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1.
Nature ; 614(7949): 659-663, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36623548

RESUMO

Transmission spectroscopy1-3 of exoplanets has revealed signatures of water vapour, aerosols and alkali metals in a few dozen exoplanet atmospheres4,5. However, these previous inferences with the Hubble and Spitzer Space Telescopes were hindered by the observations' relatively narrow wavelength range and spectral resolving power, which precluded the unambiguous identification of other chemical species-in particular the primary carbon-bearing molecules6,7. Here we report a broad-wavelength 0.5-5.5 µm atmospheric transmission spectrum of WASP-39b8, a 1,200 K, roughly Saturn-mass, Jupiter-radius exoplanet, measured with the JWST NIRSpec's PRISM mode9 as part of the JWST Transiting Exoplanet Community Early Release Science Team Program10-12. We robustly detect several chemical species at high significance, including Na (19σ), H2O (33σ), CO2 (28σ) and CO (7σ). The non-detection of CH4, combined with a strong CO2 feature, favours atmospheric models with a super-solar atmospheric metallicity. An unanticipated absorption feature at 4 µm is best explained by SO2 (2.7σ), which could be a tracer of atmospheric photochemistry. These observations demonstrate JWST's sensitivity to a rich diversity of exoplanet compositions and chemical processes.

2.
J Neurosci ; 41(4): 578-593, 2021 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-33262245

RESUMO

The dynamic regulation of DNA methylation in postmitotic neurons is necessary for memory formation and other adaptive behaviors. Ten-eleven translocation 1 (TET1) plays a part in these processes by oxidizing 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), thereby initiating active DNA demethylation. However, attempts to pinpoint its exact role in the nervous system have been hindered by contradictory findings, perhaps due in part, to a recent discovery that two isoforms of the Tet1 gene are differentially expressed from early development into adulthood. Here, we demonstrate that both the shorter transcript (Tet1S ) encoding an N-terminally truncated TET1 protein and a full-length Tet1 (Tet1FL ) transcript encoding canonical TET1 are co-expressed in the adult mouse brain. We show that Tet1S is the predominantly expressed isoform and is highly enriched in neurons, whereas Tet1FL is generally expressed at lower levels and more abundant in glia, suggesting their roles are at least partially cell type-specific. Using viral-mediated, isoform and neuron-specific molecular tools, we find that the individual repression of each transcript leads to the dysregulation of unique gene ensembles and contrasting changes in basal synaptic transmission. In addition, Tet1S repression enhances, while Tet1FL impairs, hippocampal-dependent memory in male mice. Together, our findings demonstrate that each Tet1 isoform serves a distinct role in the mammalian brain.SIGNIFICANCE STATEMENT In the brain, activity-dependent changes in gene expression are required for the formation of long-term memories. DNA methylation plays an essential role in orchestrating these learning-induced transcriptional programs by influencing chromatin accessibility and transcription factor binding. Once thought of as a stable epigenetic mark, DNA methylation is now known to be impermanent and dynamically regulated, driving neuroplasticity in the brain. We found that Tet1, a member of the ten-eleven translocation (TET) family of enzymes that mediates removal of DNA methyl marks, is expressed as two separate isoforms in the adult mouse brain and that each differentially regulates gene expression, synaptic transmission and memory formation. Together, our findings demonstrate that each Tet1 isoform serves a distinct role in the CNS.


Assuntos
Encéfalo/fisiologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Regulação da Expressão Gênica/genética , Memória/fisiologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/fisiologia , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia , Animais , Ansiedade/genética , Ansiedade/psicologia , Condicionamento Clássico , Epigênese Genética/fisiologia , Medo/psicologia , Hipocampo/fisiologia , Isomerismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuroglia/fisiologia , Neurônios/fisiologia
3.
Phys Rev Lett ; 129(18): 182501, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36374671

RESUMO

We present the first measurement of dihadron angular correlations in electron-nucleus scattering. The data were taken with the CLAS detector and a 5.0 GeV electron beam incident on deuterium, carbon, iron, and lead targets. Relative to deuterium, the nuclear yields of charged-pion pairs show a strong suppression for azimuthally opposite pairs, no suppression for azimuthally nearby pairs, and an enhancement of pairs with large invariant mass. These effects grow with increased nuclear size. The data are qualitatively described by the gibuu model, which suggests that hadrons form near the nuclear surface and undergo multiple scattering in nuclei.These results show that angular correlation studies can open a new way to elucidate how hadrons form and interact inside nuclei.

5.
Ann Oncol ; 30(4): 567-574, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30689703

RESUMO

BACKGROUND: We report longitudinal health-related quality-of-life (HRQoL) data from the international, randomized, double-blind, placebo-controlled phase III ExteNET study, which demonstrated an invasive disease-free survival benefit of extended adjuvant therapy with neratinib over placebo in human epidermal growth factor receptor-2-positive early-stage breast cancer. PATIENTS AND METHODS: Women (N = 2840) with early-stage HER2-positive breast cancer who had completed trastuzumab-based adjuvant therapy were randomly assigned to neratinib 240 mg/day or placebo for 12 months. HRQoL was an exploratory end point. Patients completed the Functional Assessment of Cancer Therapy-Breast (FACT-B) and EuroQol 5-Dimensions (EQ-5D) questionnaires at baseline and months 1, 3, 6, 9, and 12. Changes from baseline were compared using analysis of covariance with no imputation for missing values. Sensitivity analyses used alternative methods. Changes in HRQoL scores were regarded as clinically meaningful if they exceeded previously reported important differences (IDs). RESULTS: Of the 2840 patients (intention-to-treat population), 2407 patients were evaluable for FACT-B (neratinib, N = 1171; placebo, N = 1236) and 2427 patients for EQ-5D (neratinib, N = 1186; placebo, N = 1241). Questionnaire completion rates exceeded 85%. Neratinib was associated with a decrease in global HRQoL scores at month 1 compared with placebo (adjusted mean differences: FACT-B total, -2.9 points; EQ-5D index, -0.02), after which between-group differences diminished at later time-points. Except for the FACT-B physical well-being (PWB) subscale at month 1; all between-group differences were less than reported IDs. The FACT-B breast cancer-specific subscale showed small improvements with neratinib at months 3-9, but all were less than IDs. Sensitivity analyses exploring missing data did not change the results. CONCLUSIONS: Extended adjuvant neratinib was associated with a transient, reversible decrease in HRQoL during the first month of treatment, possibly linked to treatment-related diarrhea. With the exception of the PWB subscale at month 1, all neratinib-related HRQoL changes did not reach clinically meaningful thresholds. ClinicalTrials.gov: NCT00878709.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/terapia , Qualidade de Vida , Quinolinas/efeitos adversos , Receptor ErbB-2/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Placebos/administração & dosagem , Placebos/efeitos adversos , Quinolinas/administração & dosagem , Receptor ErbB-2/metabolismo , Trastuzumab/administração & dosagem , Adulto Jovem
6.
Clin Exp Immunol ; 191(2): 180-188, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28960271

RESUMO

Innate lymphocyte populations, such as innate lymphoid cells (ILCs), γδ T cells, invariant natural killer T (iNK T) cells and mucosal-associated invariant T (MAIT) cells are emerging as important effectors of innate immunity and are involved in various inflammatory and autoimmune diseases. The aim of this study was to assess the frequencies and absolute numbers of innate lymphocytes as well as conventional lymphocytes and monocytes in peripheral blood from a cohort of anti-neutrophil cytoplasm autoantibody (ANCA)-associated vasculitis (AAV) patients. Thirty-eight AAV patients and 24 healthy and disease controls were included in the study. Patients with AAV were sampled both with and without immunosuppressive treatment, and in the setting of both active disease and remission. The frequencies of MAIT and ILC2 cells were significantly lower in patients with AAV and in the disease control group compared to healthy controls. These reductions in the AAV patients remained during remission. B cell count and frequencies were significantly lower in AAV in remission compared to patients with active disease and disease controls. Despite the strong T helper type 2 (Th) preponderance of eosinophilic granulomatosis with polyangiitis, we did not observe increased ILC2 frequency in this cohort of patients. The frequencies of other cell types were similar in all groups studied. Reductions in circulating ILC2 and MAIT cells reported previously in patients with AAV are not specific for AAV, but are more likely to be due to non-specific manifestations of renal impairment and chronic illness. Reduction in B cell numbers in AAV patients experiencing remission is probably therapy-related.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Linfócitos B/imunologia , Rim/patologia , Subpopulações de Linfócitos/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Células T Matadoras Naturais/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Estudos de Coortes , Feminino , Humanos , Imunidade Inata , Terapia de Imunossupressão , Contagem de Linfócitos , Masculino , Microcirculação , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo
7.
Proc Natl Acad Sci U S A ; 112(5): 1310-5, 2015 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-25548181

RESUMO

The large discharge of radioactivity into the northwest Pacific Ocean from the 2011 Fukushima Dai-ichi nuclear reactor accident has generated considerable concern about the spread of this material across the ocean to North America. We report here the first systematic study to our knowledge of the transport of the Fukushima marine radioactivity signal to the eastern North Pacific. Time series measurements of (134)Cs and (137)Cs in seawater revealed the initial arrival of the Fukushima signal by ocean current transport at a location 1,500 km west of British Columbia, Canada, in June 2012, about 1.3 y after the accident. By June 2013, the Fukushima signal had spread onto the Canadian continental shelf, and by February 2014, it had increased to a value of 2 Bq/m(3) throughout the upper 150 m of the water column, resulting in an overall doubling of the fallout background from atmospheric nuclear weapons tests. Ocean circulation model estimates that are in reasonable agreement with our measured values indicate that future total levels of (137)Cs (Fukushima-derived plus fallout (137)Cs) off the North American coast will likely attain maximum values in the 3-5 Bq/m(3) range by 2015-2016 before declining to levels closer to the fallout background of about 1 Bq/m(3) by 2021. The increase in (137)Cs levels in the eastern North Pacific from Fukushima inputs will probably return eastern North Pacific concentrations to the fallout levels that prevailed during the 1980s but does not represent a threat to human health or the environment.

8.
Am J Transplant ; 17(1): 91-102, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27376692

RESUMO

We previously reported that transplantation (Tx) of prevascularized donor islets as composite islet-kidneys (IK) reversed diabetic hyperglycemia in both miniature swine and baboons. In order to enhance this strategy's potential clinical applicability, we have now combined this approach with hematopoietic stem cell (HSC) Tx in an attempt to induce tolerance in nonhuman primates. IKs were prepared by isolating islets from 70% partial pancreatectomies and injecting them beneath the autologous renal capsule of five rhesus monkey donors at least 3 months before allogeneic IK Tx. HSC Tx was performed after mobilization and leukapheresis of the donors and conditioning of the recipients with total body irradiation, T cell depletion, and cyclosporine. One IK was harvested for histologic analysis and four were transplanted into diabetic recipients. IK Tx was performed either 20-22 (n = 3) or 208 (n = 1) days after HSC Tx. All animals accepted IKs without rejection. All recipients required >20 U/day insulin before IK Tx to maintain <200 mg/dL, whereas after IK Tx, three animals required minimal doses of insulin (1-3 U/day) and one animal was insulin free. These results constitute a proof-of-principle that this IK tolerance strategy may provide a cure for both end-stage renal disease and diabetes without the need for immunosuppression.


Assuntos
Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Tolerância Imunológica/imunologia , Transplante das Ilhotas Pancreáticas , Ilhotas Pancreáticas/irrigação sanguínea , Transplante de Rim , Rim/irrigação sanguínea , Animais , Feminino , Rejeição de Enxerto/prevenção & controle , Macaca mulatta , Masculino , Transplante Homólogo
9.
Am J Transplant ; 16(1): 317-24, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26260215

RESUMO

Our recent studies in an inbred swine model demonstrated that both peripheral and intra-graft regulatory cells were required for the adoptive transfer of tolerance to a second, naïve donor-matched kidney. Here, we have asked whether both peripheral and intra-graft regulatory elements are required for adoptive transfer of tolerance when only a long-term tolerant (LTT) kidney is transplanted. Nine highly-inbred swine underwent a tolerance-inducing regimen to prepare LTT kidney grafts which were then transplanted to histocompatible recipients, with or without the peripheral cell populations required for adoptive transfer of tolerance to a naïve kidney. In contrast to our previous studies, tolerance of the LTT kidney transplants alone was achieved without transfer of additional peripheral cells and without strategies to increase the number/potency of regulatory T cells in the donor. This tolerance was systemic, since most subsequent, donor-matched challenge kidney grafts were accepted. These results confirm the presence of a potent tolerance-inducing and/or tolerance-maintaining cell population within LTT renal allografts. They suggest further that additional peripheral tolerance mechanisms, required for adoptive transfer of tolerance to a naïve donor-matched kidney, depend on peripheral cells that, if not transferred with the LTT kidney, require time to develop in the adoptive host.


Assuntos
Transferência Adotiva/métodos , Modelos Animais de Doenças , Rejeição de Enxerto/imunologia , Transplante de Rim , Tolerância ao Transplante/imunologia , Animais , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Suínos , Porco Miniatura , Transplante Homólogo
10.
Am J Transplant ; 16(10): 2877-2891, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27145342

RESUMO

Thymic involution is associated with age-related changes of the immune system. Utilizing our innovative technique of transplantation of a thymus as an isolated vascularized graft in MHC-inbred miniature swine, we have previously demonstrated that aged thymi are rejuvenated after transplantation into juvenile swine. Here we have studied the role of insulin-like growth factor (IGF) and forkhead-box protein-N1 (FOXN1) as well as bone marrow (BM) in thymic rejuvenation and involution. We examined thymic rejuvenation and involution by means of histology and flow cytometry. Thymic function was assessed by the ability to induce tolerance of allogeneic kidneys. Aged thymi were rejuvenated in a juvenile environment, and successfully induced organ tolerance, while juvenile thymi in aged recipients involuted and had a limited ability to induce tolerance. However, juvenile BM inhibited the involution process of juvenile thymi in aged recipients. An elevated expression of both FOXN1 and IGF1 receptors (IGF-1R) was observed in juvenile thymi and rejuvenated thymi. Juvenile BM plays a role in promoting the local thymic milieu as indicated by its ability to inhibit thymic involution in aged animals. The expression of FOXN1 and IGF-1R was noted to increase under conditions that stimulated rejuvenation, suggesting that these factors are involved in thymic recovery.


Assuntos
Medula Óssea/fisiologia , Fatores de Transcrição Forkhead/metabolismo , Receptor IGF Tipo 1/metabolismo , Rejuvenescimento/fisiologia , Timo/fisiologia , Envelhecimento/fisiologia , Animais , Diferenciação Celular , Fatores de Transcrição Forkhead/genética , Sobrevivência de Enxerto , Tolerância Imunológica , Receptor IGF Tipo 1/genética , Suínos , Porco Miniatura , Timo/transplante
11.
Osteoarthritis Cartilage ; 24(9): 1604-12, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27155345

RESUMO

OBJECTIVE: The development of effective therapies for cartilage protection has been limited by a lack of efficient quantitative cartilage imaging modalities in pre-clinical in vivo models. Our objectives were two-fold: first, to validate a new contrast-enhanced 3D imaging analysis technique, equilibrium partitioning of an ionic contrast agent-micro computed tomography (EPIC-µCT), in a rat medial meniscal transection (MMT) osteoarthritis (OA) model; and second, to quantitatively assess the sensitivity of EPIC-µCT to detect the effects of matrix metalloproteinase inhibitor (MMPi) therapy on cartilage degeneration. METHODS: Rats underwent MMT surgery and tissues were harvested at 1, 2, and 3 weeks post-surgery or rats received an MMPi or vehicle treatment and tissues harvested 3 weeks post-surgery. Parameters of disease progression were evaluated using histopathology and EPIC-µCT. Correlations and power analyses were performed to compare the techniques. RESULTS: EPIC-µCT was shown to provide simultaneous 3D quantification of multiple parameters, including cartilage degeneration and osteophyte formation. In MMT animals treated with MMPi, OA progression was attenuated, as measured by 3D parameters such as lesion volume and osteophyte size. A post-hoc power analysis showed that 3D parameters for EPIC-µCT were more sensitive than 2D parameters requiring fewer animals to detect a therapeutic effect of MMPi. 2D parameters were comparable between EPIC-µCT and histopathology. CONCLUSION: This study demonstrated that EPIC-µCT has high sensitivity to provide 3D structural and compositional measurements of cartilage and bone in the joint. EPIC-µCT can be used in combination with histology to provide a comprehensive analysis to screen new potential therapies.


Assuntos
Microtomografia por Raio-X , Animais , Imageamento Tridimensional , Meniscos Tibiais , Osteoartrite , Osteófito , Ratos
12.
Philos Trans A Math Phys Eng Sci ; 374(2081)2016 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-29035251

RESUMO

Deposition of continental mineral aerosols (dust) in the Eastern Tropical North Atlantic Ocean, between the coast of Africa and the Mid-Atlantic Ridge, was estimated using several strategies based on the measurement of aerosols, trace metals dissolved in seawater, particulate material filtered from the water column, particles collected by sediment traps and sediments. Most of the data used in this synthesis involve samples collected during US GEOTRACES expeditions in 2010 and 2011, although some results from the literature are also used. Dust deposition generated by a global model serves as a reference against which the results from each observational strategy are compared. Observation-based dust fluxes disagree with one another by as much as two orders of magnitude, although most of the methods produce results that are consistent with the reference model to within a factor of 5. The large range of estimates indicates that further work is needed to reduce uncertainties associated with each method before it can be applied routinely to map dust deposition to the ocean. Calculated dust deposition using observational strategies thought to have the smallest uncertainties is lower than the reference model by a factor of 2-5, suggesting that the model may overestimate dust deposition in our study area.This article is part of the themed issue 'Biological and climatic impacts of ocean trace element chemistry'.

13.
Am J Transplant ; 14(9): 2001-10, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25100613

RESUMO

We have previously demonstrated that long-term tolerance (LTT) of an MHC class-I mismatched renal allograft can be achieved with a short course of cyclosporine. In order to examine regulatory mechanisms underlying tolerance in this model, we assessed the contributions of factors within the graft and in the peripheral blood for their relative roles in the maintenance of stable tolerance. Twelve LTT recipients of MHC class-I mismatched primary kidneys were subjected to a treatment consisting of donor-specific transfusion followed by leukapheresis, in order to remove peripheral leukocytes, including putative regulatory T cells (Tregs). Following treatment, 2 controls were followed clinically and 10 animals had the primary graft removed and received a second, donor-MHC-matched kidney. Neither control animal showed evidence of rejection, while 8 of 10 retransplanted animals developed either rejection crisis or full rejection of the second transplant. In vitro assays confirmed that the removed leukocytes were suppressive and that CD4(+) Foxp3(+) Treg reconstitution in blood and kidney grafts correlated with return to normal renal function in animals experiencing transient rejection crises. These data indicate that components of accepted kidney grafts as well as peripheral regulatory components both contribute to the tolerogenic environment required for tolerance of MHC class-I mismatched allotransplants.


Assuntos
Tolerância Imunológica , Transplante de Rim , Animais , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Suínos , Porco Miniatura , Linfócitos T Reguladores/imunologia , Transplante Homólogo
14.
Ecol Appl ; 24(4): 633-49, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24988765

RESUMO

Marshes in the urban Jamaica Bay Estuary, New York, USA are disappearing at an average rate of 13 ha/yr, and multiple stressors (e.g., wastewater inputs, dredging activities, groundwater removal, and global warming) may be contributing to marsh losses. Among these stressors, wastewater nutrients are suspected to be an important contributing cause of marsh deterioration. We used census data, radiometric dating, stable nitrogen isotopes, and soil surveys to examine the temporal relationships between human population growth and soil nitrogen; and we evaluated soil structure with computer-aided tomography, surface elevation and sediment accretion trends, carbon dioxide emissions, and soil shear strength to examine differences among disappearing (Black Bank and Big Egg) and stable marshes (JoCo). Radiometric dating and nitrogen isotope analyses suggested a rapid increase in human wastewater nutrients beginning in the late 1840s, and a tapering off beginning in the 1930s when wastewater treatment plants (WWTPs) were first installed. Current WWTPs nutrient loads to Jamaica Bay are approximately 13 995 kg N/d and 2767 kg P/d. At Black Bank, the biomass and abundance of roots and rhizomes and percentage of organic matter on soil were significantly lower, rhizomes larger in diameter, carbon dioxide emission rates and peat particle density significantly greater, and soil strength significantly lower compared to the stable JoCo Marsh, suggesting Black Bank has elevated decomposition rates, more decomposed peat, and highly waterlogged peat. Despite these differences, the rates of accretion and surface elevation change were similar for both marshes, and the rates of elevation change approximated the long-term relative rate of sea level rise estimated from tide gauge data at nearby Sandy Hook, New Jersey. We hypothesize that Black Bank marsh kept pace with sea level rise by the accretion of material on the marsh surface, and the maintenance of soil volume through production of larger diameter rhizomes and swelling (dilation) of waterlogged peat. JoCo Marsh kept pace with sea-level rise through surface accretion and soil organic matter accumulation. Understanding the effects of multiple stressors, including nutrient enrichment, on soil structure, organic matter accumulation, and elevation change will better inform management decisions aimed at maintaining and restoring coastal marshes.


Assuntos
Conservação dos Recursos Naturais , Estuários , Nitrogênio/química , Solo/química , Animais , Cidades , New York , Poaceae/crescimento & desenvolvimento
15.
Ir J Psychol Med ; : 1-5, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38497092

RESUMO

BACKGROUND: Fluphenazine decanoate licenced as a long-acting injectable (LAI) first-generation antipsychotic (FGA) was withdrawn from sale in 2018. This study evaluates if its withdrawal resulted in increased relapse rates of psychosis in an Irish patient cohort and examines which prescribed alternative antipsychotic medications were associated with more optimal outcomes. METHODS: Fifteen participants diagnosed with a psychotic disorder were included. A mirror-image study over 24-months' pre-and post-withdrawal of fluphenazine was conducted. Kaplan-Meier survival and proportional hazards analyses were conducted. The impact of alternate antipsychotic agents (LAI flupenthixol compared to other antipsychotic medications) was evaluated. Semi-structured interviews with participants examined subjective opinions regarding the change in their treatment. RESULTS: Seven participants (46.7%) relapsed in the 24-month period subsequent to fluphenazine discontinuation compared to one individual (6.7%) in the previous identical time-period (p = 0.035). Flupenthixol treatment was associated with reduced relapse rates compared to other antipsychotics (χ2 = 5.402, p = 0.02). Thematic analysis revealed that participants believed that the discontinuation of fluphenazine deleteriously impacted the stability of their mental disorder. CONCLUSION: The withdrawal of fluphenazine was associated with increased relapse rate in individuals previously demonstrating stability of their psychotic disorder. While acknowledging the limitation of small sample size, preliminary evidence from this study suggests that treatment with the first-generation antipsychotic (FGA) flupenthixol was associated with a lower risk of relapse compared to SGAs. Reasons for this lower risk of relapse are not fully clear but could be related to dopamine hypersensitivity with this treatment change.

16.
Osteoarthritis Cartilage ; 21(8): 1132-41, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23747340

RESUMO

OBJECTIVE: Current histological scoring methods to evaluate efficacy of potential therapeutics for slowing or preventing joint degeneration are time-consuming and semi-quantitative in nature. Hence, there is a need to develop and standardize quantitative outcome measures to define sensitive metrics for studying potential therapeutics. The objectives of this study were to use equilibrium partitioning of an ionic contrast agent via Equilibrium Partitioning of an Ionic Contrast-Microcomputed tomography (EPIC-µCT) to quantitatively characterize morphological and compositional changes in the tibial articular cartilage in two distinct models of joint degeneration and define localized regions of interest to detect degenerative cartilage changes. MATERIALS AND METHODS: The monosodium iodoacetate (MIA) and medial meniscal transection (MMT) rat models were used in this study. Three weeks post-surgery, tibiae were analyzed using EPIC-µCT and histology. EPIC-µCT allowed measurement of 3D morphological changes in cartilage thickness, volume and composition. RESULTS: Extensive cartilage degeneration was observed throughout the joint in the MIA model after 3 weeks. In contrast, the MMT model showed more localized degeneration with regional thickening of the medial tibial plateau and a decrease in attenuation consistent with proteoglycan (PG) depletion. Focal lesions were also observed and 3D volume calculated as an additional outcome metric. CONCLUSIONS: EPIC-µCT was used to quantitatively assess joint degeneration in two distinct preclinical models. The MMT model showed similar features to human Osteoarthritis (OA), including localized lesion formation and PG loss, while the MIA model displayed extensive cartilage degeneration throughout the joint. EPIC-µCT imaging provides a rapid and quantitative screening tool for preclinical evaluation of OA therapeutics.


Assuntos
Artrite Experimental/patologia , Cartilagem Articular/patologia , Animais , Artrite Experimental/diagnóstico por imagem , Artrite Experimental/etiologia , Artrite Experimental/metabolismo , Cartilagem Articular/diagnóstico por imagem , Cartilagem Articular/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Processamento de Imagem Assistida por Computador/métodos , Ácido Iodoacético , Masculino , Proteoglicanas/metabolismo , Ratos , Ratos Wistar , Tíbia/patologia , Lesões do Menisco Tibial , Microtomografia por Raio-X/métodos
17.
Ir J Psychol Med ; 40(3): 396-401, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-35156601

RESUMO

OBJECTIVES: We previously demonstrated that three months into the COVID-19 pandemic, the impact on individuals with treatment-resistant psychotic disorders was modest. Here, we examined and compared the psychological and social impact of the COVID-19 pandemic on the same patient cohort 12 months after their initial study engagement. METHODS: Semi-structured interviews were conducted with 54 individuals (85.7% response rate) between June 12 and July 29, 2021, 12 months after their initial interviews. Participants' subjective experience of the impact of the COVID-19 pandemic on anxiety symptoms, social and vocational functioning was measured utilising the same Likert scales at both time points. Anxiety symptoms were additionally measured using subjective (Beck Anxiety Inventory) and objective (Hamilton Anxiety Rating Scale (HARS)) psychometric instruments. Paired t-tests or Wilcoxon ranked tests compared parametric or non-parametric data over time. Free-text responses pertaining to participants' perspectives on the impact of COVID-19 were grouped into themes. RESULTS: A minor increase in anxiety symptoms was demonstrated utilising the HARS (1.9 points, z = 3.017, p = 0.003), with a minimal increase in depressive symptoms noted using Likert ratings (0.8 points, z = 2.119, p = 0.034). Five themes were identified with the most prevalent being (i) positivity regarding vaccination, (ii) social isolation from family members and (iii) looking forward to post-COVID-19 'normality'. However, negative views pertaining to the psychosocial impact of COVID-19 and vaccination were additionally reported. CONCLUSIONS: No significant overall clinical change in symptomatology or functioning over time was noted.The study demonstrated that positive views regarding vaccination and optimism for the future were evident for some participants.


Assuntos
COVID-19 , Clozapina , Humanos , Clozapina/uso terapêutico , Pandemias , Ansiedade , Transtornos de Ansiedade/terapia
18.
Estuar Coast Shelf Sci ; 267: 1-10, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35340981

RESUMO

Authigenic molybdenum (Mo) accumulation in marine sediments has often been used as a qualitative indicator of hypoxic bottom water. To investigate its use as a quantitative indicator of hypoxic exposure, sediment cores were collected from water quality monitoring sites in Narragansett Bay (RI, USA) that experience varying periods of hypoxia. Total Mo concentrations in surficial (0-1 cm) sediments were determined by total digestion and ICP-MS analysis. Lithogenic contributions to total Mo concentrations were estimated by multiplying measured concentrations of aluminum (Al) by the mean crustal Mo:Al ratio and subtracting them from the total concentrations to yield the authigenic fraction. 210Pb dating was used to determine sediment accumulation rates at each site. Mean annual periods of hypoxia in bottom waters were determined from continuous monitoring data for the years coinciding with the top 1 cm of sediment. Results indicated a linear relationship between authigenic Mo concentrations and frequency of hypoxia, although the relationships differed between different sampling periods. These results demonstrate the potential of sedimentary Mo as a tool for assessing the spatial and temporal extent of hypoxia in coastal waters.

19.
AJNR Am J Neuroradiol ; 43(3): 388-393, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35177549

RESUMO

BACKGROUND AND PURPOSE: Contrast curve truncation in CTP protocols may introduce errors. We sought to identify risk factors and design a protocol to avoid truncation while limiting radiation. MATERIALS AND METHODS: In an initial fixed-timing cohort, patients underwent a 65-second CTP with 2-second delay postcontrast injection. Multivariable analysis identified factors associated with truncation. A later case-specific cohort underwent either the original protocol or a low cardiac output protocol with a 7-second delay and 75-second scanning window, with selection determined by CTA test-dose enhancement upswing delay. Time-density curves were assessed for truncation and compared between the 2 groups, and the radiation dose was evaluated. RESULTS: From September 2017 through May 2018, one hundred fifty-three patients underwent the standard fixed-timing protocol. Age (OR, 1.82/10-year increase; P = .019), reduced left ventricle ejection fraction (OR, 9.23; P = .001), and hypertension (OR, 0.32; P = .06) were independently associated with truncation in an exploratory multivariable model. From May 2018 through April 2019, one hundred fifty-seven patients underwent either the standard (72 patients) or low cardiac output protocol (85 patients). The fixed-timing cohort had 15 truncations (9.8%) versus 4 in the case-specific cohort (2.5%; P = .009). If the low cardiac output protocol were applied to those with >10.6% predicted risk of truncation based on age, left ventricle ejection fraction, and hypertension, the number of truncations would have decreased from 15 to 4 in the fixed-timing cohort. CONCLUSIONS: Older age, left ventricle ejection fraction, and the absence of hypertension increase the risk of time-density curve truncation. However, a CTA test-dose-directed case-specific protocol can reduce truncation to ensure accurate data while mitigating radiation dose increases.


Assuntos
Hipertensão , Acidente Vascular Cerebral , Humanos , Baixo Débito Cardíaco , Angiografia Cerebral/métodos , Software , Acidente Vascular Cerebral/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos
20.
Environ Technol ; 43(3): 402-410, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32619385

RESUMO

Potassium birnessites were prepared using two methods, sol-gel or oxidation. The solids were characterised by element chemical analysis, powder X-ray diffraction, FT-IR spectroscopy, thermal analyses, and nitrogen adsorption. The evolution of the properties as a function of the preparation method was discussed. The photocatalytic performance of these solids was preliminarily tested for the degradation of 4-nitrophenol. The degradation pathway and the nature of the by-products were investigated by mass spectrometry. The solids showed good catalytic behaviour, although their preparation must be improved, mainly concerning the calcination step involved in sol-gel synthesis, which led to the formation of Mn2O3 that worsened the catalytic behaviour.


Assuntos
Titânio , Catálise , Cromatografia Gasosa-Espectrometria de Massas , Nitrofenóis , Óxidos , Espectroscopia de Infravermelho com Transformada de Fourier
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