulated by dynamic heterogeneity of the cell membrane. Investigating such a mechanism requires near-atomistic detail at macroscopic temporal and spatial scales, which is not possible with conventional computational or experimental techniques. We demonstrate here a multiscale simulation infrastructure that uses machine learning to create a scale-bridging ensemble of over 100,000 simulations of active wild-type KRAS on a complex, asymmetric membrane. Initialized and validated with experimental data (including a new structure of active wild-type KRAS), these simulations represent a substantial advance in the ability to characterize RAS-membrane biology. We report distinctive patterns of local lipid composition that correlate with interfacially promiscuous RAS multimerization. These lipid fingerprints are coupled to RAS dynamics, predicted to influence effector binding, and therefore may be a mechanism for regulating cell signaling cascades

The EMPOWER blended digital intervention for relapse prevention in schizophrenia : a feasibility cluster randomised controlled trial in Scotland and Australia

Funding Information: AIG reports personal fees from University of Manchester, personal fees from University of Exeter, personal fees from British Association for Behavioural and Cognitive Psychotherapies and other interests with UK National Health Service (NHS) Education for Scotland outside the submitted work. JA, SL, and SB report other interests with CareLoop Health, outside the submitted work. SB reports grants from the Medical Research Council and UK National Institute for Health Research (NIHR) during the conduct of the study. SL reports grants from the UK Medical Research Council (MRC) during the conduct of the study. JA reports grants from MRC, Engineering and Physical Sciences Research Council, Economic and Social Research Council, NIHR, and the US National Institute for Health, and was a Fellow of the Alan Turing Institute during the conduct of the study. AB reports personal fees from Bayer, Merck, Janssen, Novartis, Sword Health, Amgen, and Daiichi Sankyo outside the submitted work. JF reports grants from National Health and Medical Research Council (Australia) during the conduct of the study and other interests with Melbourne Health (NorthWestern Mental Health) outside the submitted work. HMcL reports grants from NIHR Health Technology Assessment (HTA) during the conduct of the study, and grants with Academy of Medical Sciences, Glasgow Children's Hospital Charity, and Scotland's Chief Scientist's Office. CM reports grants from National Health and Medical Research Council (Australia) during the conduct of the study. JN reports grants from the University of Aberdeen and the University of Edinburgh during the conduct of the study and declares membership of the following NIHR boards: Cardio Pulmonary Resusitation decision making committee; HTA commissioning board; HTA commissioning sub-board (expression of interest); HTA funding boards policy group; HTA general board; HTA post-board funding teleconference; NIHR clinical trials unit standing advisory committee; NIHR HTA and Efficacy Mechanism Evaluation editorial board; pre-exposure prophylaxis impact review panel. PF is a member of the HTA mental health prioritisation panel. CW reports grants from NIHR during the conduct of the study and from the Royal College of Psychiatrists, and other interests with Five Areas outside the submitted work. AY reports an NIHR Senior Investigator Grant. JG reports grants from the National Health Medical Research Council. All other authors declare no competing interests. Funding Information: This project was funded in the UK by the NIHR-HTA programme (project number 13/154/04) and in Australia by the National Heath and Medical Research Council (APP1095879). The research will be published in full in the HTA. This study is supported by NHS Research Scotland, through the Chief Scientist Office and the NHS Scotland Mental Health Network. The Health Services Research Unit is funded by the Chief Scientist Office of the Scottish Government Health Directorate. MA-J is supported by an Investigator Grant (APP1177235) from the National Health and Medical Research Council and a Dame Kate Campbell Fellowship from The University of Melbourne. MB and SS are supported by NIHR Applied Research Centre (ARC) West Midlands. SA is supported by a Cremore Research Fellowship, donated to the University of Glasgow. This independent research study was funded by the UK NIHR-HTA. The views expressed in this publication are those of the authors and not necessarily of the NHS, the National Institute for Health Research, or the UK Department of Health and Social Care. The study sponsors and funders were not involved in the study design; collection, management, analysis, and interpretation of data; writing of the report; or the decision to submit the report for publication. We would like to thank health and care providers in Scotland and Australia who contributed to the study and of course to all the service users and their supporters who participated in this research. We sincerely hope we have met your expectations in taking part. We would like to acknowledge and recognise the contribution of members of the research team not listed as authors. These include Imogen Bell, Emily Castagnini, Andrea Clark, Amy Hood, Maria Lambrou, Casey Lynch, Casey McCrae, Ishani Majmudar, Claire Matrunola, Giada Micolucci, Sophie Norman, Lesley Smith, Suzy Syrett, David Thomson, Helen Whitehill, and Alison Wilson Kay. We also express our gratitude to our Study Steering Committee members: Prof David Kingdon (Chair), Prof Daniel Freeman (independent member), Prof Fiona Lobban (independent member), David Kavanagh (independent member), and Graham Morgan (Independent Public and Patient Involvement Representative). We also express our gratitude to our Data Monitoring and Ethics Committee members: Prof Emmanuelle Peters (Chair), Dr Alison Brabban (Independent Clinician), Prof Rod Taylor (Independent Statistician), and Prof Greg Murray (Independent Statistician). Funding Information: This project was funded in the UK by the NIHR-HTA programme (project number 13/154/04) and in Australia by the National Heath and Medical Research Council (APP1095879). The research will be published in full in the HTA. This study is supported by NHS Research Scotland, through the Chief Scientist Office and the NHS Scotland Mental Health Network. The Health Services Research Unit is funded by the Chief Scientist Office of the Scottish Government Health Directorate. MA-J is supported by an Investigator Grant (APP1177235) from the National Health and Medical Research Council and a Dame Kate Campbell Fellowship from The University of Melbourne. MB and SS are supported by NIHR Applied Research Centre (ARC) West Midlands. SA is supported by a Cremore Research Fellowship, donated to the University of Glasgow. This independent research study was funded by the UK NIHR-HTA. The views expressed in this publication are those of the authors and not necessarily of the NHS, the National Institute for Health Research, or the UK Department of Health and Social Care. The study sponsors and funders were not involved in the study design; collection, management, analysis, and interpretation of data; writing of the report; or the decision to submit the report for publication. We would like to thank health and care providers in Scotland and Australia who contributed to the study and of course to all the service users and their supporters who participated in this research. We sincerely hope we have met your expectations in taking part. We would like to acknowledge and recognise the contribution of members of the research team not listed as authors. These include Imogen Bell, Emily Castagnini, Andrea Clark, Amy Hood, Maria Lambrou, Casey Lynch, Casey McCrae, Ishani Majmudar, Claire Matrunola, Giada Micolucci, Sophie Norman, Lesley Smith, Suzy Syrett, David Thomson, Helen Whitehill, and Alison Wilson Kay. We also express our gratitude to our Study Steering Committee members: Prof David Kingdon (Chair), Prof Daniel Freeman (independent member), Prof Fiona Lobban (independent member), David Kavanagh (independent member), and Graham Morgan (Independent Public and Patient Involvement Representative). We also express our gratitude to our Data Monitoring and Ethics Committee members: Prof Emmanuelle Peters (Chair), Dr Alison Brabban (Independent Clinician), Prof Rod Taylor (Independent Statistician), and Prof Greg Murray (Independent Statistician). Publisher Copyright: © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licensePeer reviewe

Digital smartphone intervention to recognise and manage early warning signs in schizophrenia to prevent relapse : the EMPOWER feasibility cluster RCT

Funding Information: Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 27. See the NIHR Journals Library website for further project information. Funding in Australia was provided by the National Health and Medical Research Council (APP1095879). Funding Information: The research reported in this issue of the journal was funded by the HTA programme as project number 13/154/04. The contractual start date was in April 2016. The draft report began editorial review in September 2019 and was accepted for publication in March 2020. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report. Funding Information: Declared competing interests of authors: Andrew I Gumley reports personal fees from the University of Manchester, the University of Exeter and the British Association for Behavioural & Cognitive Psychotherapies (BABCP) (Accrington, UK), and other interests with NHS Education for Scotland outside the submitted work. John Ainsworth reports other interests with Affigo CIC (Manchester, UK) outside the submitted work. Sandra Bucci is a director of Affigo CIC, a not-for-profit social enterprise company spun out of the University of Manchester in December 2015 to enable access to social enterprise funding and to promote ClinTouch, a symptom-monitoring app, to the NHS and public sector. Andrew Briggs reports personal fees from Bayer (Leverkusen, Germany), Merck Sharp & Dohme (Kenilworth, NJ, USA), Janssen Pharmaceutica (Beerse, Belgium), Novartis (Basel, Switzerland), SWORD Health (Porto, Portugal), Amgen Inc. (Thousand Oaks, CA, USA) and Daiichi Sankyo (Tokyo, Japan) outside the submitted work. John Farhall reports grants from the National Health and Medical Research Council (Australia) during the conduct of the study and other interests with Melbourne Health (NorthWestern Mental Health, Parkville, VIC, Australia) outside the submitted work. Shôn Lewis reports grants from the Medical Research Council, non-financial support from Affigo CIC and personal fees from XenZone plc (Manchester, UK) outside the submitted work. Cathy Mihalopoulos reports grants from National Health and Medical Research Council (Australia) during the conduct of the study. John Norrie reports grants from the University of Aberdeen and the University of Edinburgh during the conduct of the study and declares membership of the following NIHR boards: CPR Decision Making Committee (2016), HTA Commissioning Board (2010–16), HTA Commissioning Sub-Board (EOI) (2012–16), HTA Funding Boards Policy Group (2016), HTA General Board (2016–19), HTA Post-Board funding teleconference (2016–19), NIHR CTU Standing Advisory Committee (2017–present), NIHR HTA and EME Editorial Board (2014–19) and Pre-exposure Prophylaxis Impact Review Panel (2017–present). Paul French is a member of the HTA Mental Health Prioritisation Panel (2017–present). Chris Williams reports grants from NIHR during the conduct of the study (HTA 10/104/34 BEAT-IT: a randomised controlled trial comparing a behavioural activation treatment for depression in adults with learning disabilities with attention control; NIHR multicentre RCT of a group psychological intervention for postnatal depression in British mothers of South Asian Origin: RP-PG-0514-20012: Integrated therapist and online CBT for depression in primary care); other from Five Areas Ltd (Clydebank, UK) outside the submitted work; and that he has twice been president of the British Association for Behavioural & Cognitive Psychotherapies, the lead body for cognitive–bahavioural therapy in the UK. This body aims to advocate use of evidence-based delivery of cognitive–bahavioural therapy. Publisher Copyright: © Queen’s Printer and Controller of HMSO 2022.Peer reviewedPublisher PD

Trans Fat Consumption and Aggression

Background: Dietary trans fatty acids (dTFA) are primarily synthetic compounds that have been introduced only recently; little is known about their behavioral effects. dTFA inhibit production of omega-3 fatty acids, which experimentally have been shown to reduce aggression. Potential behavioral effects of dTFA merit investigation. We sought to determine whether dTFA are associated with aggression/irritability. Methodolgy/Prinicpal Findings: We capitalized on baseline dietary and behavioral assessments in an existing clinical trial to analyze the relationship of dTFA to aggression. Of 1,018 broadly sampled baseline subjects, the 945 adult men and women who brought a completed dietary survey to their baseline visit are the target of this analysis. Subjects (seen 1999– 2004) were not on lipid medications, and were without LDL-cholesterol extremes, diabetes, HIV, cancer or heart disease. Outcomes assessed adverse behaviors with impact on others: Overt Aggression Scale Modified-aggression subscale (primary behavioral endpoint); Life History of Aggression; Conflict Tactics Scale; and self-rated impatience and irritability. The association of dTFA to aggression was analyzed via regression and ordinal logit, unadjusted and adjusted for potential confounders (sex, age, education, alcohol, and smoking). Additional analyses stratified on sex, age, and ethnicity, and examined the prospective association. Greater dTFA were strongly significantly associated with greater aggression, with dTFA more consistently predictive than other assessed aggression predictors. The relationship was upheld wit

Appropriate use criteria in dermatopathology: Initial recommendations from the American Society of Dermatopathology

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/145218/1/cup13142.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145218/2/cup13142_am.pd

Differential transcriptomic profiles effected by oil palm phenolics indicate novel health outcomes

Abstract Background Plant phenolics are important nutritional antioxidants which could aid in overcoming chronic diseases such as cardiovascular disease and cancer, two leading causes of death in the world. The oil palm (Elaeis guineensis) is a rich source of water-soluble phenolics which have high antioxidant activities. This study aimed to identify the in vivo effects and molecular mechanisms involved in the biological activities of oil palm phenolics (OPP) during healthy states via microarray gene expression profiling, using mice supplemented with a normal diet as biological models. Results Having confirmed via histology, haematology and clinical biochemistry analyses that OPP is not toxic to mice, we further explored the gene expression changes caused by OPP through statistical and functional analyses using Illumina microarrays. OPP showed numerous biological activities in three major organs of mice, the liver, spleen and heart. In livers of mice given OPP, four lipid catabolism genes were up-regulated while five cholesterol biosynthesis genes were down-regulated, suggesting that OPP may play a role in reducing cardiovascular disease. OPP also up-regulated eighteen blood coagulation genes in spleens of mice. OPP elicited gene expression changes similar to the effects of caloric restriction in the hearts of mice supplemented with OPP. Microarray gene expression fold changes for six target genes in the three major organs tested were validated with real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and the correlation of fold changes obtained with these two techniques was high (R2 = 0.9653). Conclusions OPP showed non-toxicity and various pleiotropic effects in mice. This study implies the potential application of OPP as a valuable source of wellness nutraceuticals, and further suggests the molecular mechanisms as to how dietary phenolics work in vivo.</p