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1.
Cancer Lett ; 432: 69-74, 2018 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-29879498

RESUMO

Breakthrough studies over the past decade have uncovered unique gene fusions implicated in acute lymphoblastic leukaemia (ALL). The critical gene, cytokine receptor-like factor 2 (CRLF2), is rearranged in 5-16% of B-ALL, comprising 50% of Philadelphia-like ALL and cooperates with genomic lesions in the Jak, Mapk and Ras signalling pathways. Children with Down Syndrome (DS) have a predisposition to developing CRLF2 rearranged-ALL which is observed in 60% of DS-ALL patients. These patients experience a poor survival outcome. Mutations of genes involved in epigenetic regulation are more prevalent in DS-ALL patients than non-DS ALL patients, highlighting the potential for alternative treatment strategies. DS-ALL patients also suffer greater treatment-related toxicity from current ALL treatment regimens compared to non-DS-ALL patients. An increased gene dosage of critical genes on chromosome 21 which have roles in purine synthesis and folate transport may contribute. As the genomic landscape of DS-ALL patients is different to non-DS-ALL patients, targeted therapies for individual lesions may improve outcomes. Therapeutically targeting each rearrangement with targeted or combination therapy that will perturb the transforming signalling pathways will likely improve the poor survival rates of this subset of patients.

2.
Br J Cancer ; 118(7): 1000-1004, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29531323

RESUMO

BACKGROUND: Zinc-finger protein 384 (ZNF384) fusions are an emerging subtype of precursor B-cell acute lymphoblastic leukaemia (pre-B-ALL) and here we further characterised their prevalence, survival outcomes and transcriptome. METHODS: Bone marrow mononuclear cells from 274 BCR-ABL1-negative pre-B-ALL patients were immunophenotyped and transcriptome molecularly characterised. Transcriptomic data was analysed by principal component analysis and gene-set enrichment analysis to identify gene and pathway expression changes. RESULTS: We exclusively detect E1A-associated protein p300 (EP300)-ZNF384 in 5.7% of BCR-ABL1-negative adolescent/young adult (AYA)/adult pre-B-ALL patients. EP300-ZNF384 patients do not appear to be a high-risk subgroup. Transcriptomic analysis revealed that EP300-ZNF384 samples have a distinct gene expression profile that results in the up-regulation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) and cell adhesion pathways and down-regulation of cell cycle and DNA repair pathways. CONCLUSIONS: Importantly, this report contributes to a better overview of the incidence of EP300-ZNF384 patients and show that they have a distinct gene signature with concurrent up-regulation of JAK-STAT pathway, reduced expression of B-cell regulators and reduced DNA repair capacity.

3.
Cancer Genet ; 216-217: 86-90, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29025600

RESUMO

We report a novel somatic mutation in the kinase domain of JAK2 (R938Q) in a high-risk pediatric case of B-cell acute lymphoblastic leukemia (ALL). The patient developed on-therapy relapse at 12 months, and interestingly, the JAK2 locus acquired loss of heterozygosity during treatment resulting in 100% mutation load. Furthermore, we show that primary ALL mononuclear cells harboring the JAK2 R938Q mutation display reduced sensitivity to the JAK1/2 ATP-competitive inhibitor ruxolitinib in vitro, compared to ALL cells that carry a more common JAK2 pseudokinase domain mutation. Our findings are in line with previous reports that demonstrate that mutations within the kinase domain of JAK2 are associated with resistance to type I JAK inhibitors. Importantly, given the recent inclusion of ruxolitinib in trial protocols for children with JAK pathway alterations, we predict that inter-patient genetic variability may result in suboptimal responses to JAK inhibitor therapy in a subset of cases. The need for alternate targeted and/or combination therapies for patients who display inherent or developed resistance to JAK inhibitor therapy will be warranted, and we propose that kinase-mutants less sensitive to type I JAK inhibitors may present a currently unexplored platform for investigation of improved therapies.


Assuntos
Janus Quinase 2/química , Janus Quinase 2/genética , Perda de Heterozigosidade/genética , Mutação/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Sequência de Bases , Criança , Feminino , Rearranjo Gênico/genética , Humanos , Domínios Proteicos , Recidiva
5.
Cancer Lett ; 408: 92-101, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28866095

RESUMO

CRLF2-rearrangements (CRLF2-r) occur frequently in Ph-like B-ALL, a high-risk ALL sub-type characterized by a signaling profile similar to Ph + ALL, however accumulating evidence indicates genetic heterogeneity within CRLF2-r ALL. We performed thorough genomic characterization of 35 CRLF2-r cases (P2RY8-CRLF2 n = 18; IGH-CRLF2 n = 17). Activating JAK2 mutations were present in 34% of patients, and a CRLF2-F232C mutation was identified in an additional 17%. IKZF1 deletions were detected in 63% of cases. The majority of patients (26/35) classified as Ph-like, and these were characterized by significantly higher levels of MUC4, GPR110 and IL2RA/CD25. In addition, Ph-like CRLF2-r samples were significantly enriched for IKZF1 deletions, JAK2/CRLF2 mutations and increased expression of JAK/STAT target genes (CISH, SOCS1), suggesting that mutation-driven CRLF2/JAK2 activation is more frequent in this sub-group. Less is known about the genomics of CRLF2-r cases lacking JAK2-pathway mutations, but KRAS/NRAS mutations were identified in 4/9 non-Ph-like samples. This work highlights the heterogeneity of secondary lesions which may arise and influence intracellular-pathway activation in CRLF2-r patients, and importantly presents distinct therapeutic targets within a group of patients harboring identical primary translocations, for whom efficient directed therapies are currently lacking.


Assuntos
Regulação Leucêmica da Expressão Gênica , Rearranjo Gênico , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Mucina-4/metabolismo , Proteínas Oncogênicas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptores de Citocinas/genética , Receptores Acoplados a Proteínas-G/metabolismo , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-2/genética , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Mucina-4/genética , Mutação/genética , Proteínas Oncogênicas/genética , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Prognóstico , Receptores Acoplados a Proteínas-G/genética , Células Tumorais Cultivadas
6.
J Mol Diagn ; 19(5): 711-721, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28732215

RESUMO

Somatic mitochondrial DNA (mtDNA) mutations have been identified in many human cancers, including leukemia. To identify somatic mutations, it is necessary to have a control tissue from the same individual for comparison. When patients with leukemia achieve remission, the remission peripheral blood may be a suitable and easily accessible control tissue, but this approach has not previously been applied to the study of mtDNA mutations. We have developed and validated a next-generation sequencing approach for the identification of leukemia-associated mtDNA mutations in 26 chronic myeloid leukemia patients at diagnosis using either nonhematopoietic or remission blood samples as the control. The entire mt genome was amplified by long-range PCR and sequenced using Illumina technology. Variant caller software was used to detect mtDNA somatic mutations, and an empirically determined threshold of 2% was applied to minimize false-positive results because of sequencing errors. Mutations were called against both nonhematopoietic and remission controls: the overall concordance between the two approaches was 81% (73/90 mutations). Some discordant results were because of the presence of somatic mutations in remission samples, because of either minimal residual disease or nonleukemic hematopoietic clones. This method could be applied to study somatic mtDNA mutations in leukemia patients who achieve minimal residual disease, and in patients with nonhematopoietic cancers who have a matched uninvolved tissue available.


Assuntos
Análise Mutacional de DNA/métodos , DNA Mitocondrial , Sequenciamento de Nucleotídeos em Larga Escala , Leucemia/diagnóstico , Leucemia/genética , Mutação , Alelos , Biomarcadores Tumorais , Análise Mutacional de DNA/normas , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/normas , Humanos , Leucemia/tratamento farmacológico , Reação em Cadeia da Polimerase , Indução de Remissão , Reprodutibilidade dos Testes , Análise de Sequência de DNA/métodos , Análise de Sequência de DNA/normas
7.
Artigo em Inglês | MEDLINE | ID: mdl-28607684

RESUMO

Acute kidney injury (AKI) is now widely recognised as a serious health care issue, occurring in up to 25% of hospital in-patients, often with worsening of outcomes. There have been several reports of substandard care in AKI. This quality improvement (QI) programme aimed to improve AKI care and outcomes in a large teaching hospital. Areas of documented poor AKI care were identified and specific improvement activities implemented through sequential Plan-Do-Study-Act (PDSA) cycles. An electronic alert system (e-alert) for AKI was developed, a Priority Care Checklist (PCC) was tested with the aid of specialist nurses whilst targeted education activities were carried out and data on care processes and outcomes monitored. The e-alert had a sensitivity of 99% for the detection of new cases of AKI. Key aspects of the PCC saw significant improvements in their attainment: Detection of AKI within 24 hours from 53% to 100%, fluid assessment from 42% to 90%, drug review 48% to 95% and adherence to nine key aspects of care from 40% to 90%. There was a significant reduction in variability of delivered AKI care. AKI incidence reduced from 9% of all hospitalisations at baseline to 6.5% (28% reduction), AKI related length of stay reduced from 22.1 days to 17 days (23% reduction) and time to recovery (AKI days) 15.5 to 9.8 days (36% reduction). AKI related deaths also showed a trend towards reduction, from an average of 38 deaths to 34 (10.5%). The number of cases of hospital acquired AKI were reduced by 28% from 120 to 86 per month. This study demonstrates significant improvements related to a QI programme combining e-alerts, a checklist implemented by a nurse and education in improving key processes of care. This resulted in sustained improvement in key patient outcomes.

8.
Oncotarget ; 7(33): 53064-53073, 2016 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-27419633

RESUMO

IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in childhood B-cell precursor acute lymphoblastic leukemia. Because of its clinical importance, we previously mapped breakpoints of intragenic deletions and developed a multiplex PCR assay to detect recurrent intragenic ΔIKZF1. Since the multiplex PCR was not able to detect complete deletions (IKZF1 Δ1-8), which account for ~30% of all ΔIKZF1, we aimed at investigating the genomic scenery of IKZF1 Δ1-8. Six samples of cases with IKZF1 Δ1-8 were analyzed by microarray assay, which identified monosomy 7, isochromosome 7q, and large interstitial deletions presenting breakpoints within COBL gene. Then, we established a multiplex ligation-probe amplification (MLPA) assay and screened copy number alterations within chromosome 7 in 43 diagnostic samples with IKZF1 Δ1-8. Our results revealed that monosomy and large interstitial deletions within chromosome 7 are the main causes of IKZF1 Δ1-8. Detailed analysis using long distance inverse PCR showed that six patients (16%) had large interstitial deletions starting within intronic regions of COBL at diagnosis, which is ~611 Kb downstream of IKZF1, suggesting that COBL is a hotspot for ΔIKZF1. We also investigated a series of 25 intragenic deletions (Δ2-8, Δ3-8 or Δ4-8) and 24 relapsed samples, and found one IKZF1-COBL tail-to-tail fusion, thus supporting that COBL is a novel hotspot for ΔIKZF1. Finally, using RIC score methodology, we show that breakpoint sequences of IKZF1 Δ1-8 are not analog to RAG-recognition sites, suggesting a different mechanism of error promotion than that suggested for intragenic ΔIKZF1.


Assuntos
Deleção de Genes , Fator de Transcrição Ikaros/genética , Proteínas dos Microfilamentos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Pré-Escolar , Pontos de Quebra do Cromossomo , Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Variações do Número de Cópias de DNA , Feminino , Humanos , Lactente , Isocromossomos/genética , Masculino , Técnicas de Amplificação de Ácido Nucleico/métodos , Homologia de Sequência de Aminoácidos , Homologia de Sequência do Ácido Nucleico
9.
J Leukoc Biol ; 96(1): 83-91, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24598054

RESUMO

Aberrant activation of ß-catenin is a common event in AML and is an independent predictor of poor prognosis. Although increased ß-catenin signaling in AML has been associated with oncogenic translocation products and activating mutations in the FLT3R, the mechanisms that activate ß-catenin in AML more broadly are still unclear. Here, we describe a novel link between IL-3 signaling and the regulation of ß-catenin in myeloid transformation and AML. In a murine model of HoxB8 and IL-3 cooperation, we show that ß-catenin protein levels are modulated by IL-3 and that Cre-induced deletion of ß-catenin abolishes IL-3-dependent growth and colony formation. In IL-3-dependent leukemic TF-1.8 cells, we observed increased ß-catenin protein levels and nuclear localization in response to IL-3, and this correlated with transcriptional induction of ß-catenin target genes. Furthermore, IL-3 promoted ß-catenin accumulation in a subset of AML patient samples, and gene-expression profiling of these cells revealed induction of WNT/ß-catenin and TCF4 gene signatures in an IL-3-dependent manner. This study is the first to link ß-catenin activation to IL-3 and suggests that targeting IL-3 signaling may be an effective approach for the inhibition of ß-catenin activity in some patients with AML.


Assuntos
Transformação Celular Neoplásica/metabolismo , Interleucina-3/metabolismo , Leucemia Mieloide Aguda/metabolismo , Proteínas de Neoplasias/metabolismo , Transdução de Sinais , Via de Sinalização Wnt , beta Catenina/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Linhagem Celular Transformada , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Regulação Leucêmica da Expressão Gênica/genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Interleucina-3/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Fator de Transcrição 4 , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , beta Catenina/genética
10.
Nat Genet ; 45(3): 242-52, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23334668

RESUMO

The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24-31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (encoding AIOLOS; 13%). In contrast, low-hypodiploid ALL with 32-39 chromosomes are characterized by alterations in TP53 (91.2%) that are commonly present in nontumor cells, IKZF2 (encoding HELIOS; 53%) and RB1 (41%). Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.


Assuntos
Aneuploidia , Aberrações Cromossômicas , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Animais , Sequência de Bases , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Haploidia , Humanos , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/metabolismo , Camundongos , Dados de Sequência Molecular , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Transdução de Sinais , Transplante Heterólogo , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
11.
J Biol Chem ; 288(12): 8679-90, 2013 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-23335510

RESUMO

Natural killer (NK) cell recognition of the nonclassical human leukocyte antigen (HLA) molecule HLA-E is dependent on the presentation of a nonamer peptide derived from the leader sequence of other HLA molecules to CD94-NKG2 receptors. However, human cytomegalovirus can manipulate this central innate interaction through the provision of a "mimic" of the HLA-encoded peptide derived from the immunomodulatory glycoprotein UL40. Here, we analyzed UL40 sequences isolated from 32 hematopoietic stem cell transplantation recipients experiencing cytomegalovirus reactivation. The UL40 protein showed a "polymorphic hot spot" within the region that encodes the HLA leader sequence mimic. Although all sequences that were identical to those encoded within HLA-I genes permitted the interaction between HLA-E and CD94-NKG2 receptors, other UL40 polymorphisms reduced the affinity of the interaction between HLA-E and CD94-NKG2 receptors. Furthermore, functional studies using NK cell clones expressing either the inhibitory receptor CD94-NKG2A or the activating receptor CD94-NKG2C identified UL40-encoded peptides that were capable of inhibiting target cell lysis via interaction with CD94-NKG2A, yet had little capacity to activate NK cells through CD94-NKG2C. The data suggest that UL40 polymorphisms may aid evasion of NK cell immunosurveillance by modulating the affinity of the interaction with CD94-NKG2 receptors.


Assuntos
Citomegalovirus/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Células Matadoras Naturais/imunologia , Polimorfismo Genético , Proteínas Virais/genética , Adulto , Sequência de Aminoácidos , Sítios de Ligação , Células Cultivadas , Citomegalovirus/imunologia , Citotoxicidade Imunológica , Feminino , Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/fisiologia , Humanos , Células Matadoras Naturais/metabolismo , Leucemia Mieloide Aguda/terapia , Linfoma não Hodgkin/terapia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Subfamília D de Receptores Semelhantes a Lectina de Células NK/metabolismo , Filogenia , Ligação Proteica , Análise de Sequência de DNA , Proteínas Virais/química , Proteínas Virais/imunologia , Adulto Jovem
12.
Transplantation ; 91(9): 1044-9, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21394075

RESUMO

BACKGROUND: Mannose-binding lectin (MBL) is a key molecule of the innate immune system and, in addition to the classical and alternative pathways, a principle driver of complement activation. Genetic mutations of MBL are common, result in low serum levels of MBL, and are associated with increased infection risk in solid-organ transplant recipients. METHODS: We performed a retrospective study of MBL2 genotype and plasma and bronchoalveolar lavage (BAL) MBL levels in 37 lung transplant recipients (LTR). Plasma MBL levels were measured pretransplant and both plasma and BAL MBL levels were measured at 3, 6, and 12 months after lung transplantation. MBL2 genotyping was performed on recipient and donor peripheral blood mononuclear cells. Clinical variables analyzed included primary graft dysfunction, intensive care unit stay, acute allograft rejection, infection, bronchiolitis obliterans syndrome (BOS), and mortality. RESULTS: Plasma MBL levels posttransplant were predicted by recipient, and not donor MBL2 genotype. Compared with pretransplant levels, plasma MBL was significantly increased at 3, 6, and 12 months posttransplant (P<0.05). LTR who developed BOS or died during the study period had higher plasma MBL levels at 6 and 12 months posttransplant (P ≤ 0.05) compared with LTR with stable graft function. MBL was not routinely detected in the lung allograft; however if present in the BAL at 3 and 6 months posttransplant, it was associated with the later development of BOS (P<0.05). CONCLUSIONS: Plasma MBL levels increase after lung transplantation and persistently increased MBL levels are associated with poor long-term outcomes.


Assuntos
Transplante de Pulmão/efeitos adversos , Transplante de Pulmão/fisiologia , Lectina de Ligação a Manose/sangue , Adolescente , Adulto , Idoso , Bronquiolite Obliterante/etiologia , Líquido da Lavagem Broncoalveolar/química , Estudos de Coortes , Feminino , Genótipo , Rejeição de Enxerto/etiologia , Humanos , Estudos Longitudinais , Masculino , Lectina de Ligação a Manose/genética , Lectina de Ligação a Manose/metabolismo , Pessoa de Meia-Idade , Pneumonia/etiologia , Estudos Retrospectivos , Doadores de Tecidos , Resultado do Tratamento , Adulto Jovem
13.
Perit Dial Int ; 29 Suppl 2: S115-6, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19270198

RESUMO

The number of patients receiving renal replacement therapy in the United Kingdom is rapidly rising. Chronic kidney disease (CKD) is a worldwide public health problem with significant comorbidity and mortality. Several organizational guidelines have been developed in an attempt to identify when appropriate referral to nephrology services should occur; however, many of these guidelines provide conflicting recommendations on referral. Recent surveys suggest that more than 30% of patients with CKD are referred later than the ideal. Late referral of patients with CKD is associated with increased patient morbidity and mortality, increased need for and duration of hospital admission, and increased initial costs of care following commencement of dialysis. Benefits of early referral include the identification and treatment of reversible causes of renal impairment and management of the multiple co-existing conditions associated with CKD. Referral time also affects the choice of modality of treatment. Patients and their families should receive sufficient information regarding the nature of their CKD and options for treatment so that they can make informed decisions concerning their care. Literature addressing the timing of referral to low-clearance or pre-dialysis clinics is limited. Existing data suggest that such clinics and patient education programs may improve the medical care of patients, promote greater patient involvement in the selection of the mode of dialysis, reduce the need for "urgent start" dialysis, and improve short-term survival and quality of life after initiation of dialysis. Audit of our pre-dialysis clinic has demonstrated improved patient outcomes, and we view this service as an essential component of the patient pathway.


Assuntos
Unidades Hospitalares de Hemodiálise/organização & administração , Falência Renal Crônica/terapia , Encaminhamento e Consulta/estatística & dados numéricos , Diálise Renal/estatística & dados numéricos , Auditoria Clínica , Humanos , Falência Renal Crônica/epidemiologia , Morbidade/tendências , Fatores de Tempo , Reino Unido/epidemiologia
14.
Perit Dial Int ; 29 Suppl 2: S128-31, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19270201

RESUMO

The number of patients receiving renal replacement therapy in the United Kingdom is rapidly rising. Chronic kidney disease (CKD) is a worldwide public health problem with significant comorbidity and mortality. Several organizational guidelines have been developed in an attempt to identify when appropriate referral to nephrology services should occur; however, many of these guidelines provide conflicting recommendations on referral. Recent surveys suggest that more than 30% of patients with CKD are referred later than is ideal. Late referral of patients with CKD is associated with increased patient morbidity and mortality, increased need for and duration of hospital admission, and increased initial costs of care following commencement of dialysis. Additional benefits of early referral include identifying and treating reversible causes of renal impairment and managing the multiple coexisting conditions associated with CKD. Referral time also affects the choice of treatment modality. Patients and their families should receive sufficient information regarding the nature of their CKD and the options for treatment so that they can make informed decisions concerning their care. Literature addressing when to refer to low-clearance or pre-dialysis clinics is limited. Existing data suggest that such clinics and patient education programs may facilitate improved medical care for patients, greater patient involvement in selection of the mode of dialysis, reduction in the need for "urgent start" dialysis, and improved short-term survival and quality of life after initiation of dialysis. Audit of our pre-dialysis clinic has demonstrated improved patient outcomes, and we view the early-referral service as an essential component of the patient pathway.


Assuntos
Auditoria Clínica/organização & administração , Falência Renal Crônica/terapia , Guias de Prática Clínica como Assunto , Encaminhamento e Consulta/normas , Terapia de Substituição Renal/estatística & dados numéricos , Humanos , Falência Renal Crônica/epidemiologia , Morbidade/tendências , Educação de Pacientes como Assunto/organização & administração , Encaminhamento e Consulta/estatística & dados numéricos , Terapia de Substituição Renal/tendências , Taxa de Sobrevida/tendências , Fatores de Tempo , Reino Unido/epidemiologia
15.
Clin Infect Dis ; 48(4): 410-7, 2009 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-19143554

RESUMO

BACKGROUND: Mannose-binding lectin (MBL) is an important mediator of innate immunity and is synthesized primarily by the liver. Low MBL levels are common, are due primarily to polymorphisms in the gene encoding MBL (MBL2), and are associated with an increased risk of infection, particularly when immunity is compromised. We report a large, retrospective study that examined the association between MBL status and clinically significant infection following orthotopic liver transplantation. METHODS: One hundred two donor-recipient orthotopic liver transplantation pairs were studied. Five polymorphisms in the promoter and coding regions of MBL2 were examined. MBL levels were measured, using the mannan-binding and C4-deposition assays, in serum samples obtained before and after transplantation. Associations between MBL status, as assessed by serum MBL levels and MBL2 genotype, and time to first clinically significant infection (CSI) after transplantation were examined in survival analysis with consideration of competing risks. RESULTS: The median duration of follow-up after orthotopic liver transplantation was 4 years. Thirty-six percent of recipients developed CSI after transplantation. The presence of MBL2 coding mutations in the donor was significantly associated with CSI in the recipient; the cumulative incidence function of infection was 55% in recipients of deficient livers, compared with 32% for recipients of wild-type livers (P = .002). Infection was not associated with recipient MBL2 genotype. Low MBL levels after orthotopic liver transplantation levels (mannan-binding <1 microg/mL or C4 deposition <0.2 C4 U/microL) were also associated with CSI (cumulative incidence function, 52% vs. 20%, P = .003; and cumulative incidence function, 54% vs. 24%, P = .007, respectively). In multivariate analysis, mutation in the MBL2 coding region of the donor (hazard ratio, 2.8; P = .005) and the use of cytomegalovirus prophylaxis (hazard ratio, 2.6; P = .005) were independently associated with CSI. CONCLUSIONS: Recipients of MBL-deficient livers have almost a 3-fold greater likelihood of developing CSI and may benefit from MBL replacement.


Assuntos
Doenças Transmissíveis/epidemiologia , Predisposição Genética para Doença/epidemiologia , Transplante de Fígado/efeitos adversos , Lectina de Ligação a Manose/deficiência , Fatores de Risco , Doadores de Tecidos , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fases de Leitura Aberta/genética , Polimorfismo Genético , Regiões Promotoras Genéticas , Estudos Retrospectivos , Adulto Jovem
16.
Blood ; 112(5): 2120-8, 2008 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-18552214

RESUMO

Mannose-binding lectin (MBL) is a mediator of innate immunity that influences the risk of infection in a range of clinical settings. We previously reported associations between MBL2 genotype and infection in a retrospective study of myeloablative allogeneic hematopoietic stem cell transplantation (allo-HCT). However, other studies have been inconclusive, and the role of MBL in reduced-intensity conditioning (RIC) transplantation is unknown. Here we report a prospective study examining MBL2 genotype, MBL levels, and risk of major infection following HLA-matched sibling myeloablative (n = 83) and RIC (n = 59) HCT. Baseline MBL levels were higher in recipients than donors (P < .001), and recipient MBL levels increased during the peritransplantation period (P = .001), most notably in MBL2 wild-type individuals receiving myeloablative total body irradiation (mTBI). MBL2 coding mutations were associated with major infection in recipients receiving mTBI. The cumulative incidence of major infection in recipient harboring an MBL2 mutation receiving mTBI was 70.6%, compared with 31.1% of those without mutations not receiving mTBI (P = .01). MBL status was not associated with infection in RIC transplants. These results confirm the association of MBL status with risk of infection in myeloablative, TBI-conditioned transplantation. Studies examining the role of MBL replacement therapy to prevent infection in this setting should be considered.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecção/etiologia , Lectina de Ligação a Manose/sangue , Lectina de Ligação a Manose/genética , Adulto , Feminino , Genótipo , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/genética , Humanos , Infecção/sangue , Infecção/genética , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Polimorfismo Genético , Estudos Prospectivos , Fatores de Risco , Irmãos , Transplante Homólogo
17.
Eur J Gastroenterol Hepatol ; 19(2): 147-52, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17273000

RESUMO

BACKGROUND: Mannose-binding lectin is an immune molecule that can bind to pathogens and initiate the complement cascade. In certain clinical situations, often characterized by immune compromise, mannose-binding lectin deficiency can increase the risk of infectious complications. Helicobacter pylori is one of the most common human infections and can bind mannose-binding lectin. Therefore, we examined whether mannose-binding lectin status influences the prevalence of H. pylori infection. METHODS: Two distinct populations were targeted. The first consisted of 166 volunteer blood donors, the second included 108 peripheral blood stem cell donors. All were tested for serological evidence of H. pylori infection, and had their mannose-binding lectin status characterized by genotyping, and quantification of mannose-binding lectin mannan-binding level and C4-deposition function in plasma. RESULTS: H. pylori positive blood donors had higher blood mannose-binding lectin levels, as measured by C4 deposition (median 0.67 vs. 0.40, P=0.009, hazard ratio 2.82, 95% confidence interval 1.29-6.19) and mannan-binding assays (median 1.83 vs. 1.26, P=0.02, hazard ratio 1.28, 95% confidence interval 1.03-1.59). A trend was also found between the presence of an MBL2 coding mutation and a reduced prevalence of H. pylori. No significant associations were found in the second population. CONCLUSIONS: Mannose-binding lectin deficiency does not increase the risk of H. pylori infection. The finding in one population that greater mannose-binding lectin activity might predispose to infection, suggests that this study should be repeated in other large cohorts of normal subjects.


Assuntos
Infecções por Helicobacter/sangue , Helicobacter pylori/isolamento & purificação , Lectina de Ligação a Manose/deficiência , Doadores de Sangue , Complemento C4/metabolismo , Suscetibilidade a Doenças , Genótipo , Infecções por Helicobacter/genética , Humanos , Lectina de Ligação a Manose/sangue , Lectina de Ligação a Manose/genética , Fatores de Risco
18.
BMC Pregnancy Childbirth ; 5(1): 4, 2005 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-15723707

RESUMO

BACKGROUND: Chorioamnionitis is a common underlying cause of preterm birth (PTB). It is hypothesised that polymorphisms in immunoregulatory genes influence the host response to infection and subsequent preterm birth. The relationship between histologic chorioamnionitis and 22 single nucleotide polymorphisms in 11 immunoregulatory genes was examined in a case-control study. METHODS: Placentas of 181 Caucasoid women with spontaneous PTB prior to 35 weeks were examined for histologic chorioamnionitis. Polymorphisms in genes IL1A, IL1B, IL1RN, IL1R1, tumour necrosis factor (TNF), IL4, IL6, IL10, transforming growth factor beta-1 (TGFB1), Fas (TNFRSF6), and mannose-binding lectin (MBL2) were genotyped by polymerase chain reaction and sequence specific primers. Multivariable logistic regression including demographic and genetic variables and Kaplan-Meier survival analyses of genotype frequencies and pregnancy outcome were performed. RESULTS: Sixty-nine (34%) women had histologic evidence of acute chorioamnionitis. Carriage of the IL10-1082A/-819T/592A (ATA) haplotype [Multivariable Odds ratio (MOR) 1.9, P = 0.05] and MBL2 codon 54Asp allele (MOR 2.0, P = 0.04), were positively associated with chorioamnionitis, while the TNFRSF6-1377A/-670G (AG) haplotype (MOR 0.4, P = 0.03) and homozygosity for TGFB1-800G/509T (GT) haplotype (MOR 0.2, P = 0.04) were negatively associated. CONCLUSION: These findings demonstrate that polymorphisms in immunoregulatory genes IL10, MBL2, TNFRSF6 and TGFB1 may influence susceptibility to chorioamnionitis.

19.
Am J Obstet Gynecol ; 191(6): 2056-67, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15592292

RESUMO

OBJECTIVE: The purpose of this study was to examine the relationship between preterm birth and 22 single nucleotide polymorphisms in genes that encode cytokines and mediators of apoptosis and host defense. STUDY DESIGN: Two hundred two white women with a spontaneous preterm birth of <35 weeks of gestation were compared with 185 white women with term births. Genotyping was performed with polymerase chain reaction and sequence specific primers. Multivariable analyses included demographic and genetic variables. RESULTS: Alcohol (multivariable odds ratio, 2.3; P = .001] and substance use (multivariable odds ratio, 3.7; P = .01) were associated with preterm birth at <35 weeks of gestation. Smoking (multivariable odds ratio, 2.3; P = .03), haplotypes IL10 -1082A/-819T/-592A (multivariable odds ratio, 2.1; P = .04), tumor necrosis factor ( TNF )+488A/-238G/-308G (multivariable odds ratio, 2.4; P = .04), and IL4 -509C/C (multivariable odds ratio, 3.4; P = .02), and the presence of MBL2 codon 54Asp (multivariable odds ratio, 2.3; P = .02) were associated independently with preterm birth at <29 weeks of gestation. Homozygosity for IL10 -1082G/-819C/-592C haplotype (multivariable odds ratio, 1.9; P = .02) was more common in women with preterm premature rupture of membranes. CONCLUSION: Polymorphisms in immunoregulatory genes may influence susceptibility to preterm birth or premature rupture of membranes.


Assuntos
Interleucinas/metabolismo , Lectina de Ligação a Manose/metabolismo , Polimorfismo Genético , Nascimento Prematuro/genética , Fator de Crescimento Transformador beta/metabolismo , Receptor fas/metabolismo , Adolescente , Adulto , Austrália/epidemiologia , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica , Marcadores Genéticos , Idade Gestacional , Humanos , Incidência , Recém-Nascido , Interleucina-1/genética , Interleucina-1/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucinas/genética , Modelos Logísticos , Lectina de Ligação a Manose/genética , Gravidez , Nascimento Prematuro/epidemiologia , Probabilidade , Valores de Referência , Medição de Risco , Sensibilidade e Especificidade , Nascimento a Termo/genética , Fator de Crescimento Transformador beta/genética , Receptor fas/genética
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