RESUMEN
Hepatitis C virus (HCV) is primarily spread through risky injection practices, including sharing needles, cookers, cottons, rinse water, and the practice of backloading. An important aspect of harm reduction for people who inject drugs (PWID) is to identify factors that contribute to safer injection. Planning ability may influence risky injection practices and gender differences in factors that drive injection practices indicate a need to examine associations between planning and injection behaviors in men versus women. Data from the NEURO-HIV Epidemiologic Study was restricted to those who had ever injected in their lifetime (n=456). Impaired planning ability was assessed with the Tower of London and defined as a standardized total excess move score below the 10th percentile. We used logistic regression to estimate the gender-specific adjusted odds ratios (AOR) and 95% confidence intervals (CI) for associations between impaired planning, each injection practice, and biologically-confirmed HCV. Impaired planning ability was associated with sharing needles (AOR=2.93, 95% CI: 1.33, 6.47), cookers (AOR=3.13, 95% CI: 1.22, 8.02), cottons (AOR=2.89, 95% CI: 1.23, 6.78), rinse water (AOR=2.43, 95% CI: 1.15, 5.14), and backloading (AOR=2.68, 95% CI: 1.26, 5.70) and HCV (AOR=3.42, 95% CI: 1.03, 11.38) among men. Planning ability was not significantly associated with the injection behaviors or HCV among women, suggesting that other factors likely contribute to risky injection practices. Interventions to promote harm reduction among PWID should ascertain and strengthen planning ability. Women may have additional barriers to practicing safe injection beyond impaired planning abilities, which should also be addressed.
Asunto(s)
Reducción del Daño , Hepatitis C/complicaciones , Hepatitis C/psicología , Asunción de Riesgos , Abuso de Sustancias por Vía Intravenosa/complicaciones , Abuso de Sustancias por Vía Intravenosa/psicología , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Compartición de Agujas/estadística & datos numéricos , Distribución por Sexo , Adulto JovenRESUMEN
Microsatellite analyses show that self-reported ethnicity often correlates poorly with true genetic ancestry. As unknown ancestral differences could potentially have an impact on transplant outcome, we developed an average allele length discrepancy (AALD) score to assess allele length discrepancy between donor/recipient (D/R) using microsatellites analysed routinely in post-transplant chimeric assessment. This was then compared with outcome in a homogeneously treated cohort of pediatric patients undergoing high-resolution sibling or matched unrelated donor transplantation for acute lymphoblastic leukemia (ALL). AALD scores formed a numeric continuum ranging from 0 to 1.4 (median 0.76) for sibling pairs and 0.8-2.17 (median 1.6) for high-resolution matched unrelated donor (HR-MUD) pairs. There was a trend for worse OS with increasing AALD score, which reached statistical significance above a threshold of 1.7 for OS. Patients whose transplants had an AALD score of ⩾1.8 had a risk of non-relapse mortality 4.9 times greater (P=0.025) and relapse risk three times greater (P=0.058) than those scoring <1.8. This approach will now be explored in a Centre International for Blood and Marrow Transplantation Research (CIBMTR) study of 750 D/R pairs across all disease groups; if confirmed, it has the potential to improve donor selection for patients with multiple prospective donors.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Repeticiones de Microsatélite , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Acondicionamiento Pretrasplante/métodos , Humanos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
We present the first detailed study analysing OS in BMT for paediatric ALL following the introduction of high-resolution (HR) HLA matching. A total of 356 consecutive paediatric ALL stem cell transplants performed between 1988 and 2007 were reviewed; 80 of them were performed following the introduction of HR HLA class I and class II matching to the transplant programme in 2002. Comparisons of matched unrelated donor (MUD) transplant outcomes before and after this period were made. Matching at the HR level for HLA-A, -B, -C, -DRB1 and -DQB1 (HR-MUD) correlated with a greater than 25% improvement in 2- and 5-year OS in paediatric ALL patients transplanted with MUDs (P=0.009, P=0.005, respectively). Two-year OS for contemporaneous HLA-matched sibling transplants (80.8%) and HR-MUD transplants (78.8%) was equivalent. At 6%, non-relapse mortality (NRM) in MUD transplants since 2002 was significantly reduced compared with previous epochs. Changes in treatment and epoch-dependent improvements in outcome were reviewed for possible confounders to the influence of HR typing using univariate and multivariate analysis.
Asunto(s)
Cadenas beta de HLA-DQ , Cadenas HLA-DRB1 , Antígenos de Histocompatibilidad Clase I , Prueba de Histocompatibilidad , Leucemia-Linfoma Linfoblástico de Células Precursoras , Trasplante de Células Madre , Donante no Emparentado , Adolescente , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante HomólogoRESUMEN
Inferring haplotypes from genotype data is commonly undertaken in population genetic association studies. Within such studies the importance of accounting for uncertainty in the inference of haplotypes is well recognised. We investigate the effectiveness of correcting for uncertainty using simple methods based on the output provided by the PHASE haplotype inference methodology. In case-control analyses investigating non-Hodgkin lymphoma and haplotypes associated with immune regulation we find little effect of making adjustment for uncertainty in inferred haplotypes. Using simulation we introduce a higher degree of haplotype uncertainty than was present in our study data. The simulation represents two genetic loci, physically close on a chromosome, forming haplotypes. Considering a range of allele frequencies, degrees of linkage between the loci, and frequency of missing genotype data, we detail the characteristics of genetic regions which may be susceptible to the influence of haplotype uncertainty. Within our evaluation we find that bias is avoided by considering haplotype probabilities or using multiple imputation, provided that for each of these methods haplotypes are inferred separately for case and control populations; furthermore using multiple imputation provides the facility to incorporate haplotype uncertainty in the estimation of confidence intervals. We discuss the implications of our findings within the context of the complexity of haplotype inference for larger marker rich regions as would typically be encountered in genetic analyses.
Asunto(s)
Predisposición Genética a la Enfermedad , Haplotipos , Desequilibrio de Ligamiento , Estudios de Casos y Controles , Simulación por Computador , Humanos , Interleucina-10/genética , Linfoma no Hodgkin/genética , Repeticiones de Microsatélite , Método de Montecarlo , Polimorfismo de Nucleótido Simple , Regiones Promotoras GenéticasRESUMEN
BACKGROUND: Non-cardiogenic pulmonary oedema is a characteristic feature of the acute respiratory distress syndrome (ARDS). The properties of vascular endothelial growth factor (VEGF) as a potent vascular permogen and mitogen have led to investigation of its potential role in this condition. Lower VEGF plasma levels have been linked to the presence of the T allele in the +936 CT polymorphism. We hypothesised that the presence of the T allele would be associated with the development and severity of ARDS. METHODS: A cohort of 137 normal subjects, 117 ventilated patients with ARDS, and 103 "at risk" of ARDS were genotyped for the VEGF+936 CT polymorphism. The severity of physiological disturbance and mortality was determined in the ventilated cohorts. RESULTS: The CT and TT genotype frequencies were increased in ARDS patients compared with both normal subjects (OR 2.01, 95% CI 1.13 to 3.58, p = 0.02) and those "at risk" (OR 2.05, 95% CI 1.02 to 2.20, p = 0.03). In patients with ARDS but not those "at risk", CT and TT genotypes were associated with a higher mean APACHE III score (80.9 (4.3) v 69.3 (2.9), p<0.05). CONCLUSION: These data support a role for VEGF in the pathogenesis of ARDS and its associated physiological derangement.
Asunto(s)
Polimorfismo Genético/genética , Síndrome de Dificultad Respiratoria/genética , Factor A de Crecimiento Endotelial Vascular/genética , Estudios de Cohortes , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Genotipo , Análisis Heterodúplex/métodos , Humanos , Masculino , Persona de Mediana Edad , Síndrome de Dificultad Respiratoria/mortalidadRESUMEN
The interleukin-1 gene cluster is a key regulator in a number of chronic disease processes. We explored the linkage between nine polymorphic loci in the IL1R1 promoter, eight in the IL1A-IL1B-IL1RN gene complex, and their association with osteoarthritis (OA), a common complex disease associated with low-level inflammation. Using 195 healthy controls, we identified eight novel polymorphisms in the IL1R1 exon 1A region. We found limited LD between IL1R1 and the IL1A-IL1B-IL1RN cluster, although LD within these two individual groups was high. To test association with knee OA, we genotyped 141 patients from Bristol (UK) at the 17 loci. IL1R1 promoter haplotypes showed no association with disease. However, within the IL1A-IL1B-IL1RN complex, we identified a common haplotype conferring a four-fold risk of OA (P=0.00043; Pc=0.0043) and one IL1B-IL1RN haplotype conferring a four-fold reduced risk (P=0.0036; Pc=0.029). To replicate these associations, we subsequently examined 163 knee OA patients from London. Here, the effects of the haplotypes were confirmed: the risk IL1A-IL1B-IL1RN haplotype conferred a two-fold risk of OA (P=0.02), and the protective IL1B-IL1RN haplotype conferred a five-fold reduced risk of OA (P=0.0000008). These results may help to explain the genome-wide scan linkage data and functional observations concerning association between IL-1 and OA.
Asunto(s)
Interleucina-1/genética , Desequilibrio de Ligamiento , Osteoartritis de la Rodilla/genética , Polimorfismo de Nucleótido Simple/genética , Receptores de Interleucina-1/genética , Sialoglicoproteínas/genética , Anciano , Secuencia de Bases , Estudios de Casos y Controles , Femenino , Genotipo , Haplotipos/genética , Humanos , Proteína Antagonista del Receptor de Interleucina 1 , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Familia de Multigenes , Regiones Promotoras Genéticas/genética , Receptores de Interleucina-1/antagonistas & inhibidores , Receptores Tipo I de Interleucina-1 , Factores de Riesgo , Homología de Secuencia de Ácido Nucleico , Secuencias Repetidas en Tándem/genéticaRESUMEN
Single-strand conformational polymorphism (SSCP) was used to identify single nucleotide polymorphisms (SNPs) in the promoter region of the human interleukin-18 receptor alpha (IL-18Ralpha). Two SNPs were identified at positions -69 and -638 relative to the transcriptional start site. Two-way comparison of the two SNPs revealed strong linkage disequilibrium (chi2 = 63.45, P < 0.001). Three haplotypes were identified, namely C-69C-638, T-69C-638 and C-69T-638, with frequencies of 0.26, 0.39 and 0.35, respectively.
Asunto(s)
Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Receptores de Interleucina/genética , Alelos , Dimerización , Frecuencia de los Genes , Genotipo , Haplotipos , Humanos , Subunidad alfa del Receptor de Interleucina-18 , Desequilibrio de Ligamiento , Mutación , Polimorfismo Genético , Polimorfismo Conformacional Retorcido-Simple , Receptores de Interleucina-18 , Análisis de Secuencia de ADNRESUMEN
Polymorphism at the TNFd locus has been implicated in a number of disease association studies. The TNFd locus consists of three regions of (GA)(n) repeats separated by an imperfect repeat of two guanine bases. TNFd alleles are genotyped by the number of repeats in the first (GA)(n) repeat region, and until now the second repeat region had been thought to be nonpolymorphic. We report the existence of suballeles present within the TNFd microsatellite locus, detected using induced heteroduplex generator (IHG) technology. These alleles cannot be detected using conventional typing strategies as they represent altered distribution of the (GA)(n) repeats or sequence variation within the repeat. The suballeles affect the frequencies of the conventional d3 and d4 alleles leading to significantly altered allele frequencies. Some studies have associated the d3 and d4 alleles with disease outcome. We re-analysed one such study cohort using IHG technology and demonstrated a high proportion of incorrectly assigned TNFd3 alleles.
Asunto(s)
Repeticiones de Microsatélite/genética , Factor de Necrosis Tumoral alfa/genética , Secuencia de Bases , Frecuencia de los Genes , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Análisis Heterodúplex , Humanos , Datos de Secuencia Molecular , Polimorfismo Genético , Alineación de SecuenciaAsunto(s)
Citocinas/genética , Bases de Datos Genéticas , Enfermedad , Polimorfismo Genético , Humanos , Internet , MEDLINERESUMEN
Although there is evidence that cytokine gene polymorphisms are associated with varying quantities of cytokine protein production, the exact role of these polymorphisms in allograft rejection remains unclear. In a previous study, we demonstrated a significant association between high IL-10 secretion in mixed lymphocyte culture (MLC), together with HLA mismatching for at least 4-6 antigens, with the occurrence of acute rejection following renal transplantation. We, therefore, wished to ascertain whether cytokine gene polymorphisms are associated with varying levels of protein secretion and/or allograft rejection in the same group of patients. Cytokine protein secretion in MLC for IL-4, IL-6, IL-10 and IFN-gamma was measured by ELISA in 49 patient-donor pairs. Protein secretion for the above cytokines was also measured in phytohaemagglutinin (PHA) stimulated cultures in 30 normal controls. In both patient and control groups, single nucleotide polymorphism analysis for IL-4 G(-590)T, IL-6 G(-174)C, IL-10 G(-1082)A, IL-10 C(-819)T, IL-10 C(-592)A, TNF-alpha G(-308)A and microsatellite analysis for IFNG (CA repeat) was performed. No correlation was found between cytokine gene polymorphisms and cytokine protein secretion in either mitogen stimulated cultures (control group) or MLC (patient group). In addition, no correlation was demonstrated between cytokine gene polymorphisms and renal allograft rejection.
Asunto(s)
Citocinas/genética , Trasplante de Riñón , Enfermedad Aguda , Sustitución de Aminoácidos , Estudios de Cohortes , Citocinas/metabolismo , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Genotipo , Rechazo de Injerto/genética , Rechazo de Injerto/metabolismo , Análisis Heterodúplex , Histocompatibilidad , Humanos , Inmunosupresores/uso terapéutico , Interleucinas/genética , Interleucinas/metabolismo , Activación de Linfocitos/efectos de los fármacos , Prueba de Cultivo Mixto de Linfocitos , Repeticiones de Microsatélite , Fitohemaglutininas/farmacología , Mutación Puntual , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Polimorfismo Conformacional Retorcido-Simple , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Multiple single nucleotide polymorphisms (SNP) in the promoter region of the human interleukin-10 (IL-10) gene and in the signal/leader sequence of the human transforming growth factor beta 1 (TGF-beta1) gene, have been associated with susceptibility, severity and clinical outcome for a number of diseases. One common explanation for this, is that different haplotypes of these SNPs regulate the expression of the respective cytokines. Therefore, accurate determination of haplotypes by physical linkage analysis represents an important tool in investigating the pathogenesis of such diseases. Here, we demonstrate that the use of induced heteroduplex generators (IHGs) may be used to identify haplotypes within target sequences in the IL-10 and TGF-beta1 genes. Four haplotypes were observed within the IL-10 promoter region, consisting of -1082, -851, -819 and -592 SNPs. For the TGF-beta1 signal/leader sequence, we observed three haplotypes of the T869C (Leu10Pro) and G915C (Arg25Pro) SNPs. In both cases, all combinations of these haplotypes could be resolved unequivocally with a single IHG reagent.
Asunto(s)
Citocinas/genética , ADN/análisis , Haplotipos , Secuencia de Bases , Citocinas/inmunología , ADN/genética , Electroforesis , Humanos , Datos de Secuencia Molecular , Sensibilidad y EspecificidadRESUMEN
CONTEXT: Hyperphosphatemia has an important role in the development of bone and mineral abnormalities in end-stage renal disease (ESRD). OBJECTIVE: To compare the phosphorus binding power and the hypercalcemic effect of calcium acetate and calcium carbonate in hemodialysis patients. TYPE OF STUDY: Crossover, randomized, double-blind study. PLACE: A private hospital dialysis center. PARTICIPANTS: Fifty-two patients who were undergoing regular hemodialysis three times a week ([Ca++] dialysate = 3.5 mEq/L). PROCEDURES: Half of the patients were started on 5.6 g/day of calcium acetate and, after a 2 week washout period, received 6.2 g/day of calcium carbonate. The other half followed an inverse protocol. MAIN MEASUREMENTS: Clinical interviews were conducted 3 times a week to monitor for side effects. Determinations of serum urea, calcium, phosphorus, hematocrit, Kt/V and blood gas analysis were obtained before and after each treatment. RESULTS: Twenty-three patients completed the study. A significant increase in calcium plasma levels was only observed after treatment with calcium carbonate [9.34 mg/dl (SD 0.91) vs. 9.91 mg/dl (SD 0.79), P < 0.01]. The drop in phosphorus levels was substantial and significant for both salts [5.64 mg/dl (SD 1.54) vs. 4.60 mg/dl (SD 1.32), P < 0.01 and 5.89 mg/dl (SD 1.71) vs. 4.56 mg/dl (SD 1.57), P < 0.01, for calcium acetate and calcium carbonate respectively]. The percentage reduction in serum phosphorus (at the end of the study) per milliequivalent of salt administered per day tended to be higher with calcium acetate but statistical significance was not found. CONCLUSION: Calcium acetate can be a good alternative to calcium carbonate in the handling of hyperphosphatemia in ESRD patients. When calcium acetate is used, control of hyperphosphatemia can be achieved with a lower administration of calcium, perhaps with a lower risk of hypercalcemia.
Asunto(s)
Acetatos/uso terapéutico , Antiácidos/uso terapéutico , Carbonato de Calcio/uso terapéutico , Fallo Renal Crónico/terapia , Trastornos del Metabolismo del Fósforo/tratamiento farmacológico , Diálisis Renal/efectos adversos , Acetatos/efectos adversos , Adulto , Análisis de Varianza , Antiácidos/efectos adversos , Carbonato de Calcio/efectos adversos , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Fallo Renal Crónico/sangre , Masculino , Persona de Mediana Edad , Trastornos del Metabolismo del Fósforo/etiologíaRESUMEN
Using PCR-SSCP and automated nucleotide sequencing we have identified a novel single nucleotide C --> T polymorphism in the human IL-13 promoter, at position -1055 relative to the transcription start site. Allele frequency analysis in a population of normal cord blood donors indicated frequencies of 0.833 (C) and 0. 167 (T).
Asunto(s)
Interleucina-13/genética , Polimorfismo Genético , Regiones Promotoras Genéticas , Secuencia de Bases , Humanos , Datos de Secuencia Molecular , Polimorfismo Conformacional Retorcido-Simple , Homología de Secuencia de Ácido NucleicoRESUMEN
We have identified a single nucleotide polymorphism in the 5' region of the human interleukin-1 receptor type I (IL-1RI) gene, a C-->A transversion at position 52 in exon 1C (GenBank accession number AF172151) which creates a Bsr BI restriction endonuclease site. Allele frequencies in a Caucasian population were 0.72 (C allele) and 0.28 (A allele).
Asunto(s)
Polimorfismo de Longitud del Fragmento de Restricción , Receptores de Interleucina-1/genética , Alelos , Secuencia de Bases , ADN/genética , Cartilla de ADN/genética , Inglaterra , Exones , Femenino , Frecuencia de los Genes , Humanos , Masculino , Datos de Secuencia Molecular , Polimorfismo de Nucleótido Simple , Homología de Secuencia de Ácido NucleicoRESUMEN
We describe the construction and use of 7 induced heteroduplex generators, reagents for the rapid and unequivocal genotyping of nucleotide sequence polymorphism in TNF-alpha, IL-1beta, IL-6 and IL-10. Polymorphisms detected are those previously associated with regulation of gene transcription: TNF-alpha positions -308 and -238; IL-1beta position +3953; IL-6 position -174; and IL-10 positions -1082, -819 and -592. The reagents were used for analysis of allele and haplotype frequencies in a population of healthy Caucasian volunteer blood donors.
Asunto(s)
Regulación de la Expresión Génica , Análisis Heterodúplex/métodos , Interleucinas/genética , Polimorfismo Genético/genética , Transcripción Genética/genética , Factor de Necrosis Tumoral alfa/genética , Disparidad de Par Base/genética , Secuencia de Bases , Frecuencia de los Genes , Genotipo , Haplotipos/genética , Humanos , Interleucina-1/genética , Interleucina-10/genética , Interleucina-6/genética , Mutagénesis Sitio-Dirigida , Conformación de Ácido Nucleico , Ácidos Nucleicos Heterodúplex/genética , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas/genética , Población Blanca/genéticaRESUMEN
We describe a bi-allelic VNTR polymorphism within a 42 bp region in the promoter of the tumour necrosis factor receptor 2 gene (TNFR2). Within this region there are one (Allele 1) or two (Allele 2) repeats of a 15 bp sequence, 5'-GCCGGGC AGGTGGAG-3'. Allele frequencies observed in a Caucasian population were 0.3 (Allele 1) and 0.7 (Allele 2).