Greater Epoetin alfa Responsiveness Is Associated With Improved Survival in Hemodialysis Patients

Background and objectives: Among hemodialysis patients, achieved hemoglobin is associated with Epoetin alfa dose and erythropoietin responsiveness. A prospective erythropoietin responsiveness measure was developed and its association with mortality evaluated.Design, setting, participants, & measurements: Data from 321 participants were used and randomized to the hematocrit normalization arm of the Normal Hematocrit Cardiac Trial. Subjects were to receive a 50% Epoetin alfa dose increase at randomization. The prospective erythropoietin responsiveness measure was defined as the ratio of weekly hematocrit change (over the 3 wk after randomization) per Epoetin alfa dose increase (1000 IU/wk) corresponding to the mandated 50% dose increase at randomization. The distribution of responsiveness was divided into quartiles. Over a 1-yr follow-up, Cox proportional hazard modeling evaluated associations between this responsiveness measure and mortality.Results: Erythropoietin responsiveness values ranged from −2.1% to 2.4% per week per 1000 IU. Although subjects were similar across response quartiles, mortality ranged between 14% and 34% among subjects in the highest and lowest response quartiles (P = 0.0004), respectively. After adjusting for baseline prognostic indicators, highest versus lowest responsiveness was associated with a hazard ratio of 0.41 (95% confidence interval, 0.20 to 0.87).Conclusion: Lower erythropoietin responsiveness is a strong, independent predictor of mortality risk and should be considered when evaluating associations between clinical outcomes and potential prognostic indicators, such as Epoetin alfa dose and achieved hemoglobin values.More than 90% of end-stage renal disease patients require exogenous erythropoietin or transfusion to achieve and maintain target hemoglobin values (1,2) because of decreased endogenous erythropoietin production. The ability to achieve and maintain target hemoglobin levels is complicated by a variety of mediating factors that impact responsiveness to erythropoietin, including comorbidities, inflammation, and malnutrition. These factors are independently associated with poor clinical outcomes (3–9).The impact of erythropoietin responsiveness on mortality is not well understood. Although higher hemoglobin levels have been associated with reduction in mortality in observational studies (10,11), evidence from randomized clinical trials of hemodialysis patients does not suggest a mortality benefit (12). Paradoxically, in the Normal Hematocrit Cardiac Trial (13), the largest randomized trial conducted to date in hemodialysis patients, survival rates were higher among those achieving higher hematocrit values, but targeting a higher hematocrit was associated with a 1.3-fold increased risk of mortality or nonfatal myocardial infarction (95% confidence interval [CI], 0.9 to 1.9). This suggests that unknown/unmeasured patient characteristics associated with the ability to achieve greater hemoglobin values may confound analyses assessing mortality risks among dialysis patients.Achieved hemoglobin level is associated with both the Epoetin alfa doses administered and patient responsiveness to erythropoietin. Greater survival among patients with higher hemoglobin values may be partly due to greater erythropoietin responsiveness (14) in addition to a direct result of anemia correction. Likewise, lower survival among those with lower achieved hemoglobin values may be partly the result of lower relative erythropoietin responsiveness. Patients who require higher Epoetin alfa doses to achieve a given hemoglobin level, that is, who are less responsive to erythropoietin, may experience poorer outcomes at any achieved hemoglobin value (15).In this study, data from the hematocrit normalization arm of the Normal Hematocrit Cardiac Trial (13) were used to develop a prospective measure of erythropoietin responsiveness, which was then evaluated in relation to mortality.     

Estimation of the Bidomain Conductivity Parameters of Cardiac Tissue From Extracellular Potential Distributions Initiated by Point Stimulation

A method for determining the bidomain conductivity values is developed. The study was generated because the different sets of measured conductivity values reported in the literature each produce significantly different bidomain simulation results. The method involves mapping the propagation of the electrical activation of cardiac tissue, initiated by point stimulation, via extracellular electrodes. A time-dependent bidomain model is used to simulate the electrical phenomena. The optimum set of conductivity values is achieved by minimizing the difference between the bidomain model output and the measured extracellular potential, by means of inverse techniques in parameter estimation least-squares and singular value decomposition. The method is validated with synthetic data with added random noise. Other parameters in the model such as membrane capacitance and fiber angle can also be estimated. The method takes a different approach to the conventional four-electrode technique, as it does not require the small electrode separation needed to separate the extracellular current from the intracellular.     

Targets of the nuclear factor I regulon involved in early and late development of postmitotic cerebellar granule neurons

Recent studies have shown that the nuclear factor I (NFI) family controls multiple stages of the postmitotic differentiation of cerebellar granule neurons (CGNs). Regulation of cell–cell signaling is an integral part of this NFI program, which involves expression of the cell adhesion molecules N cadherin and ephrin B1 throughout postmitotic CGN development. Here, we identify two additional downstream targets of NFI that are involved in extracellular CGN interactions. The cell adhesion molecule Tag‐1 is highly enriched in CGNs undergoing parallel fiber formation and is down‐regulated prior to onset of radial migration. We found that Tag‐1 expression was strongly reduced by NFI dominant repression in immature primary CGNs and in the cerebella of E18 Nfib‐null mice. Transient transfection and chromatin immunoprecipitation suggested that the Tag‐1 gene is directly regulated by NFI. Furthermore, functional, Nfi knockout and chromatin immunoprecipitation studies implicated Wnt7a as a direct target of NFI in maturing CGNs. Wnt7a is secreted by developing CGNs and is required for maturation of mossy fiber–CGN synaptic rosettes. Consistent with this, synapsin I was greatly reduced within the internal granule cell layer of P17 Nfia‐null mice. These findings indicated that NFI controls CGN postmitotic maturation through a combination of extracellular signaling molecules that operate either continuously to regulate multiple stages of development (N cadherin and ephrin B1) or primarily at early (Tag‐1) or late (Wnt7a) maturation steps. They also illustrate the importance of NFI as a critical link between cell‐intrinsic mechanisms and cell–cell interactions in the development of the mouse cerebellum. © 2009 Wiley‐Liss, Inc.     

Percutaneous fluoroscopic removal of a knotted Swan–Ganz catheter in a patient with a persistent left‐sided superior vena cava

Knotting of intravascular catheters is an uncommon but a well‐recognized occurrence. The Swan–Ganz catheter (SGC) is the one that knots most commonly. A case of a knotted SGC is described in a patient with a persistent left‐sided superior vena cava, and we propose that the presence of a left‐sided superior vena cava is a risk factor for knot formation not previously reported. We review the published work on the risk factors for knot formation and on the techniques used to remove knotted SGC. We describe a technique using a gooseneck snare and Omni Flush catheter (Angiodynamics, Queensbury, NY, USA) to loosen and untie a knotted SGC.     

Comorbidity of bulimia nervosa and alcohol use disorders: results from the National Women's Study

OBJECTIVE: The nature of the relationship between bulimia nervosa (BN) and alcohol abuse/alcohol dependence (AA/AD) and the extent to which women with BN+AA differ from women with BN-AA were examined in a national sample of women (N = 3,006). METHOD: The sample of was generated by multistage geographic sampling and interviews were conducted by telephone. RESULTS: AA was higher in women with BN compared to women without BN or binge eating disorder, only when the influence of major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) was controlled. Prevalence rates of AA and AD were similar in women with BN, MDD, and PTSD. Analyses indicated that the relationship between BN and AA/AD may be indirect and influenced by associations with MDD and PTSD. Women with BN+AA did not differ from those with BN-AA on most variables concerning victimization, family of origin, and disordered eating. DISCUSSION: Evaluation of MDD and PTSD in women presenting for treatment of BN and/or alcohol use disorders (AUDs) is recommended.     

Which comes first in the pathogenesis of bulimia nervosa: dieting or bingeing?

OBJECTIVE: Clinical experience has indicated that dieting usually precedes the onset of binge eating in the development of bulimia nervosa (BN). However, data confirming this in nonclinical, representative samples are lacking. METHOD: Using results obtained from the National Women's Study (NWS), we were able to determine the chronological relationship between age of onset of significant dieting (attempting to lose 15 lbs) and onset of bingeing in 85 respondents who met DSM-III-R criteria for BN. These respondents were a subset of over 3,000 female adult U.S. women who completed a random telephone interview (averaging 40 min and including screenings for rape, sexual molestation, aggravated assault, posttraumatic stress disorder [PTSD], and BN). RESULTS: We found that the age of first serious attempt to diet preceded the age of first binge in 46% of cases. There were no significant differences in histories of victimization experiences among the groups. First binge preceded first serious diet in 37% of cases, and these behaviors occurred during the same age in 17% of cases. DISCUSSION: These data confirm that dieting is more likely to precede binge eating, although binge eating precedes significant dieting in a substantial proportion of bulimic respondents.