Polycyclic Indoline Derivatives by Dearomatizing Anionic Cyclization of Indole and Tryptamine-Derived Ureas

The base-promoted dearomatizing cyclization of anionic indole-containing urea derivatives provided tri- or tetracyclic indoline-containing scaffolds from lithiated urea intermediates. 3-Substituted indoles, including tryptamine derivatives, generally underwent the reaction in high yield and with excellent diastereoselectivity. In situ IR spectroscopy suggests a deprotonation–carbolithiation–reprotonation mechanism

Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting

Abstract Autoimmune hemolytic anemias (AIHAs) are rare and heterogeneous disorders characterized by the destruction of red blood cells through warm or cold antibodies. There is currently no licensed treatment for AIHA. Due to the paucity of clinical trials, recommendations on diagnosis and therapy have often been based on expert opinions and some national guidelines. Here we report the recommendations of the First International Consensus Group, who met with the aim to review currently available data and to provide standardized diagnostic criteria and therapeutic approaches as well as an overview of novel therapies. Exact diagnostic workup is important because symptoms, course of disease, and therapeutic management relate to the type of antibody involved. Monospecific direct antiglobulin test is considered mandatory in the diagnostic workup, and any causes of secondary AIHA have to be diagnosed. Corticosteroids remain first-line therapy for warm-AIHA, while the addition of rituximab should be considered early in severe cases and if no prompt response to steroids is achieved. Rituximab with or without bendamustine should be used in the first line for patients with cold agglutinin disease requiring therapy. We identified a need to establish an international AIHA network. Future recommendations should be based on prospective clinical trials whenever possible

The prevention of glucocorticoid‐induced osteoporosis in patients with immune thrombocytopenia receiving steroids:a British Society for Haematology Good Practice Paper

Methodology This Good Practice Paper was compiled according to the British Society for Haematology (BSH) process at http://www.b-s-h.org.uk/guidelines/proposing-and-writing-a-new-bsh-guideline/. The BSH produces Good Practice Papers to recommend good practice in areas where there is a limited evidence base but for which a degree of consensus or uniformity is likely to be beneficial to patient care. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org

Trial protocol: a multicentre randomised trial of first-line treatment pathways for newly diagnosed immune thrombocytopenia: standard steroid treatment versus combined steroid and mycophenolate. The FLIGHT trial

Introduction Immune thrombocytopenia (ITP) is an autoimmune condition that may cause thrombocytopenia-related bleeding. Current first-line ITP treatment is with high-dose corticosteroids but frequent side effects, heterogeneous responses and high relapse rates are significant problems with only 20% remaining in sustained remission with this approach. Mycophenolate mofetil (MMF) is often used as the next treatment with efficacy in 50%–80% of patients and good tolerability but can take up to 2 months to work. Objective To test the hypothesis that MMF combined with corticosteroid is a more effective first-line treatment for immune thrombocytopenia (ITP) than current standard of corticosteroid alone. Design Multicentre, UK-based, open-label, randomised controlled trial. Setting Haematology departments in secondary care. Participants We plan to recruit 120 patients >16 years old with a diagnosis of ITP and a platelet count <30x109/L who require first-line treatment. Patients will be followed up for a minimum of 12 months following randomisation. Primary outcome Time from randomisation to treatment failure defined as platelets <30x109/L and a need for second-line treatment. Secondary outcomes Side effects, bleeding events, remission rates, time to relapse, time to next therapy, cumulative corticosteroid dose, rescue therapy, splenectomy, socioeconomic costs, patient-reported outcomes (quality of life, fatigue, impact of bleeding, care costs). Analysis The sample size of 120 achieves a 91.5% power to detect a doubling of the median time to treatment failure from 5 to 10 months. This will be expressed as an HR with 95% CI, median time to event if more than 50% have had an event and illustrated with Kaplan-Meier curves. Cost-effectiveness will be based on the first 12 months from diagnosis

Influence of neutropenia on mortality of critically ill cancer patients : results of a meta-analysis on individual data

Background: The study objective was to assess the influence of neutropenia on outcome of critically ill cancer patients by meta-analysis of individual data. Secondary objectives were to assess the influence of neutropenia on outcome of critically ill patients in prespecified subgroups (according to underlying tumor, period of admission, need for mechanical ventilation and use of granulocyte colony stimulating factor (G-CSF)). Methods: Data sources were PubMed and the Cochrane database. Study selection included articles focusing on critically ill cancer patients published in English and studies in humans from May 2005 to May 2015. For study selection, the study eligibility was assessed by two investigators. Individual data from selected studies were obtained from corresponding authors. Results: Overall, 114 studies were identified and authors of 30 studies (26.3% of selected studies) agreed to participate in this study. Of the 7515 included patients, three were excluded due to a missing major variable (neutropenia or mortality) leading to analysis of 7512 patients, including 1702 neutropenic patients (22.6%). After adjustment for confounders, and taking study effect into account, neutropenia was independently associated with mortality (OR 1.41; 95% CI 1.23-1.62; P = 0.03). When analyzed separately, neither admission period, underlying malignancy nor need for mechanical ventilation modified the prognostic influence of neutropenia on outcome. However, among patients for whom data on G-CSF administration were available (n = 1949; 25.9%), neutropenia was no longer associated with outcome in patients receiving G-CSF (OR 1.03; 95% CI 0.70-1.51; P = 0.90). Conclusion: Among 7512 critically ill cancer patients included in this systematic review, neutropenia was independently associated with poor outcome despite a meaningful survival. Neutropenia was no longer significantly associated with outcome in patients treated by G-CSF, which may suggest a beneficial effect of G-CSF in neutropenic critically ill cancer patients

Comorbid anxiety-like behavior in a rat model of colitis is mediated by an upregulation of corticolimbic fatty acid amide hydrolase

Peripheral inflammatory conditions, including those localized to the gastrointestinal tract, are highly comorbid with psychiatric disorders such as anxiety and depression. These behavioral symptoms are poorly managed by conventional treatments for inflammatory diseases and contribute to quality of life impairments. Peripheral inflammation is associated with sustained elevations in circulating glucocorticoid hormones, which can modulate central processes, including those involved in the regulation of emotional behavior. The endocannabinoid (eCB) system is exquisitely sensitive to these hormonal changes and is a significant regulator of emotional behavior. The impact of peripheral inflammation on central eCB function, and whether this is related to the development of these behavioral comorbidities remains to be determined. To examine this, we employed the trinitrobenzene sulfonic acid-induced model of colonic inflammation (colitis) in adult, male, Sprague Dawley rats to produce sustained peripheral inflammation. Colitis produced increases in behavioral measures of anxiety and elevations in circulating corticosterone. These alterations were accompanied by elevated hydrolytic activity of the enzyme fatty acid amide hydrolase (FAAH), which hydrolyzes the eCB anandamide (AEA), throughout multiple corticolimbic brain regions. This elevation of FAAH activity was associated with broad reductions in the content of AEA, whose decline was driven by central corticotropin releasing factor type 1 receptor signaling. Colitis-induced anxiety was reversed following acute central inhibition of FAAH, suggesting that the reductions in AEA produced by colitis contributed to the generation of anxiety. These data provide a novel perspective for the pharmacological management of psychiatric comorbidities of chronic inflammatory conditions through modulation of eCB signaling

Daratumumab monotherapy in refractory warm autoimmune hemolytic anemia and cold agglutinin disease

Autoimmune hemolytic anemia (AIHA) is a rare autoantibody-mediated disease. For steroid and/or rituximab-refractory AIHA, there is no consensus on optimal treatment. Daratumumab, a monoclonal antibody targeting CD38, could be beneficial by suppression of CD38+ plasma cells and thus autoantibody secretion. In addition, because CD38 is also expressed by activated T cells, daratumumab may also act via immunomodulatory effects. We evaluated the efficacy and safety of daratumumab monotherapy in an international retrospective study including 19 adult patients with heavily pretreated refractory AIHA. In warm AIHA (wAIHA, n = 12), overall response was 50% with a median response duration of 5.5 months (range, 2-12), including ongoing response in 2 patients after 6 and 12 months. Of 6 nonresponders, 4 had Evans syndrome. In cold AIHA (cAIHA, n = 7) overall hemoglobin (Hb) response was 57%, with ongoing response in 3 of 7 patients. One additional patient with nonanemic cAIHA was treated for severe acrocyanosis and reached a clinical acrocyanosis response as well as a Hb increase. Of 6 patients with cAIHA with acrocyanosis, 4 had improved symptoms after daratumumab treatment. In 2 patients with wAIHA treated with daratumumab, in whom we prospectively collected blood samples, we found complete CD38+ T-cell depletion after daratumumab, as well as altered T-cell subset differentiation and a severely diminished capacity for cell activation and proliferation. Reappearance of CD38+ T cells coincided with disease relapse in 1 patient. In conclusion, our data show that daratumumab therapy may be a treatment option for refractory AIHA. The observed immunomodulatory effects that may contribute to the clinical response deserve further exploration.</p

CO2/pH-responsive particles with built-in fluorescence read-out

yesA novel fluorescent monomer was synthesized to probe the state of CO2-responsive cross-linked polymeric particles. The fluorescent emission of this aminobromomaleimide-bearing monomer, being sensitive to protic environments, can provide information on the core hydrophilicity of the particles and therefore indicates the swollen state and size of the particles. The particles’ core, synthesized from DEAEMA (N,N-diethylaminoethyl methacrylate), is responsive to CO2 through protonation of the tertiary amines of DEAEMA. The response is reversible and the fluorescence emission can be recovered by simply bubbling nitrogen into the particle solution. Alternate purges of CO2 and N2 into the particles’ solution allow several ON/OFF fluorescence emission cycles and simultaneous particle swelling/shrinking cycles.British Petroleum Company (BP), Engineering and Physical Sciences Research Council (EPSRC

Rare-metal granites as a potential source of critical metals: A geometallurgical case study

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordBecause of their low grades in critical metals such as Light Rare Earth Elements (LREE) or Sn, rare-metal granites are not considered as economic for metal recovery but, when altered, they are often exploited for their industrial minerals. The St Austell rare-metal granite is well known for its world-class kaolin deposits which formed as a result of the extensive weathering and alteration of the underlying granite. The St Austell granite body is composed of several granite components, each having its own accessory minerals assemblage. As a result of the kaolinisation process, some metal-bearing accessory minerals of the granite, such as monazite (LREE) or cassiterite (Sn), are partially liberated from the gangue which allow their pre-concentration in the micaceous residue which is considered as a potential source for critical metals recovery. Similarities with other similar rare-metal granites suggest that topaz granite is the most prospective for disseminated magmatic Sn-Nb-Ta-REE mineralization. However, comparison of the potentiality of 3 granite types i.e., biotite, topaz and tourmaline granites suggest that biotite granites is actually the most prospective due to higher degree of kaolinisation of the biotite granite which favour pre-concentration of its accessory mineral in the micaceous residue. In order to develop a geometallurgical framework for extraction of kaolin and metals from the selected granite component, a field sampling campaign is performed. Core samples are processed in the laboratory using a characterisation program that mimics the full-scale kaolin refining route. Two main products are recovered through this program, viz. MR180 (−180 +53 µm) and P5 (−5 µm), which correspond to a fine micaceous residue and a fine kaolin product respectively. These products are both analysed routinely for major and minor trace elements by XRF and yields are recorded to indicate process performance. A selected number of MR180 samples are also being characterised in terms of particle size by laser light scattering, geochemistry by ICP-MS, and mineralogy by QEMSCAN®. Comparison of characterisation results of MR180 samples and corresponding industrial residue samples shows a good correlation, suggesting that sample analyses are representative for the in-situ deposit and the processing behaviour. Monazite is found to be either fully liberated or fully locked from one sample to the other. Next, pilot-scale gravity concentration tests are performed on micaceous residue samples. Characterisation of the processing products shows that monazite lost in the tailings is mostly locked within tourmaline or micas and is fine grained. Then, predictive regression models for spiral separation performance in terms of recovery, product grade and enrichment as a function of the feed grade are developed for MR180 LREE grade data. Finally, kaolin resources can be classified using quantitative indicators such as yield of the P5 product and the iron oxides content which provides insight into the kaolin quality in terms of whiteness. This geometallurgical classification can be used to delineate zones of interest within the deposit. Although kaolin quality and recovery primarily inform extraction planning, zones which are also of interest for metal recovery can be identified. The proposed model predicts whether the expected LREE grade and recovery satisfy the by-product requirements.European CommissionNatural Environment Research Council (NERC)French National Research Agenc