Novel Synthesis of C-Methylated Phytocannabinoids Bearing Anti-inflammatory Properties.

There is growing interest in non-psychoactive phytocannabinoids, namely cannabidiol (CBD), cannabigerol (CBG), and cannabichromene, as potential leads for novel therapeutic agents. In this study, we report on the development of new derivatives in which we methylated either position 4 of olivetol or the phenolic positions of olivetol, or both. We introduce a refinement on previously reported chemical procedures for phytocannabinoid derivatization as well as the biological evaluation of all derivatives in anti-inflammatory in vivo models.

SME viability in the COVID-19 recovery.

Abstract: Using survey data from a representative sample of Irish Small and Medium Enterprises (SMEs), we study how firms are likely to perform under macroeconomic forecasts of the pandemic recovery. The rate of financial distress among firms is expected to fall under baseline forecasts from a peak of 12% in 2020 to 7% by 2024. We find that those firms that struggle to recover by the end of our scenario window were mostly unprofitable or distressed prior to the pandemic.

Novel CBG Derivatives Can Reduce Inflammation, Pain and Obesity.

Interest in CBG (cannabigerol) has been growing in the past few years, due to its anti-inflammatory properties and other therapeutic benefits. Here we report the synthesis of three new CBG derivatives (HUM-223, HUM-233 and HUM-234) and show them to possess anti-inflammatory and analgesic properties. In addition, unlike CBG, HUM-234 also prevents obesity in mice fed a high-fat diet (HFD).

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300.

Fibrotic diseases remain a major cause of morbidity and mortality, yet there are few effective therapies. The underlying pathology of all fibrotic conditions is the activity of myofibroblasts. Using cells from freshly excised disease tissue from patients with Dupuytren's disease (DD), a localized fibrotic disorder of the palm, we sought to identify new therapeutic targets for fibrotic disease.

Author Correction: Cellular census of human fibrosis defines functionally distinct stromal cell types and states.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cellular census of human fibrosis defines functionally distinct stromal cell types and states.

Fibrotic disorders are some of the most devastating and poorly treated conditions in developed nations, yet effective therapeutics are not identified for many of them. A major barrier for the identification of targets and successful clinical translation is a limited understanding of the human fibrotic microenvironment. Here, we construct a stromal cell atlas of human fibrosis at single cell resolution from patients with Dupuytren's disease, a localized fibrotic condition of the hand.

Single cell force profiling of human myofibroblasts reveals a biophysical spectrum of cell states.

Mechanical force is a fundamental regulator of cell phenotype. Myofibroblasts are central mediators of fibrosis, a major unmet clinical need characterised by the deposition of excessive matrix proteins. Traction forces of myofibroblasts play a key role in remodelling the matrix and modulate the activities of embedded stromal cells.

Identification of TNFR2 and IL-33 as therapeutic targets in localized fibrosis.

Dissecting the molecular landscape of fibrotic disease, a major unmet need, will inform the development of novel treatment strategies to target disease progression and identify desperately needed therapeutic targets. Here, we provide a detailed single-cell analysis of the immune landscape in Dupuytren's disease, a localized fibrotic condition of the hand, and identify a pathogenic signaling circuit between stromal and immune cells. We demonstrate M2 macrophages and mast cells as key cellular sources of tumor necrosis factor (TNF) that promotes myofibroblast development.

TNF receptor 2 signaling prevents DNA methylation at the promoter and prevents pathogenic conversion of regulatory T cells.

Regulatory T (Treg) cells expressing the transcription factor Foxp3 play an important role in maintaining immune homeostasis. Chronic inflammation is associated with reduced Foxp3 expression, function, and loss of phenotypic stability. Previous studies have established the importance of TNF receptor 2 (TNFR2) in the generation and/or activation of Treg cells.

A genetics-led approach defines the drug target landscape of 30 immune-related traits.

Most candidate drugs currently fail later-stage clinical trials, largely due to poor prediction of efficacy on early target selection. Drug targets with genetic support are more likely to be therapeutically valid, but the translational use of genome-scale data such as from genome-wide association studies for drug target discovery in complex diseases remains challenging. Here, we show that integration of functional genomic and immune-related annotations, together with knowledge of network connectivity, maximizes the informativeness of genetics for target validation, defining the target prioritization landscape for 30 immune traits at the gene and pathway level.

Target Identification Using Chemical Probes.

Chemical probes are small molecules with potency and selectivity for a single or small number of protein targets. A good chemical probe engages its target intracellularly and is accompanied by a chemically similar, but inactive molecule to be used as a negative control in cellular phenotypic screening. The utility of these chemical probes is ultimately governed by how well they are developed and characterized.

Anti-Tumour Necrosis Factor Therapy for Dupuytren's Disease: A Randomised Dose Response Proof of Concept Phase 2a Clinical Trial.

Background: Dupuytren's disease is a common fibrotic condition of the hand that causes irreversible flexion contractures of the fingers, with no approved therapy for early stage disease. Our previous analysis of surgically-excised tissue defined tumour necrosis factor (TNF) as a potential therapeutic target. Here we assessed the efficacy of injecting nodules of Dupuytren's disease with a TNF inhibitor.

TNFR signalling and its clinical implications.

Tumour necrosis factor-α (TNF-α) is a highly pleiotropic cytokine with effects on multiple pathological and physiological functions via two distinct receptors, TNFR1 and TNFR2. Much of the pro- inflammatory action of TNF-α is mediated by TNFR1 whereas TNFR2 is thought to play an immunoregulatory and tissue protective role. Anti-TNF- α biologics have been extremely successful in treating a number of immune mediated pathologies, including rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis and inflammatory bowel disease.

Mapping tenascin-C interaction with toll-like receptor 4 reveals a new subset of endogenous inflammatory triggers.

Pattern recognition underpins innate immunity; the accurate identification of danger, including infection, injury, or tumor, is key to an appropriately targeted immune response. Pathogen detection is increasingly well defined mechanistically, but the discrimination of endogenous inflammatory triggers remains unclear. Tenascin-C, a matrix protein induced upon tissue damage and expressed by tumors, activates toll-like receptor 4 (TLR4)-mediated sterile inflammation.

Investigating the Role of Toll-Like Receptors in Models of Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation leading to tissue destruction and progressive loss of joint function. Here we describe two methods that can be used to assess the contribution of toll-like receptors (TLRs), and their potential ligands, to RA pathogenesis. We focus on the antigen-induced model of murine arthritis and human synovial tissue explant models.

Physician response to a medication alert system in inpatients with levodopa-treated diseases.

Objective: To evaluate the appropriateness of dopamine receptor antagonist prescriptions in hospitalized patients with dopamine-requiring diseases after implementation of an automated prescription alert system.

Methods: We examined dopamine receptor antagonist prescriptions in hospitalized patients with dopamine-requiring diseases and physician response to an automated drug contraindication alert system at Barnes-Jewish Hospital from 2009 to 2013. A detailed review of patient medical records was performed for all alert events generated when a physician prescribed a dopamine receptor antagonist concurrently with a dopamine receptor agonist in hospitalized patients.

Family carers' experience of caring for an older parent with severe and persistent mental illness.

While the burden of caring for older people with chronic medical illness and dementia has been well documented, considerably less is known about how carers develop the strength and resilience to sustain this important role with older family members with mental illness. The aim of the study was to understand the lived experience of primary caregivers of older people with severe and persistent mental illness, and to explore what, if anything, helps to sustain them in their caring role. An interpretative phenomenological analysis approach was adopted, and qualitative interviews were used with 30 primary caregivers.

IFN-λ resolves inflammation via suppression of neutrophil infiltration and IL-1β production.

The most studied biological role of type III interferons (IFNs) has so far been their antiviral activity, but their role in autoimmune and inflammatory diseases remains largely unexplored. Here, we show that treatment with IFN-λ2/IL-28A completely halts and reverses the development of collagen-induced arthritis (CIA) and discover cellular and molecular mechanisms of IL-28A antiinflammatory function. We demonstrate that treatment with IL-28A dramatically reduces numbers of proinflammatory IL-17-producing Th17 and γδ T cells in the joints and inguinal lymph nodes, without affecting T cell proliferative responses or levels of anticollagen antibodies.

Multisite Direct Determination of the Potential for Environmental Contamination of Urine Samples Used for Diagnosis of Sexually Transmitted Infections.

Background: The detection of a sexually transmitted infection (STI) agent in a urine specimen from a young child is regarded as an indicator of sexual contact. False positives may conceivably arise from the transfer of environmental contaminants in clinic toilet or bathroom facilities into urine specimens.

Methods: The potential for contamination of urine specimens with environmental STI nucleic acid was tested empirically in the male and female toilets or bathrooms at 10 Northern Territory (Australia) clinics, on 7 separate occasions at each.

Selective tumor necrosis factor receptor I blockade is antiinflammatory and reveals immunoregulatory role of tumor necrosis factor receptor II in collagen-induced arthritis.

Objective: Tumor necrosis factor (TNF) signals via 2 receptors, TNFR type I (TNFRI) and TNFRII, with distinct cellular distribution and signaling functions. In rheumatoid arthritis (RA), the net effect of TNFR signaling favors inflammatory responses while inhibiting the activity of regulatory T cells. TNFRII signaling has been shown to promote Treg cell function.

OX40L blockade is therapeutic in arthritis, despite promoting osteoclastogenesis.

An immune response is essential for protection against infection, but, in many individuals, aberrant responses against self tissues cause autoimmune diseases such as rheumatoid arthritis (RA). How to diminish the autoimmune response while not augmenting infectious risk is a challenge. Modern targeted therapies such as anti-TNF or anti-CD20 antibodies ameliorate disease, but at the cost of some increase in infectious risk.

Congenital esophageal stenosis associated with esophageal atresia.

Congenital esophageal stenosis (CES) is a rare clinical condition but is frequently associated with esophageal atresia (EA). The aim of this study is to report the diagnosis, management, and outcome of CES associated with EA. Medical charts of CES-EA patients from Lille University Hospital, Sainte-Justine Hospital, and Montreal Children's Hospital were retrospectively reviewed.

TNFR2 increases the sensitivity of ligand-induced activation of the p38 MAPK and NF-κB pathways and signals TRAF2 protein degradation in macrophages.

Tumour necrosis factor (p55 or p60) receptor (TNFR) 1 is the major receptor that activates pro-inflammatory signalling and induces gene expression in response to TNF. Consensus is lacking for the function of (p75 or p80) TNFR2 but experiments in mice have suggested neuro-, cardio- and osteo-protective and anti-inflammatory roles. It has been shown in various cell types to be specifically required for the induction of TNFR-associated factor-2 (TRAF2) degradation and activation of the alternative nuclear factor (NF)-kappaB pathway, and to contribute to the activation of mitogen-activated protein kinases (MAPK) and the classical NF-kappaB pathway.

Does radiographic beam angle affect the radiocapitellar ratio measurement of subluxation in the elbow?

Background: Radial head alignment is the key to determine elbow reduction after treatment of subluxations or Monteggia fractures. The radiocapitellar ratio (RCR) quantifies the degree of subluxation, by evaluating radial head alignment with the capitellum of the humerus; this ratio is reproducible when measured on true lateral radiographs of nonsubluxated elbows. However, the impact of beam angulation on RCR measurement is unknown.