The first total synthesis of (+)-mucosin

The first total synthesis of (+)-mucosin has been completed allowing assignment of the absolute stereochemistry of the natural product. A zirconium induced co-cyclisation was utilised to install the correct stereochemistry of the four contiguous stereocentres around the unusual bicyclo[4.3.0]nonene core

Discovery of a Bright Field Methane (T-type) Brown Dwarf by 2MASS

We report the discovery of a bright (J = 13.83$\pm$0.03) methane brown dwarf, or T dwarf, by the Two Micron All Sky Survey. This object, 2MASSI J0559191-140448, is the first brown dwarf identified by the newly commissioned CorMASS instrument mounted on the Palomar 60-inch Telescope. Near-infrared spectra from 0.9 - 2.35 \micron show characteristic CH$_4$ bands at 1.1, 1.3, 1.6, and 2.2 \micron, which are significantly shallower than those seen in other T dwarfs discovered to date. Coupled with the detection of an FeH band at 0.9896 \micron and two sets of K I doublets at J-band, we propose that 2MASS J0559-14 is a warm T dwarf, close to the transition between L and T spectral classes. The brightness of this object makes it a good candidate for detailed investigation over a broad wavelength regime and at higher resolution.Comment: 21 pages, 3 figures, 2 tables, accepted to AJ for publication August 200

Reactions of (-)-sparteine with alkali metal HMDS complexes : conventional meets the unconventional

Conventional (-)-sparteine adducts of lithium and sodium 1,1,1,3,3,3-hexamethyldisilazide (HMDS) were prepared and characterised, along with an unexpected and unconventional hydroxyl-incorporated sodium sodiate, [(-)-sparteine·Na(-HMDS)Na·(-)-sparteine]+[Na4(-HMDS)4(OH)]--the complex anion of which is the first inverse crown ether anion

Activating transcription factor 3 is a negative regulator of allergic pulmonary inflammation

We recently demonstrated the pivotal role of the transcription factor (TF) activating TF 3 (ATF3) in dampening inflammation. We demonstrate that ATF3 also ameliorates allergen-induced airway inflammation and hyperresponsiveness in a mouse model of human asthma. ATF3 expression was increased in the lungs of mice challenged with ovalbumin allergen, and this was associated with its recruitment to the promoters of genes encoding Th2-associated cytokines. ATF3-deficient mice developed significantly increased airway hyperresponsiveness, pulmonary eosinophilia, and enhanced chemokine and Th2 cytokine responses in lung tissue and in lung-derived CD4+ lymphocytes. Although several TFs have been associated with enhanced inflammatory responses in the lung, ATF3 attenuates the inflammatory responses associated with allergic airway disease

Advance Statements for Black African and Caribbean people (AdStAC):protocol for an implementation study

Background Advance Choice Documents (ACDs) have been recommended for inclusion in new mental health legislation for England and Wales. This is based on evidence-based interventions to reduce compulsory psychiatric admission, with particular benefit for Black people, whose rates of compulsory psychiatric admission in the UK are over three times higher than those of White British people. Our aim was to explore potential barriers and enablers to effective implementation of ACDs for use by Black people with previous experience of compulsory admission. Methods Seven online and in-person workshops were held with: Black service users who had previously been compulsorily admitted, carers/supporters of Black service users, and mental health professionals. Workshops were recorded and transcribed. Results Inductive analysis was employed to identify recommendations and determine where there was a lack of consensus. Thematic analysis identified key themes of ‘people’, ‘process’ and ‘power’ pertaining to ACD implementation. Discussion Our results reinforce the need for independent facilitation for ACD creation and their potential to empower Black service users in relation to their care. They suggest that explicit acknowledgement of, and time spent listening to, the historical and individual poor experiences that underlie the treatment preferences Black people express are important aspects of ACD creation

Cocaine-induced granulomatosis with polyangiitis—an under-recognized condition

Objectives: Cocaine and cocaine mixed with levamisole are increasingly used in the UK and result in significant direct nasal damage in addition to promoting vasculitis. Our aims were as follows: (1) to identify the main symptoms and presentation of cocaine-induced vasculitis; (2) to provide evidence regarding the best practice for the investigation and diagnosis of cocaine-induced vasculitis; and (3) to analyse the clinical outcomes of patients in order to understand the optimal management for the condition./ Methods: We performed a retrospective case series analysis of patients presenting with cocaine-induced midline destructive lesions or vasculitis compatible with granulomatosis with polyangiitis (GPA) from two large tertiary vasculitis clinics between 2016 and 2021./ Results: Forty-two patients (29 Birmingham, 13 London) with cocaine-induced midline lesions or systemic disease were identified. The median age was 41 years (range 23–66 years). Current cocaine use was common, and 20 of 23 samples provided were positive when routine urine toxicology was performed; 9 patients who denied ever using cocaine were identified as using cocaine based on urine toxicology analysis, and 11 who stated they were ex-users still tested positive. There was a high incidence of septal perforation (75%) and oronasal fistula (15%). Systemic manifestations were less common (27%), and only one patient had acute kidney injury. Fifty-six per cent of our patients were PR3-ANCA positive, with none testing positive for MPO-ANCA. Symptom remission required cocaine discontinuation even when immunosuppression was administered./ Conclusion: Patients with destructive nasal lesions, especially young patients, should have urine toxicology performed for cocaine before diagnosing GPA and considering immunosuppressive therapy. The ANCA pattern is not specific for cocaine-induced midline destructive lesions. Treatment should be focused on cocaine cessation and conservative management in the first instance in the absence of organ-threatening disease

Unilateral spontaneous rupture of a testicular implant thirteen years after bilateral insertion: a case report

<p>Abstract</p> <p>Introduction</p> <p>We describe a case of spontaneous, non traumatic rupture of a single artificial testis in a patient who had undergone bilateral, staged radical orchidectomy followed by prosthesis insertion. The consequences and radiological appearances of implant rupture are discussed. We believe it is the longest time interval recorded between prosthesis insertion and rupture.</p> <p>Case presentation</p> <p>A 50 year old Caucasian man presented to our outpatient department with an altered consistency in his right testicular prosthesis without any systemic symptoms or local inflammation. His left testicular prosthesis had retained its consistency since insertion.</p> <p>Conclusion</p> <p>The majority of cases reported to date have required exploration due to symptoms but we describe a case that was managed conservatively.</p

Proteinase 3 promotes formation of multinucleated giant cells and granuloma-like structures in patients with granulomatosis with polyangiitis

OBJECTIVES: Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are autoimmune vasculitides associated with antineutrophil cytoplasm antibodies that target proteinase 3 (PR3) or myeloperoxidase (MPO) found within neutrophils and monocytes. Granulomas are exclusively found in GPA and form around multinucleated giant cells (MGCs), at sites of microabscesses, containing apoptotic and necrotic neutrophils. Since patients with GPA have augmented neutrophil PR3 expression, and PR3-expressing apoptotic cells frustrate macrophage phagocytosis and cellular clearance, we investigated the role of PR3 in stimulating giant cell and granuloma formation. METHODS: We stimulated purified monocytes and whole peripheral blood mononuclear cells (PBMCs) from patients with GPA, patients with MPA or healthy controls with PR3 or MPO and visualised MGC and granuloma-like structure formation using light, confocal and electron microscopy, as well as measuring the cell cytokine production. We investigated the expression of PR3 binding partners on monocytes and tested the impact of their inhibition. Finally, we injected zebrafish with PR3 and characterised granuloma formation in a novel animal model. RESULTS: In vitro, PR3 promoted monocyte-derived MGC formation using cells from patients with GPA but not from patients with MPA, and this was dependent on soluble interleukin 6 (IL-6), as well as monocyte MAC-1 and protease-activated receptor-2, found to be overexpressed in the cells of patients with GPA. PBMCs stimulated by PR3 formed granuloma-like structures with central MGC surrounded by T cells. This effect of PR3 was confirmed in vivo using zebrafish and was inhibited by niclosamide, a IL-6-STAT3 pathway inhibitor. CONCLUSIONS: These data provide a mechanistic basis for granuloma formation in GPA and a rationale for novel therapeutic approaches