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BACKGROUND AND OBJECTIVES: While adult chronic cough has high burden, its phenotypes, particularly those without aetiologically related underlying conditions, are understudied. We investigated the prevalence, lung function and comorbidities of adult chronic cough phenotypes. METHODS: Data from 3608 participants aged 53 years from the Tasmanian Longitudinal Health Study (TAHS) were included. Chronic cough was defined as cough on most days for >3 months in a year. Chronic cough was classified into "explained cough" if there were any one of four major cough-associated conditions (asthma, COPD, gastroesophageal reflux disease or rhinosinusitis) or "unexplained cough" if none were present. Adjusted regression analyses investigated associations between these chronic cough phenotypes, lung function and non-respiratory comorbidities at 53 years. RESULTS: The prevalence of chronic cough was 10% (95%CI 9.1,11.0%) with 46.4% being "unexplained". Participants with unexplained chronic cough had lower FEV1/FVC (coefficient: -1.2% [95%CI:-2,3, -0.1]) and increased odds of comorbidities including obesity (OR=1.6 [95%CI: 1.2, 2.3]), depression (OR=1.4 [95%CI: 1.0, 2.1]), hypertension (OR=1.7 [95%CI: 1.2, 2.4]) and angina, heart attack or myocardial infarction to a lesser extent, compared to those without chronic cough. Participants with explained chronic cough also had lower lung function than both those with unexplained chronic cough and those without chronic cough. CONCLUSIONS: Chronic cough is prevalent in middle-age and a high proportion is unexplained. Unexplained cough contributes to poor lung function and increased comorbidities. Given unexplained chronic cough is not a symptom of major underlying respiratory conditions it should be targeted for better understanding in both clinical settings and research.
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Purpose: There is an increasing interest in the use of non-nutritive sweeteners to replace added sugar in food and beverage products for reasons of improving consumer health. Much work has been done to understand safety of sweeteners, but very little on sustainability. To address that gap, this study presents the results of a life cycle assessment (LCA) of production of rebaudioside A 60%, 95% pure (RA60) steviol glycoside mix from Stevia rebaudiana leaf grown in Europe. Methods: An attributional cradle-to-factory-gate life cycle assessment was conducted on growing of stevia leaves and extraction of steviol glycosides in Europe. Primary data were used from a case study supply chain. Results are reported in impact categories from the ReCiPe 2016 (H) method, with focus given to global warming potential, freshwater eutrophication, water consumption, and land use. Impacts are expressed both in terms of production mass and sweetness equivalence, a common metric for understanding high intensity sweetener potency. Sweetness equivalence of RA60 is typically 200 to 300 times that of sugar. Comparison of environmental impact is made to sugar (sucrose) produced from both cane and beets. The research is part of the EU project SWEET (sweeteners and sweetness enhancers: impact on health, obesity, safety, and sustainability). Results and discussion: Global warming potential for production of RA60 was found to be 20.25 kgCO2-eq/kgRA60 on a mass basis and 0.081 kgCO2-eq/kgSE on a sweetness equivalence basis. Field production of stevia leaves was found to be the main source of impact for most impact categories, and for all four focus categories. Extraction of the RA60 was the main source of impact for the others. Leaf processing and seedling propagation were minor contributors to life cycle impact. Removal of international transport from the supply chain reduced global warming potential by 18.8%. Compared with sugar on a sweetness equivalence basis, RA60 has approximately 5.7% to 10.2% the impact for global warming potential, 5.6% to 7.2% the impact for land use, and is lower across most other impact categories. Conclusion: This is the first LCA of steviol glycoside mix RA60 produced from leaf in Europe. The results indicate that RA60 can be used to reduce environmental impact of providing a sweet taste by replacing sugar across all impact categories. However, it is important to note that specific formulations in which RA60 is used will have a bearing on the final environmental impact of any food or beverage products. For solid foods, this requires further research. Supplementary Information: The online version contains supplementary material available at 10.1007/s11367-022-02127-9.
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Modern radiotherapy techniques (intensity-modulated radiotherapy, volumetric-modulated arctherapy, image-guided radiotherapy) or stereotactic radiotherapy are in expansion in most French cancer centres. The arrival of such techniques requires updates of existing equipment or implementation of new radiotherapy devices with adapted options. With the arrival of these new devices, there is a need to develop a quality and safety policy. This is necessary to ease the process from the setup to the first treated patient. The quality and safety policy is maintained to ensure the quality assurance of the radiotherapy equipment. We conducted a review of the literature on the quality and safety policy in the French legal framework that can be proposed when implementing a new radiotherapy device.
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Controle de Qualidade , Radioterapia/instrumentação , Gestão da Segurança , Desenvolvimento de Pessoal , Equipamentos e Provisões , Humanos , Política Organizacional , Garantia da Qualidade dos Cuidados de Saúde , Gestão de RiscosRESUMO
BACKGROUND: The menopausal transition may have significant consequences for respiratory health, risk of chronic respiratory disease and management strategies. OBJECTIVE: To systematically summarize the literature regarding the impact of menopause status on respiratory health outcomes. METHODS: PubMed was searched systematically to identify population-based studies investigating the associations between menopause status and respiratory outcomes including asthma, chronic obstructive pulmonary disease (COPD), respiratory symptoms and lung function. RESULTS: Ten publications were identified for full review. Evidence on menopause and asthma was conflicting, while studies on COPD were scarce. The findings generally support an association between menopause and clinically significant reductions in lung function in a non-obstructive pattern. However, the effects of menopause are clouded by aging, menopausal hormone therapy use, and increased risk of metabolic syndrome during this period. CONCLUSIONS: As the global burden associated with respiratory conditions continues to rise, the need to understand the associations between menopause and respiratory health is essential to identify potentially modifiable risk factors for respiratory disease in adult women. More studies are needed to clarify the impact of menopause on obstructive lung disease.
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Asma/fisiopatologia , Pulmão/fisiopatologia , Menopausa , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Feminino , Humanos , Fatores de RiscoRESUMO
To evaluate the association between pre-natal and post-natal exposure to pet ownership and lung function in children, a cross-sectional study named Seven Northeastern Cities (SNEC) study was conducted. In this study, children's lung function including the forced expiratory volume in 1 second (FEV1 ), forced vital capacity (FVC), maximal mid-expiratory flow (MMEF), and peak expiratory flow (PEF) were measured by spirometers, and pet ownership situations were collected by questionnaire. Analyzed by multiple logistic regression and generalized linear modeling, we found that for all subjects, pet exposure in the first 2 years of life was significantly associated with lung function impairment of FVC<85% predicted (adjusted odds ratio [aOR]=1.28; 95% confidence interval [CI]: 1.01, 1.63). For current pet exposure, the increased odds of lung function impairment ranged from 35% (aOR=1.35; 95%CI: 1.12, 1.62) for FVC<85% predicted to 57% (aOR=1.57; 95%CI: 1.29, 1.93) for FEV1 <85% predicted. The in utero exposure was not related to lung function impairment. Compared with other pets, higher odds were observed among children with dogs. When stratified by gender, girls with current pet exposure were more likely to have lung function impairment than boys. It implies self-reported exposures to pets were negatively associated with lung function among the children under study.
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Pulmão/fisiologia , Animais de Estimação , Efeitos Tardios da Exposição Pré-Natal , Adolescente , Animais , Aves , Gatos , Criança , Estudos Transversais , Cães , Feminino , Humanos , Masculino , Gravidez , Testes de Função RespiratóriaRESUMO
STUDY OBJECTIVE: The current study examines patients' comprehension of their emergency department (ED) encounter, using physician observers to document both physician communication and details of the encounter. METHODS: Eighty-nine patients were recruited from a convenience sample in an urban ED. To be included in this study, patients had to have low triage levels (4 and 5) and be discharged from the ED. Physician observers were present throughout the encounter, documenting physician communication and procedures performed. Patients were then interviewed by physician observers about their communication with physicians, accuracy in recalling facts about the encounter, and understanding of information provided during the encounter. RESULTS: The majority of patients were black and had a high school education. Physicians typically engaged in behaviors related to building rapport and diagnosing patients. However, physicians informed patients about test results and diagnoses less frequently. In terms of patients' accuracy and understanding of the visit, patients were generally aware of basic facts in regard to their ED encounter (ie, whether they had blood drawn), but 65.9% of patients demonstrated less than "good" understanding in at least 1 area assessed. CONCLUSION: The findings of the current study indicate physicians could improve communication with patients, particularly in regard to care received in the ED. This study also indicates that a large percentage of patients fail to understand information about their ED encounter even when physicians provide it. A primary limitation of the current study is the relatively homogenous physician sample.
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Comunicação , Compreensão , Serviço Hospitalar de Emergência , Adolescente , Adulto , Negro ou Afro-Americano , Idoso , Feminino , Pesquisa sobre Serviços de Saúde , Hospitais Urbanos , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Relações Médico-Paciente , Projetos Piloto , Adulto JovemRESUMO
The impact of early childhood traffic-related air pollution (TRAP) exposure on development of asthma and allergies remains unclear. Birth cohort studies are the best available study design to answer this question, but the evidence from such studies has not been synthesized to date. We conducted a systematic review and meta-analyses of published birth cohort studies to understand the association between early childhood TRAP exposure, and subsequent asthma, allergies and sensitization. Increased longitudinal childhood exposure to PM2.5 and black carbon was associated with increasing risk of subsequent asthma in childhood (PM2.5 : OR 1.14, 95%CI 1.00 to 1.30 per 2 µg/m(3) and black carbon: OR 1.20, 95%CI 1.05 to 1.38 per 1 × 10(-5) m(-1) ). Also, early childhood exposure to TRAP was associated with development of asthma across childhood up to 12 years of age. The magnitude of these associations increased with age, and the pattern was prominent for PM2.5 . Increasing exposure to PM2.5 was associated with sensitization to both aero- and food allergens. There was some evidence that TRAP was associated with eczema and hay fever. In summary, exposure to TRAP was related to asthma and allergic diseases. However, the substantial variability across studies warrants long-term birth cohort studies with regular repeated follow-ups to confirm these findings.
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Poluentes Atmosféricos/efeitos adversos , Poluição do Ar/efeitos adversos , Exposição Ambiental/efeitos adversos , Hipersensibilidade/epidemiologia , Hipersensibilidade/etiologia , Veículos Automotores , Alérgenos/imunologia , Asma/epidemiologia , Asma/etiologia , Criança , Pré-Escolar , Estudos de Coortes , Humanos , Incidência , Lactente , Recém-NascidoRESUMO
Advances in mobile phone technology now provide a myriad of resources to physicians' fingertips. However, the medical profession continues to struggle with potential for misuse of these devices. There is a need for better understanding of physicians' uses of smartphones in order to establish guidelines for appropriate and professional behavior. The purpose of the current study was to survey physicians' and medical students' practices concerning smartphone use in the healthcare setting. Physicians and medical students were asked to complete anonymous surveys regarding uses of smartphones within the past month in various healthcare settings. Overall, the participants reported distinctly different patterns in the uses they made of their phones in different settings (P<.001), with most individuals engaging in most behaviors while on break but few using their smartphones while with patients or during procedures. It appears that physicians and medical students make decisions about using their smartphones according to some combination of three considerations: degree of relevance to patient care, the appropriateness of the behavior in front of patients, and the issue of how disruptive that behavior may be.
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Telefone Celular/estatística & dados numéricos , Médicos , Estudantes de Medicina , Centros Médicos Acadêmicos , Feminino , Humanos , Masculino , Assistência ao PacienteRESUMO
OBJECTIVE: The purpose of this study was to determine if patients with nontraumatic causes of elevated intracranial pressure (ICP) could be identified by ultrasound measurement of optic nerve sheath diameter (ONSD). It was hypothesized that an ONSD greater than or equal to 5 mm would identify patients with elevated ICP. METHOD: This was a prospective observational trial comparing ONSD with ICP measured by opening pressure manometry on lumbar puncture (LP). The cohort consisted of a convenience sample of adult patients presenting to the emergency department, requiring LP. The ONSD measurement was performed before computed tomography and LP. The physician performing the LP was blinded to the result of the ONSD measurement. An opening pressure on manometry of greater than or equal to 20 cm H2O and an ONSD greater than or equal to 5 mm were considered elevated. RESULTS: Fifty-one patients were included in our study, 24 (47%) with ICP greater than or equal to 20 cm H2O and 27 (53%) with ICP less than 20 cm H2O. The sensitivity of ONSD greater than or equal to 5 for identifying elevated ICP was 75% (95% confidence interval, 53%-90%) with specificity of 44% (25%-65%). The area under the receiver operator characteristic curve was 0.69 (0.54-0.84), suggesting a relationship between ONSD and ICP. CONCLUSION: An ONSD greater than or equal to 5 mm was associated with elevated ICP in nontraumatic causes of elevated ICP. Although a relationship exists, a sensitivity of 75% does not make ONSD measurement an adequate screening examination for elevated ICP in this patient population.
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Hipertensão Intracraniana/patologia , Nervo Óptico/patologia , Punção Espinal , Adulto , Biomarcadores , Estudos Transversais , Feminino , Humanos , Hipertensão Intracraniana/diagnóstico , Pressão Intracraniana , Masculino , Manometria , Nervo Óptico/diagnóstico por imagem , Estudos Prospectivos , Sensibilidade e Especificidade , UltrassonografiaRESUMO
Osmotic changes occur in many tissues and profoundly influence cell function. Herein, we investigated the effect of hyperosmotic stress on retinal pigmented epithelial (RPE) cells using a microarray approach. Upon 4-h exposure to 100 mM NaCl or 200 mM sucrose, 79 genes were downregulated and 72 upregulated. Three gene ontology categories were significantly modulated: cell proliferation, transcription from RNA polymerase II promoter and response to abiotic stimulus. Fluorescent-activated cell sorting analysis further demonstrated that owing to hyperosmotic stimulation for 24 h, cell count and cell proliferation, as well as the percentage of cells in G0/G1 and S phases were significantly decreased, whereas the percentage of cells in G2/M phases increased, and apoptosis and necrosis remained unaffected. Accordingly, hyperosmotic conditions induced a decrease of cyclin B1 and D1 expression, and an activation of the p38 mitogen-activated protein kinase. In conclusion, our results demonstrate that hypertonic conditions profoundly affect RPE cell gene transcription regulating cell proliferation by downregulation cyclin D1 and cyclin B1 protein expression.
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Pontos de Checagem do Ciclo Celular , Células Epiteliais/metabolismo , Pressão Osmótica , Epitélio Pigmentado da Retina/citologia , Linhagem Celular , Proliferação de Células , Ontologia Genética , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação , Processamento de Proteína Pós-Traducional , Cloreto de Sódio/farmacologia , Estresse Fisiológico , Transcriptoma , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Acaricide resistance of the cattle tick Rhipicephalus (Boophilus) microplus is widespread in most of the countries where this parasite is present. Bioassays are used to diagnose the level and pattern of resistance in tick populations. In the present study, we describe a detailed protocol of the Larval Tarsal Test (LTT) using simplified equipment and data on the resistance of 17 tick field populations originating from 5 Brazilian states. Nine acaricidal compounds from 5 major classes were tested: organophosphates (OP), synthetic pyrethroids (SP), macrocyclic lactones (ML), phenylpyrazols (PYZ) and amidines. For comparison, four of the tick populations were also tested with the Larval Packet Test (LPT) with one compound per class. The most common resistances were to SP, amitraz and OP, with frequencies of 94%, 88% and 82%, respectively. Resistance to PYZ was also found to be widespread (65%), suggesting a rapid development of fipronil resistance in Brazil. One case of ML resistance and 2 cases of suspected ML resistance were identified with the LTT. The LTT led to higher resistance ratios to all compounds than the LPT, reflecting its high sensitivity to detect resistance. Finally, the LTT allowed testing a larger number of compounds and doses with reduced labour in comparison to the LPT and turned out to be a reliable bioassay to detect resistance in field populations.
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Acaricidas/farmacologia , Rhipicephalus/efeitos dos fármacos , Animais , Brasil , Resistência a Inseticidas , Larva/efeitos dos fármacos , Dose Letal Mediana , Análise de SobrevidaRESUMO
Aquaglyceroporin 7 (AQP7) is a glycerol transporter expressed in adipocytes. Its expression has been shown to be modulated in obesity. Metabolic syndrome is characterized by abdominal obesity, insulin resistance, dyslipidemia, and hypertension. An animal model displaying several features of metabolic syndrome was used to study the AQP7 expression at both mRNA and protein level and glycerol flux in adipocytes. Second generation n3-PUFA depleted female rats is a good animal model for metabolic syndrome as it displays characteristic features such as liver steatosis, visceral obesity, and insulin resistance. Our data show a reduced expression of AQP7 at the protein level in adipose tissue from n3-PUFA-depleted rats, without any changes at the mRNA levels. [U-(14)C]-Glycerol uptake was not modified in adipocytes from n3-PUFA-depleted animals.
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Adipócitos/metabolismo , Ácidos Graxos Insaturados/deficiência , Glicerol/metabolismo , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Tecido Adiposo/metabolismo , Animais , Aquaporinas/genética , Aquaporinas/metabolismo , Modelos Animais de Doenças , Ácidos Graxos Insaturados/metabolismo , Feminino , Regulação da Expressão Gênica , Espaço Intracelular/metabolismo , Metabolismo dos Lipídeos , Ratos , Fatores de TempoAssuntos
Autoanticorpos/sangue , Infarto do Miocárdio/sangue , Troponina/sangue , Troponina/imunologia , Síndrome Coronariana Aguda/diagnóstico , Biomarcadores/sangue , Índice de Massa Corporal , Dor no Peito/etiologia , Diagnóstico Diferencial , Eletrocardiografia , Feminino , Humanos , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/terapia , Obesidade Mórbida/complicações , Recidiva , Fatores de Risco , Resultado do TratamentoRESUMO
In this article we present a new bioassay to assess the resistance status of ticks to acaricides. The Larval Tarsal Test (LTT) is a sensitive, highly time-effective in vitro test. It allows the investigation of a large number of compounds and doses on the cattle tick Rhipicephalus (Boophilus) microplus in a short period of time. The ability of the LTT to assess the lethal concentration at 50% mortality (LC(50)) and resistance ratios (RRs) of a susceptible and a resistant R. microplus strain was compared with the FAO-recommended Larval Packet Test (LPT). Representative compounds of the carbamate, organophosphate (OP), synthetic pyrethroid (SP), formamidine (FOR), macrocyclic lactone and pyrazole classes were used for this comparison. The resistance status against OP, SP and FOR of the resistant R. microplus strain was confirmed in vivo. The LTT resulted in resistance ratios comparable to those obtained with the LPT. However, the lethal concentrations were up to 150-fold lower in the LTT than in the LPT. The advantage of the LTT is to simplify the methodology by avoiding the handling of larvae and using multi-well plates. The LTT is therefore a suitable test for the assessment of the level of resistance of R. microplus and is very promising to evaluate the resistance profile of field strains. Additionally, the LTT is also suitable to test other ixodid species.
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Acaricidas/farmacologia , Resistência a Inseticidas , Ixodidae/efeitos dos fármacos , Animais , Bovinos , Doenças dos Bovinos/parasitologia , Relação Dose-Resposta a Droga , Masculino , Infestações por Carrapato/tratamento farmacológico , Infestações por Carrapato/parasitologiaRESUMO
Many women of childbearing age from sub-Saharan Africa use topical skin lighteners, some of which present a risk of toxic systemic effects. The goals of this study were to evaluate, in this environment, the frequency of this practice during pregnancy, as well as eventual consequences on pregnancy. Ninety-nine women from 6 to 9 months pregnant were randomly selected among those attending a standard maternal centre in Dakar for a prenatal visit. Investigations consisted of questions about the use of skin lighteners, a standard clinical examination, follow-up until delivery and a morning blood sample for plasma cortisol levels. Sixty-eight of the 99 selected women used skin lighteners during their current pregnancy, the main active ingredients being hydroquinone and highly potent steroids (used by 64 and 28 women, respectively). No difference in the main outcomes of pregnancy were found between skin-lightener users and the others; however, women using highly potent steroids, when compared with those who did not, had a statistically significant lower plasma cortisol level and a smaller placenta, and presented a higher rate of low-birth-weight infants. Skin lightening is a common practice during pregnancy in Dakar, and the use of steroids may result in consequences in the mother and her child.
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Cosméticos/efeitos adversos , Fármacos Dermatológicos/efeitos adversos , Substâncias Perigosas/efeitos adversos , Complicações na Gravidez/induzido quimicamente , Adolescente , Adulto , Cáusticos/efeitos adversos , Feminino , Humanos , Hidroquinonas/efeitos adversos , Gravidez , Complicações na Gravidez/epidemiologia , Resultado da Gravidez , Salicilatos/efeitos adversos , Senegal/epidemiologia , Esteroides/efeitos adversosRESUMO
UNLABELLED: Hereditary Hemorrhagic Telangiectasia is a systemic autosomal dominant disorder involving blood vessels. The most common symptom is recurrent epistaxis. The treatments of these epistaxis are numerous but such treatments are often symptomatic and their effects are often not sustained. Some of these treatments may be complicated by visceral vascular malformations. The aim of this study is to propose a treatment plan for these patients with hierarchical organisation of therapeutic options taking into account of their previous therapy. METHOD: H. Plauchu organized in Paris, december 2002 a meeting with any medical specialists of this disease. They have analysed variety of therapies that have been proposed for epistaxis control in Hereditary Haemorrhagic Télangiectasia. RESULTS: Most common use packing of nasal fossa and then hyperselective embolization of the internal maxillary and facial arteries for severe epistaxis. For chronic epistaxis, best treatment use sclerotics products (Ethibloc) and laser. After discussion, primary embolization could be useful to reduce vascularization of nasal fossa. CONCLUSION: Treatment of epistaxis in Hereditary Haemorrhagic Telangiectasia could increase in few years. Use of an index card of for epistaxis in the disease of Rendu-Osler could help to find treatment of choice.
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Epistaxe/terapia , Planejamento de Assistência ao Paciente , Telangiectasia Hemorrágica Hereditária/terapia , Doença Aguda , Doença Crônica , Embolização Terapêutica , Humanos , Fotocoagulação a Laser , Artéria Maxilar , Mucosa Nasal/irrigação sanguínea , Soluções Esclerosantes/uso terapêutico , Escleroterapia , Tampões CirúrgicosRESUMO
INTRODUCTION: Selectivity of cyclooxygenase-2 inhibitors (Cox2 inhibitors) decreased gastroduodenal toxicity of nonsteroidal anti-inflammatory drugs. Effects on colic mucosa are little known. OBSERVATION: A case history is described of a 38-year-old women, without digestive past, who presented with hemorrhagic ulcerated acute colitis beginning 2 days after starting celecoxib (200 mg/d) prescribed for sciatica. DISCUSSION: Intrinsic imputability of celecoxib is very probable in this case report by combination of chronological and semiological criteria. Extrinsic imputability is discussed, starting from the available bibliographical data which relate primarily to rofecoxib. CONCLUSION: This observation, which constitutes, as far as we know, the first case report of hemorrhagic ulcerated colitis related to celecoxib, confirms the colic toxicity of anti-Cox2 and identify a new cause of acute colitis. Report of colic side effects with Cox2 inhibitors is required because of their new marketing.
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Anti-Inflamatórios não Esteroides/efeitos adversos , Colite Ulcerativa/induzido quimicamente , Hemorragia Gastrointestinal/etiologia , Pirazóis/efeitos adversos , Sulfonamidas/efeitos adversos , Doença Aguda , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , Celecoxib , Colite Ulcerativa/complicações , Feminino , Humanos , Pirazóis/uso terapêutico , Ciática/tratamento farmacológico , Sulfonamidas/uso terapêuticoRESUMO
INTRODUCTION: Among the new identified causes of so-called idiopathic acute pancreatitis are chronic inflammatory diseases of the intestine. OBSERVATION: A 21 year-old man was hospitalised for the third episode of unexplained acute pancreatitis. Digestive endoscopies revealed an ulcerated terminal ileitis compatible with Crohn's disease. DISCUSSION: The frequency of idiopathic pancreatitis in patients exhibiting a chronic inflammatory disease of the intestine is of around 1%. Pancreatic involvement may precede the digestive manifestations of Crohn's disease and its clinical expression varies. An auto-immune mechanism appears to be responsible.