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1.
J Intern Med ; 281(2): 179-188, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27696568

RESUMO

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is considered a diagnostic marker for chronic fatigue syndrome (CFS). OBJECTIVES: The aims of this study were to (i) compare POTS prevalence in a CFS cohort with fatigued patients not meeting CFS criteria, and (ii) assess activity, impairment and response to cognitive behavioural therapy (CBT) in CFS patients with POTS (POTS-CFS) and without POTS (non-POTS-CFS). METHODS: Prospective cohort study at the Radboud University Medical Centre in the Netherlands. Between June 2013 and December 2014, 863 consecutive patients with persistent fatigue were screened. Patients underwent an active standing test, filled out questionnaires and wore an activity-sensing device for a period of 12 days. RESULTS: A total of 419 patients with CFS and 341 non-CFS fatigued patients were included in the study. POTS prevalence in adult patients with CFS was 5.7% vs. 6.9% in non-CFS adults (P = 0.54). In adolescents, prevalence rates were 18.2% and 17.4%, respectively (P = 0.93). Adult patients with POTS-CFS were younger (30 ± 12 vs. 40 ± 13 years, P = 0.001) and had a higher supine heart rate (71 ± 11 vs. 65 ± 9 beats per min, P = 0.009) compared with non-POTS-CFS patients. Severity and activity patterns did not differ between groups. In patients with CFS, criteria for Systemic Exertion Intolerance Disease (SEID) were met in 76% of adults and 67% of adolescents. In these patients with CFS fulfilling the SEID criteria, the prevalence of POTS was not different from that in the overall CFS population. POTS-CFS adolescents had less clinically significant improvement after CBT than non-POTS-CFS adolescents (58% vs. 88%, P = 0.017). CONCLUSION: In adults with CFS, the prevalence of POTS was low, was not different from the rate in non-CFS fatigued patients and was not related to disease severity or treatment outcome. In POTS-CFS adolescents, CBT was less successful than in non-POTS-CFS patients. The evaluation of POTS appears to be of limited value for the diagnosis of CFS.


Assuntos
Síndrome de Fadiga Crônica/diagnóstico , Síndrome de Fadiga Crônica/epidemiologia , Síndrome da Taquicardia Postural Ortostática/epidemiologia , Adolescente , Adulto , Pressão Sanguínea , Terapia Cognitivo-Comportamental , Comorbidade , Fadiga/diagnóstico , Fadiga/epidemiologia , Fadiga/terapia , Síndrome de Fadiga Crônica/fisiopatologia , Síndrome de Fadiga Crônica/terapia , Humanos , Países Baixos/epidemiologia , Síndrome da Taquicardia Postural Ortostática/fisiopatologia , Prevalência , Estudos Prospectivos
3.
Clin Exp Immunol ; 181(3): 434-40, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25880788

RESUMO

Patients with signal transducer and activator of transcription-1 (STAT1)-dependent chronic mucocutaneous candidiasis (CMC) and patients with STAT3-dependent hyper-immunoglobulin (Ig)E syndrome (HIES) display defects in T helper type 17 (Th17) cytokine production capacity. Despite this similar immune defect in Th17 function, they show important differences in the type of infections to which they are susceptible. Recently, our group reported differential regulation of STAT-1 and STAT-3 transcription factors during epigenetic reprogramming of trained immunity, an important host defence mechanism based on innate immune memory. We therefore hypothesized that STAT1 and STAT3 defects have different effects on trained immunity, and this may partly explain the differences between CMC and HIES regarding the susceptibility to infections. Indeed, while trained immunity was normally induced in cells isolated from patients with HIES, the induction of innate training was defective in CMC patients. This defect was specific for training with Candida albicans, the main pathogen encountered in CMC, and it involved a type II interferon-dependent mechanism. These findings describe the role of STAT-1 for the induction of trained immunity, and may contribute to the understanding of the differences in susceptibility to infection between CMC and HIES patients. This study could also provide directions for personalized immunotherapy in patients suffering from these immunodeficiencies.


Assuntos
Candidíase Mucocutânea Crônica/imunologia , Síndrome de Job/imunologia , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT3/imunologia , Candida albicans/imunologia , Candida albicans/fisiologia , Candidíase Mucocutânea Crônica/sangue , Candidíase Mucocutânea Crônica/microbiologia , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Interações Hospedeiro-Patógeno/imunologia , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-6/imunologia , Interleucina-6/metabolismo , Síndrome de Job/sangue , Síndrome de Job/genética , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Mutação , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT3/genética , Células Th17/imunologia , Células Th17/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , beta-Glucanas/imunologia , beta-Glucanas/farmacologia
4.
Br J Dermatol ; 173(2): 448-56, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25904179

RESUMO

BACKGROUND: Schnitzler's syndrome (SchS) is an autoinflammatory disease characterized by a chronic urticarial rash, a monoclonal component and signs of systemic inflammation. Interleukin (IL)-1ß is pivotal in the pathophysiology. OBJECTIVES: Here we investigated the cellular source of proinflammatory mediators in the skin of patients with SchS. METHODS: Skin biopsies of lesional and nonlesional skin from eight patients with SchS and healthy controls, and patients with cryopyrin-associated periodic syndrome (CAPS), delayed-pressure urticaria (DPU) and cold-contact urticaria (CCU) were studied. We studied in vivoIL-1ß, IL-17 and antimicrobial protein (AMP) expression in resident skin cells and infiltrating cells. In addition we investigated the in vitro effect of IL-1ß, IL-17 and polyinosinic-polycytidylic acid (poly:IC) stimulation on cultured epidermal keratinocytes. RESULTS: Remarkably, we found IL-1ß-positive dermal mast cells in both lesional and nonlesional skin of patients with SchS, but not in healthy control skin and CCU, and fewer in CAPS. IL-17-positive neutrophils were observed only in lesional SchS and DPU skin. In lesional SchS epidermis, mRNA and protein expression levels of AMPs were strongly increased compared with nonlesional skin and that of healthy controls. When exposed to IL-1ß, poly:IC or IL-17, patient and control primary human keratinocytes produced AMPs in similar amounts. CONCLUSIONS: Dermal mast cells of patients with SchS produce IL-1ß. This presumably leads to activation of keratinocytes and neutrophil influx, and further amplification of inflammation by IL-17 (from neutrophils and mast cells) and epidermal AMP production leading to chronic histamine-independent neutrophilic urticarial dermatosis.


Assuntos
Peptídeos Catiônicos Antimicrobianos/metabolismo , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Síndrome de Schnitzler/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Síndromes Periódicas Associadas à Criopirina/metabolismo , Feminino , Humanos , Indutores de Interferon/farmacologia , Queratinócitos/metabolismo , Masculino , Mastócitos/metabolismo , Neutrófilos/metabolismo , Poli I-C/farmacologia , Proteína A7 Ligante de Cálcio S100 , Proteínas S100/metabolismo , Urticária/metabolismo , beta-Defensinas/metabolismo
6.
Infect Immun ; 80(5): 1917-22, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22354034

RESUMO

Upon the invasion of the host by microorganisms, innate immunity is triggered through pathogen recognition by pattern recognition receptors (PRRs). Toll-like receptors (TLRs) are the best-studied class of PRRs, and they recognize specific pathogen-associated molecular patterns (PAMPs) from various microorganisms. A large number of studies have shown that genetic variation in TLRs may influence susceptibility to infections. We assessed the genetic variation of TLR2, which encodes one of the most important TLRs, in various populations around the globe and correlated it with changes in the function of the molecule. The three best-known nonsynonymous TLR2 polymorphisms (1892C>A, 2029C>T, and 2258G>A) were assessed in different populations from the main continental masses: Romanians, Vlax-Roma, Dutch (European populations), Han Chinese (East Asia), Dogon, Fulani (Africa), and Trio Indians (America). The 2029C>T polymorphism was absent in both European and non-European populations, with the exception of the Vlax-Roma, suggesting that this polymorphism most likely arose in Indo-Aryan people after migration into South Asia. The 1892C>A polymorphism that was found exclusively in European populations, but not in Asian, African, or American volunteers, probably occurred in proto-Indo-Europeans. Interestingly, 2258G>A was present only in Europeans, including Vlax-Roma, but at a very low frequency. The differential pattern of the TLR2 polymorphisms in various populations may explain some of the differences in susceptibility to infections between these populations.


Assuntos
Etnicidade/genética , Polimorfismo Genético , Grupos Raciais/genética , Receptor 2 Toll-Like/genética , Alelos , Regulação da Expressão Gênica/imunologia , Regulação da Expressão Gênica/fisiologia , Genótipo , Humanos , Imunidade Inata , Interleucina-6/genética , Interleucina-6/metabolismo , Ligantes
8.
J Intern Med ; 272(6): 517-27, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22891878

RESUMO

Primary immunodeficiencies (PIDs) are severe defects in the capacity of the host to mount a proper immune response, and are characterized by an increased susceptibility to infections. Although classical immunodeficiencies have been characterized based on broad defects in cell populations (e.g. T/B cells or polymorphonuclear leukocytes) or humoral factors (e.g. antibodies or complement), specific immune defects based on well-defined molecular targets have been described more recently. Among these, genetic defects in pattern recognition receptors (PRRs), leading to impaired recognition of invading pathogens by the innate immune system, play an important role in specific defects against human pathogens. Defects have been described in three of the major families of PRRs: the Toll-like receptors, the C-type lectin receptors and the nucleotide-binding domain leucine-rich repeat-containing receptors. By contrast, no defects in the intracellular viral receptors of the RigI helicase family have been described to date. Defects in the PRRs show a broad variation in severity, have a narrow specificity for certain classes of pathogens, and often decrease in severity with age; these characteristics distinguish them from other forms of PIDs. Their discovery has led to important insights into the pathophysiology of infections, and may offer potential novel therapeutic targets for immunotherapy.


Assuntos
Imunidade Inata/genética , Síndromes de Imunodeficiência , Receptores de Reconhecimento de Padrão , Fatores Etários , Predisposição Genética para Doença , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/terapia , Imunoterapia/métodos , Infecções/imunologia , Lectinas Tipo C/imunologia , Proteínas de Repetições Ricas em Leucina , Proteínas/imunologia , Receptores Citoplasmáticos e Nucleares , Receptores de Reconhecimento de Padrão/classificação , Receptores de Reconhecimento de Padrão/genética , Receptores de Reconhecimento de Padrão/imunologia , Índice de Gravidade de Doença
9.
Ann Rheum Dis ; 70(12): 2155-8, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21859689

RESUMO

BACKGROUND: Mevalonate kinase deficiency (MKD) is a hereditary autoinflammatory syndrome marked by recurrent attacks of fever and inflammation. Severe enzyme deficiency results in mevalonic aciduria (MA) and milder deficiency in hyperimmunoglobulin D syndrome (HIDS). Treatment remains a challenge. OBJECTIVE: To observe the effect of the recombinant interleukin-1 receptor antagonist anakinra in patients with MKD. METHODS: A prospective observational study was undertaken. Two patients with MA started continuous treatment with anakinra (1-2 mg/kg/day) and nine patients with HIDS chose between continuous treatment and on-demand treatment (starting at first symptoms of attack, 100 mg/day or 1 mg/kg/day for 5-7 days). RESULTS: Anakinra induced partial remission in one patient with MA but there was no response in the other patient with MA. In one patient with HIDS continuous treatment induced complete remission for 7 months but was stopped because of side effects. Eight patients with HIDS preferred on-demand treatment from the start. This induced a clinical response (≥50% reduction in duration) in 8 of 12 treated attacks without a change in attack frequency. Anakinra prevented fever attacks due to vaccination without inhibiting antibody induction. No major side effects were seen. CONCLUSIONS: On-demand treatment with anakinra in HIDS decreases the duration and severity of fever attacks. Because of the burden of daily injections and relatively long asymptomatic intervals of HIDS, all patients with HIDS preferred on-demand treatment.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Deficiência de Mevalonato Quinase/tratamento farmacológico , Adolescente , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , Proteína C-Reativa/metabolismo , Criança , Pré-Escolar , Esquema de Medicação , Feminino , Febre/tratamento farmacológico , Febre/etiologia , Humanos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Masculino , Deficiência de Mevalonato Quinase/sangue , Deficiência de Mevalonato Quinase/complicações , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
10.
Vox Sang ; 101(2): 138-46, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21749402

RESUMO

BACKGROUND AND OBJECTIVES: In the production process of a new 5% liquid intravenous immunoglobulin (IVIG-L) product (Nanogam(®) ), a combined pepsin/pH 4·4 treatment/15-nm filtration (pH 4·4/15NF) step and a solvent-detergent (SD) treatment step were incorporated to improve the virus inactivating/reducing capacity of the manufacturing process. Two prospective uncontrolled multicentre studies were performed to evaluate the safety and efficacy of this product. MATERIALS AND METHODS: Efficacy, including pharmacokinetics, of IVIG-L was studied for 6 months in 18 primary immunodeficiency (PID) patients, succeeded by a long-term follow-up study (mean 2·2 years, n=17). Second, in 24 patients with idiopathic thrombocytopenic purpura (ITP), IVIG-L was studied for efficacy for 14 days. In both studies, adverse events and vital signs were recorded to study safety. RESULTS: In PID patients treated with IVIG-L, 0·60 and 0·38 severe infections per patient per year were reported during, respectively, the short-term and long-term follow-up. Pharmacokinetic studies resulted in an IgG half-life of 30·9 ± 11·3 days and a mean IgG trough level of 6·8 ± 1·2 g/l. In the ITP study, all patients showed an increase in platelet counts after infusion with IVIG-L, and 20/24 patients responded with a platelet count >50 × 10(9) /l (83·3%) within 1 week. IVIG-L infusions did not cause clinical relevant changes in laboratory parameters or vital signs. CONCLUSIONS: In clinical studies, IVIG-L (Nanogam®) demonstrated to be efficacious, well tolerated and safe.


Assuntos
Imunoglobulinas Intravenosas/administração & dosagem , Síndromes de Imunodeficiência/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Adolescente , Adulto , Idoso , Feminino , Humanos , Imunoglobulinas Intravenosas/efeitos adversos , Imunoglobulinas Intravenosas/química , Imunoglobulinas Intravenosas/farmacocinética , Síndromes de Imunodeficiência/metabolismo , Masculino , Pessoa de Meia-Idade , Nanotecnologia/métodos , Estudos Prospectivos , Púrpura Trombocitopênica Idiopática/metabolismo , Adulto Jovem
11.
Clin Exp Immunol ; 159(1): 57-64, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19878510

RESUMO

Mutations in the signal transducer and activator of transcription 3 (STAT3) were reported to cause hyperimmunoglobulin E syndrome (HIES). The present study investigates T helper type 17 (Th17) responses triggered by the relevant stimuli Staphylococcus aureus and Candidia albicans in five 'classical' HIES patients, and a family with three patients who all had a milder HIES phenotype. We demonstrate that patients with various forms of HIES have different defects in their Th17 response to S. aureus and C. albicans, and this is in line with the clinical features of the disease. Interestingly, a partial deficiency of interleukin (IL)-17 production, even when associated with STAT3 mutations, leads to a milder clinical phenotype. We also observed defective Th17 responses in patients with the 'classical' presentation of the disease but without STAT3 mutations. These data demonstrate that defective IL-17 production in response to specific pathogens can differ between patients with HIES and that the extent of the defective Th17 response determines their clinical phenotype.


Assuntos
Interleucina-17/deficiência , Síndrome de Job/diagnóstico , Síndrome de Job/metabolismo , Adulto , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Candida albicans/imunologia , Feminino , Humanos , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-10/farmacologia , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/farmacologia , Síndrome de Job/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Linhagem , Fator de Transcrição STAT3/genética , Transdução de Sinais/imunologia , Staphylococcus aureus/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
12.
Clin Exp Immunol ; 156(3): 434-9, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19438595

RESUMO

The two major primary antibody deficiency disorders are X-linked hypogammaglobulinaemia (XLA) and common variable immunodeficiency (CVID). CVID patients have an elevated risk for gastric cancer and extra-nodal marginal zone lymphoma. Both diseases are associated with Helicobacter pylori infection. We investigated whether antibody deficiency leads to defective serum bactericidal activity against H. pylori. We also investigated the correlation with immunoglobulin (Ig)M levels and observed the terminal complement complex (TCC) activity. Sera of 13 CVID patients (four H. pylori positive), one patient with hyper-IgM syndrome, one patient with Good syndrome (both H. pylori positive), five XLA patients, four H. pylori seropositive controls, four H. pylori seronegative controls and a sample of pooled human serum (PHS) were incubated in vitro with bacterial suspensions of H. pylori for 30 min. After 72 h of culture, colony-forming units were counted. TCC formation was measured by enzyme-linked immunosorbent assay. We found that normal human serum is bactericidal for H. pylori, whereas heat-inactivated serum shows hardly any killing of H. pylori. Serum (1%) of hypogammaglobulinaemia patients has a decreased bactericidal activity against H. pylori. Helicobacter pylori-positive (HP(+)) normal individuals show more than 90% killing of H. pylori, whereas CVID patients show 35% killing (P = 0.007) and XLA patients only 19% (P = 0.003). Serum (1%) of HP(+) volunteers showed significantly better killing compared with serum of H. pylori-negative (HP(-)) volunteers (P = 0.034). No correlation between (substituted) IgG levels and serum bactericidal activity was found, but a weak correlation between total serum IgM and serum bactericidal activity was found. In conclusion, serum bactericidal activity against H. pylori is decreased in patients with hypogammaglobulinaemia. Heat treatment of the serum abolished the bactericidal capacity, indicating that complement activity is essential for the bactericidal effect.


Assuntos
Agamaglobulinemia/imunologia , Atividade Bactericida do Sangue , Infecções por Helicobacter/imunologia , Helicobacter pylori , Infecções Oportunistas/imunologia , Adulto , Agamaglobulinemia/complicações , Idoso , Contagem de Colônia Microbiana , Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/imunologia , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Infecções por Helicobacter/complicações , Humanos , Pessoa de Meia-Idade , Infecções Oportunistas/complicações , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/complicações , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologia , Adulto Jovem
13.
Ann Rheum Dis ; 68(2): 273-8, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18390571

RESUMO

OBJECTIVE: Recent studies suggest that crystals of monosodium urate (MSU), deposited in joints of patients with acute gouty arthritis, activate the NACHT domain, leucine-rich repeat and pyrin domain-containing protein (NALP)3 inflammasome. In the present study we have investigated whether production of proinflammatory cytokines by crystals was exacerbated during costimulation with Toll-like receptor (TLR) ligands. METHODS: Mononuclear cells of 22 healthy donors were stimulated by various concentrations of MSU crystals in the absence or presence of lipopolysaccharide (LPS), Pam3Cys and flagellin. Production of tumour necrosis factor alpha (TNFalpha), interleukin (IL)1 beta and IL6, as well as the intracellular concentrations of proIL1 beta were measured by ELISA. mRNA transcripts of TNFalpha and IL1 beta were assessed by real-time PCR. Stimulation experiments were also performed with peripheral blood mononuclear cells (PBMCs) of one patient carrying a NALP3 mutation. RESULTS: MSU induced a moderate release of IL1 beta and IL6, but not of TNFalpha. Urate crystals amplified IL1 beta production stimulated by the TLR4 ligand LPS, while no synergy was apparent for IL6 production. In addition, no synergy between urate crystals and Pam3Cys (TLR2 ligand) or flagellin (TLR5 ligand) was apparent. The synergy between urate crystals and LPS was directed at the level of the NALP3 inflammasome, as it was present only when active IL1 beta was measured, but not at the level of IL1 mRNA or proIL1 beta. The synergy between LPS and MSU crystals ceased to exist in the presence of a caspase 1 inhibitor. CONCLUSIONS: MSU crystals act in synergy with LPS for the induction of enhanced release of IL1 beta. Increased cleavage of proIL1 beta by urate-activated caspase 1 is proposed as the underlying mechanism.


Assuntos
Caspase 1/imunologia , Interleucina-1beta/biossíntese , Leucócitos Mononucleares/imunologia , Lipopolissacarídeos/imunologia , Ácido Úrico/imunologia , Adulto , Proteínas de Transporte/genética , Células Cultivadas , Cristalização , Citocinas/biossíntese , Relação Dose-Resposta Imunológica , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-1beta/genética , Masculino , Mutação , Proteína 3 que Contém Domínio de Pirina da Família NLR , Reação em Cadeia da Polimerase/métodos , RNA Mensageiro/genética , Adulto Jovem
14.
Eur J Clin Invest ; 39(5): 412-6, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19740371

RESUMO

BACKGROUND: The extracellular, fibrillar deposits of reactive (secondary) amyloidosis are composed of amyloid A (AA) protein, a proteolytically derived fragment of the acute phase protein serum amyloid A (SAA). While complete degradation of SAA precludes amyloid formation, limited cleavage which generates AA protein is considered part of the pathogenic mechanism. MATERIALS AND METHODS: In this study, we investigated SAA degradation by lysosomal enzymes cathepsins B, D, and K, and assessed the impact of cathepsin activity on AA amyloid formation in a cell culture model using peripheral blood mononuclear cells from healthy volunteers. RESULTS: Lysates of human mononuclear cells were capable of degrading SAA. Degradation was significantly reduced by inhibition of cathepsin D with pepstatin A. Inhibition of cathepsin B or cathepsin K, however, had no effect. The SAA fragment pattern generated by mononuclear cell lysates was similar to that produced by incubating SAA with purified human cathepsin D. Consistent with in vitro findings, amyloid formation in human monocyte cultures was increased by 43% when cathepsin D was inhibited, but remained unaffected by inhibition of cathepsin B or cathepsin K. CONCLUSION: These data provide evidence that cathepsin D but not cathepsin B or cathepsin K is physiologically important in SAA degradation and hence in preventing SAA from accumulating and serving as precursor of AA amyloid fibrils.


Assuntos
Amiloide/metabolismo , Catepsina D/metabolismo , Proteína Amiloide A Sérica/metabolismo , Catepsina B/antagonistas & inibidores , Catepsina D/antagonistas & inibidores , Catepsina K , Catepsinas/antagonistas & inibidores , Células Cultivadas , Eletroforese em Gel de Poliacrilamida , Humanos , Concentração de Íons de Hidrogênio , Leucócitos Mononucleares/enzimologia
15.
Int J Tuberc Lung Dis ; 13(6): 755-9, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19460253

RESUMO

OBJECTIVE: To identify nutritional and socio-demographic factors for the development of tuberculosis (TB) in Timor and Rote Island, Indonesia, so that intervention programmes can be developed to address these factors. METHODS: In a case-control study, we enrolled new sputum smear-positive pulmonary TB patients as cases, and neighbours matched for sex and age as controls. Data obtained included history of TB, socio-demographic factors and nutritional status. RESULTS: In the study, 121 TB patients and 371 controls participated. The mean age was 30 years: 56.3% were male and 43.7% female. Of the TB patients, 87% had malnutrition compared to 33% among controls. The mean body mass index (BMI) of the patients was significantly lower than that of the controls (16.1 +/- 2.3 kg/m(2) vs. 19.4 +/- 3.0 kg/m(2)). Factors associated with the development of TB were BMI (OR 0.5, 95%CI 0.4-0.6), family history of TB (OR 3.2, 95%CI 1.6-6.4), living in an extended family (OR 2.7, 95%CI 1.5-4.8), being non-indigenous to Timor and Rote Islands (OR 2.9, 95%CI 1.2-6.8) and being unemployed (OR 3.8, 95%CI 1.7-8.6). CONCLUSION: Among patients with active pulmonary TB, the prevalence of malnutrition was very high. Malnutrition, which is a general problem for the whole community and particularly among people not indigenous to Timor and Rote, should be addressed in the fight against TB.


Assuntos
Desnutrição/epidemiologia , Tuberculose Pulmonar/epidemiologia , Adulto , Índice de Massa Corporal , Estudos de Casos e Controles , Comorbidade , Demografia , Emprego , Feminino , Humanos , Indonésia/epidemiologia , Masculino , Prevalência , Fatores de Risco
16.
J Leukoc Biol ; 83(5): 1295-9, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18285405

RESUMO

Amyloid A (AA) amyloidosis is a severe complication of many chronic inflammatory disorders, including the hereditary periodic fever syndromes. However, in one of these periodic fever syndromes, the hyper IgD and periodic fever syndrome, amyloidosis is rare despite vigorous, recurring inflammation. This hereditary syndrome is caused by mutations in the gene coding for mevalonate kinase, an enzyme of the isoprenoid pathway. In this study, we used a cell culture system with human monocytes to show that inhibition of the isoprenoid pathway inhibits amyloidogenesis. Inhibition of the isoprenoid pathway by lovastatin resulted in a dose-dependent reduction of amyloid formed [53% at 10 microM (P=0.01)] compared with mononuclear cells that are exposed only to serum AA. The inhibitory effects of lovastatin are reversible by addition of farnesol but not geranylgeraniol. Farnesyl transferase inhibition also inhibited amyloidogenesis. These results implicate that the isoprenoid metabolism could be a potential target for prevention and treatment of AA amyloidosis.


Assuntos
Lovastatina/farmacologia , Proteína Amiloide A Sérica/antagonistas & inibidores , Proteína Amiloide A Sérica/biossíntese , Amiloidose/patologia , Amiloidose/prevenção & controle , Animais , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lovastatina/uso terapêutico , Camundongos , Proteínas Recombinantes/antagonistas & inibidores , Proteína Amiloide A Sérica/metabolismo
17.
Int J Obes (Lond) ; 32(9): 1407-14, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18645574

RESUMO

OBJECTIVE: Interleukin-18 (IL-18) has been recently demonstrated to improve experimental hyperphagia and insulin resistance. Paradoxically, concentrations of circulating IL-18 in obese subjects and in patients with type 2 diabetes are increased. The objective of this study is to provide an explanation for this paradox. DESIGN: We have hypothesized that cells from obese individuals or from patients with type 2 diabetes mellitus have a diminished response to stimulation with IL-18. IL-18 responsiveness was tested by stimulating blood monocytes of obese or diabetes patients with rIL-18 or microbial components. RESULTS: Obese individuals and patients with type 2 diabetes mellitus exhibit increased circulating concentrations of IL-18. More importantly, leukocytes isolated from obese or type 2 diabetes patients respond poorly after stimulation with IL-18, as reflected by defective interferon-gamma (IFN gamma) production. The defective response to IL-18 stimulation was accompanied by a 50% reduction in the expression of IL-18R alpha and beta chains. In addition, cells of patients with obesity and diabetes displayed an impaired release of IFN gamma after challenge with bacterial or fungal pathogens, which was due to defective IL-18-mediated signaling. CONCLUSION: Patients with obesity or type 2 diabetes mellitus are characterized by lower responses after stimulation with IL-18. This IL-18 resistance explains the association of obesity and diabetes with high IL-18 circulating concentrations, similar to hyperinsulinemia and hyperleptinemia. IL-18 resistance may represent an important mechanism of the increased susceptibility of these patients to a number of infections.


Assuntos
Diabetes Mellitus Tipo 2/imunologia , Interleucina-18/imunologia , Obesidade/imunologia , Adulto , Candida albicans/imunologia , Células Cultivadas , Feminino , Humanos , Interferon gama/biossíntese , Interleucina-18/sangue , Lipopolissacarídeos/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Proteínas Recombinantes/imunologia , Staphylococcus aureus/imunologia , Magreza/imunologia
18.
Rheumatology (Oxford) ; 47(11): 1651-4, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18815155

RESUMO

OBJECTIVE: Genetic polymorphisms in serum amyloid A (SAA) have been shown to substantially influence the risk of developing type AA amyloidosis. Recently, a role for MMP-1 has been suggested in the pathogenesis of AA amyloidosis. Therefore, we investigated if the SAA1 isotypes are differentially degraded by MMP-1. METHODS: Degradation of different SAA isotypes by MMP-1 was assessed by immunoblotting. MALDI-TOF mass spectrometry was used to identify degradation fragments. RESULTS: We found that SAA1.5 is more resistant to degradation by MMP-1 than SAA1.1. This difference is caused by the capacity of MMP-1 to cleave at the site of the polymorphism at position 57. CONCLUSION: These results may explain the higher risk of amyloidosis in patients with a SAA1.1/1.1 genotype vs SAA1.5/1.5 or SAA1.1/1.5 genotype. In addition, the impaired degradation of SAA1.5 by MMP-1 could also explain the higher serum SAA concentrations in persons with a SAA1.5 genotype.


Assuntos
Amiloidose/etiologia , Metaloproteinase 1 da Matriz/metabolismo , Isoformas de Proteínas/genética , Proteína Amiloide A Sérica/metabolismo , Amiloidose/genética , Western Blotting/métodos , Suscetibilidade a Doenças , Eletroforese em Gel de Poliacrilamida , Genótipo , Humanos , Fragmentos de Peptídeos/análise , Polimorfismo Genético , Isoformas de Proteínas/metabolismo , Proteínas Recombinantes/metabolismo , Risco , Proteína Amiloide A Sérica/genética , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
19.
Clin Microbiol Infect ; 14(4): 344-9, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18261128

RESUMO

Ceftazidime and cefotaxime are beta-lactam antibiotics with dose-related affinities for penicillin-binding protein (PBP)-3 and PBP-1. At low concentrations, these antibiotics inhibit PBP-3, leading to filament formation. Filaments are long strands of non-dividing bacteria that contain enhanced quantities of endotoxin molecules. Higher concentrations of ceftazidime or cefotaxime cause inhibition of PBP-1, resulting in rapid bacterial lysis, which is associated with low endotoxin release. In the present study, 37 isolates of Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa and Acinetobacter spp. were studied over a 4-h incubation period in the presence of eight concentrations of ceftazidime or cefotaxime. As resistance of Gram-negative bacteria is an emerging problem in clinical practice, 14 isolates of E. coli and Klebsiella pneumoniae that produced extended-spectrum beta-lactamases (ESBLs) were also investigated. Morphological changes after exposure to the beta-lactam antibiotics revealed recognisable patterns in various bacterial families, genera and isolates. In general, all isolates of Enterobacteriaceae produced filaments within a relatively small concentration range, with similar patterns for E. coli and K. pneumoniae. Pseudomonas and Acinetobacter spp. produced filaments in the presence of clinically-relevant concentrations of both antibiotics as high as 50 mg/L. In all genera, filament-producing capacity was clearly related to the MIC. Ceftazidime induced filament production in more isolates and over wider concentration ranges than did cefotaxime. Interestingly, ESBL-producing isolates were not protected against filament induction. The induction of filament production may lead to additional risks during empirical treatment of severe infections.


Assuntos
Antibacterianos/farmacologia , Endotoxinas/metabolismo , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/crescimento & desenvolvimento , beta-Lactamas/farmacologia , Acinetobacter/efeitos dos fármacos , Acinetobacter/crescimento & desenvolvimento , Cefotaxima/farmacologia , Ceftazidima/farmacologia , Contagem de Colônia Microbiana , Relação Dose-Resposta a Droga , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/crescimento & desenvolvimento , Bactérias Gram-Negativas/metabolismo , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Pseudomonas/efeitos dos fármacos , Pseudomonas/crescimento & desenvolvimento , Resistência beta-Lactâmica
20.
Neth J Med ; 66(8): 340-34, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18809981

RESUMO

BACKGROUND: Patients with hairy cell leukaemia (HCL) have an increased susceptibility to intracellular pathogens, such as mycobacteria and Listeria. Although several abnormalities of T-cell populations have been described in HCL, the effector mechanism responsible for the increased susceptibility to infections is not known. METHODS: Blood was collected from 11 patients with HCL and 22 age- and gender-matched volunteers. Proinflammatory cytokine production by freshly isolated mononuclear cells was stimulated with either lipopolysaccharide or various heat-killed microorganisms. Cytokine concentrations were assessed by specific ELISAs. RESULTS: We demonstrate that mononuclear cells harvested from HCL patients have a specific defect of IFNgamma production when stimulated with a broad panel of bacterial stimuli. In contrast, the production of other proinflammatory cytokines, such as TNF, IL-1beta and IL-6, did not differ between HCL patients and controls. CONCLUSION: The specific defect in IFNgamma production may play a role in the susceptibility of patients with hairy cell leukaemia towards intracellular pathogens.


Assuntos
Interferon gama/biossíntese , Leucemia de Células Pilosas/fisiopatologia , Adulto , Citocinas , Feminino , Humanos , Leucemia de Células Pilosas/diagnóstico , Masculino , Mycobacterium , Projetos Piloto
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