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1.
Environ Geochem Health ; 46(3): 81, 2024 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-38367190

RESUMO

This study presents an environmentally sustainable method for minimizing sludge production in the textile effluent sector through the combined application of electrokinetic (EK) and electrooxidation (EO) processes. AAS and XRF analyses reveal that utilizing acidic electrolytes in the EK method successfully eliminates heavy metals (Cu, Mn, Zn, and Cr) from sludge, demonstrating superior efficiency compared to alkaline conditions. In addition, the total removal efficiency of COD contents was calculated following the order of EK-3 (60%), EK-1 (51%) and EK-2 (34%). Notably, EK-3, leveraging pH gradient fluctuations induced by anolyte in the catholyte reservoir, outperforms other EK systems in removing COD from sludge. The EK process is complemented by the EO process, leading to further degradation of dye and other organic components through the electrochemical generation of hypochlorite (940 ppm). At an alkaline pH of 10.0, the color and COD removal were effectively achieved at 98 and 70% in EO treatment, compared to other mediums. In addition, GC-MS identified N-derivative residues at the end of the EO. This study demonstrates an integrated approach that effectively eliminates heavy metals and COD from textile sludge, combining EK with EO techniques.


Assuntos
Metais Pesados , Esgotos , Esgotos/química , Metais Pesados/análise , Têxteis
2.
FASEB J ; 36(3): e22196, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35137455

RESUMO

Parathyroid hormone (PTH) signaling downstream of the PTH 1 receptor (Pth1r) results in both bone anabolic and catabolic actions by mechanisms not yet fully understood. In this study, we show that Pth1r signaling upregulates the expression of several components of the Notch pathway and that Notch signals contribute to the catabolic actions of PTH in bone. We found that constitutive genetic activation of PTH receptor signaling in osteocytes (caPth1rOt ) or treatment with PTH daily increased the expression of several Notch ligands/receptors in bone. In contrast, sustained elevation of endogenous PTH did not change Notch components expression. Deletion of the PTH receptor or sclerostin overexpression in osteocytes abolished Notch increases by PTH. Further, deleting the canonical Notch transcription factor Rbpjk in osteocytes decreased bone mass and increased resorption and Rankl expression in caPth1rOt mice. Moreover, pharmacological bone-targeted Notch inhibition potentiated the bone mass gain induced by intermittent PTH by reducing bone resorption and preserving bone formation. Thus, Notch activation lies downstream of anabolic signaling driven by PTH actions in osteocytes, and Notch pharmacological inhibition maximizes the bone anabolic effects of PTH.


Assuntos
Reabsorção Óssea/metabolismo , Osteogênese , Hormônio Paratireóideo/metabolismo , Receptores Notch/metabolismo , Animais , Reabsorção Óssea/genética , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Osteócitos/metabolismo , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Receptores Notch/genética , Transdução de Sinais
3.
Analyst ; 145(13): 4532-4539, 2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-32420579

RESUMO

This work addresses the synthetic optimization of carbon dots (CDs) and their application in sensing picric acid from latent fingerprints by exploiting a smartphone-based RGB tool. The optimization of the synthesis of CDs is investigated towards achieving shorter reaction time, better product yield and fluorescence quantum efficiency. Precursors such as citric acid and thiourea were chosen for the synthesis of CDs. Among the various synthetic methodologies, it is found that the pyrolysis method offers ∼50% product yield within 15 min. The morphology and optical properties of the prepared CDs are characterized using the typical microscopic and spectroscopic techniques, respectively. The synthesized CDs exhibit quasi-spherical shape with an average particle size of 1.7 nm. The excitation dependent emissive properties of CDs are investigated by time resolved fluorescence spectroscopy. Furthermore, the excellent fluorescence properties (φ = 11%) of CDs are explored as a fluorescent fingerprint powder for the identification of latent fingerprints on various substrates. In addition, the presence of picric acid in latent fingerprints was detected. Furthermore, this study is extended to perform real time detection of fingerprints and harmful contaminants in fingerprints by utilizing a smartphone-based RGB color analysis tool. Based on these investigations, the prepared CDs could be a prospective fluorescent material in the field of forensics.

4.
Phys Chem Chem Phys ; 19(4): 3125-3135, 2017 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-28083594

RESUMO

Pyrene derivatives show immense potential as sensitizers for dye-sensitized solar cells (DSCs). Therefore, this work focuses on the impact of π-spacers on the photophysical, electrochemical and photovoltaic properties of pyrene based D-π-A dyes, since the insertion of π-spacers is one of the doable strategies to improve the light harvesting properties of the dye. In this respect, three new pyrene based D-π-A dyes have been synthesized and characterized by 1H, 13C NMR, and elemental analyses and EI-MS spectrometry. The selected π-spacers are benzene, thiophene and furan. Compared with a benzene spacer, the introduction of a heterocyclic ring spacer reduces the band gap of the dye and brings about the broadening of the absorption spectra to the longer wavelength region through intramolecular charge-transfer (ICT). Combined experimental and theoretical studies were performed to investigate the ICT process involved in the pyrene derivatives. The profound solvatochromism with increased nonradiative rate constants (knr) has been construed in terms of ICT from the pyrene core to rhodanine-3-acetic acid via conjugated π-spacers. Electrochemical data also reveal that the HOMO and LUMO energy levels are fine-tuned by incorporating different π-spacers between pyrene and rhodanine-3-acetic acid. On the basis of the optimized DSC test conditions, the best performance was found for PBRA, in which a benzene group is the conjugated π-spacer. The divergence in the photovoltaic behaviors of these dyes was further explicated by femtosecond fluorescence and electrochemical impedance spectroscopy.

5.
Phys Chem Chem Phys ; 18(19): 13332-45, 2016 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-27121202

RESUMO

Anchoring groups play an important role in dye sensitized solar cells (DSCs). In order to acquire a suitable anchoring group for DSCs, a deeper understanding of the effect of anchoring groups on the ground and excited state properties of the dye is significant. In this context, various anchoring group connected pyrene derivatives are successfully synthesized and well characterized by using (1)H, (13)C-NMR, FT-IR and EI-MS spectrometry. The anchoring groups employed are carboxylic acid, malonic acid, acrylic acid, malononitrile, cyanoacrylic acid, rhodanine and rhodanine-3-acetic acid. The optimized geometries, HOMO-LUMO energy gap, light harvesting efficiency (LHE) and electronic absorption spectra of these dyes are studied by using density functional theory (DFT) calculations. The results show that pyrene connected with anchoring groups with weak electron pulling strength (PC, PAC and PMC) has a larger HOMO-LUMO energy gap, whereas that connected with anchoring groups with strong electron pulling strength (PCC, PMN, PR and PRA) has a reduced HOMO-LUMO energy gap. These molecules with a reduced energy gap are primarily preferred for DSC applications. Moreover, P, PC, PAC and PMC molecules undergo π→π* transition, whereas PCC, PMN, PR and PRA molecules show significant charge transfer along with π→π* transition. UV-visible absorption spectral studies on these dyes reveal that connecting various anchoring groups with different electron pulling abilities enables the pyrene chromophore to absorb in the longer wavelength region. Notably, an efficient bathochromic shift is observed for PCC, PMN, PR and PRA molecules in both electronic absorption and fluorescence spectral measurements, which suggests that the excitation is delocalized throughout the entire π-system of the molecules. Both theoretical and spectral studies reveal that dyes with an ICT character (PCC, PMN, PR and PRA) are suitable for dye sensitized solar cell applications.

6.
Phys Chem Chem Phys ; 17(43): 28647-57, 2015 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-26444694

RESUMO

An electron rich donor moiety plays an important role in dye sensitized solar cells (DSCs). In order to attain a suitable donor moiety for DSCs, a deeper understanding of the role of a donor moiety in the dye excited state is significant. In this context, different arylamine dye-based electron donor moieties (TRA, CRA and PyRA) were successfully synthesized and well characterized using (1)H-NMR, (13)C-NMR and EI-MS spectrometry. Their photophysical properties and solvatochromic behavior were studied using UV-visible absorption, steady state and time resolved fluorescence spectroscopic techniques. The absorption of arylamine dyes is due to intramolecular charge transfer (ICT) between the donor and rhodanine-3-acetic acid via a π-bridge, which is further confirmed by DFT calculations. Lippert-Mataga analysis on the solvatochromic data implies that these molecules are more polar in the excited state, which is additional support for ICT. Furthermore, nanocrystalline TiO2-based dye sensitized solar cells (DSCs) were fabricated using these dyes to investigate the influence of donor moieties on their photovoltaic performance. The overall power conversion efficiencies of 2.57%, 1.68% and 1.25% were obtained for the TRA, PyRA and CRA dyes, respectively. The enhanced power conversion efficiency of TRA is due to a longer lifetime of injected electrons as demonstrated by the electrochemical impedance spectroscopy (EIS) measurements.

7.
Spectrochim Acta A Mol Biomol Spectrosc ; 316: 124286, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-38663135

RESUMO

A simple single step one pot multicomponent reaction was performed to synthesize N-(tert-butyl)-2-(furan-2-yl)imidazo[1,2-a]pyridine-3-amine (TBFIPA). The synthesized TBFIPA was subjected to library of cations to study its ability for selective and sensitive detection of specific metal ions. Selective detection of chromium ions by TBFIPA were found from the significant hypsochromic shift (335 nm â†’ 285 nm) in the UV-Visible spectra. The fluorescent TBFIPA displays complete quenching of fluorescence under UV lamp (365 nm) only in the presence of chromium without the interference of common metal ions. Binding constant (ka) obtained from Benesi-Hildebrand plot is 0.21 × 105 M-1, limit of detection (LOD) and limit of quantification (LOQ) of TBFIPA toward Cr3+ ions are 4.70 × 10-7 M and 1.56 × 10-7 M, respectively. The mechanism proposed during complex formation were supported by stoichiometric Job continuous variation plot, 1H NMR titration and ESI-MS spectroscopic data. All the experimental confirmation for complex formation were corroborated with theoretical DFT studies optimized using RB3LYP/6-31G(d) basis set. The selectivity and sensitivity of TBFIPA toward Cr3+ ions are found suitable to design a user-friendly silica based portable test kit. Alongside, TBFIPA was successfully utilized for imaging onion epidermal cells. Furthermore, the results obtained for biological, environmental, and industrial samples provided solid evidence to estimate chromium ions using TBFIPA in these real samples.


Assuntos
Cromo , Corantes Fluorescentes , Limite de Detecção , Espectrometria de Fluorescência , Cromo/análise , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Espectrometria de Fluorescência/métodos , Cebolas/química , Piridinas/química , Espectrofotometria Ultravioleta , Íons/análise
8.
Res Sq ; 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38746138

RESUMO

Osteoporosis is incurable because there are no dual antiresorptive and anabolic therapeutic agents that can be administered long-term. The most widely used antiresorptive agents, bisphosphonates (BPs), also inhibit bone formation and thus have limited effect in preventing osteoporotic fracture. Hydroxychloroquine (HCQ), which is used to treat rheumatoid arthritis, prevents the lysosomal degradation of TNF receptor-associated factor 3 (TRAF3), an NF-κB adaptor protein that limits bone resorption and maintains bone formation. We attempted to covalently link HCQ to a hydroxyalklyl BP (HABP) with anticipated low antiresorptive activity, to target delivery of HCQ to bone to test if this targeting increases its efficacy to prevent TRAF3 degradation in the bone microenvironment and thus reduce bone resorption and increase bone formation, while reducing its systemic side effects. Unexpectedly, HABP-HCQ was found to exist as a salt in aqueous solution, composed of a protonated HCQ cation and a deprotonated HABP anion. Nevertheless, it inhibited osteoclastogenesis, stimulated osteoblast differentiation, and increased TRAF3 protein levels in vitro. HABP-HCQ significantly inhibited both osteoclast formation and bone marrow fibrosis in mice given multiple daily PTH injections. In contrast, HCQ inhibited fibrosis, but not osteoclast formation, while the HABP alone inhibited osteoclast formation, but not fibrosis, in the mice. HABP-HCQ, but not HCQ, prevented trabecular bone loss following ovariectomy in mice and, importantly, increased bone volume in ovariectomized mice with established bone loss because HABP-HCQ increased bone formation and decreased bone resorption parameters simultaneously. In contrast, HCQ increased bone formation, but did not decrease bone resorption parameters, while HABP also restored the bone lost in ovariectomized mice, but it inhibited parameters of both bone resorption and formation. Our findings suggest that the combination of HABP and HCQ could have dual antiresorptive and anabolic effects to prevent and treat osteoporosis.

9.
Chemosphere ; 323: 138263, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36858116

RESUMO

Green synthesis of nanomaterials has emerged as an ecofriendly sustainable technology for the removal of dyes in the last few decades. Especially, plant leaf extracts have been considered as inexpensive and effective materials for the synthesis of nanoparticles. In this study, zinc oxide nanoparticles (ZnO NPs) were prepared using leaves extract of Brassica oleracea var. botrytis (BO) by co-precipitation and applied for photocatalytic/antibacterial activity. The synthesized BO-ZnO NPs was characterized by different instrumental techniques. The UV-vis Spectrum of the synthesized material showed maximum absorbance at a wavelength of 311 nm, which confirmed the formation of BO-ZnO NPs. The XRD pattern of BO-ZnO NPs represents a hexagonal wurtzite structure and the average size of particles was about 52 nm. FT-IR spectrum analysis confirms the presence of hydroxyl, carbonyl, carboxylic, and phenol groups. SEM images exhibited a flower like morphology and EDX spectrum confirming the presence of the elements Zn and O. Photo-catalytic activity of BO-ZnO NPs was tested against thiazine dye (methylene blue-MB) degradation under direct sunlight irradiation. Around 80% of the MB dye got degraded at pH 8 under 75 min of sunlight irradiation. Further, the study examined that the antimicrobial and larvicidal activity of BO-ZnO NPs obtained through green synthesis. The antimicrobial study results showed that the BO-ZnO NPs formed zones against bacterial pathogens. The results showed the formation of an inhibition zone against B. subtills (16 mm), S.aureus (13 mm), K. pneumonia (13 mm), and E. coli (9 mm) respectively at a concentration of 100 µg/mL of BO-ZnO NPs. The larvicidal activity of the BO-ZnO NPs was tested against the fourth instar of Culex quinquefasciatus mosquito larvae The LC50 and LC90 values estimated through the larvicidal activity of BO-ZnO NPs were 76.03, 190.03 ppm respectively. Hence the above findings propose the synthesized BO-ZnO NPs by the ecofriendly method can be used for various environmental and antipathogenic applications.


Assuntos
Anti-Infecciosos , Brassica , Nanopartículas Metálicas , Óxido de Zinco , Animais , Óxido de Zinco/farmacologia , Óxido de Zinco/química , Botrytis , Espectroscopia de Infravermelho com Transformada de Fourier , Escherichia coli , Nanopartículas Metálicas/toxicidade , Nanopartículas Metálicas/química , Anti-Infecciosos/farmacologia , Antibacterianos/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química
10.
Food Funct ; 12(11): 5038-5050, 2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-33960359

RESUMO

Rheumatoid Arthritis (RA) is an autoimmune disease that commences as inflammation and progressively destroys the articular joint. In this study, we assess the anti-rheumatic potential of the monoterpenoid class of thymol conjugated with Carbon Dots (CDs). Waste biomass in the form of dried rose petals was chosen as a precursor for the synthesis of CDs via a one-step hydrothermal bottom-up methodology. The prepared CDs exhibited absorption in the near-visible region, and unique excitation-dependent emission behaviour was confirmed from UV-Visible and fluorescence measurements. The surface morphology of CDs was confirmed by SEM and HR-TEM analysis to be quasi-spherical particles with an average size of ∼5-6 nm. The presence of various functional moieties (hydroxyl, carbonyl, and amino) was confirmed via FT-IR measurement. The graphitization of CDs was confirmed by the D and G bands for sp2 and sp3 hybridization, respectively, through Raman analysis. Esterification methodology was adopted to prepare the CDs-thymol conjugate and confirmed via FT-IR analysis. CDs play the role of a nanocarrier for thymol, an anti-arthritic agent. The bioactive compound of thymol showed potent anti-arthritic activity against RA targets through in silico docking studies. Further, the in vivo studies revealed that CDs-thymol conjugates (10 mg per kg body weight) showed a significant reduction in rat paw volume along with reduced levels of RF and CRP (2.23 ± 0.42 IU ml-1 and 16.96 ± 0.22 mg ml-1) when compared to the disease control rats. X-ray radiography and ultrasonic imaging revealed less bone destruction, joint derangement, and swelling in arthritis-induced Wistar rats. They could also potentially improve the Hb (14.14 ± 0.19), RBC (6.01 ± 0.11), PCV (6.01 ± 0.11) levels and elevate the status of antioxidant enzymes (GPx, SOD, MDA), and the activity was comparable to the standard drug, ibuprofen (10 mg kg-1), suggesting that the CDs-thymol conjugate at 10 mg kg-1 could act as a strong anti-arthritic agent. This work is evidence for the utilization of waste biomass as a value-added product such as a nanocarrier for biomedical applications.


Assuntos
Antirreumáticos/química , Antirreumáticos/farmacologia , Carbono/química , Pontos Quânticos , Timol/química , Animais , Antioxidantes , Artrite Reumatoide/tratamento farmacológico , Feminino , Interleucinas/química , Metaloproteinase 1 da Matriz/química , Metaloproteinase 3 da Matriz/química , Simulação de Acoplamento Molecular , Ratos , Ratos Wistar , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/química , Espectroscopia de Infravermelho com Transformada de Fourier , Fator de Crescimento Transformador beta/química
11.
Br J Pharmacol ; 178(9): 2008-2025, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32876338

RESUMO

Advances in the design of potential bone-selective drugs for the treatment of various bone-related diseases are creating exciting new directions for multiple unmet medical needs. For bone-related cancers, off-target/non-bone toxicities with current drugs represent a significant barrier to the quality of life of affected patients. For bone infections and osteomyelitis, bacterial biofilms on infected bones limit the efficacy of antibiotics because it is hard to access the bacteria with current approaches. Promising new experimental approaches to therapy, based on bone-targeting of drugs, have been used in animal models of these conditions and demonstrate improved efficacy and safety. The success of these drug-design strategies bodes well for the development of therapies with improved efficacy for the treatment of diseases affecting the skeleton. LINKED ARTICLES: This article is part of a themed issue on The molecular pharmacology of bone and cancer-related bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc.


Assuntos
Difosfonatos , Preparações Farmacêuticas , Animais , Bactérias , Biofilmes , Humanos , Qualidade de Vida
12.
Spectrochim Acta A Mol Biomol Spectrosc ; 221: 117150, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31176291

RESUMO

Herein, we have meticulously derived the nanosized fluorescent aggregates from pyrene Schiff base (PS) in DMSO:water (10:90) ratio. The aggregation property of PS molecule was characterized by SEM and TEM measurements, revealed the aggregated particles are in spherical shape with ~3 nm in size. Moreover, aggregates exhibit a high fluorescence quantum yield (48%) which was effectively used for the in vitro bioimaging of two different cancer cells such as A549 and MCF-7 cells in which it exhibiting excellent biocompatibility. Further, it was estimated the capability of twofold acridine orange/ethidium bromide (AO/EB) staining to identify the apoptotic associated changes in cancer cells. Additionally, the aggregates were successfully demonstrated as a luminescent probe for the perceptive biomolecule detection of bilirubin. On the other hand, the PS molecule was successfully utilized for protein binding and metal ion sensing studies. The interaction of bovine serum albumin (BSA) with PS molecule in DMSO was using fluorescence spectroscopic method and nature of interaction was also confirmed through molecular docking analysis. The PS molecule also acts as an excellent sensor for biologically important Fe3+ ion with detection limit of 336 nM. Overall, PS molecule can be a prospective material in biological field both in solution as well as aggregated forms.


Assuntos
Bilirrubina/análise , Corantes Fluorescentes/química , Ferro/análise , Pirenos/química , Soroalbumina Bovina/metabolismo , Células A549 , Laranja de Acridina , Sobrevivência Celular/efeitos dos fármacos , Etídio , Corantes Fluorescentes/toxicidade , Humanos , Limite de Detecção , Células MCF-7 , Simulação de Acoplamento Molecular , Imagem Molecular/métodos , Nanoestruturas/química , Nanoestruturas/toxicidade , Tamanho da Partícula , Bases de Schiff/química , Soroalbumina Bovina/química , Espectrometria de Fluorescência
13.
ACS Omega ; 3(8): 9096-9104, 2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31459044

RESUMO

Herein, we report the preparation of graphene oxide dots (GO dots) by fine-tuning the carbonization degree of citric acid. The structure of GO dots was characterized by absorption spectroscopy, Fourier transform infrared spectroscopy, Raman spectroscopy, as well as high-resolution scanning electron microscopy and transmission electron microscopy analyses. The typical particle size of the GO dots was 42 nm. The fluorescent characteristics of the GO dots were analyzed by fluorescence spectroscopy. Once excited at 360 nm, the GO dots were fluorescent in the range of 450-550 nm, which was dependent on the excitation wavelength. Further, GO dots were effectively utilized for multifarious applications such as photoinduced electron transfer and detection of explosives and biomolecules. The emission property of GO dots was competently quenched by viologens, picric acid (PA), and bilirubin (BR). The mechanism of quenching by viologens and explosives/biomolecules was found to be due to photoinduced electron transfer and the internal filter effect, respectively. Intriguingly, the detection minimum of PA is in the nanomolar level. Toward commercialization, the economic test strips have also been introduced for the identification of PA. Furthermore, the GO dots have been applied as an efficient luminescent bioprobe for a selective and perceptive finding of BR.

15.
J Cachexia Sarcopenia Muscle ; 2(4): 201-207, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22207908

RESUMO

AIMS: Cachexia, the wasting disorder associated with a wide range of serious illnesses including cancer, is a major cause of morbidity and mortality. There is currently no widely approved therapeutic agent for treating or preventing cancer-associated cachexia. Colorectal cancer and non-small cell lung cancer have relatively high incidences of cachexia, approximately 28% and 34%, respectively. Neurohormonal overactivity has been implicated in the genesis and progression of cachexia and beta receptor antagonism has been proposed as a potential therapy. MT-102, a novel anabolic/catabolic transforming agent, has a multi-functional effect upon three potential pharmacological targets in cancer cachexia, namely reduced catabolism through non-selective ß-blockade, reduced fatigue, and thermogenesis through central 5-HT1a antagonism and increased anabolism through partial ß-2 receptor agonism. METHODS: At least 132 male and female patients, aged between 25 and 80 years with a confirmed diagnosis of late-stage non-small cell lung cancer or colorectal cancer, with cachexia will be randomised to either one of the two MT-102 doses or placebo in a 3:1:2 ratio (MT-102 10 mg BD(-1)/MT-102 2.5 mg BD/placebo). Patients will continue on study treatment for maximally 16 weeks. The primary endpoint, to be analysed by assigned treatment group, will be body weight change over 16 weeks. For this endpoint, the study has 85% power (0.05% significance level) to detect per 4-week period a mean change of -0.8 kg in the placebo group and 0 kg in the high-dose MT-102 arm. The first patient was randomised in February 2011 and patient recruitment is expected to continue until mid-2012. PERSPECTIVE: The ACT-ONE trial is designed to test whether the anabolic/catabolic transforming agent MT-102 will positively impact on the rate of change of body weight in cancer cachexia, thereby evaluating a novel therapeutic strategy in this hitherto poorly treatable condition. A separate ACT-TWO trial will recruit patients who complete the ACT-ONE trial and remain on randomised double-blind medication. Participants in ACT-TWO will be followed for an additional period with a separate primary endpoint.

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