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1.
Ann Rheum Dis ; 82(12): 1594-1605, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37666646

RESUMO

BACKGROUND: The vacuoles, E1-enzyme, X linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease (AID) due to postzygotic UBA1 variants. OBJECTIVES: To investigate the presence of VEXAS syndrome among patients with adult-onset undiagnosed AID. Additional studies evaluated the mosaicism distribution and the circulating cytokines. METHODS: Gene analyses were performed by both Sanger and amplicon-based deep sequencing. Patients' data were collected from their medical charts. Cytokines were quantified by Luminex. RESULTS: Genetic analyses of enrolled patients (n=42) identified 30 patients carrying UBA1 pathogenic variants, with frequencies compatible for postzygotic variants. All patients were male individuals who presented with a late-onset disease (mean 67.5 years; median 67.0 years) characterised by cutaneous lesions (90%), fever (66.7%), pulmonary manifestations (66.7%) and arthritis (53.3%). Macrocytic anaemia and increased erythrocyte sedimentation rate and ferritin were the most relevant analytical abnormalities. Glucocorticoids ameliorated the inflammatory manifestations, but most patients became glucocorticoid-dependent. Positive responses were obtained when targeting the haematopoietic component of the disease with either decitabine or allogeneic haematopoietic stem cell transplantation. Additional analyses detected the UBA1 variants in both haematopoietic and non-haematopoietic tissues. Finally, analysis of circulating cytokines did not identify inflammatory mediators of the disease. CONCLUSION: Thirty patients with adult-onset AID were definitively diagnosed with VEXAS syndrome through genetic analyses. Despite minor interindividual differences, their main characteristics were in concordance with previous reports. We detected for the first time the UBA1 mosaicism in non-haematopoietic tissue, which questions the previous concept of myeloid-restricted mosaicism and may have conceptual consequences for the disease mechanisms.


Assuntos
Artrite , Mosaicismo , Adulto , Humanos , Masculino , Feminino , Citocinas/genética , Ferritinas , Glucocorticoides , Mutação
2.
Arthritis Rheumatol ; 74(4): 692-699, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34672126

RESUMO

OBJECTIVE: Autoinflammatory diseases are inherited disorders of innate immunity that usually start during childhood. However, several recent reports have described an increasing number of patients with autoinflammatory disease starting in adulthood. This study was undertaken to investigate the underlying cause of a case of late-onset uncharacterized autoinflammatory disease. METHODS: Genetics studies were performed using Sanger sequencing and next-generation sequencing (NGS) methods. In silico, in vitro, and ex vivo analyses were performed to determine the functional consequences of the detected variant. RESULTS: We studied a 57-year-old woman who at the age of 47 years began to have recurrent episodes of fever, myalgias, arthralgias, diffuse abdominal pain, diarrhea, adenopathies, and systemic inflammation, which were relatively well controlled with anti-interleukin-1 (anti-IL-1) drugs. NGS analyses did not detect germline variants in any of the known autoinflammatory disease-associated genes, but they identified the p.Ser171Phe NLRC4 variant in unfractionated blood, with an allele fraction (2-4%) compatible with gene mosaicism. Structural modeling analyses suggested that this missense variant might favor the open, active conformation of the NLRC4 protein, and in vitro and ex vivo analyses confirmed its propensity to oligomerize and activate the NLRC4 inflammasome, with subsequent overproduction of IL-18. CONCLUSION: Our findings indicate that the postzygotic p.Ser171Phe NLRC4 variant is a plausible cause of the disease in the enrolled patient. Functional and structural studies clearly support, for the first time, its gain-of-function behavior, consistent with previously reported NLRC4 pathogenic variants. These novel findings should be considered in the diagnostic evaluation of patients with adult-onset uncharacterized autoinflammatory disease.


Assuntos
Proteínas Adaptadoras de Sinalização CARD , Doenças Hereditárias Autoinflamatórias , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas de Ligação ao Cálcio , Feminino , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Inflamassomos , Transtornos de Início Tardio , Pessoa de Meia-Idade , Mosaicismo
3.
Rev. chil. anest ; 51(2): 213-216, 2022. ilus
Artigo em Inglês | LILACS | ID: biblio-1567548

RESUMO

BACKGROUND: One of the newest antibiotics against multidrug-resistant (MDR) bacteria is Cefiderocol, a siderophore cephalosporin able to overcome most resistance mechanisms, including metallo-beta-lactamases. Several studies are being carried to prove its clinical benefit. CASE PRESENTATION: A 55-year-old male patient was admitted in the ICU undergoing septic shock due to surgical wound infection. Multidrug-resistant Pseudomonasputida grew in blood cultures and Pseudomonas aeruginosa grew in soft tissue cultures. He was treated with colistin and tobramycin, developing nephro and ototoxicity. Compassionate use of cefiderocol was ordered, and the infection was cured within 14 days. CONCLUSIONS: This is the first evidence of cefiderocol treatment in a soft tissue infection within a surgical wound infection. Our experience with cefiderocol in surgical wound infection suggests that it may be helpful in treating infections at that level, but more clinical trials are still needed.


ANTECEDENTES: Uno de los antibióticos más nuevos contra las bacterias multirresistentes (MDR) es el cefiderocol, una cefalos- porina siderófora capaz de superar la mayoría de los mecanismos de resistencia, incluidas las metalobetalactamasas. Se están realizando varios estudios para demostrar su beneficio clínico. PRESENTACIÓN DEL CASO: Paciente masculino de 55 años que ingresó en la UCI con shock séptico por infección de herida quirúrgica. Pseudomonas putida multirresistente creció en hemocultivos y Pseudomonas aeruginosa crecieron en cultivos de tejidos blandos. Fue tratado con colistina y tobramicina, desarrollando nefro y ototoxicidad. Se indicó cefiderocol y la infección se curó en 14 días. CONCLUSIONES: Esta es la primera evidencia de cefiderocol en el tratamiento de una infección de partes blandas dentro de una infección de herida quirúrgica. Nuestra experiencia con cefiderocol en infección de herida quirúrgica sugiere que puede ser útil en el tratamiento de infecciones a ese nivel, pero aún se necesitan más ensayos clínicos.


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Pseudomonas aeruginosa , Infecções por Pseudomonas/tratamento farmacológico , Cefiderocol/uso terapêutico , Antibióticos beta Lactam/uso terapêutico , Choque Séptico , Infecção da Ferida Cirúrgica , Pseudomonas putida , Estado Terminal , Resistência a Múltiplos Medicamentos
4.
Clin Exp Rheumatol ; 35 Suppl 108(6): 27-31, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28079503

RESUMO

OBJECTIVES: Cryopyrin-associated periodic syndromes (CAPS) usually start during infancy as an urticarial-like rash and a marked acute phase response, with additional manifestations appearing during its evolution. The aim of this study was to expand the clinical diversity of CAPS by the description of novel atypical features. METHODS: Clinical data were collected from patients' medical charts. Sanger sequencing analyzed NLRP3. Response to anti-IL-1 blockade was evaluated by clinical assessments and by measurements of laboratory parameters. RESULTS: Seventeen patients from two families (A and B), carrying the p.Ala439Thr and p.Arg260Trp NLRP3 mutations respectively, were enrolled. The disease was unexpectedly atypical in all members of Family A, with a 16-year-old asymptomatic carrier, and onset in adulthood associated with absence of skin lesions in four affected members. Surprisingly, one patient from each family suffered from severe haemorrhagic cystitis due to AA amyloidosis in the urinary bladder. Members of Family B displayed a classical phenotype, with two patients suffering from olfactive disorders. CONCLUSIONS: Our evidence suggests that CAPS may occasionally be presented as a late-onset, recurrent inflammatory disease without urticarial-like rash. In some patients, AA amyloidosis in strange locations like urinary bladder may complicate the clinical course. The response to IL-1 blockade in these atypical CAPS was similar to that described in classical forms. Consequently, we suggest that CAPS should be included in the differential diagnosis of adult patients with unexplained, recurrent inflammatory diseases, and once confirmed, the early initiation of anti-IL-1 blockade will probably prevent the development of life-threatening complications.


Assuntos
Amiloidose/etiologia , Síndromes Periódicas Associadas à Criopirina/complicações , Cistite/etiologia , Nefropatias/etiologia , Adolescente , Idade de Início , Idoso , Amiloidose/tratamento farmacológico , Amiloidose/genética , Amiloidose/imunologia , Doenças Assintomáticas , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Síndromes Periódicas Associadas à Criopirina/genética , Síndromes Periódicas Associadas à Criopirina/imunologia , Cistite/tratamento farmacológico , Cistite/genética , Cistite/imunologia , Feminino , Predisposição Genética para Doença , Hematúria/etiologia , Humanos , Imunossupressores/uso terapêutico , Interleucina-1/antagonistas & inibidores , Interleucina-1/imunologia , Nefropatias/tratamento farmacológico , Nefropatias/genética , Nefropatias/imunologia , Masculino , Mutação , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Linhagem , Fenótipo , Resultado do Tratamento
5.
Eur J Intern Med ; 26(10): 772-5, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26563937

RESUMO

BACKGROUND: Targeting patients with prolonged hospitalizations may represent an effective strategy for reducing average hospital length of stay (LOS). OBJECTIVE: We sought to characterize predictors of prolonged hospitalization among internal medicine patients in an effort to guide future improvement efforts. DESIGN: We conducted a retrospective cohort study using administrative data of internal medicine patients from all hospitals of the Spanish Public Health Service between January 1st, 2005 and December 31st, 2013. Multivariable logistic regression was performed to assess the association between sociodemographic and clinical variables and prolonged LOS, defined as >30days. KEY RESULTS: Of 5,275,139 discharges, 166,470 (3.2%) had a prolonged LOS. Prolonged hospitalizations accounted for 17.4% of total inpatient days and contributed 0.5days to an average LOS of 9.8days during the study period. Prolonged hospitalizations were associated with younger age (odds ratio [OR]: 0.97 per 10-year increase in age, 95% confidence interval [CI]: 0.96-0.98) and male gender (OR 0.88 IC95% 0.87-0.89). Compared to patients without prolonged LOS, prolonged LOS patients were more likely to require a palliative care consult (OR: 2.48, 95% CI: 2.39-2.58), surgery (OR: 6.9 95% CI: 6.8-7.0); and be discharged to a post-acute-care facility (OR: 2.91, 95% CI: 2.86-2.95). CONCLUSIONS: Prolonged hospitalizations in a small proportion of patients were an important contributor to overall LOS and particularly affected complex hospital stays who were not discharged home.


Assuntos
Medicina Interna , Tempo de Internação/estatística & dados numéricos , Alta do Paciente/estatística & dados numéricos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Medicina Interna/métodos , Medicina Interna/organização & administração , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos/organização & administração , Cuidados Paliativos/estatística & dados numéricos , Quartos de Pacientes/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Espanha , Fatores de Tempo
6.
J Am Med Dir Assoc ; 13(1): 82.e13-7, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21450238

RESUMO

OBJECTIVE: Hospitalization of nursing home residents is costly and potentially exposes residents to iatrogenic disease and psychological harm. DESIGN AND SETTING: In this study, we analyzed the data from the Basic Minimum Data Set of patients hospitalized from the nursing home who were discharged from all the internal medicine departments at the National Health Service hospitals in Spain between 2005 and 2008, according to the data provided by the Ministry of Health and Consumer Affairs. RESULTS: Between January 2005 and December 2008, 2,134,363 patients were admitted to internal medicine departments in Spain, of whom 45,757 (2.1%) were nursing home residents. Overall, 7898 (17.3%) patients died during hospitalization, 2442 (30.91%) of them in the first 48 hours. The following variables were the significant predictors of in-hospital mortality in multivariate analysis: age (odds ratio [OR] 1.02, 95% confidence intervals [CI] 1.02-1.03), female gender (OR 1.13, 95% CI 1.13-1.17), dementia (OR 1.09, 95% CI 1.03-1.16), previous feeding tube (OR 1.34, 95% CI 1.09-1.79), malignant disease (OR 2.03, 95% CI 1.86-2.23), acute infectious disease (OR 1.18, 95% CI 1.12-1.25), pressure sores (OR 1.88, 95% CI 1.62-1.95), acute respiratory failure (OR 2.00, 95% CI 1.90-2.10), and nosocomial pneumonia (OR 2.5, 95% CI 2.23-2.72). CONCLUSIONS: Two of every 100 patients admitted to internal medicine departments came from nursing homes. The rate of mortality is very high in these patients, with almost one third of patients dying in the first 48 hours, which suggests that many of these transfers were unnecessary. The cost of these admissions for 1 year was equivalent to the annual budget of a 300- to 400-bed public hospital in Spain. The mechanism of coordination between nursing homes and public hospitals must be reviewed with the aim of containing costs and facilitating the care of patients in the last days of life.


Assuntos
Departamentos Hospitalares , Medicina Interna , Casas de Saúde , Admissão do Paciente/tendências , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Feminino , Humanos , Masculino , Transferência de Pacientes , Espanha
7.
J Thromb Thrombolysis ; 33(1): 82-7, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22016148

RESUMO

Patients with chronic obstructive pulmonary disease (COPD) are at increased risk for venous thromboembolism (VTE). We analyzed a large Spanish database to determine the incidence of VTE in these patients during hospitalization. A retrospective chart review of cohort of consecutive patients admitted with COPD as the primary reason for discharge in Spain between January 1st 2006 and December 31st 2007 was performed. For each patient, demographic data, risk factors for VTE and the diagnosis of VTE during hospitalization was recorded. We analyzed the clinical data of 313,233 adults with acute exacerbations of COPD admitted to the hospital at any public centre in Spain, in 2006 and 2007. We identify 3,562 new diagnosed VTE events among 270,840 COPD patients hospitalized more than two days (incidence 1.32%). Hospitalized-acquired VTE risk factors were male gender (odds ratio [OR] 1.77; CI95% 1.66-1.90), neoplasic disease (OR 2.93 CI95% 2.69-3.16, systemic arterial disease (OR 1.17 CI95% 1.10-1.36), decubitus ulcer (OR 1.19 CI95% 1.01-1.43), diabetes (OR 0.74 IC95% 0.69-0.81), and atrial fibrillation (OR 0.79 CI95% 0.72-0.87). VTE appears as a major threat to patients admitted for acute exacerbation of COPD, and pharmacologic prophylaxis should be considered in all high risk situations.


Assuntos
Hospitalização/tendências , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Espanha/epidemiologia
8.
Gastroenterol. latinoam ; 22(3): 232-237, jul.-sept. 2011. tab, graf
Artigo em Espanhol | LILACS | ID: lil-661665

RESUMO

It has been suggested that the R92Q mutation of the tumour necrosis factor receptor superfamily 1A (TNFRS1A) gene may be implicated in different inflammatory disorders. The aim of this study was to establish the role of this mutation as a determinant of Crohn`s disease (CD) susceptibility and/or clinical phenotype. One hundred and sixty-five CD patients and 203 healthy controls were prospectively included. The frequency of individuals carrying the R92Q mutation was similar between CD patients (4.24 percent) and controls (4.43 percent) (OR: 0.95; 95 percent CI = 0.34-2.62). In the genotype-phenotype evaluation, the univariate analysis showed that extra-intestinal manifestations were positively associated with the presence of R92Q mutation (p = 0.025; OR: 5.56; 95 percent CI = 1.04-29.6). In the multivariate analysis, presence of R92Q mutation was independently associated to extra-intestinal manifestations of CD, specially cutaneous manifestations (p = 0.02; OR: 5.17, 95 percent CI = 1.07-24.8). The R92Q mutation of TNFRSF1A gene is not a determinant of CD susceptibility, but contributes to the appearance of extra-intestinal manifestations of the disease.


Se ha sugerido que la mutación R92Q del gen de la super-familia del receptor del factor de necrosis tumoral 1A (TNFRS1A) podría estar relacionada con diversos trastornos inflamatorios. El objetivo de este estudio fue determinar el papel de esta mutación como factor determinante de la susceptibilidad y/o fenotipo clínico de la enfermedad de Crohn (EC). Ciento sesenta y cinco pacientes con EC y 203 controles sanos fueron incluidos de manera prospectiva. La frecuencia de individuos portadores de la mutación R92Q fue similar entre los pacientes con EC (4,24 por ciento) y los controles (4,43 por ciento) (OR: 0,95; 95 por ciento IC = 0,34-2,62). En la evaluación genotipo-fenotipo, el análisis univariado indicó que las manifestaciones extra-intestinales estaban relacionadas con la presencia de la mutación R92Q (p = 0,025; OR: 5,56; 95 por ciento IC = 1,04-29,6). En el análisis multivariado, la presencia de la mutación R92Q estuvo relacionada de manera independiente con las manifestaciones extra-intestinales de la EC, especialmente manifestaciones cutáneas (p = 0,02; OR: 5,17, 95 por ciento IC = 1,07-24,8). La mutación R92Q del gen TNFRSF1A no es un factor determinante de susceptibilidad a EC, pero contribuye a la aparición de manifestaciones extra-intestinales de la enfermedad.


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Doença de Crohn/complicações , Doença de Crohn/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Doenças Inflamatórias Intestinais/genética , Dermatopatias/etiologia , Estudos de Casos e Controles , Seguimentos , Fenótipo , Genótipo , Mutação
9.
Clin Nutr ; 30(4): 450-4, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21300420

RESUMO

BACKGROUND & AIMS: Detection and notification of malnutrition are essential to adopt a support plan and take costs into account. The aim of this study was to describe how often discharge sheets from Internal Medicine (IM) units include malnutrition among diagnoses (notification frequency) using the International Classification of Diseases, 9th Revision Clinical Modification -ICD-9. Factors associated with this diagnosis and its prognostic implications are also assessed. MATERIAL AND METHODS: The Minimum Basic Data Set from the Spanish hospitals (Ministry of Health and Consumer Affairs) was revised, and patients with diagnosis of malnutrition (ICD-9: 260-263.9) were identified. RESULTS: 1,567,659 patients were analysed (21,804-1.4%- with malnutrition). These patients were older (72.4 vs 70.8 years of age), had a greater degree of comorbidity (Charlson >2: 28% vs 23.5%), and resided in nursing homes more often (3.9% vs 1.9%) than the non-undernourished. The malnutrition associated diagnoses were: dementia, cancer, HIV infection and chronic renal failure. Mortality (19.5% vs 9.8%), hospital stay (18.1 vs 9.8 days), costs (5228.46 vs 3537.8 €) and relative weights applied to each Diagnosis Related Group (2.6 vs 1.1) were higher (p < 0.001 for all comparisons). CONCLUSIONS: Notification of malnutrition in IM departments is low, below the prevalence described in inpatients. This diagnosis is associated with an increase in morbidity, mortality and costs.


Assuntos
Demência/epidemiologia , Infecções por HIV/epidemiologia , Falência Renal Crônica/epidemiologia , Desnutrição/mortalidade , Neoplasias/epidemiologia , Avaliação Nutricional , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Custos Hospitalares , Humanos , Medicina Interna , Classificação Internacional de Doenças/estatística & dados numéricos , Tempo de Internação , Modelos Logísticos , Masculino , Desnutrição/economia , Pessoa de Meia-Idade , Prevalência , Espanha
10.
Eur J Intern Med ; 22(1): 49-52, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21238893

RESUMO

SUMMARY: Patients over 90 years of age (the "very elderly") account for an increasing number of admissions to departments of internal medicine (IM). The aim of this study was to analyse the demographic data, hospitalization characteristics, medical complications, and predictors of mortality in patients over 90 admitted to IM departments. MATERIAL AND METHODS: All patients admitted to IM departments in Spain between the years 2005 and 2007 were analysed. Clinical and demographic data were compared with records from "younger elderly" patients (65-90). RESULTS: During the study period, there were 1,567,659 patient admissions to IM departments in Spain, and 90,679 (5.8%) were older than 90. Hospital mortality occurred in 22.3% of very elderly patients. The main predictors for hospital death were pressure ulcer (Odds Ratio [OR] 1.55, CI95% 1.45-1.66), thromboembolic disease (OR 1.83, CI95% 1.61-2.09), nosocomial pneumonia (OR 2.53, CI95% 2.39-2.69), hip fracture (OR 2.20, CI95% 1.53-3.18), male gender (OR 1.06, CI95% 1.03-1.10), age (OR 1.05, CI95% 1.04-1.06), dementia (OR 1.13, CI95% 1.08-1.18), cancer (OR 1.60, CI95% 1.51-1.71), acute respiratory failure (OR 1.83, CI95% 1.76-1.89), acute infectious disease (OR 2.30, IC95% 2.11-2.52), and Charlson comorbidity index (OR 1.21, CI95% 1.16-1.26). CONCLUSIONS: Very elderly patients represent a large and growing fraction of the total admissions to IM departments in Spain. They are at higher risk for complications during their hospital stay and mortality rate is double that of the younger elderly.


Assuntos
Mortalidade Hospitalar , Pacientes Internados/estatística & dados numéricos , Medicina Interna/estatística & dados numéricos , Admissão do Paciente/estatística & dados numéricos , Distribuição por Idade , Idoso de 80 Anos ou mais , Estudos de Coortes , Doenças Transmissíveis/mortalidade , Infecção Hospitalar/mortalidade , Demência/mortalidade , Feminino , Fraturas do Quadril/mortalidade , Departamentos Hospitalares/estatística & dados numéricos , Mortalidade Hospitalar/tendências , Humanos , Medicina Interna/tendências , Masculino , Neoplasias/mortalidade , Razão de Chances , Admissão do Paciente/tendências , Alta do Paciente/estatística & dados numéricos , Úlcera por Pressão/mortalidade , Insuficiência Respiratória/mortalidade , Estudos Retrospectivos , Fatores de Risco , Distribuição por Sexo , Espanha/epidemiologia , Tromboembolia/mortalidade
11.
Thromb Res ; 126(4): 276-9, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20659763

RESUMO

BACKGROUND: Acute and chronic illness, immobility, and procedural and pharmacologic interventions may predispose patients in the Internal Medicine Wards to venous thromboembolic disease (VTE). The purpose of this study was to determine the incidence of VTE in these patients. MATERIALS AND METHODS: A retrospective chart review of cohort of consecutive patients admitted to Internal Medicine wards in Spain between January 1st 2005 and December 31st 2007 was performed. For each patient, demographic data, risk factors for VTE and the diagnosis of VTE during hospitalization was recorded. RESULTS: We analyzed 1,567,659 patients, excluding 28,226 patients who had DVT or PE before admission, and 196,555 who were discharged in the first 48 hours. We identify 12,458 new diagnosed VTE events among 1,344,959 patients (incidence 0.93%) hospitalized more than two days. Hospitalized-acquired VTE risk factors were feminine gender (odds ratio [OR] 1.31; CI95% 1.26-1.35), age >70 (OR 1.08 CI95% 1.04-1.13), acute infectious disease (OR 1.27 CI95% 1.17-1.38), acute respiratory disease (OR 1.23 CI95% 1.17-1.28), dementia (OR 1.22 CI95% 1.14-1.31), neoplasic disease (OR 2.29, CI95% 2.19-2.49), and hemiplegia (OR 1.49, CI95% 1.31-1.69). CONCLUSIONS: The number of patients with VTE in an Internal Medicine ward is higher than expected. Several independent risk factors for VTE were identified. Based on the large number of patients who developed a VTE during hospitalization, our data add strength to the argument that VTE prevention should be high on the list of priorities when health care policies are being formed.


Assuntos
Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiologia , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Espanha/epidemiologia
12.
Arthritis Rheum ; 62(4): 1158-66, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20131270

RESUMO

OBJECTIVE: Chronic infantile neurologic, cutaneous, articular syndrome (CINCA), also known as neonatal-onset multisystem inflammatory disease (NOMID), is a severe, early-onset autoinflammatory disease characterized by an urticaria-like rash, arthritis/arthropathy, variable neurologic involvement, and dysmorphic features, which usually respond to interleukin-1 blockade. CINCA/NOMID has been associated with dominant Mendelian inherited NLRP3 mutations. However, conventional sequencing analyses detect true disease-causing mutations in only approximately 55-60% of patients, which suggests the presence of genetic heterogeneity. We undertook the current study to assess the presence of somatic, nongermline NLRP3 mutations in a sporadic case of CINCA/NOMID. METHODS: Clinical data, laboratory results, and information on treatment outcomes were gathered through direct interviews. Exhaustive genetic studies, including Sanger method sequencing, subcloning, restriction fragment length polymorphism assay, and pyrosequencing, were performed. RESULTS: The patient's CINCA/NOMID was diagnosed based on clinical features (early onset of the disease, urticaria-like rash, knee arthropathy, and dysmorphic features). The patient has exhibited a successful response to anakinra within the last 28 months. Analysis of NLRP3 identified a novel heterozygous variant (p.D303H) that was detected in approximately 30-38% of circulating leukocytes. The absence of this variant in healthy controls and in the patient's parents suggested a de novo true disease-causing mutation. Additional analyses showed that this novel mutation was present in both leukocyte subpopulations and epithelial cells. CONCLUSION: Our findings identify the novel p.D303H NLRP3 variant in a Spanish patient with CINCA/NOMID as a new disease-causing mutation, which was detected as a somatic, nongermline mutation in hematopoietic and nonhematopoietic cell lineages. Our data provide new insight into the role of low-level mosaicism in NLRP3 as the pathophysiologic mechanism underlying cryopyrin-associated periodic syndrome.


Assuntos
Proteínas de Transporte/genética , Síndromes Periódicas Associadas à Criopirina/genética , Doenças do Recém-Nascido/genética , Mosaicismo , Polimorfismo de Nucleotídeo Único , Síndromes Periódicas Associadas à Criopirina/patologia , Síndromes Periódicas Associadas à Criopirina/fisiopatologia , DNA/sangue , DNA/genética , DNA/isolamento & purificação , Análise Mutacional de DNA , Primers do DNA , Humanos , Lactente , Recém-Nascido , Doenças do Recém-Nascido/patologia , Doenças do Recém-Nascido/fisiopatologia , Leucócitos/patologia , Leucócitos/fisiologia , Mutação , Proteína 3 que Contém Domínio de Pirina da Família NLR , Plasmídeos , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Mapeamento por Restrição , Urticária/genética
13.
Arthritis Rheum ; 56(11): 3805-13, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17968944

RESUMO

OBJECTIVE: Blau syndrome and early-onset sarcoidosis are NOD2 gene-associated chronic autoinflammatory diseases characterized by skin rash, arthritis, and/or eye involvement, with noncaseating granulomata as their pathologic hallmark. This study was undertaken to describe the expanded clinical phenotype, treatment outcomes, and NOD2 gene mutation analysis in a Spanish cohort with pediatric granulomatous arthritis, a chronic disease resembling Blau syndrome/early-onset sarcoidosis. METHODS: Clinical, laboratory, and treatment data on the 12 patients in the cohort were obtained through direct interviews. NOD2 gene analysis was performed in a central laboratory, by bidirectional sequencing. Cytokine levels were measured using the human Flex-Set cytokine bead array. RESULTS: The classic Blau syndrome/early-onset sarcoidosis triad of skin rash, arthritis, and recurrent uveitis was identified in 5 patients (41.7%), whereas 7 patients (58.3%) presented with fewer than 3 of the classic features. Novel atypical manifestations such as persistent fever and myocardiopathy were also observed. NOD2 analysis revealed 1 heterozygous mutation in each patient, and familial studies confirmed its full penetrance. Of the 12 cases, 58.3% were sporadic, due to de novo mutations. Four different missense mutations on exon 4 were detected. Two of them (R334W and R334Q) were recurrent mutations and were found in 77.8% of the Spanish families, whereas the other 2 (C495Y and R587C) were novel. In the patient who received anakinra treatment, all clinical inflammatory symptoms improved and plasma cytokine levels normalized. CONCLUSION: These findings indicate that the expanding clinical heterogeneity of the disease (that is, the presentation of incomplete forms of the classic triad and atypical manifestations) and the high prevalence of sporadic cases should alert clinicians to the possible genetic basis of the condition and support the inclusion of DNA analysis as a diagnostic test. The positive response to anakinra observed in 1 patient suggests a new potential therapeutic approach that merits further investigation, and suggests that the pathogenesis of pediatric granulomatous arthritis may involve interleukin-1-mediated events.


Assuntos
Artrite/genética , Granuloma/genética , Proteína Adaptadora de Sinalização NOD2/genética , Síndrome , Uveíte/genética , Adolescente , Adulto , Antirreumáticos/uso terapêutico , Artrite/tratamento farmacológico , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Granuloma/tratamento farmacológico , Humanos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Recidiva , Espanha , Uveíte/tratamento farmacológico
14.
Haematologica ; 91(10): 1372-6, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17018387

RESUMO

BACKGROUND AND OBJECTIVES: Three single nucleotide polymorphisms (SNP) in the NOD2/CARD15 gene have been associated with the incidence and the severity of acute graft-versus-host disease (GVHD) following allogeneic stem cell transplantation (SCT). We hypothesized that the clinical effect of SNP in NOD2/CARD15 might be different in patients submitted to T-cell-depleted allogeneic SCT, in which donor T cells, the main effectors of GVHD, are eliminated. DESIGN AND METHODS: SNP 8, 12 and 13 in NOD2/CARD15 were studied using a Taqman protocol in 85 patients undergoing HLA-identical, T-cell-depleted SCT and in 71 of their sibling donors. RESULTS: NOD2/CARD15 variants were present in nine (11%) patients and six (8%) donors. The incidences of acute GVHD and chronic GVHD were not associated with either the donors' or recipients' NOD2/CARD15 variants. In contrast, these genetic variants were associated with a lower disease-free survival (17% vs. 48%, p=0.03). Death due to pulmonary infection was more frequent in the group of patients with NOD2/CARD15 variants. In the multivariate analysis, only NOD2/CARD15 variants (RR 2.3, p=0.04) and older age (RR 2.2; p=0.04) were independent prognostic factors for disease-free survival. INTERPRETATION AND CONCLUSIONS: NOD2/CARD15 variants have a deleterious effect on clinical outcome in T-cell-depleted allogeneic SCT, which is independent of GVHD. These results supports the hypothesis that the detrimental effect of NOD2/CARD15 variants in such a transplant setting might be produced by an alteration of the innate immune system more than by activation of the adaptive immune system.


Assuntos
Variação Genética , Depleção Linfocítica , Proteína Adaptadora de Sinalização NOD2/genética , Transplante de Células-Tronco/mortalidade , Linfócitos T , Adulto , Feminino , Marcadores Genéticos/genética , Marcadores Genéticos/imunologia , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Linfócitos T/citologia , Linfócitos T/imunologia , Transplante Homólogo/imunologia , Transplante Homólogo/mortalidade
15.
Ann Surg ; 242(5): 693-700, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16244543

RESUMO

OBJECTIVE: To study the predictive value of Nod2/CARD15 gene variants along with disease phenotypic characteristics for requirement of initial surgery and for surgical recurrence in Crohn's disease (CD). SUMMARY BACKGROUND DATA: Nod2/CARD15 gene variants play an important role in the susceptibility to CD. Studies of genotype-phenotype relationship suggest that these variants are associated with development of intestinal strictures. Preliminary reports analyzing the association between these variants and need for surgery have produced inconsistent results. METHODS: A total of 170 CD patients were included prospectively in the study and followed up regularly for a mean of 7.4 +/- 6.1 years. Clinical characteristics of CD, time and indication for surgery, and recurrence were registered. Nod2/CARD15 gene variants were determined by DNA sequencing analysis. RESULTS: Surgery for stricturing disease was significantly more frequent in patients with Nod2/CARD15 variants in the univariate analysis (odds ratio [OR], 3.63; 95% confidence interval [CI], 1.42-9.27), and it was required at an earlier time (P = 0.004). Only Nod2/CARD15 variants (OR, 3.58; 95% CI, 1.21-10.5) and stricturing phenotype at diagnosis of CD (OR, 9.34; 95% CI, 2.56-33.3) were independent predictive factors of initial surgery for stricturing lesions in the multivariate analysis. Among 70 patients that required surgery, postoperative recurrence was also more frequent in patients with Nod2/CARD15 variants in the univariate and multivariate analysis (OR, 3.29; 95% CI, 1.13-9.56), and reoperation was needed at an earlier time (P = 0.03). CONCLUSION: Nod2/CARD15 variants are associated with early initial surgery due to stenosis and with surgical recurrence in Crohn's disease. Patients with these variants could benefit from preventive and/or early therapeutic strategies.


Assuntos
Biomarcadores Tumorais/análise , Doença de Crohn/genética , Doença de Crohn/cirurgia , Predisposição Genética para Doença/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Polimorfismo Genético , Adulto , Análise de Variância , Sequência de Bases , Estudos de Coortes , Colectomia/métodos , Doença de Crohn/epidemiologia , DNA de Neoplasias/análise , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Avaliação das Necessidades , Proteína Adaptadora de Sinalização NOD2 , Complicações Pós-Operatórias/epidemiologia , Valor Preditivo dos Testes , Probabilidade , Prognóstico , Estudos Prospectivos , Recidiva , Reoperação , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Medição de Risco , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
16.
Eur J Pediatr ; 164(1): 13-6, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15549379

RESUMO

UNLABELLED: We investigated the cause of hereditary periodic fever syndrome in a Spanish child with recurrent long episodes of fever, migratory skin rash, myalgia, arthralgia, conjunctivitis and abdominal pain. Infectious and autoimmune causes were ruled out. No familial history was reported. Analysis of the tumour necrosis factor receptor superfamily 1A (TNFRSF1A) gene identified a missense mutation (G36E) on exon 3. The absence of this variant in the patient's parents and in controls identified it as a de novo disease-associated mutation. Clinical symptoms disappeared with administration of etanercept; however, levels of acute-phase reactants remained increased and could not be stabilised by the addition of colchicine. We believe that this patient gained some symptomatic relief with etanercept therapy, although not enough to completely avoid the risk of amyloidosis. Thus it is debatable whether etanercept alone or combined with other drugs, is the treatment of choice for patients with tumour necrosis factor receptor-associated periodic syndrome. CONCLUSION: Since there is variability in treatment responses among different patients with tumour necrosis factor receptor-associated periodic syndrome, we suggest that a systematic evaluation of acute-phase reactants, especially SAA-1, could be useful in maintaining or modifying a given therapeutic approach in these patients.


Assuntos
Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Imunossupressores/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Criança , Diagnóstico Diferencial , Quimioterapia Combinada , Etanercepte , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Humanos , Masculino , Receptores Tipo I de Fatores de Necrose Tumoral/genética
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