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Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis3-6-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.
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Inflamação , Macrófagos , Proteína Proto-Oncogênica c-ets-2 , Feminino , Humanos , Masculino , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Células Cultivadas , Cromossomos Humanos Par 21/genética , Bases de Dados Factuais , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Genômica , Haplótipos/genética , Inflamação/genética , Doenças Inflamatórias Intestinais/genética , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Proteína Proto-Oncogênica c-ets-2/genética , Proteína Proto-Oncogênica c-ets-2/metabolismo , Reprodutibilidade dos Testes , Fatores de Necrose Tumoral/metabolismo , Interleucina-23/metabolismoRESUMO
PURPOSE: An average parathyroid adenoma (PA) weighs < 1 g. This study aimed to characterise giant PAs ≥ 10 g (GPAs) to facilitate surgical management of primary hyperparathyroidism (PHPT). METHODS: All patients with a GPA confirmed on histology were recruited from the Monash University Endocrine Surgery Unit database. Clinical and demographic data were collected and compared to a group of non-GPA patients. RESULTS: A total of 14 GPAs were identified between 2007 and 2018 out of 863 patients (1.6%) with a single PA excised for PHPT. The GPA patients were compared to a control group of 849 non-GPA patients in the same period with similar mean age (62 ± 16 vs 63 ± 14, P = 0.66) and gender distribution (64% vs 75% female, P = 0.35). Pre-operative calcium (Ca) and parathyroid hormone (PTH) levels were significantly higher in GPA patients (P < 0.001). A higher percentage of GPA patients (79%) had concordant localisation studies (ultrasound and sestamibi) than control patients (59%), (P = 0.13), but they were significantly less likely to undergo MIP (55% vs 82%, P = 0.02). The median GPA weighed 12.5 g (IQR 10.5-24.3). Median serum Ca normalised by day 1 post-operatively, while PTH remained elevated. Both serum Ca and PTH levels were in the normal range at 3 months. All GPA lesions were benign on histopathology. CONCLUSION: GPAs are rare and display severe clinical and biochemical abnormalities. Despite their large size, concordant pre-operative imaging was not always achieved, and a few patients were suitable for MIP.
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Adenoma , Hiperparatireoidismo Primário , Neoplasias das Paratireoides , Humanos , Feminino , Masculino , Neoplasias das Paratireoides/cirurgia , Neoplasias das Paratireoides/patologia , Tecnécio Tc 99m Sestamibi , Paratireoidectomia/métodos , Adenoma/cirurgia , Hormônio Paratireóideo , Hiperparatireoidismo Primário/diagnóstico , Hiperparatireoidismo Primário/cirurgiaRESUMO
INTRODUCTION: The Carica papaya L. leaf is gaining interest as a potential therapeutic agent for alleviating dengue- and non-dengue-associated thrombocytopaenia. In that regard, safety considerations are as important as efficacy potential. The safety evaluation of botanical products for human use is complicated by variable formulations, complex phytochemical composition, and extrinsic toxicants. This review aimed to systematically collate related safety clinical and preclinical data, as well as reports on herb-drug interactions of C. papaya leaf consumption. METHODS: A systematic search using predetermined keywords on electronic databases (MEDLINE, Cochrane Library Central, LILACS, and Web of Science) and grey literature was conducted. Relevant clinical and preclinical studies were identified, screened, and analysed to present an overall safety profile of C. papaya leaf consumption. RESULTS: A total of 41 articles were included (23 clinical, 5 ongoing trials, and 13 preclinical) for descriptive analysis on study characteristics, adverse reactions, toxicity findings, and herb-drug interactions, from which 13 randomised controlled and quasiexperimental trials were further assessed for risk of bias and reporting quality. Overall, C. papaya leaf consumption (in the form of juice and standardised aqueous extract) was well tolerated by adult humans for short durations (
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BACKGROUND: Postoperative colorectal anastomotic strictures are quite common. As such, many techniques have been available to address such a problem, one of which is endoscopic dilation. The aim of the present study was to evaluate the long-term outcomes following endoscopic dilation using a multidiameter balloon. METHODS: A retrospective study was conducted on patients with postoperative anastomotic stenosis treated with endoscopic dilation using a multidiameter balloon at our institution, in January 2005-December 2019 were retrospectively reviewed, excluding those with tumor recurrence. Perioperative factors, complications, and recurrence rates were analyzed. RESULTS: There were 40 patients, (22 males and 18 females, mean age 64.6 ± 10.7 years, range 33-84 years). The median follow-up period was 56 months (interquartile range 22.5-99 months). Only 1 complication occurred, micro-perforation due to guided wire injury, which was managed conservatively. Five (12.5%) patients developed restenosis and underwent repeat balloon dilation. None of the five recurrences required more aggressive management, such as redo anastomosis. CONCLUSIONS: Endoscopic multidiameter balloon dilation is a safe and effective method for treating benign colorectal anastomotic strictures.
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Neoplasias Colorretais , Complicações Pós-Operatórias , Adulto , Idoso , Idoso de 80 Anos ou mais , Anastomose Cirúrgica/efeitos adversos , Neoplasias Colorretais/cirurgia , Constrição Patológica/etiologia , Constrição Patológica/cirurgia , Dilatação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/terapia , Estudos Retrospectivos , Resultado do TratamentoAssuntos
Coronavirus , Pneumonia Viral , Betacoronavirus , COVID-19 , Infecções por Coronavirus , Feminino , Humanos , Pandemias , Período Pós-Parto , Gravidez , SARS-CoV-2Assuntos
Infecções por Coronavirus/prevenção & controle , Transmissão de Doença Infecciosa do Paciente para o Profissional/prevenção & controle , Transmissão de Doença Infecciosa do Profissional para o Paciente/prevenção & controle , Pandemias/prevenção & controle , Equipamento de Proteção Individual , Pneumonia Viral/prevenção & controle , Ultrassonografia Pré-Natal/métodos , COVID-19 , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/transmissão , Contaminação de Equipamentos/prevenção & controle , Dispositivos de Proteção dos Olhos , Feminino , Luvas Protetoras , Ginecologia , Higiene das Mãos , Pessoal de Saúde , Humanos , Máscaras , Programas de Rastreamento , Obstetrícia , Pneumonia Viral/diagnóstico , Pneumonia Viral/transmissão , Gravidez , Dispositivos de Proteção Respiratória , Triagem , Ultrassonografia/métodos , VentilaçãoAssuntos
Infecções por Coronavirus/complicações , Pessoal de Saúde , Pneumonia Viral/complicações , Período Pós-Parto , Complicações Infecciosas na Gravidez/virologia , COVID-19 , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/terapia , Feminino , Humanos , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/terapia , Guias de Prática Clínica como Assunto , Gravidez , Papel Profissional , Sociedades Médicas , UltrassonografiaRESUMO
AIMS: The concept of using specific dietary components to selectively modulate the gut microbiota to confer a health benefit, defined as prebiotics, originated in 1995. In 2018, a group of scientists met at the International Scientific Association for Probiotics and Prebiotics annual meeting in Singapore to discuss advances in the prebiotic field, focussing on issues affecting functionality, research methodology and geographical differences. METHODS AND RESULTS: The discussion ranged from examining scientific literature supporting the efficacy of established prebiotics, to the prospects for establishing health benefits associated with novel compounds, isolated from different sources. CONCLUSIONS: While many promising candidate prebiotics from across the globe have been highlighted in preliminary research, there are a limited number with both demonstrated mechanism of action and defined health benefits as required to meet the prebiotic definition. Prebiotics are part of a food industry with increasing market sales, yet there are great disparities in regulations in different countries. Identification and commercialization of new prebiotics with unique health benefits means that regulation must improve and remain up-to-date so as not to risk stifling research with potential health benefits for humans and other animals. SIGNIFICANCE AND IMPACT OF STUDY: This summary of the workshop discussions indicates potential avenues for expanding the range of prebiotic substrates, delivery methods to enhance health benefits for the end consumer and guidance to better elucidate their activities in human studies.
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Pesquisa Biomédica/normas , Congressos como Assunto , Indústria Alimentícia/normas , Prebióticos/normas , Animais , Dieta , Indústria Alimentícia/legislação & jurisprudência , Microbioma Gastrointestinal , Humanos , Prebióticos/administração & dosagem , Prebióticos/análise , Singapura , Sociedades CientíficasRESUMO
B cells are important in the pathogenesis of many, and perhaps all, immune-mediated diseases. Each B cell expresses a single B cell receptor (BCR)1, and the diverse range of BCRs expressed by the total B cell population of an individual is termed the 'BCR repertoire'. Our understanding of the BCR repertoire in the context of immune-mediated diseases is incomplete, and defining this could provide new insights into pathogenesis and therapy. Here, we compared the BCR repertoire in systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Crohn's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis, and immunoglobulin A (IgA) vasculitis by analysing BCR clonality, use of immunoglobulin heavy-chain variable region (IGHV) genes and-in particular-isotype use. An increase in clonality in systemic lupus erythematosus and Crohn's disease that was dominated by the IgA isotype, together with skewed use of the IGHV genes in these and other diseases, suggested a microbial contribution to pathogenesis. Different immunosuppressive treatments had specific and distinct effects on the repertoire; B cells that persisted after treatment with rituximab were predominately isotype-switched and clonally expanded, whereas the inverse was true for B cells that persisted after treatment with mycophenolate mofetil. Our comparative analysis of the BCR repertoire in immune-mediated disease reveals a complex B cell architecture, providing a platform for understanding pathological mechanisms and designing treatment strategies.
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Doenças do Sistema Imunitário/imunologia , Isotipos de Imunoglobulinas/análise , Isotipos de Imunoglobulinas/imunologia , Receptores de Antígenos de Linfócitos B/análise , Receptores de Antígenos de Linfócitos B/imunologia , Adulto , Idoso , Células Clonais/citologia , Células Clonais/imunologia , Humanos , Imunoglobulina A/análise , Imunoglobulina A/imunologia , Switching de Imunoglobulina/imunologia , Imunoglobulina G/análise , Imunoglobulina G/imunologia , Pessoa de Meia-Idade , Adulto JovemRESUMO
A 16-year-old male Russian blue cat was presented with acute onset of paraparesis of the forelimbs that progressed to tetraparesis. Neurological examination revealed non-ambulatory tetraparesis with decreased postural reactions in all four limbs. Magnetic resonance imaging revealed multifocal nerve root swelling on the right at C6/C7 and C7/T1, while ultrasonography demonstrated swelling of the right brachial plexus. To understand the cause of the nerve swelling, the right musculocutaneous nerve arising from the brachial plexus and the pectoralis muscle were biopsied. Histologically, there was evidence of neurolymphomatosis (neurotropic lymphoma) with Wallerian degeneration and denervation atrophy of myofibres. The neoplastic lymphoid cells expressed CD79a, CD20 and CD56. Based on these findings, a diagnosis of B-cell neurolymphomatosis was made. Expression of CD56, synonymous with neural cell adhesion molecule, is rare in B-cell lymphomas and has not been reported in feline B-cell lymphomas or feline neurolymphomatosis. CD56 expression was suspected to have played an important role in neurotropism of the neoplastic cells in this case.
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Doenças do Gato/patologia , Linfoma de Células B/veterinária , Neurolinfomatose/veterinária , Animais , Antígeno CD56 , Gatos , MasculinoRESUMO
The origin of deterministic macroscopic properties often lies in microscopic stochastic motion. Magnetic fluctuations that manifest as domain avalanches and chaotic magnetization jumps exemplify such stochastic motion and have been studied in great detail. Here we report Fourier space studies of avalanches in a system exhibiting competing magnetic stripe and skyrmion phase using a soft X-ray speckle metrology technique. We demonstrate the existence of phase boundaries and underlying critical points in the stripe and skyrmion phases. We found that distinct scaling and universality classes are associated with these domain topologies. The magnitude and frequency of abrupt magnetic domain jumps observed in the stripe phase are dramatically reduced in the skyrmion phase. Our results provide an incisive way to probe and understand phase stability in systems exhibiting complex spin topologies.
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The original version of this Article contained an error in Fig. 4d, in which the label of the region to the left of the white dashed lines incorrectly read 'Order stripes'. The correct version states 'Disorder stripes'. This has been corrected in both the PDF and HTML versions of the Article.
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BACKGROUND: Azelastine hydrochloride (azelastine) nasal spray is a histamine receptor-1 (H1) antagonist often used in treating allergic rhinitis to relieve its symptoms. However, the effects of azelastine to influence decongestion on human nasal mucosa in patients with allergic rhinitis are not yet fully explored and merit further exploration. The effects of azelastine on the vasocontractile responses generated by smooth muscles in the vascular structures of human nasal mucosa were investigated directly in vitro. METHODS: We examined the effectiveness of azelastine on isolated human nasal mucosa by testing: 1) the effect on mucosa resting tension; 2) the effect on mucosal contraction caused by 10-6 M methoxamine as a sympathetic mimetic; 3) the effect of the drugs on electrically induced mucosal contractions. RESULTS: The results indicated that addition of methoxamine to the incubation medium caused the nasal mucosa to contract in a dose-dependent manner. Addition of azelastine at doses of 10â"6 M or above elicited a significant dilation response to 10â"6 M methoxamine-induced mucosal contraction. Azelastine could inhibit electrical field stimulation-induced spike mucosal contraction. Moreover, increase in concentration of azelastine had minimal effect on basal tension of nasal mucosa. CONCLUSIONS: The technique in our study is simple and reproducible. Azelastine could inhibit both EFS and methoxamine-induced nasal mucosal contractions in vitro. This study highlights that although azelastine nasal spray is often used in treating allergic rhinitis to improve symptoms, nasal obstruction may be not relieved immediately due to the anti-sympathetic effect of azelastine.
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Anti-Inflamatórios não Esteroides , Mucosa Nasal , Ftalazinas , Rinite Alérgica , Rinite , Administração Intranasal , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Método Duplo-Cego , Humanos , Mucosa Nasal/efeitos dos fármacos , Sprays Nasais , Ftalazinas/farmacologia , Ftalazinas/uso terapêutico , Rinite/tratamento farmacológicoRESUMO
BACKGROUND: The number and calibre of myelinated and unmyelinated fibres of the sacrococcygeal dorsal roots innervating the tail of rats were studied by means of light and electron microscopy. MATERIALS AND METHODS: There were an estimated total of 12,500 myelinated and 25,500 unmyelinated dorsal root fibres innervating the tail of a rat. RESULTS: The results showed that from the second sacral (S2) to the fourth sacral (S4) segment, the fibre diameter spectrum of myelinated fibres within each dorsal root was bimodal with two peaks at 5 microns and 10 microns, respectively. The first sacral (S1) segment was composed of numerous smaller-size myelinated fibres, thus forming a right-skewed distribution. The coccygeal (Co) segments showed a unimodal distribution peaking at 10 microns for the first (Co1) segment and gradually shifting to 7 microns for the third (Co3) segment. Overall, there was a continuous relative increase of the larger vs. the smaller myelinated fibres from the sacral to coccygeal segments. The fibre diameter of unmyelinated fibres of all these roots was unimodal with a single peak at 0.5 microns. The ratio of unmy- elinated to myelinated fibre numbers was on average 2.83 for the S1-S2 roots, 1.66 for the S3-S4 roots, and 1.24 for the coccygeal roots. CONCLUSIONS: The comparison of the left- and right-side nerve fibres show that there was no significant difference, thus implying a symmetrical sensory innervation of the rat's tail.
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Bainha de Mielina/fisiologia , Fibras Nervosas/fisiologia , Região Sacrococcígea/anatomia & histologia , Raízes Nervosas Espinhais/anatomia & histologia , Animais , Axônios/ultraestrutura , Masculino , Bainha de Mielina/ultraestrutura , Fibras Nervosas/ultraestrutura , Ratos Wistar , Raízes Nervosas Espinhais/ultraestruturaRESUMO
GABAergic interneurons regulate the degree of glutamatergic excitation and output of projection neurons. In this study, we investigated the distribution of calbindinD-28k (CB) and parvalbumin (PV) in the somatosensory area of the pigeon pallium using immunohistochemical method. Our results show that anatomical structures of the somatosensory area of the pigeon pallium consisted of several subdivisions including the hyperpallium, intercalated hyperpallium, mesopallium, nidopallium and basorostralis. Neuronal density was significantly higher in the intercalated hyperpallium and basorostralis than that in the other subdivisions. The density of the CB immunoreactive neurons was generally similar in all the subdivisions; however, the density of PV immunoreactive neurons was particularly prominent in the basorostralis compared with that in the other subdivisions. In addition, the mean proportion of PV immunoreactive neurons to total neurons was higher than that in the CB immunoreactive neurons in all the subdivisions. In brief, our present study shows that PV immunoreactive neurons in the somatosensory area of the pigeon pallium were significantly abundant compared with CB immunoreactive neurons. This finding needs more studies regarding CB- and PV-related functions in the somatosensory area of the avian pallium.
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Calbindina 1/metabolismo , Columbidae/metabolismo , Neurônios/metabolismo , Parvalbuminas/metabolismo , Córtex Somatossensorial/metabolismo , Animais , Benzoxazinas , Contagem de Células/veterinária , Corantes , Substância Cinzenta/citologia , Substância Cinzenta/metabolismo , Imuno-Histoquímica/veterinária , Masculino , Neurônios/citologia , Córtex Somatossensorial/citologia , Telencéfalo/citologia , Telencéfalo/metabolismo , Substância Branca/citologia , Substância Branca/metabolismoRESUMO
Genetic studies in complex diseases have been highly successful, but have also been largely one-dimensional: predominantly focusing on the genetic contribution to disease susceptibility. While this is undoubtedly important-indeed it is a pre-requisite for understanding the mechanisms underlying disease development-there are many other important aspects of disease biology that have received comparatively little attention. In this review, I will discuss how existing genetic data can be leveraged to provide new insights into other aspects of disease biology, why such insights could change the way we think about complex disease, and how this could provide opportunities for better therapies and/or facilitate personalised medicine. To do this, I will use the example of Crohn's disease-a chronic form of inflammatory bowel disease that has been one of the main success stories in complex disease genetics. Indeed, thanks to genetic studies, we now have a much more detailed understanding of the processes involved in Crohn's disease development, but still know relatively little about what determines the subsequent disease course (prognosis) and why this differs so considerably between individuals. I will discuss how we came to realise that genetic variation plays an important role in determining disease prognosis and how this has changed the way we think about Crohn's disease genetics. This will illustrate how phenotypic data can be used to leverage new insights from genetic data and will provide a broadly applicable framework that could yield new insights into the biology of multiple diseases.
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Doença de Crohn/genética , Regulação da Expressão Gênica , Predisposição Genética para Doença , Variação Genética , Genoma Humano , Alelos , Doença de Crohn/diagnóstico , Doença de Crohn/imunologia , Doença de Crohn/patologia , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/imunologia , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/imunologia , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/imunologia , Prognóstico , Índice de Gravidade de Doença , Proteína Smad3/genética , Proteína Smad3/imunologia , Receptor 10 Toll-Like/genética , Receptor 10 Toll-Like/imunologiaRESUMO
Few studies regarding the anatomical distribution of motor neurons innervating muscles of the arm have been demonstrated in avian brains. The purpose of this study was to finely determine the localization of cerebral neurons innervating the biceps brachii muscle in the pigeon. The cholera toxin B subunit (CTB) was employed as a retrograde tracer to determine the location of neurons controlling the biceps brachii muscle in the telencephalon following intramuscular injection in male pigeons (n = 7), which were killed 14 days after intramuscular injection with CTB. We found that CTB-labelled neurons were located contralaterally in the hyperpallium apicale of the rostral telencephalon and that most of the CTB-labelled neurons were pyramidal in shape. This study shows that CTB is easily taken up by nerve terminals which innervate the biceps brachii muscle of the pigeon and that cerebral motor neurons controlling the biceps brachii muscle are located in the hyperpallium apicale.
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Columbidae/anatomia & histologia , Músculo Esquelético/inervação , Neurônios/citologia , Telencéfalo/citologia , Asas de Animais/inervação , Animais , Benzoxazinas , Toxina da Cólera , Corantes , Columbidae/fisiologia , Masculino , Músculo Esquelético/citologia , Músculo Esquelético/fisiologia , Asas de Animais/citologia , Asas de Animais/fisiologiaRESUMO
We report an x-ray photon correlation spectroscopy method that exploits the recent development of the two-pulse mode at the Linac Coherent Light Source. By using coherent resonant x-ray magnetic scattering, we studied spontaneous fluctuations on nanosecond time scales in thin films of multilayered Fe/Gd that exhibit ordered stripe and Skyrmion lattice phases. The correlation time of the fluctuations was found to differ between the Skyrmion phase and near the stripe-Skyrmion boundary. This technique will enable a significant new area of research on the study of equilibrium fluctuations in condensed matter.