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Background: There is an urgent need to evaluate the quality of healthcare systems to improve and deliver high-quality care. Clinical registries have become important platforms for performance measurements, improvements, and clinical research. Hence, the quality of data in registries is crucial. This study aimed to assess the validity of data in the Swedish Colorectal Cancer Register (SCRCR). Methods: Seven hundred patients from 12 hospitals were randomly selected and proportionally distributed among three different hospital categories in Sweden using two-stage cluster sampling. Validity was assessed by re-abstracting data from the medical files of patients reported to the SCRCR in 2015. Data on histopathology, postoperative complications, and a 3-year follow-up were selected for validation. Re-abstracted data were defined as source data, and validity was defined as the proportion of cases in the SRCRC dataset that agreed with the source data. Validity was expressed as the percentage of exact agreement of non-missing data in both data sets, and Cohen´s kappa coefficient (κ) was used to measure the strength of the agreement. Results: The median agreement of the categorical histopathology variables was 93.4% (κ = 0.83). The general postoperative complication variable showed substantial agreement (84.3%, κ = 0.61). Likewise, the variable for overall cancer recurrence showed an almost perfect agreement (95.7%, κ = 0.86), whereas specific variables for local recurrence and distant recurrence displayed only moderate and fair agreement (85.9% and 89.1%, κ = 0.58 and 0.34, respectively). Conclusion: Validation of the SCRCR data showed high validity of pathology data and recurrence rates, whereas detailed data on recurrence were not as good. Data on postoperative complications were less reliable, although the incidence and Clavien-Dindo grading of severe complications (grade 3b or higher) were reliable.
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AIM: Population-based data on incidence and risk factors of adhesive small bowel obstruction (SBO) are limited. The aims of this study were to assess the risk of SBO and SBO surgery after bowel resection for colorectal cancer (CRC) and to assess whether this risk is modified by minimally invasive surgery (MIS) and radiotherapy in a retrospective national study. METHODS: CRCBaSe, a nationwide register linkage originating from the Swedish Colorectal Cancer Register, was used to identify Stage I-III CRC patients who underwent resection in 2007-2016, with follow-up throughout 2017. Matched CRC-free comparators (1:6) were included as a reference of SBO and SBO surgery incidence. The association between MIS and preoperative radiotherapy and the incidence rate of SBO was evaluated in adjusted multivariable Cox regression models. RESULTS: Among 33 632 CRC patients and 198 649 comparators, the 5-year cumulative incidence of SBO and SBO surgery was 7.6% and 2.2% among patients and 0.6% and 0.2% among comparators, with death as a competing risk. In all patients, MIS was associated with a reduced incidence of SBO (hazard ratio [HR] 0.7, 95% CI 0.6-0.8) and SBO surgery (HR 0.5, 95% CI 0.3-0.7). In rectal cancer patients, radiotherapy was associated with an increased incidence of SBO (HR 1.6, 95% CI 1.4-1.8) and SBO surgery (HR 1.7, 95% CI 1.3-2.3). DISCUSSION: Colorectal cancer surgery is associated with a marked increase in risk of SBO, compared with the general population. The incidence is further increased if open surgery or radiotherapy is performed.
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Obstrução Intestinal , Neoplasias Retais , Humanos , Incidência , Suécia/epidemiologia , Estudos Retrospectivos , Obstrução Intestinal/epidemiologia , Obstrução Intestinal/etiologia , Obstrução Intestinal/cirurgia , Neoplasias Retais/cirurgiaRESUMO
Background and Aims: Most patients develop adhesions after abdominal surgery, some will be hospitalized with small bowel obstruction (SBO), and some also require surgery. The operations and follow-up are expensive, but recent data of costs are scarce. The aim of this study was to describe the direct costs of SBO-surgery and follow-up, in a population-based setting. The association between cost of SBO and peri- and postoperative data was also studied. Methods: In a retrospective cohort study, all patients (n = 402) operated for adhesive SBO in Gävleborg and Uppsala counties (2007-2012) were studied. The median follow-up was 8 years. Costs were calculated according to the pricelist of Uppsala University Hospital, Uppsala, Sweden. Results: Overall total costs were 16.267 million, corresponding to a mean total cost per patient of 40,467 during the studied period. Diffuse adhesions and postoperative complications were associated with increased costs for SBO in a multivariable analysis (P < 0.001). Most costs, about 14 million (85%), arouse in conjunction with the SBO-index surgery period. In-hospital stay was the dominating cost, accounting for 70% of the total costs. Conclusion: Surgery for SBO generates substantial economic burden for healthcare systems. Measures that reduce the incidence of SBO, the frequency of postoperative complication, or the length of stay have the potential to reduce this economic burden. The cost estimates from this study may be valuable for future cost-benefit analyses in intervention studies.
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BACKGROUND: There are little data on diverticular disease and cancer development other than colorectal cancer. METHODS: We conducted a population-based, matched cohort study with linkage of nationwide registers to the Epidemiology Strengthened by histoPathology Reports in Sweden histopathology cohort. We included 75â704 patients with a diagnosis of diverticular disease and colorectal histopathology and 313â480 reference individuals from the general population matched on age, sex, calendar year, and county. Cox proportional hazards models estimated multivariable-adjusted hazard ratios (HRs) for associations between diverticular disease and overall cancer and specific cancers. RESULTS: Over a median follow-up of 6 years, we documented 12â846 incident cancers among patients with diverticular disease and 43â354 incident cancers among reference individuals from the general population. Compared with reference individuals, patients with diverticular disease had statistically significantly increased overall cancer incidence (24.5 vs 18.1 per 1000 person-years), equivalent to 1 extra cancer case in 16 individuals with diverticular disease followed-up for 10 years. After adjusting for covariates, having a diagnosis of diverticular disease was associated with a 33% increased risk of overall cancer (95% confidence interval [CI] = 1.31 to 1.36). The risk increases also persisted compared with siblings as secondary comparators (HR = 1.26, 95% CI = 1.21 to 1.32). Patients with diverticular disease also had an increased risk of specific cancers, including colon cancer (HR = 1.71, 95% CI = 1.60 to 1.82), liver cancer (HR = 1.72, 95% CI = 1.41 to 2.10), pancreatic cancer (HR = 1.62, 95% CI = 1.42 to 1.84), and lung cancer (HR = 1.50, 95% CI = 1.39 to 1.61). The increase in colorectal cancer risk was primarily restricted to the first year of follow-up, and especially early cancer stages. CONCLUSIONS: Patients with diverticular disease who have colorectal histopathology have an increased risk of overall incident cancer.
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Neoplasias do Colo , Doenças Diverticulares , Humanos , Estudos de Coortes , Doenças Diverticulares/complicações , Doenças Diverticulares/epidemiologia , Incidência , Suécia/epidemiologia , Fatores de Risco , Modelos de Riscos ProporcionaisRESUMO
INTRODUCTION: There are limited population cohort data on overall and cause-specific mortality in colonic diverticular disease. OBJECTIVE: To measure overall and cause-specific mortality in colonic diverticular disease, compared to matched reference individuals and siblings. METHODS: Population-based cohort study ("the ESPRESSO study") in Sweden. There were 97,850 cases with a medical diagnosis of diverticular disease (defined by international classification of disease codes) and colorectal histology identified in 1987-2017 from histopathology reports. The mortality risk between individuals with colonic diverticular disease and matched reference individuals (n = 453/634) from the general population was determined. Cox regression models adjusted for comorbidity estimated hazard ratios (HRs) for all-cause mortality. RESULTS: During follow-up, there were 32,959 deaths in individuals with colonic diverticular disease (44/1000 person-years) compared with 127,153 in matched reference individuals (34/1000 person-years), resulting in an HR of 1.27 (95%CI 1.25-1.29). Also compared to siblings, colonic diverticular disease patients were at increased risk of death, HR 1.39 (95%CI 1.33-1.45). Mortality risks were further increased in colonic diverticular disease patients with a colorectal biopsy showing any mucosal inflammation HR 1.36; (95%CI 1.33-1.38), with the most significant increase during the first year after diagnosis HR 2.18; (95%CI 2.05-2.32). CONCLUSIONS: Mortality in colonic diverticular disease is increased over reference individuals in the general population. The presence of mucosal inflammation on colorectal biopsies is a predictor of increased risk of mortality.
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Neoplasias Colorretais , Doenças Diverticulares , Humanos , Estudos de Coortes , Incidência , Neoplasias Colorretais/epidemiologia , Inflamação , Fatores de RiscoRESUMO
Background: Obesity is a risk factor for colorectal cancer (CRC). Objective: The objective of this article is to investigate whether anthropometric measures reflecting visceral obesity are better predictors of CRC than body mass index (BMI). Methods: Data were analysed from the Malmö Diet and Cancer study in Sweden, comprising 16,669 women and 10,805 men (median age 56.6 and 59.1 years) followed for a median 21.5 years. Diagnoses of CRC were identified using Swedish national registers. Cox regression was used to test the associations of BMI, waist circumference (WC), waist-hip ratio, waist-to-height ratio, waist-to-hip-to-height ratio, A Body Shape Index (ABSI) and percentage body fat with the development of CRC adjusted for age, alcohol consumption, smoking, education and physical activity in men and women. Results: None of the measures were significantly associated with an increased risk for CRC in women. WC was the strongest predictor of colon cancer (CC) in men and the only measure that was independent of BMI. ABSI was the only measure significantly associated with the risk of rectal cancer in men. Conclusions: Visceral obesity, best expressed as WC, is a risk factor for CC in men but a poor predictive marker for CRC in women.
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Índice de Massa Corporal , Neoplasias Colorretais/epidemiologia , Obesidade Abdominal/epidemiologia , Circunferência da Cintura , Tecido Adiposo , Adulto , Idoso , Antropometria , Composição Corporal , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores Sexuais , Suécia/epidemiologia , Razão Cintura-Estatura , Relação Cintura-QuadrilRESUMO
BACKGROUND: The Swedish Colorectal Cancer Registry (SCRCR) is a national registry established in 1995 for rectal cancer, and also including colon cancer since 2007. Knowledge of the quality of the registry is vital in order to draw correct conclusions from studies based on the registry. The aim of this study was to assess the completeness, timeliness, comparability and validity of the SCRCR. MATERIAL AND METHODS: Completeness, timeliness and comparability of the registry were estimated. From the SCRCR year 2008, 500 cases were randomly selected to examine the validity of the registry and 486 cases were retrieved. Using hospital patient records as source documents, 130 variables in the SCRCR were reabstracted using the SCRCR registration forms and then compared with the original files. RESULT: During the period 2008-2015, the average completeness of the SCRCR was 98.5% for colon cancer and 98.8% for rectal cancer. Timeliness improved between the years 2008 and 2015, with 98% of the patients registered within 12 months for the year 2015. For most of the variables, comparability was estimated to be reproducible and comparable with other registries. Regarding the validity of the registry, when comparing reabstracted data with the original SCRCR data, average agreement was 90%. CONCLUSION: The SCRCR can be considered a reliable registry useful for quality assurance and research. Standardization and improvements in journal documentation are needed to improve future evaluation of the source documents.
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Neoplasias do Colo/epidemiologia , Confiabilidade dos Dados , Garantia da Qualidade dos Cuidados de Saúde/métodos , Neoplasias Retais/epidemiologia , Sistema de Registros/estatística & dados numéricos , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Registros de Saúde Pessoal , Humanos , Neoplasias Retais/diagnóstico , Neoplasias Retais/patologia , Neoplasias Retais/cirurgia , Sistema de Registros/normas , Suécia/epidemiologia , Fatores de TempoRESUMO
BACKGROUND: Appendicitis and acute diverticulitis share clinical features and are both influenced by genetic and environmental factors. Appendectomy has been positively associated with diverticular disease in hospital-based case-control studies. OBJECTIVE: The aim of the present study was to investigate, in a population-based setting, whether appendectomy, with or without appendicitis, is associated with an altered risk of hospitalization with diverticular disease. DESIGN: This was a population-based case-control study. SETTINGS: The study was based on national healthcare and population registers. PATIENTS: We studied 41,988 individuals hospitalized between 2000 and 2010 with a first-time diagnosis of colonic diverticular disease and 413,115 matched control subjects. MAIN OUTCOME MEASURES: The association between appendectomy with or without appendicitis and diverticular disease was investigated by conditional logistic regression, including a model adjusting for hospital use. RESULTS: A total of 2813 cases (6.7%) and 19,037 controls (4.6%) had a previous record of appendectomy (appendectomy with acute appendicitis: adjusted OR = 1.31 (95% CI, 1.24-1.39); without appendicitis: adjusted OR = 1.30 (95% CI, 1.23-1.38)). Appendectomy was most strongly associated with an increased risk of diverticular disease within 1 year (with appendicitis: adjusted OR = 2.26 (95% CI, 1.61-3.16); without appendicitis: adjusted OR = 3.98 (95% CI, 2.71-5.83)), but the association was still present ≥20 years after appendectomy (with appendicitis: adjusted OR = 1.22 (95% CI, 1.12-1.32); without appendicitis: adjusted OR = 1.19 (95% CI, 1.10-1.28)). LIMITATIONS: Detailed clinical information on the cases was not available. There were unmeasured potential confounders, such as smoking and dietary factors. CONCLUSIONS: The findings are consistent with a hypothesis of appendectomy causing an increased risk of diverticular disease, for example, by affecting the mucosal immune system or the gut microbiome. However, several other mechanisms may contribute to, or account for, the positive association, including a propensity for abdominal pain increasing the risk of both the exposure and the outcome. See Video Abstract at http://links.lww.com/DCR/A604.
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Apendicectomia/estatística & dados numéricos , Apendicite/epidemiologia , Doença Diverticular do Colo/epidemiologia , Sistema de Registros , Adulto , Idoso , Idoso de 80 Anos ou mais , Apendicite/cirurgia , Estudos de Casos e Controles , Diverticulose Cólica/epidemiologia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Suécia/epidemiologiaRESUMO
BACKGROUND & AIMS: The burden of diverticular disease on society is high and is increasing with an aging population. It is therefore important to identify risk factors for disease development or progression. Many lifestyle behaviors during adolescence affect risk for later disease. We searched for adolescent lifestyle factors that affect risk of diverticular disease later in life. METHODS: We performed a retrospective analysis of data from 43,772 men (age, 18-20 y) conscripted to military service in Sweden from 1969 through 1970, with a follow-up period of 39 years. All conscripts underwent an extensive mental and physical health examination and completed questionnaires covering alcohol consumption, smoking, and use of recreational drugs; cardiovascular fitness was assessed using an ergometer cycle at the time of conscription. Outcome data were collected from national registers to identify discharge diagnoses of diverticular disease until the end of 2009. We performed Cox regression analysis to determine whether body mass index, cardiovascular fitness, smoking, use of recreational drugs, alcohol consumption, and risky use of alcohol, at time of conscription are independent risk factors for development of diverticular disease. RESULTS: Overweight and obese men had a 2-fold increased risk of diverticular disease compared to normal-weight men (hazard ratio, 2.00; P < .001). A high level of cardiovascular fitness was associated with a reduced risk of diverticular disease requiring hospitalization (P = .009). Smoking (P = .003), but not use of recreational drugs (P = .11), was associated with an increased risk of diverticular disease requiring hospitalization. Risky use of alcohol, but not alcohol consumption per se, was associated with a 43% increase in risk of diverticular disease requiring hospitalization (P = .007). CONCLUSIONS: In a retrospective analysis of data from 43,772 men in Sweden, we associated being overweight or obese, a smoker, a high-risk user of alcohol, and/or having a low level of cardiovascular fitness in late adolescence with an increased risk of developing diverticular disease requiring hospitalization later in life. Improving lifestyle factors among adolescents might reduce the economic burden of diverticular disease decades later.
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Progressão da Doença , Doenças Diverticulares/epidemiologia , Doenças Diverticulares/patologia , Hospitalização/estatística & dados numéricos , Estilo de Vida , Adolescente , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Fatores de Risco , Inquéritos e Questionários , Suécia/epidemiologia , Adulto JovemRESUMO
OBJECTIVE: A reduced risk of perforated diverticular disease among individuals with current statin exposure has been reported. The aim of the present study was to investigate whether statins reduce the risk of acute diverticular disease. MATERIAL AND METHODS: A nation-wide population-based case-control study was performed, including 13,127 cases hospitalised during 2006-2010 with a first-time diagnosis of colonic diverticular disease, and 128,442 control subjects (matched for sex, age, county of residence and calendar year). Emergency surgery, assumed to be a proxy for complicated diverticulitis, was performed on 906 of the cases during the index admission, with 8818 matched controls. Statin exposure was classified as "current" or "former" if a statin prescription was last dispensed ≤ 125 days or >125 days before index date, respectively. The association between statin exposure and acute diverticular disease was investigated by conditional logistic regression, including models adjusting for country of birth, educational level, marital status, comorbidities, nonsteroidal anti-inflammatory drug/steroid exposure and healthcare utilisation. RESULTS: A total of 1959 cases (14.9%) and 16,456 controls (12.8%) were current statin users (crude OR 1.23 [95% CI 1.17-1.30]; fully adjusted OR 1.00 [0.94-1.06]). One hundred and thirty-two of the cases subjected to surgery (14.6%), and 1441 of the corresponding controls (16.3%) were current statin users (crude OR 0.89 [95% CI 0.73-1.08]; fully adjusted OR 0.70 [0.55-0.89]). CONCLUSIONS: The results do not indicate that statins affect the development of symptomatic diverticular disease in general. However, current statin use was associated with a reduced risk of emergency surgery for diverticular disease.
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Doença Diverticular do Colo/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Doença Diverticular do Colo/epidemiologia , Doença Diverticular do Colo/cirurgia , Emergências , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Proteção , Fatores de Risco , Suécia/epidemiologiaRESUMO
BACKGROUND: The importance of absent neoplastic epithelium in specimens from cytoreductive surgery (CRS) is unknown. This study aimed to investigate the prevalence and prognostic value of histopathology without neoplastic epithelium in patients treated with CRS and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: Data were extracted from medical records and histopathology reports for patients treated with initial CRS and HIPEC at Uppsala University Hospital, Sweden, between 2004 and 2012. Patients with inoperable disease and patients undergoing palliative non-CRS surgery were excluded from the study. Patients lacking neoplastic epithelium in surgical specimens from CRS, with or without mucin, were classified as "neoplastic epithelium absent" (NEA), and patients with neoplastic epithelium were classified as "neoplastic epithelium present" (NEP). RESULTS: The study observed NEA in 78 of 353 patients (22 %). Mucin was found in 28 of the patients with NEA. For low-grade appendiceal mucinous neoplasms and adenomas, the 5-year overall survival rate was 100 % for NEA and 84 % for NEP, and the 5-year recurrence-free survival rate was 100 % for NEA and 59 % for NEP. For appendiceal/colorectal adenocarcinomas (including tumors of the small intestine), the 5-year overall survival rate was 61 % for NEA and 38 % for NEP, and the 5-year recurrence-free survival rate was 60 % for NEA and 14 % for NEP. Carcinoembryonic antigen level, peritoneal cancer index, and completeness of the cytoreduction score were lower in patients with NEA. CONCLUSIONS: A substantial proportion of patients undergoing CRS and HIPEC have NEA. These patients have a favorable prognosis and a decreased risk of recurrence. Differences in patient selection can affect the proportion of NEA and hence explain differences in survival rates between reported series.
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Adenocarcinoma Mucinoso/patologia , Neoplasias do Apêndice/patologia , Neoplasias Colorretais/patologia , Procedimentos Cirúrgicos de Citorredução , Epitélio/patologia , Hipertermia Induzida , Neoplasias Peritoneais/patologia , Adenocarcinoma Mucinoso/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Apêndice/terapia , Quimioterapia do Câncer por Perfusão Regional , Neoplasias Colorretais/terapia , Terapia Combinada , Feminino , Seguimentos , Humanos , Injeções Intraperitoneais , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Peritoneais/terapia , Prognóstico , Taxa de SobrevidaRESUMO
Variants in the gene encoding the enzyme glutamic acid decarboxylase like 1 (GADL1) have been associated with response to lithium therapy. Both GADL1 and the related enzyme cysteine sulfinic acid decarboxylase (CSAD) have been proposed to be involved in the pyridoxal-5'-phosphate (PLP)-dependent biosynthesis of taurine. In the present study, we compared the catalytic properties, inhibitor sensitivity and expression profiles of GADL1 and CSAD in brain tissue. In mouse and human brain we observed distinct patterns of expression of the PLP-dependent decarboxylases CSAD, GADL1 and glutamic acid decarboxylase 67 (GAD67). CSAD levels were highest during prenatal and early postnatal development; GADL1 peaked early in prenatal development, while GAD67 increased rapidly after birth. Both CSAD and GADL1 are being expressed in neurons, whereas only CSAD mRNA was detected in astrocytes. Cysteine sulfinic acid was the preferred substrate for both mouse CSAD and GADL1, although both enzymes also decarboxylated cysteic acid and aspartate. In silico screening and molecular docking using the crystal structure of CSAD and in vitro assays led to the discovery of eight new enzyme inhibitors with partial selectivity for either CSAD or GADL1. Lithium had minimal effect on their enzyme activities. In conclusion, taurine biosynthesis in vertebrates involves two structurally related PLP-dependent decarboxylases (CSAD and GADL1) that have partially overlapping catalytic properties but different tissue distribution, indicating divergent physiological roles. Development of selective enzyme inhibitors targeting these enzymes is important to further dissect their (patho)physiological roles.
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Encéfalo/metabolismo , Carboxiliases/metabolismo , Neurônios/metabolismo , Taurina/metabolismo , Animais , Humanos , Camundongos , RNA Mensageiro/metabolismo , Taurina/químicaRESUMO
Patients with autoimmune polyendocrine syndrome type 1 (APS-1) suffer from multiple organ-specific autoimmunity with autoantibodies against target tissue-specific autoantigens. Endocrine and nonendocrine organs such as skin, hair follicles, and liver are targeted by the immune system. Despite sporadic observations of pulmonary symptoms among APS-1 patients, an autoimmune mechanism for pulmonary involvement has not been elucidated. We report here on a subset of APS-1 patients with respiratory symptoms. Eight patients with pulmonary involvement were identified. Severe airway obstruction was found in 4 patients, leading to death in 2. Immunoscreening of a cDNA library using serum samples from a patient with APS-1 and obstructive respiratory symptoms identified a putative potassium channel regulator (KCNRG) as a pulmonary autoantigen. Reactivity to recombinant KCNRG was assessed in 110 APS-1 patients by using immunoprecipitation. Autoantibodies to KCNRG were present in 7 of the 8 patients with respiratory symptoms, but in only 1 of 102 APS-1 patients without respiratory symptoms. Expression of KCNRG messenger RNA and protein was found to be predominantly restricted to the epithelial cells of terminal bronchioles. Autoantibodies to KCNRG, a protein mainly expressed in bronchial epithelium, are strongly associated with pulmonary involvement in APS-1. These findings may facilitate the recognition, diagnosis, characterization, and understanding of the pulmonary manifestations of APS-1.
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Autoantígenos/imunologia , Autoimunidade/imunologia , Brônquios/imunologia , Pneumopatias/imunologia , Poliendocrinopatias Autoimunes/complicações , Poliendocrinopatias Autoimunes/imunologia , Canais de Potássio/imunologia , Obstrução das Vias Respiratórias , Autoanticorpos/análise , Bronquíolos/imunologia , Bronquíolos/patologia , Causas de Morte , Células Epiteliais/imunologia , Biblioteca Gênica , Humanos , Imunoprecipitação , Pneumopatias/etiologia , Canais de Potássio/análise , Canais de Potássio/genética , Doença Pulmonar Obstrutiva Crônica/imunologia , RNA Mensageiro/análise , Proteínas Recombinantes/imunologiaRESUMO
Patients with autoimmune polyglandular syndrome type I (APS1) often display high titers of autoantibodies (autoAbs) directed against aromatic L-amino acid decarboxylase (AADC), tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), and glutamic acid decarboxylase (GAD). Neurological symptoms, including stiff-man syndrome and cerebellar ataxia, can occur in subjects with high levels of GAD autoAbs, particularly when patient sera can immunohistochemically stain gamma-aminobutyric acid (GABA) neurons. However, it was not known if APS1 sera can also stain major monoamine systems in the brain. Therefore, in this work we applied sera from 17 APS1 patients known to contain autoAbs against AADC, TH, TPH, and/or GAD to rat brain sections and processed the sections according to the sensitive immunohistochemical tyramide signal amplification method. We found that autoAbs in sera from 11 patients were able to stain AADC-containing dopaminergic, serotonergic, and noradrenergic as well as AADC only (D-group) neurons and fibers in the rat brain, in several cases with a remarkably high quality and sensitivity (dilution up to 1:1,000,000); and, since they are human antibodies, they offer a good opportunity for performing multiple-labeling experiments using antibodies from other species. Six APS1 sera also stained GABAergic neuronal circuitries. Similar results were obtained in the mouse and primate brain. Our data demonstrate that many APS1 sera can immunostain the major monoamine and GABA systems in the brain. Only in a few cases, however, there was evidence that these autoAbs can be associated with neurological manifestations in APS1 patients, as, e.g., shown in previous studies in stiff-man syndrome.
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Autoanticorpos , Encéfalo/metabolismo , Neurotransmissores/imunologia , Poliendocrinopatias Autoimunes/imunologia , Animais , Descarboxilases de Aminoácido-L-Aromático/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Encéfalo/anatomia & histologia , Encéfalo/imunologia , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/imunologia , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Transgênicos , Poliendocrinopatias Autoimunes/complicações , Ratos , Ratos Sprague-Dawley , Soro/imunologia , Rigidez Muscular Espasmódica/sangue , Rigidez Muscular Espasmódica/etiologia , Rigidez Muscular Espasmódica/imunologia , Triptofano Hidroxilase/imunologia , Tirosina 3-Mono-Oxigenase/imunologiaRESUMO
Autoimmune polyendocrine syndrome type I (APS I) is a rare hereditary condition considered a model disease for organ specific autoimmunity. A wide range of autoantibodies targeting antigens present in the affected organs have been identified. Autoantibodies against aromatic L-amino acid decarboxylase (AADC) are present in about 50% of APS I patients. In order to increase our understanding of autoantibody specificity in APS I, the aim of the present study was to localize target regions on AADC recognized by sera from APS I patients. Using several complementing strategies, we have shown that autoantibodies against AADC mainly recognize conformational epitopes. The major antigenic determinants were detected N-terminally to amino acid residue 237. Replacement of amino acids 227-230 (ERDK) with alanine residues reduced the reactivity towards AADC by >80% in all patient sera tested, suggesting that amino acids 227-230 are an important part of an immunodominant epitope.
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Descarboxilases de Aminoácido-L-Aromático/imunologia , Mapeamento de Epitopos/métodos , Descarboxilases de Aminoácido-L-Aromático/genética , Autoanticorpos , Carboxiliases/genética , Carboxiliases/imunologia , Humanos , Modelos Moleculares , Mutagênese Sítio-Dirigida , Poliendocrinopatias Autoimunes/enzimologia , Poliendocrinopatias Autoimunes/imunologia , Proteínas Recombinantes de Fusão/imunologiaRESUMO
Autoimmune polyglandular syndrome type I (APS I) is an autosomal recessive disorder characterized by a combination of autoimmune manifestations affecting endocrine and non-endocrine organs. APS I usually presents in childhood. The three most common manifestations are chronic mucocutaneous candidiasis, hypoparathyroidism and Addison's disease. At least two of these must be present to fulfill the diagnostic criteria of this syndrome. The spectrum of other associated diseases includes gonadal insufficiency, alopecia, vitiligo and chronic active hepatitis. APS I is caused by a mutation in the AIRE-gene (autoimmune regulator) located on chromosome 21. Analysis of specific autoantibodies against intracellular enzymes, particularly enzymes in the synthesis of steroids and neurotransmittors, can be used in the diagnosis of APS I and to predict different manifestations of the disease.
Assuntos
Poliendocrinopatias Autoimunes , Doença de Addison/genética , Doença de Addison/imunologia , Insuficiência Adrenal/genética , Insuficiência Adrenal/imunologia , Adulto , Alopecia/genética , Alopecia/imunologia , Alopecia/patologia , Autoanticorpos/genética , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/imunologia , Criança , Cromossomos Humanos Par 21/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Hepatite Autoimune/genética , Hepatite Autoimune/imunologia , Humanos , Hipoparatireoidismo/genética , Hipoparatireoidismo/imunologia , Síndromes de Malabsorção/genética , Síndromes de Malabsorção/imunologia , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/imunologia , Poliendocrinopatias Autoimunes/patologia , Vitiligo/genética , Vitiligo/imunologiaRESUMO
The structurally related group II pyridoxal phosphate (PLP)-dependent amino acid decarboxylases glutamic acid decarboxylase (GAD), aromatic L-amino acid decarboxylase (AADC), and histidine decarboxylase (HDC) are known autoantigens in endocrine disorders. We report, for the first time, the prevalence of serum autoantibody reactivity against cysteine sulfinic acid decarboxylase (CSAD), an enzyme that shares 50% amino acid identity with the 65- and 67-kDa isoforms of GAD (GAD-65 and GAD-67), in endocrine autoimmune disease. Three of 83 patients (3.6%) with autoimmune polyendocrine syndrome type 1 (APS1) were anti-CSAD positive in a radioimmunoprecipitation assay. Anti-CSAD antibodies cross-reacted with GAD-65, and the anti-CSAD-positive sera were also reactive with AADC and HDC. The low frequency of anti-CSAD reactivity is in striking contrast to the prevalence of antibodies against GAD-65, AADC, and HDC in APS1 patients, suggesting that different mechanisms control the immunological tolerance toward CSAD and the other group II decarboxylases. Moreover, CSAD may be a useful mold for the construction of recombinant chimerical antigens in attempts to map conformational epitopes on other group II PLP-dependent amino acid decarboxylases.
Assuntos
Autoanticorpos/sangue , Carboxiliases/imunologia , Poliendocrinopatias Autoimunes/imunologia , Doença de Addison/imunologia , Descarboxilases de Aminoácido-L-Aromático/imunologia , Autoanticorpos/imunologia , Reações Cruzadas , Diabetes Mellitus Tipo 1/imunologia , Feminino , Glutamato Descarboxilase/imunologia , Histidina Descarboxilase/imunologia , Humanos , Isoenzimas/imunologia , Masculino , Fosfato de Piridoxal/metabolismo , Ensaio de RadioimunoprecipitaçãoRESUMO
Patients with autoimmune polyendocrine syndrome type 1 often have autoantibodies against neurotransmitter synthesizing enzymes, including the pyridoxal phosphate-dependent enzymes glutamic acid decarboxylase and aromatic L-amino acid decarboxylase. Using a candidate approach, we have identified the histamine-synthesizing enzyme histidine decarboxylase, also pyridoxal phosphate dependent, as an autoantigen in this disorder. Anti-histidine decarboxylase antibodies reacting with in vitro translated antigen were found in 36/97 (37%) of autoimmune polyendocrine syndrome type 1 patients studied. The antibodies also reacted with the native enzyme in HMC-1 cell lysates and did not cross-react with the highly homologous aromatic L-amino acid decarboxylase. Anti-histidine decarboxylase antibodies were associated with a history of intestinal dysfunction (P = 0.017). Gastric and duodenal biopsies from a patient with anti-histidine decarboxylase antibodies were studied by immunohistochemistry. The oxyntic mucosa was found to lack the histamine producing enterochromaffin-like cells, suggestive of an autoimmune destruction. To our knowledge, this is the first report of autoantibodies against histidine decarboxylase and absence of gastric enterochromaffin-like cells.
Assuntos
Autoantígenos/imunologia , Celulas Tipo Enterocromafim/enzimologia , Histidina Descarboxilase/imunologia , Poliendocrinopatias Autoimunes/imunologia , Fosfato de Piridoxal/farmacologia , Adulto , Especificidade de Anticorpos , Autoanticorpos/sangue , Ligação Competitiva , Biópsia , Linhagem Celular , Celulas Tipo Enterocromafim/imunologia , Feminino , Mucosa Gástrica/imunologia , Expressão Gênica , Histidina Descarboxilase/genética , Humanos , Immunoblotting , Imuno-Histoquímica , Técnicas de Imunoadsorção , Mastócitos/enzimologia , Células Parietais Gástricas/imunologiaRESUMO
To identify candidate autoantigens associated with arthritis, a rat chondrocyte cDNA library was immunoscreened with serum from a patient with rheumatoid arthritis. One isolated cDNA encoded part of AHNAK, a 700-kDa phosphoprotein with DNA binding properties, that appears to be involved in several signal transduction pathways. Immunoreactivity against an in vitro translated human AHNAK fragment was detected in 4.6% (5/109) of patients with rheumatoid arthritis, 29.5% (18/61) of patients with systemic lupus erythematosus (SLE), and 1.2% (2/172) of blood donors. Anti-AHNAK antibodies reacted with a recombinant human AHNAK fragment and with native AHNAK from C32 cell lysates. In vitro translated AHNAK fragment could be cleaved by granzyme B and caspase-3. Anti-AHNAK positive SLE patients had a higher frequency of homogeneous antinuclear antibody staining patterns and a lower frequency of recent mucosal ulcerations. This is the first report that AHNAK can be targeted by the immune system in autoimmune disease.