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Automation has allowed clinicians to program PD treatment parameters, all while obtaining extensive individual treatment data. This data populates in a centralized online platform shortly after PD treatment completion. Individual treatment data available to providers includes patients' vital signs, alarms, bypasses, prescribed PD treatment, actual treatment length, individual cycle fill volumes, ultrafiltration volumes, as well as fill, dwell, and drain times. However, there is no guidance about how often or if this data should be assessed by the clinical team members. We set out to determine current practice patterns by surveying members of the home dialysis team managing PD patients across the United States and Canada. A total of 127 providers completed the survey. While 91% of respondents reported having access to a remote monitoring platform, only 31% reported having a standardized protocol for data monitoring. Rating their perceived importance of having a standard protocol for remote data monitoring, on a scale of 0 (not important at all) to 10 (extremely important), the average response was 8 (physicians 7; nurses 9). Most nurses reported reviewing the data multiple times per week, whereas most physicians reported viewing the data only during regular/monthly visits. Although most of the providers who responded have access to remote monitoring data and feel that regular review is important, the degree of its utilization is variable, and the way in which the information is used is not commonly protocolized. Working to standardize data interpretation, testing algorithms, and educating providers to help process and present the data are important next steps.
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AIMS: To perform the first psychometric analysis of the Norwegian version of the eHLQ using confirmative factor analysis (CFA) procedures in a population of patients admitted to hospital using a cross-sectional design. The eHLQ consists of 35 items capturing the 7-dimensional eHealth Literacy Framework (eHLF) which describes users' attributes, user's interaction with technologies and user's experience with digital health systems. METHODS: The 7 independent scales of the eHLQ was translated from Danish and culturally adapted into the Norwegian language following a standardised protocol. Assessment of construct validity of the eHLQ was undertaken using data from a cross-sectional survey of 260 patients hospitalized at a Norwegian University Hospital in the Oslo area during a two-week period in June 2021. The analysis included using correlation analysis (Pearsons R), internal consistency (Cronbach's alpha) and confirmatory factor analysis (CFA). RESULTS: All factor loadings were high to acceptable (i.e. > 0.6), except for five items which had somewhat lower loadings. Regarding internal consistency, alpha ranged from 0.73 to 0.90. For optimal CFA fit for the different scale models, correlated residuals were required for five of the seven scales. Overall our analysis shows an intermediate fit of the orginal construct. Scale intercorrelations were all below 0.8, indicating an overall acceptable discriminant validity between the 7 dimensions. CONCLUSIONS: The results from the CFA analysis indicate that for almost all 7 eHLQ scales, an acceptable model fit was achieved. The 260 hospitalized patients included in this study represented a variety of diagnoses, recruited from a geographically limited area. Further studies on psychometric properties of the Norwegian version of eHLQ in larger samples, diverse settings and by using more comprehensive approaches are warranted.
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Alfabetización , Telemedicina , Humanos , Estudios Transversales , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , Lenguaje , Telemedicina/métodos , Noruega , Análisis Factorial , Psicometría/métodosRESUMEN
Despite their crucial role in health and disease, our knowledge of immune cells within human tissues remains limited. We surveyed the immune compartment of 16 tissues from 12 adult donors by single-cell RNA sequencing and VDJ sequencing generating a dataset of ~360,000 cells. To systematically resolve immune cell heterogeneity across tissues, we developed CellTypist, a machine learning tool for rapid and precise cell type annotation. Using this approach, combined with detailed curation, we determined the tissue distribution of finely phenotyped immune cell types, revealing hitherto unappreciated tissue-specific features and clonal architecture of T and B cells. Our multitissue approach lays the foundation for identifying highly resolved immune cell types by leveraging a common reference dataset, tissue-integrated expression analysis, and antigen receptor sequencing.
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Linfocitos B , Aprendizaje Automático , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Linfocitos T , Transcriptoma , Células Cultivadas , Humanos , Especificidad de ÓrganosRESUMEN
BACKGROUND: The Human Cell Atlas is a large international collaborative effort to map all cell types of the human body. Single-cell RNA sequencing can generate high-quality data for the delivery of such an atlas. However, delays between fresh sample collection and processing may lead to poor data and difficulties in experimental design. RESULTS: This study assesses the effect of cold storage on fresh healthy spleen, esophagus, and lung from ≥ 5 donors over 72 h. We collect 240,000 high-quality single-cell transcriptomes with detailed cell type annotations and whole genome sequences of donors, enabling future eQTL studies. Our data provide a valuable resource for the study of these 3 organs and will allow cross-organ comparison of cell types. We see little effect of cold ischemic time on cell yield, total number of reads per cell, and other quality control metrics in any of the tissues within the first 24 h. However, we observe a decrease in the proportions of lung T cells at 72 h, higher percentage of mitochondrial reads, and increased contamination by background ambient RNA reads in the 72-h samples in the spleen, which is cell type specific. CONCLUSIONS: In conclusion, we present robust protocols for tissue preservation for up to 24 h prior to scRNA-seq analysis. This greatly facilitates the logistics of sample collection for Human Cell Atlas or clinical studies since it increases the time frames for sample processing.
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Análisis de Secuencia de ARN , Análisis de la Célula Individual , Conservación de Tejido/métodos , Frío , Esófago/citología , Humanos , Pulmón/citología , Refrigeración , Bazo/citologíaRESUMEN
BACKGROUND: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. METHODS: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. RESULTS: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. CONCLUSION: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.
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Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Estudios de Casos y Controles , Femenino , Variación Genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Polimorfismo de Nucleótido Simple/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 5 de Factor de Crecimiento de Fibroblastos/genéticaRESUMEN
The phenomenon of teratozoospermia in felids is not fully understood. In this study, we investigated the testicular androgen:estrogen balance in domestic cats and correlated these data with epididymal sperm morphology and the degree of spermatogenic activity. During spring and summer, testes and blood samples were obtained from 37 mixed-breed domestic cats (12 to 48 mo). The epididymal sperm were harvested and evaluated for sperm counts, motility, and morphology. Distal cytoplasmic droplets were not considered a defect, and samples were considered normozoospermic if they contained more than 60% normal sperm (N = 25) or teratozoospermic if they contained less than 45% normal sperm (N = 12). The testicular and serum concentrations of testosterone (T) and 17ß-estradiol (E2) were determined with an enzyme immunoassay. The gonadosomatic index and epididymal sperm numbers and motility did not differ between groups. The percentage of normal sperm was higher in normozoospermic (74.3 ± 2.0, mean ± SEM) than in teratozoospermic samples (43.1 ± 1.4). The most prevalent sperm defects in the teratozoospermic group were abnormal acrosomes (9.7 ± 2.0) and bent midpieces (12.2 ± 2.0) or tails (24.0 ± 2.7) with cytoplasmic droplets. Histomorphometric data were similar between groups, although there was a lower Leydig cell nuclear volume in teratozoospermic samples. Normozoospermic samples contained a higher percentage of haploid cells and had a higher index of total spermatogenic transformation than teratozoospermic samples. Serum concentrations of T (0.5 ± 0.1 vs. 0.8 ± 0.4 ng/mL) and E2 (9.5 ± 1.2 vs. 11.4 ± 2.3 pg/mL) and testicular T concentrations (471.6 ± 65.3 vs. 313.4 ± 57.6 ng/g) were similar between groups. However, compared with normozoospermic samples, teratozoospermic samples had higher testicular E2 concentrations (8.5 ± 3.6 vs. 5.4 ± 0.5 ng/g) and a lower T:E2 ratio (31.8 ± 4.1 vs. 87.2 ± 11.6). There were significant correlations between testicular E2 values and percentages of normal sperm (r = -0.55) as well as those with primary sperm defects (r = 0.58) or abnormal acrosomes (r = 0.64). The T:E2 ratio was also correlated with meiotic index (r = 0.45) and percentage of normal sperm (r = 0.58). In conclusion, a high testicular E2 concentration and a reduced T:E2 ratio were significantly associated with higher ratios of abnormal sperm types, suggesting that the balance between androgens and estrogens is an important endocrine component in the genesis of teratozoospermia in felids.
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Gatos/fisiología , Estradiol/sangre , Espermatogénesis/fisiología , Espermatozoides/anomalías , Testículo/química , Testosterona/sangre , Animales , Enfermedades de los Gatos/fisiopatología , Epidídimo/citología , Estradiol/análisis , Infertilidad Masculina/fisiopatología , Infertilidad Masculina/veterinaria , Masculino , Recuento de Espermatozoides , Motilidad Espermática , Testosterona/análisisRESUMEN
Intravenous vitamin D is standard therapy for secondary hyperparathyroidism in hemodialysis (HD) patients. In for-profit dialysis clinics, mortality was higher for patients on calcitriol compared to paricalcitol. Doxercalciferol, a second vitamin D2 analog, is currently available. We assessed mortality associated with each vitamin D analog and with lack of vitamin D therapy in patients who began HD at Dialysis Clinic Inc. (DCI), a not-for-profit dialysis provider. During the 1999-2004 study period we studied 7731 patients (calcitriol: n=3212; paricalcitol: n=2087; doxercalciferol: n=2432). Median follow-up was 37 weeks. Mortality rates (deaths/100 patient-years) were identical in patients on doxercalciferol (15.4, 95% confidence interval (13.6-17.1)) and paricalcitol (15.3 (13.6-16.9)) and higher in patients on calcitriol (19.6 (18.2-21.1)) (P<0.0001). In all models mortality was similar for paricalcitol versus doxercalciferol (hazard ratios=1.0). In unadjusted models, mortality was lower in patients on doxercalciferol (0.80 (0.66, 0.96)) and paricalcitol (0.79 (0.68, 0.92)) versus calcitriol (P<0.05). In adjusted models, this difference was not statistically significant. In all models mortality was higher for patients who did not receive vitamin D versus those who did (1.2 (1.1-1.3)). Mortality in doxercalciferol- and paricalcitol-treated patients was virtually identical. Differences in survival between vitamin D2 and D3 may be smaller than previously reported.
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Conservadores de la Densidad Ósea/uso terapéutico , Calcitriol/uso terapéutico , Ergocalciferoles/uso terapéutico , Hiperparatiroidismo Secundario/tratamiento farmacológico , Diálisis Renal/mortalidad , Vitamina D/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Óseas Metabólicas/sangre , Calcio/sangre , Femenino , Humanos , Hiperparatiroidismo Secundario/mortalidad , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Fósforo/sangre , Diálisis Renal/efectos adversos , Estudios Retrospectivos , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
BACKGROUND: The Hemodialysis (HEMO) Study is a multicenter trial designed to determine whether hemodialysis dose and membrane flux affect survival. Comorbid conditions are also important determinants of survival, and thus, an accurate and reliable method to assess comorbidity was required. Comorbidity was being assessed at baseline and annually in the HEMO Study using the Index of Coexistent Disease (ICED). We describe the instrument, its implementation in the HEMO Study, and the results of comorbidity assessment in the first 1000 randomized patients in the trial. METHODS: The ICED aggregated the presence and severity of 19 medical conditions and 11 physical impairments within two scales: the Index of Disease Severity (IDS) and the Index of Physical Impairment (IPI). The final ICED score was determined by an algorithm combining the peak scores for the IDS and IPI. The range of the ICED was from 0 to 3, reflecting increasing severity. RESULTS: Study personnel at 15 clinical centers were trained to update and abstract data from the dialysis medical records. Availability of data, measures of construct validity, and measures of reliability were adequate; 99.8% and 60.6% of patients had comorbid conditions in at least one IDS or IPI category, respectively. The distribution of patients by ICED level was 0 (0.2%), 1 (34.9%), 2 (31.2%), and 3 (33.7%). In multivariable analysis, the following factors were significantly associated with more severe comorbidity: older age, diabetes and other causes of renal disease, a lower level of education, employment status (unemployed and retired), longer duration of dialysis, and lower serum creatinine. There was a significant variation in the severity of comorbidity among clinical centers after adjustment for other factors. The R2 of the model was 25.3%, indicating that a substantial proportion of the variation in the ICED was not explained by these factors. CONCLUSIONS: We conclude that comorbidity assessment using the ICED is feasible in multicenter clinical trials of dialysis patients. There is a large burden of comorbidity in dialysis patients, which is not well explained by the cause of renal disease, demographic, and socioeconomic factors and common clinical and laboratory measurements. These variables should not be considered substitutes for comorbid conditions in case-mix adjustment. Comorbidity assessment is useful to describe the sample population, to improve the precision of the treatment effect, and to use possibly as an outcome measurement.
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Indicadores de Salud , Enfermedades Renales/epidemiología , Enfermedades Renales/terapia , Diálisis Renal , Comorbilidad , Estudios de Factibilidad , Humanos , Variaciones Dependientes del Observador , Proyectos Piloto , Estudios ProspectivosRESUMEN
The Choices for Healthy Outcomes in Caring for End-Stage Renal Disease ([ESRD] CHOICE) Study was designed to evaluate the effectiveness of alternative dialysis prescriptions. As part of CHOICE, we developed an instrument for measuring health-related quality of life (HRQOL) for patients with ESRD that would complement the Medical Outcomes Study 36-Item Short-Form Survey (SF-36) and be sensitive to differences in dialysis modality (hemodialysis [HD] and peritoneal dialysis [PD]) and dialysis dose. The selection of HRQOL domains to be included was based on: (1) a structured literature review of 47 articles describing 53 different instruments; (2) content analysis of five focus groups with HD and PD patients, nephrologists, and other providers; (3) a survey of 110 dialysis providers about features of different modalities that affect patient HRQOL; and (4) a semistructured survey of 25 patients with ESRD on the effects of dialysis on functioning and HRQOL. To help prioritize domains and items identified by these methods, a representative sample of 136 dialysis patients rated each item for frequency and bother. A panel of nephrologists provided advice about the salience of items to modality or dose. Items and scales were selected with a preference for existing measures tested in patients with ESRD and were tested for reliability and validity. The first four steps yielded 22 HRQOL domains that included 96 items: 8 generic domains in the SF-36 (health perceptions, physical, social, physical and emotional role function, pain, mental health, and energy); 8 additional generic domains (cognitive functioning, sexual functioning, sleep, work, recreation, travel, finances, and general quality of life); and 6 ESRD-specific domains (diet, freedom, time, body image, dialysis access [catheters and/or vascular], and symptoms). New items were developed or adapted to assess ESRD-specific domains. Scales for these items showed adequate internal consistency (Cronbach's alpha > 0.70, except for time [alpha = 0.57] and quality of life [alpha = 0.68]), as well as convergent and discriminant construct validity in a sample of 928 patients. The final questionnaire included 21 domains (time was deleted) and 83 items. We have designed a patient-centered instrument, the CHOICE Health Experience Questionnaire, that addresses domains that may be sensitive to differences in dialysis modality and dose and shows evidence for reliability and validity as a measure of HRQOL in ESRD.
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Recolección de Datos/instrumentación , Fallo Renal Crónico/terapia , Diálisis Peritoneal Ambulatoria Continua/normas , Calidad de Vida , Diálisis Renal/normas , Adulto , Baltimore , Grupos Focales , Humanos , Persona de Mediana Edad , Vigilancia de la Población/métodos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Encuestas y Cuestionarios , Resultado del Tratamiento , Estados UnidosRESUMEN
The purpose of this paper is to describe the ICED, summarize outcomes of prior studies in which it was used, and describe the adaptations that have lead to the present instrument. We will then demonstrate its use in quantifying the burden of comorbid conditions in a sample of hemodialysis and peritoneal dialysis patients from our center, and show the relationship between ICED levels and outcomes in peritoneal dialysis patients.
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Indicadores de Salud , Cardiopatías/epidemiología , Fallo Renal Crónico/epidemiología , Diálisis Peritoneal , Diálisis Renal , Comorbilidad , Humanos , Índice de Severidad de la EnfermedadRESUMEN
Although quality-of-life assessment is an important complement to conventional clinical evaluation, there are limited opportunities for researchers in end-stage renal disease (ESRD) to examine evidence for a range of quality-of-life measures. To better understand how quality of life has been conceptualized, measured, and evaluated for ESRD, we conducted a structured literature review. Eligible articles were identified from a MEDLINE search, expert input, and review of references from eligible articles. A standardized instrument was created for article review and included type of measure, instrument development process, study sample characteristics, quality-of-life domains, and reliability and validity testing. From 436 citations, 78 articles were eligible for final review, and of those, 47 articles contained evidence of reliability or validity testing. Within this set, there were 113 uses of 53 different instruments: 82% were generic and 18% were disease specific. Only 32% defined quality of life. The most frequently assessed domains were depression (41%), social functioning (32%), positive affect (30%), and role functioning (27%). Testing was completed for test-retest reliability (20%), interrater reliability (13%), internal consistency (22%), content validity (24%), construct validity (41%), criterion validity (55%), and responsiveness (59%). Few articles measuring quality of life in ESRD defined quality-of-life domains or adequately described instrument development and testing. Generic measures, such as the Sickness Impact Profile, and disease-specific measures, such as the Kidney Disease Questionnaire, had been tested more thoroughly than others. Standardized reporting and more rigorous testing could help researchers make informed choices about instruments that would best serve their own and their patients' needs.
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Fallo Renal Crónico , Calidad de Vida , Encuestas y Cuestionarios , HumanosRESUMEN
The transcription factor E2A plays a crucial role in B cell development, the control of immunoglobulin gene rearrangement and expression. Here we report that in primary mouse B cells lipopolysaccharide (LPS) is able to induce the level of E2A protein by over 50-fold in days of culture. In contrast, CD40 signaling is insufficient to cause an E2A increase and can in fact prevent the LPS-mediated induction of E2A. These results suggest that E2A induction requires both proliferation and differentiation. We find that E2A protein induction is regulated post-transcriptionally since E2A mRNA is not induced by LPS. We have thus identified an important additional layer of regulation affecting the activity of E2A transcription factors.
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Linfocitos B/inmunología , Antígenos CD40/inmunología , Proteínas de Unión al ADN/inmunología , Transducción de Señal/inmunología , Factores de Transcripción , Animales , Diferenciación Celular/inmunología , Proteínas de Unión al ADN/genética , Regulación de la Expresión Génica/inmunología , Lipopolisacáridos/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Procesamiento Postranscripcional del ARN , Factores de Transcripción TCF , Proteína 1 Similar al Factor de Transcripción 7RESUMEN
BACKGROUND: Patients with end-stage renal disease (ESRD) may have quality-of-life (QOL) concerns that are not fully appreciated by their providers. The authors conducted focus groups with dialysis patients and dialysis professionals to determine whether this qualitative method would reveal differences between patients' and providers' views about: 1) domains of QOL that are affected by ESRD and dialysis; and 2) aspects of dialysis that affect QOL. METHODS: Separate focus group discussions were held with: 8 adult hemodialysis patients (mean age 50 years; 3 women; mean duration of dialysis 8.5 years), 5 adult peritoneal dialysis patients (mean age 54 years; 3 women; mean duration of dialysis 4.6 years), 8 nephrologists (mean of 12 years of dialysis practice), and 9 other health professionals involved in dialysis care (3 nurses, 2 dietitians, 2 social workers, and 2 technicians; mean of 10 years experience in dialysis care). Discussions were audiotaped, transcribed verbatim, and reviewed independently by three investigators to identify and categorize distinct thoughts. RESULTS: 1,271 distinct thoughts were identified and grouped into 20 related categories, which included ten QOL domains and ten aspects of dialysis that affect QOL. Compared with the professionals, the patients identified one additional relevant QOL domain (10 vs 9), and one additional aspect of dialysis that affects QOL (10 vs 9), and expressed more thoughts per domain (p < 0.05), although the contents of their comments were frequently similar. Among QOL domains, the numbers of related thoughts identified by patients and professionals, respectively, were: freedom/control (60, 89); social relationships (36, 11); anxiety (37, 4); role function (24, 10); energy (12, 10); body image (16, 4); sex (11, 21); mental attitude (21, 0); sleep (15, 1), and cognitive function (13, 7). Among aspects of dialysis that affect QOL, the numbers of thoughts identified by patients and professionals were: general dialysis issues (159, 105); relationships with staff (62, 110); patient education (63, 68); diet (44, 40); scheduling (57, 3); vascular or peritoneal access issues (31, 17), adaptation to dialysis (16, 14); dialysis dose (18, 8); symptoms (25, 0), and self-care (5, 24). CONCLUSIONS: Although health professionals have a good understanding of patient concerns about the effects of ESRD and dialysis, the focus group discussions revealed a breadth and depth of QOL concerns that they may not fully appreciate.
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Grupos Focales , Fallo Renal Crónico/terapia , Grupo de Atención al Paciente , Participación del Paciente , Diálisis Peritoneal Ambulatoria Continua/psicología , Calidad de Vida , Diálisis Renal/psicología , Adaptación Psicológica , Adulto , Anciano , Técnicas de Apoyo para la Decisión , Femenino , Humanos , Fallo Renal Crónico/psicología , Masculino , Persona de Mediana Edad , Diálisis Peritoneal Ambulatoria Continua/efectos adversos , Diálisis Renal/efectos adversos , Rol del EnfermoRESUMEN
Despite improvements in dialysis care, mortality of patients with end-stage renal disease (ESRD) remains high. One factor that has thus far received little attention, but might contribute to morbidity and mortality, is the timing of referral to the nephrologist. This study examines the hypothesis that late referral of patients to the nephrologist might lead to suboptimal pre-ESRD care. Clinical and laboratory data were obtained from the patient records and electronic databases of New England Medical Center, its affiliated dialysis unit (Dialysis Clinics, Inc., Boston), and the office records of the outpatient nephrology clinic. Early (ER) and late (LR) referral were defined by the time of first nephrology encounter greater than or less than 4 mo, respectively, before initiation of dialysis. Multivariate models were built to explore factors associated with LR, and whether LR is associated with hypoalbuminemia or late initiation of dialysis. Of the 135 patients, 30 (22%) were referred late. There were no differences in age, gender, race, and cause of ESRD between ER and LR patients. However, there were significant differences in insurance coverage between these two groups. In the multivariate analysis, patients covered by health maintenance organizations were more likely to be referred late (odds ratio = 4.5) than patients covered by Medicare. Compared to ER, LR patients were more likely to have hypoalbuminemia (56% versus 80%), hematocrit <28% (33% versus 55%), and predicted GFR <5 ml/min per 1.73 m2 (17% versus 40%) at the start of dialysis, and less likely to have received erythropoietin (40% versus 17%) or have a functioning permanent vascular access for the first hemodialysis (40% versus 4%). It is concluded that late referral to the nephrologist is common in the United States and is associated with poor pre-ESRD care. Pre-ESRD care of patients treated by nephrologists was also less than ideal. The patient-, physician-, and system-related factors behind this observation are unclear. Meanwhile, pre-ESRD educational efforts need to target patients, generalists, and nephrologists.
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Unidades de Hemodiálisis en Hospital/normas , Fallo Renal Crónico/terapia , Nefrología , Evaluación de Resultado en la Atención de Salud , Derivación y Consulta/normas , Diálisis Renal/normas , Adulto , Anciano , Boston/epidemiología , Recolección de Datos , Estudios de Evaluación como Asunto , Femenino , Unidades de Hemodiálisis en Hospital/estadística & datos numéricos , Humanos , Fallo Renal Crónico/mortalidad , Masculino , Persona de Mediana Edad , Nefrología/estadística & datos numéricos , Valor Predictivo de las Pruebas , Derivación y Consulta/estadística & datos numéricos , Diálisis Renal/estadística & datos numéricos , Medición de Riesgo , Tasa de Supervivencia , Factores de TiempoRESUMEN
Upon treatment with lipopolysaccharide (LPS), primary B cells proliferate and differentiate into plasma cells with concomitant up-regulation of immunoglobulin (Ig) gene expression. Here we examine the role of the Igkappa 3' enhancer in this process using a kappa3'-enhancer-driven beta-globin reporter gene in transgenic mice. We find that LPS treatment up-regulates kappa3' enhancer activity as a function of differentiation rather than proliferation, since proliferation only (induced by cross-linking of CD40) is insufficient to activate the element, whilst differentiation with only limited proliferation (LPS + transforming growth factor-beta) does allow activation to occur. The Igkappa 3' enhancer is also induced by cross-linking of surface Ig and this signal can synergize with LPS activation, suggesting that distinct activation pathways are used. Nevertheless, both of these pathways can be inhibited by co-cross-linking of CD40. Thus Ig enhancers in the heavy and light chain loci are differentially regulated in response to CD40.
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Antígenos de Diferenciación de Linfocitos T/metabolismo , Antígenos CD40/metabolismo , Elementos de Facilitación Genéticos , Regulación de la Expresión Génica , Genes de Inmunoglobulinas , Cadenas kappa de Inmunoglobulina/genética , Glicoproteínas de Membrana/metabolismo , Transducción de Señal , Animales , Ligando de CD40 , Diferenciación Celular , División Celular , Células Cultivadas , Reactivos de Enlaces Cruzados , Regulación de la Expresión Génica/efectos de los fármacos , Cadenas mu de Inmunoglobulina/metabolismo , Ligandos , Lipopolisacáridos/farmacología , Ratones , Ratones Transgénicos , Transducción de Señal/efectos de los fármacosAsunto(s)
Cardiopatías/prevención & control , Fallo Renal Crónico/complicaciones , Brotes de Enfermedades/prevención & control , Medicina Basada en la Evidencia , Femenino , Humanos , Fallo Renal Crónico/terapia , Masculino , Tamizaje Masivo , Metaanálisis como Asunto , Evaluación de Resultado en la Atención de Salud , Investigación , Factores de RiesgoAsunto(s)
Enfermedades Cardiovasculares , Fallo Renal Crónico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Enfermedad Coronaria/epidemiología , Enfermedad Coronaria/prevención & control , Medicina Basada en la Evidencia , Humanos , Hipertrofia Ventricular Izquierda/epidemiología , Hipertrofia Ventricular Izquierda/prevención & control , Fallo Renal Crónico/complicaciones , Literatura de Revisión como Asunto , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Hypertension may play an important role in the pathogenesis of the excess cardiovascular and cerebrovascular (CV) morbidity observed in hemodialysis patients (HD). However, the optimal blood pressure (BP) range for HD patients has not been defined. We postulated that there is a "U" curve relationship between BP and CV mortality. To explore this hypothesis we studied 5,433 HD patients in Dialysis Clinic Inc., a large not-for-profit chain, over a five year period. METHODS: Cox regression, with fixed and time-varying covariates, was used to assess the effect of systolic blood pressure (SBP) and diastolic blood pressure (DBP), pre- and post-dialysis, on CV mortality, while adjusting for age, gender, ethnicity, primary cause of end-stage renal disease, Kt/V, serum albumin, and antihypertensive medications. RESULTS: The overall impact of BP on CV mortality was modest. Pre-dialysis, neither systolic nor diastolic hypertension were associated with an increase in CV mortality. Post-dialysis, SBP > or = 180 mm Hg (RR = 1.96, P < 0.015) and DBP > or = 90 mm Hg (RR = 1.73, P < 0.05) were associated with increased CV mortality. Low SBP (SBP < 110 mm Hg) was associated with increased CV mortality, pre- and post-dialysis. CONCLUSIONS: The results suggest the presence of a "U" curve relationship between SBP post-dialysis and CV mortality in HD patients.
Asunto(s)
Presión Sanguínea , Diálisis Renal/mortalidad , Adulto , Factores de Edad , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis MultivarianteRESUMEN
The Ig kappa 3' enhancer is required for high levels of Ig kappa gene expression. We now show that kappa 3' enhancer function increases five- to eightfold after stimulation of primary murine B cells with phorbol 12-myristate 13-acetate (PMA) and the calcium ionophore ionomycin. In the presence of cyclosporin A this induction is almost halved, suggesting that transcription factors of the NFAT family contribute to kappa 3' enhancer induction. Indeed, we identify a novel NFAT binding site which is required for full enhancer function. We find that this site is transcriptionally active in stimulated B cells, T cells and fibroblasts and that both PMA and ionomycin are required for maximal induction. Time course analysis of the components of the protein-DNA complex in primary lymphocytes reveals that both NFATp and NFATc are present in the complex after 15 min, while only NFATc is detectable after 4 h. This suggests that NFATc plays the dominant role in controlling long-term responses of this transcription factor family. Furthermore, JunB, JunD, FosB and cFos form part of the DNA-protein complex in Bal-17 B cells. Complex formation as well as transcriptional activity can also be induced by crosslinking of surface Ig. We have, thus, identified a unique NFAT complex in B cells that contributes to Ig kappa gene expression.
Asunto(s)
Proteínas de Unión al ADN/fisiología , Elementos de Facilitación Genéticos/inmunología , Regulación de la Expresión Génica/inmunología , Cadenas kappa de Inmunoglobulina/genética , Ionomicina/farmacología , Proteínas Nucleares , Acetato de Tetradecanoilforbol/farmacología , Factores de Transcripción/fisiología , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Línea Celular , Ciclosporina/farmacología , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/metabolismo , Sinergismo Farmacológico , Elementos de Facilitación Genéticos/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Cadenas kappa de Inmunoglobulina/biosíntesis , Cadenas kappa de Inmunoglobulina/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Factores de Transcripción NFATC , Unión Proteica/genética , Unión Proteica/inmunología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-jun/metabolismo , Receptores de Antígenos de Linfocitos B/metabolismo , Factores de Transcripción/biosíntesis , Factores de Transcripción/metabolismo , Activación Transcripcional/efectos de los fármacos , Activación Transcripcional/inmunología , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunologíaRESUMEN
Among the several disadvantages of reprocessed dialyzers is the concern that reuse could decrease the clearance of uremic toxins, leading to a decrease in the delivered dose of dialysis. To examine this possibility in the clinical setting, the clearances of small molecular weight solutes (urea and creatinine) and middle molecular weight substances (beta 2 microglobulin) were compared during dialysis with "high-efficiency" cellulose (T220L) and "high-flux" polysulfone (F80B) dialyzers reprocessed with formaldehyde and bleach. In a crossover study, six chronic hemodialysis patients were alternately assigned to undergo 21 dialysis treatments with a single T220L dialyzer or F80B dialyzer. Each patient was studied during first use (0 reuse), 2nd reuse (3rd use), and 5th, 10th, 15th, and 20th reuse of each dialyzer. Urea, creatinine, and beta 2 microglobulin clearances were measured at blood flow rates of 300 ml/min (Qb 300) and 400 ml/min (Qb 400). Total albumin loss into the dialysate was measured during each treatment. Urea or creatinine clearance of new T220L dialyzers was not significantly different from that of new F80B dialyzers at either Qb. Urea clearance of F80B dialyzers at Qb 300 decreased from 241 +/- 2 ml/min for new dialyzers to 221 +/- 5 ml/min after 20 reuses (P < 0.001), and Qb 400 from 280 +/- 4 ml/min for new dialyzers to 253 +/- 7 ml/min after 20 reuses (P = 0.001). Similarly, with reuse, creatinine clearance of F80B dialyzers also decreased at Qb 300 (P = 0.07) and Qb 400 (P = 0.03). In contrast, urea or creatinine clearance of T220L dialyzers did not decrease with reuse at either Qb. Urea clearance of T220L dialyzers was significantly higher than that of F80B at Qb 300 at the 5th, 10th, 15th, and 20th reuse (P < 0.001, = 0.005, = 0.004, and = 0.006, respectively), and Qb 400 at the 2nd, 5th, 10th, 15th, and 20th reuse (P = 0.04, 0.008, 0.03, 0.02, and 0.008, respectively). Beta 2 microglobulin clearance of T220L dialyzers was < 5.0 ml/min across the reuses studied. Beta 2 microglobulin clearance of F80B was < 5.0 ml/min for new dialyzers, but increased to 21.2 +/- 5.3 ml/min (Qb 300) and 23.6 +/- 3.3 ml/min (Qb 400) after 20 reuses (P < 0.001). Throughout the study, albumin was undetectable in the dialysate with T220L dialyzers. With F80B dialyzers, albumin was detected in the dialysate in four instances (total loss during dialysis, 483 mg to 1.467 g). In summary, the results of this study emphasize the greater need for information on dialyzer clearances during clinical dialysis, especially with reprocessed dialyzers. A more accurate knowledge of dialyzer performance in vivo would help to ensure that the dose of dialysis prescribed is indeed delivered to the patients.