RESUMO
N6-methyladenosine (m6A) is an abundant internal RNA modification1,2 that is catalysed predominantly by the METTL3-METTL14 methyltransferase complex3,4. The m6A methyltransferase METTL3 has been linked to the initiation and maintenance of acute myeloid leukaemia (AML), but the potential of therapeutic applications targeting this enzyme remains unknown5-7. Here we present the identification and characterization of STM2457, a highly potent and selective first-in-class catalytic inhibitor of METTL3, and a crystal structure of STM2457 in complex with METTL3-METTL14. Treatment of tumours with STM2457 leads to reduced AML growth and an increase in differentiation and apoptosis. These cellular effects are accompanied by selective reduction of m6A levels on known leukaemogenic mRNAs and a decrease in their expression consistent with a translational defect. We demonstrate that pharmacological inhibition of METTL3 in vivo leads to impaired engraftment and prolonged survival in various mouse models of AML, specifically targeting key stem cell subpopulations of AML. Collectively, these results reveal the inhibition of METTL3 as a potential therapeutic strategy against AML, and provide proof of concept that the targeting of RNA-modifying enzymes represents a promising avenue for anticancer therapy.
Assuntos
Antineoplásicos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Metiltransferases/antagonistas & inibidores , Adenosina/análogos & derivados , Animais , Apoptose , Diferenciação Celular , Linhagem Celular Tumoral , Feminino , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
7-methylguanosine (m7G) is present at mRNA caps and at defined internal positions within tRNAs and rRNAs. However, its detection within low-abundance mRNAs and microRNAs (miRNAs) has been hampered by a lack of sensitive detection strategies. Here, we adapt a chemical reactivity assay to detect internal m7G in miRNAs. Using this technique (Borohydride Reduction sequencing [BoRed-seq]) alongside RNA immunoprecipitation, we identify m7G within a subset of miRNAs that inhibit cell migration. We show that the METTL1 methyltransferase mediates m7G methylation within miRNAs and that this enzyme regulates cell migration via its catalytic activity. Using refined mass spectrometry methods, we map m7G to a single guanosine within the let-7e-5p miRNA. We show that METTL1-mediated methylation augments let-7 miRNA processing by disrupting an inhibitory secondary structure within the primary miRNA transcript (pri-miRNA). These results identify METTL1-dependent N7-methylation of guanosine as a new RNA modification pathway that regulates miRNA structure, biogenesis, and cell migration.
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Guanosina/análogos & derivados , Metiltransferases/genética , MicroRNAs/genética , Processamento Pós-Transcricional do RNA , Células A549 , Sequência de Bases , Bioensaio , Células CACO-2 , Movimento Celular , Proliferação de Células , Guanosina/metabolismo , Células HEK293 , Humanos , Metilação , Metiltransferases/metabolismo , MicroRNAs/metabolismo , Conformação de Ácido NucleicoRESUMO
The magnetic resonance imaging (MRI) appearance of the brain and spinal cord in humans with neuroangiostrongyliasis (NA) due to Angiostrongylus cantonensis infection has been well reported. Equivalent studies in animals are lacking. This case series describes clinical and MRI findings in 11 dogs with presumptively or definitively diagnosed NA. MRI of the brain and/or spinal cord was performed using high-field (1.5 T) or low-field (0.25 T) scanners using various combinations of transverse, sagittal, dorsal and three-dimensional (3D) T1-weighted (T1W), transverse, sagittal and dorsal T2-weighted (T2W), T2W fluid-attenuated inversion recovery (FLAIR) and T2*-weighted (T2*W) gradient echo (GRE), dorsal T2W short tau inversion recovery (STIR) and post-gadolinium transverse, sagittal, dorsal and 3D T1W and transverse T2W FLAIR sequences. In 4/6 cases where the brain was imaged, changes consistent with diffuse meningoencephalitis were observed. Evidence of meningeal involvement was evident even when not clinically apparent. The spinal cord was imaged in 9 dogs, with evidence of meningitis and myelitis detected in regions consistent with the observed neuroanatomical localization. Pathognomonic changes of neural larva migrans, as described in some human patients with NA, were not detected. NA should be considered in the differential diagnosis of dogs with MRI evidence of focal or diffuse meningitis, myelitis and/or encephalitis, especially in areas where A. cantonensis is endemic. If not precluded by imaging findings suggestive of brain herniation, cerebrospinal fluid (CSF) collection for cytology, fluid analysis, real-time polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) testing should be considered mandatory in such cases after the MRI studies.
Assuntos
Doenças do Cão/diagnóstico por imagem , Imageamento por Ressonância Magnética/veterinária , Infecções por Strongylida/veterinária , Angiostrongylus cantonensis/fisiologia , Animais , Doenças do Cão/parasitologia , Cães , Feminino , Masculino , Meningite/diagnóstico por imagem , Meningite/parasitologia , Meningite/veterinária , Meningoencefalite/diagnóstico por imagem , Meningoencefalite/parasitologia , Meningoencefalite/veterinária , Infecções por Strongylida/diagnóstico por imagem , Infecções por Strongylida/parasitologiaRESUMO
AIMS AND OBJECTIVES: To explore newly qualified nurses' support needs and their perceptions of online peer support. BACKGROUND: The experience of being a newly qualified nurse is stressful and isolating. Support from colleagues and peers can enhance perceptions of competence and confidence in newly qualified nurses, improve well-being and aid retention. However, despite initiatives such as preceptorship, support needs may remain unmet in busy clinical environments. Online support has potential to offer a partial solution to professional isolation, but there is a lack of research into how technology can support nurses' emotional and social well-being. DESIGN: A qualitative exploratory study was designed, employing semi-structured focus groups, analysed using thematic analysis. The study is reported in accordance with the COnsolidated criteria for REporting Qualitative research checklist. METHODS: Eight focus groups, supplemented by one individual interview, were conducted with newly qualified nurses between June 2018-January 2019. FINDINGS: Two main themes arose. The first was Drowning, a lot of the time with two sub-themes: (i) Feelings and emotions about being a Newly Qualified Nurse: 'Absolutely terrified' and (ii) Support within the role: 'Somebody you can count on'. The second was Potential advantages and disadvantages of online modality: 'Somebody is going to get in that phone!' which included three sub-themes (i) Potential advantages, (ii) Potential disadvantages and (iii) Preferences and recommendations. CONCLUSIONS: This study demonstrates that if barriers can be overcome, then online support has potential to contribute to newly qualified nurses' well-being. Further research is needed to explore technical and ethical issues around online support and evaluate its effectiveness for newly qualified nurses. RELEVANCE TO CLINICAL PRACTICE: Online support has the potential to add to existing strategies to support nurses during stressful times. This may be particularly relevant when many staff are working under increased pressure due to the COVID-19 pandemic.
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COVID-19 , Enfermeiras e Enfermeiros , Competência Clínica , Humanos , Pandemias , Percepção , Pesquisa Qualitativa , SARS-CoV-2RESUMO
AIMS: (a) To review the literature on the use of technology to offer emotional and social support to nurses; (b) to identify and evaluate gaps in the research; (c) to assess whether a systematic review would be valuable and (d) to make recommendations for future research. DESIGN: A robust methodological scoping framework was used as the basis for this review design. A manualized systematic approach to quality appraisal was implemented. DATA SOURCES: Between 11-12 June 2018, five databases were searched. A search of the grey literature was conducted alongside hand searching reference lists of included studies. REVIEW METHODS: Two researchers conducted the literature search, data extraction and quality appraisal. Three searches were conducted, combining nursing and technological terms. A narrative review approach to knowledge synthesis was used to compare and evaluate included studies. RESULTS: Eleven articles were retrieved. Results are presented under three subheadings: (a) text messaging and messenger apps; (b) social media and online forums; and (c) online interventions accessible via PC, smartphone and tablet. All included studies described how such provision could be beneficial; decreasing stress, isolation and anxiety and fostering a sense of community. CONCLUSION: The review identified a dearth of research into how technology can support the well-being of nurses. A high proportion of studies were based on student nurse populations using small sample sizes, therefore further research is needed. IMPACT: Technology may offer a sustainable and accessible means of providing support for nurses who find it difficult to communicate in person due to time pressures at work. It is important that the psychological well-being of nurses is seriously addressed as more nurses are now leaving than joining the profession. Online interventions may offer a sustainable and accessible means of providing support for busy nursing staff who have difficulty finding time to communicate with one another face-to-face. Nurse retention is an international issue linked to quality of patient care. There are financial implications for healthcare providers who compensate for the workforce deficit by employing costly agency staff. This scoping review aims to map and evaluate the available literature on technology-mediated support for the emotional and social well-being of nurses. Recommendations for future research, policy and practice will be offered from the findings of the review.
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Emoções , Recursos Humanos de Enfermagem/psicologia , Tecnologia , Humanos , Apoio Social , Reino UnidoRESUMO
AIM AND OBJECTIVE: To identify training strategies and determine how registered health and social care practitioners change their practice after Mental Capacity Act training. DESIGN: Narrative literature review. DATA SOURCES: Seventeen databases were searched up to December 2019: CINAHL, Social Care Online, PubMed, Social Policy and Practice, Discover, MEDLINE, Science Direct, Ovid, 0of Science, British Nursing Index, DH-Data and King's Fund Library Catalogue. REVIEW METHODS: Empirical studies of any design investigating Mental Capacity Act training were searched and screened. Data were extracted to a bespoke spreadsheet and quality assessed. Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: Of 162 papers identified, 16 were included comprising qualitative, quantitative and mixed-methods studies. Trainees valued interactive training with close alignment to practice. Training did not lead to demonstrable practice change. Barriers in the context and cultures of care environments were identified. CONCLUSION: To facilitate application of Mental Capacity Act legislation, identified barriers should be addressed. Future training should be interactive, scenario-based and relevant to trainees' practice. RELEVANCE TO CLINICAL PRACTICE: The Mental Capacity Act is widely misunderstood and implemented poor. Training is proposed as a solution, but the nature of training that will positively affect practice remains unknown. This review aims to address this gap in the evidence base. Interactive training, using scenarios that reflect practice complexities, has the most positive impact. Cultural norms in care environments may impede application of this legislation. The review has international relevance as there is a global imperative to adhere to the United Nations Convention on the Rights of Persons with Disabilities. The review will inform training design and delivery to ensure that people with impaired capacity to make decisions are given the best opportunity to act autonomously.
Assuntos
Atenção à Saúde/métodos , Pessoal de Saúde/educação , Competência Mental/legislação & jurisprudência , Humanos , Reino UnidoRESUMO
OBJECTIVE: To report anconeus muscle injury in a greyhound. ANIMAL: One 11-month-old female greyhound. STUDY DESIGN: Case report METHODS: The dog presented with a 6-week history of mild left foreleg lameness. Moderate pain was noted by palpation over the proximolateral ulna and distolateral humerus and by maximal elbow flexion. A laminar periosteal reaction on the caudodistal humerus was present on radiographs. At ultrasonic examination, disorganization of anconeus muscle fibers, and focal mixed echogenicity were noted. Precontrast and postcontrast computed tomography (CT) revealed a thin rim of periosteal new bone on the caudodistal humerus as well as heterogeneous contrast enhancement of soft tissue immediately caudal to the distal humerus. An unrelated greyhound cadaver dissection confirmed only the anconeus muscle attached to the site of noted periosteal reaction. A partial tear of the anconeus muscle was diagnosed. Treatment consisted of 4 weeks of oral meloxicam. Confinement space and exercise were incrementally increased over 14 weeks. RESULTS: Muscle healing was confirmed by ultrasonography and CT. The dog was able to have a successful racing career spanning 2 years with no lameness attributable to the previous anconeus muscle injury and retired for unrelated reasons. CONCLUSION: Radiography and ultrasonography helped diagnose anconeal muscle injury, and conservative management led to full return to function. CLINICAL SIGNIFICANCE: Clinicians should include anconeus muscle injury as a differential diagnosis in dogs with lameness and pain over the proximolateral ulna or distolateral humerus or on elbow flexion.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Meloxicam/uso terapêutico , Músculo Esquelético/lesões , Animais , Cães , Feminino , Resultado do TratamentoRESUMO
AIMS: (a) To review the published literature on the use of technology to provide social or emotional support to nurses, (b) to evaluate and identify gaps in the research, (c) to assess whether a systematic review would be valuable, (d) to make recommendations for future developments. DESIGN: The protocol for the scoping review has been developed in accordance with recommendations from several methodological frameworks, as no standardized protocol currently exists for this purpose. METHODS: Our protocol incorporates information about the aims and objectives of the scoping review, inclusion criteria, search strategy, data extraction, quality appraisal, data synthesis, and plans for dissemination. Funding for this project was approved by Burdett Trust for Nursing in December 2016. DISCUSSION: Technology to support patient emotional and social well-being has seen a rapid growth in recent years and is offered in a variety of formats. However, similar support for nursing staff remains under-researched with no literature review undertaken on this topic to date. This is despite nurses working in emotionally demanding environments which can be socially isolating. The scoping review will map current evidence on the use of technology to support nursing staff and explore the range, extent, and nature of this activity. It will also give a basis for deciding if a full systematic review would be desirable. IMPACT: It is important that the psychological well-being of nurses is seriously addressed as more nurses are now leaving than joining the profession. This is an international concern. High staff turnover has an interpersonal cost and is associated with reduced quality of patient care. Financial implications are also important to consider as healthcare providers employ costly agency staff to address the workforce deficit. Online technology may offer a sustainable and accessible means of providing support for nurses who find it difficult to communicate in person due to time pressures at work.
Assuntos
Tecnologia Biomédica/estatística & dados numéricos , Emoções , Enfermeiras e Enfermeiros/psicologia , Apoio Social , Revisões Sistemáticas como Assunto , Humanos , Saúde Mental , Enfermeiros Obstétricos/psicologia , Estresse Ocupacional/prevenção & controle , Estresse Ocupacional/psicologia , Projetos de PesquisaRESUMO
AIM: To explore experiences of online peer support for newly qualified nurses. DESIGN: Qualitative study using semi-structured interviews and thematic analysis. METHOD: Phase one involves conducting focus groups with newly qualified nurses in the West Midlands area to refine the online peer support environment. Phase two involves 30-40 new nurses joining an online peer group for 3 months; participants will be able to access a general chat community alongside a more structured discussion board. Phase 3 will collect written interview data from all participants about their experiences of online peer support. Face-to-face interviews with 10-12 participants will also be undertaken. The study will run from May 2018-October 2019. FINDINGS: Data from focus groups, written and verbal interviews will be analysed using thematic analysis with the aid of NVivo software. Findings will be disseminated to participants and key stakeholders involved in the study and also via publication and networking events. CONCLUSION: If online peer support is found to be beneficial to new nurses, it may be adopted by local NHS trusts as part of an innovation scheme. IMPACT: It is important that the psychological well-being of nurses is addressed as more nurses are now leaving than joining the profession; this is an international concern. Online peer support may offer a sustainable and accessible means of promoting psychological well-being in the nursing workforce. In such a way, contributory factors to low retention rates such as burnout, stress and job dissatisfaction may also be reduced.
Assuntos
Internet , Recursos Humanos de Enfermagem/psicologia , Grupo Associado , Apoio Social , Grupos Focais , Humanos , Reino UnidoRESUMO
Across China and Southeast Asia, over 17,000 bears are currently farmed for bile, predominantly for traditional Chinese medicines. Bears on farms in China are cage confined and undergo repeated daily bile extraction facilitated by surgically implanted catheters or gallbladder fistulas. Numerous health problems have been reported in bile-farmed bears including peritonitis, abdominal hernias, and extraction site abscessation. Between 2009 and 2014, five Asiatic black bears ( Ursus thibetanus) and one Asiatic black/Eurasian brown bear ( Ursus arctos arctos) hybrid, rescued from the bear bile industry in China, died from ruptured and/or dissecting aortic aneurysm. Medical records were reviewed and two bears exhibited no clinical signs prior to death. In four bears, clinical findings varied and included increased stereotypic behavior prior to death, epistaxis, retinal lesions, dysphagia, weight loss, and acute onset of hyporexia. On postmortem examination, hemopericardium with dissection and/or rupture of the ascending aorta and left ventricular wall hypertrophy were present in all cases. No evidence of infectious disease, connective tissue disorders, or congenital cardiac disease was identified. Based on these observations screening thoracic radiography was performed on all bears at the rescue center and aortic dilation was identified in 73 of 134 (54.5%) bile-extracted bears. To the authors' knowledge, aortic aneurysm, rupture, and/or dissection have not been previously reported in any bear species and the high prevalence in this population of bears suggests an association with bile-farming practices. Future studies are needed to investigate the etiopathogenesis of this condition to aid in early diagnosis and improved management of bears being rescued from bile farms across Asia.
Assuntos
Aneurisma Aórtico/veterinária , Dissecção Aórtica/veterinária , Ruptura Aórtica/veterinária , Ursidae , Dissecção Aórtica/patologia , Animais , Aneurisma Aórtico/patologia , Ruptura Aórtica/patologiaRESUMO
After thyroidectomy for primary thyroid malignancies, patients are closely monitored for recurrence or metastasis. Fine needle aspiration (FNA) has been used as the appropriate diagnostic modality for occult masses identified radiographically in the thyroid bed. In this study, we report our institutional experience with FNA of the thyroid bed and propose practical diagnostic categories. A retrospective chart review of all thyroid bed FNAs between April 2008 and January 2013 was performed, and a cohort of 39 patients was retrieved. The cytology diagnoses were divided into 5 categories including nondiagnostic, inflammatory/reactive, bland follicular cells, suspicious for neoplasm/malignancy, and malignant. The follow-up histologic and/or clinical findings were collected for each category. The 39 patients included 9 males and 30 females (ages 15-79 years). Prior thyroidectomies were due to papillary thyroid carcinoma (31 cases), follicular carcinoma (3 cases), medullary carcinoma (1 case), Hürthle cell carcinoma (1 case), malignancy unspecified (1 case), follicular adenoma (1 case), and multinodular goiter (1 case). Overall, 33% (13 cases) of thyroid bed FNAs were nondiagnostic, and 10% (4 cases) were categorized as "inflammatory/reactive." None of the patients in these 2 categories demonstrated evidence of clinical recurrence. One patient with a "bland follicular cells" thyroid bed FNA diagnosis had metastatic papillary thyroid carcinoma on follow-up histology. Of 14 patients in the "suspicious" and "malignant" categories, 10 had malignant follow-up diagnosis on histology. In conclusion, thyroid bed FNA with standardized diagnostic categories is a useful modality for follow-up in patients who have undergone thyroidectomy.
Assuntos
Adenocarcinoma Folicular/patologia , Adenoma/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias da Glândula Tireoide/patologia , Adenocarcinoma Folicular/cirurgia , Adenoma/cirurgia , Adolescente , Adulto , Idoso , Biópsia por Agulha Fina , Carcinoma/patologia , Carcinoma/cirurgia , Carcinoma Neuroendócrino , Carcinoma Papilar , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Estudos Retrospectivos , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Adulto JovemRESUMO
BACKGROUND: Vitamin E has a positive effect in the management of osteoarthritis in humans, and in a previous study of dogs. It has been suggested to decrease C-reactive protein concentrations and liver enzyme activities in humans and animals. OBJECTIVE: To assess the effect of vitamin E supplementation on lameness, pain, pain medication requirement, clinical pathology variables, and quality of life in large-breed dogs with naturally occurring osteoarthritis. ANIMALS: Fifty-seven client-owned dogs with naturally occurring osteoarthritis. METHODS: Dogs received either vitamin E or placebo for 90 days in a randomized, placebo-controlled, double-blinded, prospective clinical trial. Clinical lameness scores, pain medication requirements, and owner questionnaires were used to assess response to treatment every 30 days. Blood samples were collected at enrollment and at the end of the study period. RESULTS: Vitamin E administration did not improve pain, lameness, or quality of life as assessed by owners and veterinarians. Vitamin E supplementation did not decrease the requirement for rescue pain relief. No changes in clinical pathology variables were observed after 90 days of vitamin E supplementation. Body weight was negatively associated with the lameness scores and requirement for rescue pain relief. CONCLUSION: Vitamin E supplementation did not have any observable positive effects in dogs with naturally occurring osteoarthritis.
Assuntos
Doenças do Cão , Osteoartrite , Animais , Cães , Suplementos Nutricionais , Doenças do Cão/tratamento farmacológico , Coxeadura Animal/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Osteoartrite/veterinária , Dor/tratamento farmacológico , Dor/veterinária , Estudos Prospectivos , Bem-Estar do AnimalRESUMO
BACKGROUND: People with upper limb amputation are potentially at increased risk of shoulder pain because they often perform compensatory movements to operate their prostheses and rely more heavily on their nonamputated limb for everyday activities. OBJECTIVE: To describe the frequency, severity, associated factors, and implications of shoulder pain in people with unilateral major upper limb amputation who use prostheses. DESIGN: Cross-sectional, observational design. SETTING: National recruitment of people living in the community. PARTICIPANTS: U.S. veterans and civilians (N = 107) with unilateral major upper limb amputation. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Shoulder pain (any, ipsilateral and contralateral to amputation), activity performance (Activities Measure for Upper Limb Amputation), health-related quality of life (Veterans RAND 12-Item Health Survey mental component summary [MCS] and physical component summary [PCS]), and disability (Quick Version of the Disabilities of the Arm, Shoulder and Hand Score [QuickDASH]). RESULTS: All participants completed a comprehensive in-person assessment. Participants were 97% male with a mean age of 57.1 years and a mean time since amputation of 23.4 years. The prevalence of any shoulder pain was 30% (15% ipsilateral, 25% contralateral, 10% bilateral). Shoulder pain intensity (0 to 10 scale) was moderate for both ipsilateral (mean 4.9, SD 2.0) and contralateral (mean 4.2, SD 2.0) pain. No significant difference in shoulder pain frequency was observed by amputation level. The prevalence of any shoulder pain was greater in those using a body-powered prosthesis (38% compared to 18% in externally powered users). Each additional year since amputation was associated with an increased likelihood of having contralateral shoulder pain (odds ratio: 1.05, confidence interval: 1.01, 1.10). In linear regression models, those with contralateral shoulder pain had worse PCS (ß = -7.07, p = .008) and worse QuickDASH (ß = 18.25, p < .001) scores. CONCLUSIONS: In our sample of predominantly male veterans with major upper limb amputation, shoulder pain was a common condition associated with functional and quality of life implications. Among prosthesis users, the shoulder contralateral to the amputation was at greatest risk, with risk increasing with every year since amputation.
Assuntos
Membros Artificiais , Dor de Ombro , Amputação Cirúrgica/efeitos adversos , Amputação Cirúrgica/métodos , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Dor de Ombro/epidemiologia , Dor de Ombro/etiologia , Extremidade Superior/cirurgiaRESUMO
SINEUPs are a novel class of natural and synthetic non-coding antisense RNA molecules able to increase the translation of a target mRNA. They present a modular organization comprising an unstructured antisense target-specific domain, which sets the specificity of each individual SINEUP, and a structured effector domain, which is responsible for the translation enhancement. In order to design a fully functional in vitro transcribed SINEUP for therapeutics applications, SINEUP RNAs were synthesized in vitro with a variety of chemical modifications and screened for their activity on endogenous target mRNA upon transfection. Three combinations of modified ribonucleotides-2'O methyl-ATP (Am), N6 methyl-ATP (m6A), and pseudo-UTP (ψ)-conferred SINEUP activity to naked RNA. The best combination tested in this study was fully modified with m6A and ψ. Aside from functionality, this combination conferred improved stability upon transfection and higher thermal stability. Common structural determinants of activity were identified by circular dichroisms, defining a core functional structure that is achieved with different combinations of modifications.
RESUMO
A 12-year-old cat was presented for investigation of weight loss and inappetence. Radiography and conventional grey-scale ultrasonography showed a large mid-body splenic mass. Contrast enhanced ultrasonography of the liver demonstrated a hypoechoic left lateral lobe nodular mass during the peak and late portal-phases of liver enhancement. Histopathology of the splenic mass and hepatic nodular mass confirmed haemangiosarcoma. The use of ultrasound microbubble contrast media in the diagnosis of hepatic metastasis in the cat has not been previously reported in the cat.
Assuntos
Doenças do Gato/diagnóstico por imagem , Meios de Contraste/administração & dosagem , Hemangiossarcoma/veterinária , Neoplasias Hepáticas/veterinária , Neoplasias Esplênicas/veterinária , Ultrassonografia/veterinária , Animais , Doenças do Gato/cirurgia , Gatos , Hemangiossarcoma/diagnóstico por imagem , Hemangiossarcoma/cirurgia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Masculino , Neoplasias Esplênicas/diagnóstico por imagem , Neoplasias Esplênicas/cirurgia , Resultado do Tratamento , Ultrassonografia/métodosRESUMO
BACKGROUND: The Dachshund is a chondrodystrophic breed of dog predisposed to premature degeneration and calcification, and subsequent herniation, of intervertebral discs (IVDs). This condition is heritable in Dachshunds and breeding candidates are screened for radiographically detectable intervertebral disc calcification (RDIDC), a feature of advanced disc degeneration and a prognostic factor for clinical disease. RDIDC scoring has been previously shown to be consistent within scorers; however, strong scorer effect (subjectivity) was also reported. The aim of this study was to estimate the within- and between-scorer agreement (repeatability and reproducibility, respectively) of computed tomography (CT) scanning and magnetic resonance imaging (MRI) for scoring IVD calcification, and to compare these modalities with radiographic scoring. RESULTS: Twenty-one Dachshund dogs were screened for IVD calcification using the three imaging modalities. Three scorers scored each case twice, independently. Repeatability was highest for radiography (95.4%), and significantly higher than for CT (90.4%) but not MRI (93.8%). Reproducibility was also highest for radiography (92.9%), but not significantly higher than for CT or MRI (89.4% and 86.4%, respectively). Overall, CT scored IVDs differently than radiography and MRI (64.8% and 62.7% agreement, respectively), while radiography and MRI scored more similarly (85.7% agreement). CONCLUSIONS: Despite high precision for radiography, previous evidence of scorer subjectivity was confirmed, which was not generally observed with CT and MRI. The increased consistency of radiography may be related to prior scorer experience with the modality and RDIDC scoring. This study does not support replacing radiography with CT or MRI to screen for heritable IVD calcification in breeding Dachshunds; however, evaluation of dog-level precision and the accuracy of each modality is recommended.
Assuntos
Doenças do Cão/diagnóstico por imagem , Degeneração do Disco Intervertebral/veterinária , Animais , Calcificação Fisiológica , Cães , Feminino , Degeneração do Disco Intervertebral/diagnóstico por imagem , Imageamento por Ressonância Magnética/veterinária , Masculino , Variações Dependentes do Observador , Linhagem , Reprodutibilidade dos Testes , Tomografia Computadorizada por Raios X/veterináriaRESUMO
Herein we describe the identification of 4-{[1,2,4]triazolo[1,5-a]pyridin-5-yl}benzonitrile-based inhibitors of the hypoxia-inducible factor prolylhydroxylase domain-1 (PHD-1) enzyme. These inhibitors were shown to possess a novel binding mode by X-ray crystallography, in which the triazolo N1 atom coordinates in a hitherto unreported monodentate interaction with the active site Fe2+ ion, while the benzonitrile group accepts a hydrogen-bonding interaction from the side chain residue of Asn315. Further optimization led to potent PHD-1 inhibitors with good physicochemical and pharmacokinetic properties.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Triazóis/química , Triazóis/farmacologia , Animais , Cristalografia por Raios X , Cães , Inibidores Enzimáticos/farmacocinética , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/química , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Piridinas/farmacocinética , Triazóis/farmacocinéticaRESUMO
Among dog breeds, the Dachshund has the highest lifetime incidence of intervertebral disc disease (IVDD). Intervertebral disc (IVD) calcification is an indicator of severe degeneration that predisposes to disc herniation. IVDD is heritable in Dachshunds, and in some countries, breeding candidates are screened to reduce IVDD occurrence by selecting dogs according to their score of radiographically detectable intervertebral disc calcification (RDIDC) and excluding dogs with ≥5 RDIDCs from breeding. This study evaluated the precision of scoring spinal radiographs for IVD calcification and subsequent classification of Dachshund dogs for breeding based on their RDIDC score. Digital radiographs of the spine were obtained in 19 clinically healthy, young adult Dachshunds, and scored for RDIDC independently by five scorers with varying levels of experience, three times each. Within scorer (repeatability) and between scorer (reproducibility) variability was estimated both at the individual IVD level and at the whole dog level for breeding classification purposes. At the IVD level, some degree of scorer effect was supported by the pairwise repeatability (92.3%; 95% CI: 88.8-94.7%) being marginally higher than the reproducibility (89.2%; 95% CI: 85.7-91.8%). Scorer-specific patterns confirmed the presence of scorer subjectivity. Repeatability significantly increased with scorer experience but the reproducibility did not. RDIDC scoring repeatability and reproducibility substantially decreased at the cervicothoracic spine region, likely due to anatomical superimpositions. At the dog level, a breeding classification could be repeated by the same scorer for 83.6% (95% CI: 73.8-90.2%) of the dogs, and was reproduced between two scorers for 80.2% (95% CI: 66.6-89.1%) of the dogs. The repeatability of breeding classification also seemed to increase with scorer experience but not the reproducibility. Overall, RDIDC scoring revealed some degree of inconsistency explained by scorer subjectivity and inexperience, and anatomical superimpositions. Scorer training and experience is strongly recommended to improve test precision and ensure appropriate classification of Dachshunds for breeding.