Characterizing cognitive control abilities in children with 16p11.2 deletion using adaptive 'video game' technology: a pilot study.

Assessing cognitive abilities in children is challenging for two primary reasons: lack of testing engagement can lead to low testing sensitivity and inherent performance variability. Here we sought to explore whether an engaging, adaptive digital cognitive platform built to look and feel like a video game would reliably measure attention-based abilities in children with and without neurodevelopmental disabilities related to a known genetic condition, 16p11.2 deletion. We assessed 20 children with 16p11.2 deletion, a genetic variation implicated in attention deficit/hyperactivity disorder and autism, as well as 16 siblings without the deletion and 75 neurotypical age-matched children. Deletion carriers showed significantly slower response times and greater response variability when compared with all non-carriers; by comparison, traditional non-adaptive selective attention assessments were unable to discriminate group differences. This phenotypic characterization highlights the potential power of administering tools that integrate adaptive psychophysical mechanics into video-game-style mechanics to achieve robust, reliable measurements.

Are conventional cardiovascular risk factors predictive of two-year mortality in hemodialysis patients?

BACKGROUND: In general population hypertension, diabetes mellitus, overweight, hyperlipidemia and smoking are well-established risk factors for cardiovascular disease. However, the effect of these conventional risk factors on cardiovascular disease and mortality of patients on hemodialysis is not well understood. Indeed, some risk factors such as high blood pressure, hyperlipidemia and excess weight have been recently claimed to correlate with improved survival. OBJECTIVE: This study was undertaken to define the prevalence of these conventional risk factors in 453 hemodialysis patients, predominantly African-Americans, to determine their influence on two-year survival. RESULT: High cholesterol was found in 30% of the patients, high LDL-cholesterol in 25% and high triglycerides in 16%. Lipoprotein(a) (LP(a)) was elevated in 68% of the patients. 31% of our patients had predialysis mean arterial blood pressure (MAP) over 114, and 25% were obese based on a body mass index (BMI) over 30, 26% were diabetic and 25% were active smokers. Smoking was more common among our male and Caucasian patients. The aggregate score for the risk factors were 2.4+/-0.1 per patient, which increased to 3.2+/-0.1 in patients with obesity or diabetes, to 3.0+/-0.1 with hypertension and to 2.8+/-0.1 with active smoking. In multivariate Cox model analysis, prealbumin, body weight and blood pressure showed a positive correlation with two-year survival whereas diabetes mellitus had a negative correlation. Hyperlipidemia did not correlate to patients' two-year mortality. Smoking was associated with higher mortality, but that did not reach statistical significance. CONCLUSION: Conventional risk factors at least over a two-year period do not readily account for the higher mortality of a group of predominantly African-American patients on hemodialysis. The lack of prediction is speculated to be partly due to the overriding beneficial effects of better nutrition and due to the presence of other yet to be well-defined factors such as hyperhomocysteinemia, oxidative stress, coronary calcification, hitherto unidentified uremic toxins or a combination of these factors.

Anemia and iron target realization in 1998: clinical management of anemia in 1,639 patients on hemodialysis.

Anemia management in hemodialysis patients continues to evolve, and recently, greater emphasis has been placed on the wider use of intravenous iron to maintain adequate iron levels. This survey provides scarcely available yet potentially useful information on the clinical treatment of anemia in a large cohort of hemodialysis patients. The erythropoietin and iron administration details and pertinent laboratory measurements from 1,639 patients were analyzed for the month of December, 1998. A standardized protocol had been used in that erythropoietin was begun at a total weekly dose of 150 U/kg IV or 100 U/kg subcutaneously and was then adjusted to maintain a hematocrit (Hct) of 33-36%. Iron supplements, oral, IV, or both, were administered to maintain percent transferrin saturation (TSAT) at 20-30% and/or a serum ferritin of 100-500 ng/ml. No intravenous iron was administered if the ferritin was more than 500 ng/ml. Although 82% of patients were on iron supplementation and, among them, 58% were on IV iron, the percentage of patients with TSAT >20, i.e., bioavailable iron, was only 51%. The serum ferritin was high at 498 +/- 10 ng/ml (mean +/- SEM) and 88% and 10% of patients had serum ferritin >100 and >1,000 ng/ml, respectively, suggestive of sequestration of part of the infused iron. Erythropoietin was administered to 96% of patients, 99.5% by IV route. The latter was consistent with the US dialysis population at large but in variance with DOQI preference for the subcutaneous route. The target Hct range of 33-36 was found in 33%, with a mean Hct of 34.0 +/- 0.12. When the data were reanalyzed by excluding patients who had not been receiving erythropoietin and had not been on dialysis for at least 3 months, the percentage of patients achieving the target Hct increased to 37%. Paired analysis of 875 patients present in 1996 and 1998 showed that, although there was a marked increase in the use of IV iron, the improvement in anemia was modest, and there was evidence for increased iron accumulation. In summary, this 1998 survey on the clinical practice of anemia management in a large hemodialysis population indicates that there is a marked increase in need-based IV iron usage that was associated with modest improvement in anemia and evidence for increased iron storage. A maintenance iron dosing protocol with smaller doses of iron, such as 25 mg of iron dextran per hemodialysis, may make bioavailable iron continuously present for erythropoiesis, yet may reduce the chance for iron catalyzed lipid peroxidation and tissue iron deposition.

Increase in plasma esterified F2-isoprostanes following intravenous iron infusion in patients on hemodialysis.

BACKGROUND: In epoetin-treated dialysis patients, currently iron is administered by the intravenous route to maintain optimum erythropoiesis. However, rapid infusion of iron in excess of transferrin binding capacity can lead to the availability of unbound iron that can theoretically catalyze peroxidation of lipids, such as low-density lipoprotein (LDL), which when oxidatively modified is proinflammatory and promotes atherogenesis. METHODS: To address this issue, our study used one of the most specific measures of lipid peroxidation available, namely gas chromatography/mass spectometry (GC/MS) analysis of F2-isoprostanes. Using a prospective design, blood samples were collected 15 minutes before (pre) and 30 minutes after (post) a one-hour infusion of 700 mg bolus of intravenous iron in 22 adult home-hemodialysis patients on a non-hemodialysis day. RESULTS: With iron-dextran infusion, serum iron markedly increased (mean +/- SE, 42 +/- 4 vs. 311 +/- 92 microg/dL, P < 0.0001) and exceeded the transferrin saturation of 100% in 22 out of 22 patients (pre 23 +/- 3 vs. post 165 +/- 8%, P < 0.0001). Plasma concentrations of free F2-isoprostanes did not change significantly following infusion of iron (pre 40 +/- 5 vs. post 39 +/- 6 pg/mL). However, levels of F2-isoprostanes esterified in plasma lipoproteins increased significantly in the postinfusion samples (pre 199 +/- 19 vs. post 233 +/- 25 pg/mL, P < 0.004). Pre-infusion levels of serum iron correlated directly with pre-infusion levels of esterified F2-isoprostanes (r = 0.56, P = 0.008), which persisted in the postinfusion period (r = 0.43, P = 0.04). However, there was no correlation between esterified F2-isoprostanes and serum ferritin levels. In the last four patients in whom blood samples were collected five hours after the intravenous iron infusion, there were further increases in esterified F2-isoprostanes that very closely correlated with postinfusion serum iron levels (r = 0.99, P = 0.013). In a control study, the in vitro addition of iron dextran to blood samples did not increase free or esterified F2-isoprostanes, suggesting that the increase in esterified F2-isoprostanes seen in vivo after iron infusion in patients is not due to a procedural artifact. CONCLUSION: Collectively our data suggest that high levels of serum iron appearing soon after a large bolus of iron infusion is associated with significant, albeit modest, increases in levels of F2-isoprostanes esterified in plasma lipoproteins that tended to increase with time. Although it is uncertain whether this degree of lipid peroxidation may have deleterious effects, it may be sagacious to explore whether this can be prevented by slow infusion of frequent smaller doses of iron and, if necessary, along with administration of antioxidants.

Efficacy and side effects of intermittent intravenous and oral doxercalciferol (1alpha-hydroxyvitamin D(2)) in dialysis patients with secondary hyperparathyroidism: a sequential comparison.

Most reports on the effectiveness and side effects of oral versus parenteral calcitriol or alfacalcidol in hemodialysis patients with secondary hyperparathyroidism show no advantage of parenteral treatment. The efficacy and safety of intravenous doxercalciferol (1alphaD(2)) were studied in hemodialysis patients with secondary hyperparathyroidism (plasma intact parathyroid hormone [iPTH]: range, 266 to 3,644 pg/mL; median, 707 pg/mL). These results were compared with those of a previous trial using intermittent oral 1alphaD(2); the same 70 patients were entered onto both trials, and 64 patients completed both trials per protocol. Twelve weeks of open-label treatment in both trials were preceded by identical 8-week washout periods. Degrees of iPTH suppression from baseline were similar in the two trials, with iPTH level reductions less than 50% in 89% and 78% of patients during oral and intravenous treatment, respectively. Grouping patients according to entry iPTH levels (<750 and >/=750 pg/mL) showed similar but more rapid iPTH suppression in the low-iPTH groups, whereas longer treatment and larger doses were required by the high-iPTH groups. Highest serum calcium levels averaged 9.82 +/- 0.14 and 9.67 +/- 0.11 mg/dL during oral and intravenous 1alphaD(2) treatment, respectively (P: = not significant [NS]). Prevalences of serum calcium levels greater than 11.2 mg/dL during oral and intravenous treatment were 3.62% and 0.86% of calcium measurements, respectively (P: < 0.001). Highest serum phosphorus levels during oral and intravenous treatment averaged 5.82 +/- 0.21 and 5.60 +/- 0.21 mg/dL, respectively (P: = NS). The percentage of increments in serum phosphorus levels during oral treatment exceeded that during intravenous treatment during 5 of 12 treatment weeks. Thus, intermittent oral and intravenous therapy with 1alphaD(2) reduced iPTH levels effectively and similarly, hypercalcemia was less frequent, and serum phosphorus levels increased less during intravenous than oral 1alphaD(2) therapy, suggesting that intravenous 1alphaD(2) therapy may be advantageous in patients prone to hypercalcemia or hyperphosphatemia.

Risk factor paradox in hemodialysis: better nutrition as a partial explanation.

The higher mortality rate in patients on hemodialysis is primarily due to the higher rate of cardiovascular disease. Yet, paradoxically, overweight, hypertension, and hyperlipidemia, which are cardiovascular risk factors in the general population, have been reported to correlate with better patient survival in hemodialysis. To examine whether this "risk factor paradox" in hemodialysis is due to the positive influence of accompanying better nutrition, we prospectively obtained data on fasting lipids, biochemical markers of nutrition, body mass index (BMI), and blood pressure (BP) in 453 hemodialysis patients and related them to 1 year mortality. As previously noted, body weight, blood pressure, and certain serum lipids positively correlated with survival. Serum prealbumin, one of the most sensitive and specific biochemical markers for nutrition, correlated positively with hypercholesterolemia (r = 0.30, p < 0.001) and BMI (r = 0.12, p < 0.02), but not with mean arterial pressure (MAP) (r = 0.01, p = NS). By analysis of variance, patients in the upper tertile (i.e., higher levels) of BMI and cholesterol but not MAP had significantly higher serum prealbumin and creatinine compared with those in the lower tertile. Our data lend support to the hypothesis that, in patients on hemodialysis, the positive effect of higher BMI and hyperlipidemia but not of high BP could be partially explained on the basis of the accompanying better nutrition. Although not proven, correcting risk factors while improving nutrition may offer better outcomes for patients on dialysis.

Race-dependent survival disparity on hemodialysis: higher serum aluminum as an independent risk factor for higher mortality in whites.

The mortality rate on hemodialysis therapy remains unacceptably high, and it is worse in whites than blacks. Substantially elevated serum aluminum levels have been shown to predict mortality on hemodialysis. However, whether this is a factor in the race-dependent survival difference on hemodialysis therapy is presently unknown. To determine the relevance of serum aluminum level on race-dependent survival disparity on chronic hemodialysis therapy, 1-year survival of 118 whites was prospectively compared with 473 age- and sex-matched blacks. The variables predictive for survival, including serum aluminum level, were defined separately in whites and blacks using Cox univariate and multivariate analyses. The 1-year mortality rate was significantly greater in whites than blacks (18% versus 12%; P: < 0.001). Serum albumin level, body mass index (BMI), and creatinine level had a positive influence, whereas age had a negative influence on survival in both groups in the univariate analysis. The mean serum aluminum level was significantly greater in whites (n = 118) than blacks (n = 473; 20 +/- 2.3 versus 14 +/- 0.6 [SE] ng/mL; P: = 0.0009) and was not caused by increased duration on dialysis, increased prescription of aluminum-containing phosphate binders, or reduced delivered dose of dialysis. Unlike the blacks, serum aluminum levels had a significant negative influence on the survival of whites, and this persisted in multivariate analysis after controlling for age, sex, diabetes, albumin level, creatinine level, and BMI (relative risk, 1.013; 95% confidence interval, 1.004 to 1.023; P: < 0.007). In summary, this study suggests that whites undergoing hemodialysis may have greater serum aluminum levels than blacks, which might contribute to the whites' greater rate of mortality. Because hyperaluminemia is a modifiable risk factor, studies are required to verify our findings, explore the mechanism of elevated aluminum levels in whites, and test the hypothesis that reducing serum aluminum levels in whites may improve their survival.

Intermittent doxercalciferol (1alpha-hydroxyvitamin D(2)) therapy for secondary hyperparathyroidism.

Hypercalcemia and hyperphosphatemia frequently necessitate vitamin D withdrawal in hemodialysis patients with secondary hyperparathyroidism. In short-term trials, doxercalciferol (1alpha-hydroxyvitamin D(2) [1alphaD(2)]) suppressed intact parathyroid hormone (iPTH) effectively with minimal increases in serum calcium and phosphorus (P) levels. This modified, double-blinded, controlled trial examined the efficacy and safety of 1alphaD(2) use in 138 hemodialysis patients with moderate to severe secondary hyperparathyroidism by using novel dose titration; 99 patients completed the study. Hemodialysis patients with secondary hyperparathyroidism were enrolled onto this study, consisting of washout (8 weeks), open-label 1alphaD(2) treatment (16 weeks), and randomized, double-blinded treatment with 1alphaD(2) or placebo (8 weeks). Oral 1alphaD(2) was administered at each hemodialysis session, with doses titrated to achieve target iPTH levels of 150 to 300 pg/mL. Baseline iPTH levels (897 +/- 52 [SE] pg/mL) decreased by 20% +/- 3.4% by week 1 (P: < 0.001) and by 55% +/- 2.9% at week 16; iPTH levels returned to baseline during placebo treatment but remained suppressed with 1alphaD(2) treatment. In 80% of the patients, iPTH level decreased by 70%, reaching the target level in 83% of the patients. Grouping patients by entry iPTH level (<600, 600 to 1,200, and >1,200 pg/mL) showed rapid iPTH suppression in the group with the lowest level; greater doses and longer treatment were required in the group with the highest level. During open-label treatment, serum calcium and P levels were 9.2 +/- 0.84 (SD) to 9.7 +/- 1.05 mg/dL and 5.4 +/- 1.10 to 5.9 +/- 1.55 mg/dL, respectively. During double-blinded treatment, serum calcium levels were slightly greater with 1alphaD(2) than placebo, but P levels did not differ. During double-blinded treatment, 3.26% and 0.46% of serum calcium measurements exceeded 11.2 mg/dL with 1alphaD(2) and placebo, respectively (P: < 0.01); median level was 11.6 mg/dL during hypercalcemia. Intermittent oral 1alphaD(2) therapy effectively suppresses iPTH in hemodialysis patients with secondary hyperparathyroidism, with acceptable mild hypercalcemia and hyperphosphatemia.

Impact of lower delivered Kt/V on the survival of overweight patients on hemodialysis.

UNLABELLED: Impact of lower delivered Kt/V on the survival of overweight patients on hemodialysis. BACKGROUND: A recent study suggests that overweight (OW) patients on hemodialysis are more likely to receive inadequate doses of dialysis. Because underdialysis is associated with higher mortality, OW patients might be at risk for higher mortality. This is in contrast with our recent observation in which survival was better in OW patients on hemodialysis. The objective of this study was to verify whether being OW was associated with underdialysis and to determine the influence of underdialysis on the survival of OW patients. METHOD: Kt/V measurements were obtained in 1151 patients on hemodialysis for two consecutive months, and their survival was prospectively followed for nine months. Body weights were defined by body mass index (BMI): OW if BMI was> 27.5, underweight (UW) if BMI was <20, and normal weight (NW) if BMI was 20 to 27.5. RESULTS: The Kt/V was inversely related to BMI (r = -0. 30, P < 0.0001). Kt/V in the OW patients was significantly lower than Kt/V in the NW or UW patients. By using a Kt/V threshold of 1.2, more patients were underdialyzed in the OW group (24%) than in the NW (15%) or UW (7%) groups. Underdialysis in the whole study group was associated with a 1.6-fold increase in the relative risk (RR) for mortality. The risk was more pronounced (RR, 2.6) in the underdialyzed OW patients compared with adequately dialyzed OW patients. In multivariate analysis, underdialysis in OW patients (RR, 4.3), but not in UW or NW patients, was a significant and independent risk factor for mortality. CONCLUSION: Our results verify that in the current practice of dialysis prescription, OW patients are less likely to receive adequate dialysis, and, to our knowledge for the first time, suggest that such underdialysis in OW patients might exert a negative influence on their survival. Prospective studies are required to test whether ensuring adequate delivery of dialysis in the OW patients might further improve their survival.

Effects of normal hematocrit on ambulatory blood pressure in epoetin-treated hemodialysis patients with cardiac disease.

BACKGROUND: Hypertension is a recognized complication of partial correction of anemia with recombinant human erythropoietin (epoetin) in hemodialysis patients. We used interdialytic ambulatory blood pressure (ABP) monitoring to study the effects of partially corrected anemia versus normal hematocrit (hct) on BP in hemodialysis patients. METHODS: Repeated interdialytic ABP monitoring was performed for up to one year in 28 chronic hemodialysis patients with cardiac disease who were randomized to achieve and maintain normal hct levels (42 +/- 3%, group A) or anemic hct levels (30 +/- 3%, group B) with epoetin. Routine BP measurements obtained at dialysis treatments were also evaluated. RESULTS: Mean hct levels were 30.7 +/- 0.7% in group A and 30.6 +/- 0.7% in group B at baseline, then 39.3 +/- 1.2% (group A) and 33.5 +/- 0.6% (group B) at four months, and 42.0 +/- 1.1% (group A) and 30.4 +/- 1.0% (group B) at 12 months. Baseline ABP and routine dialysis unit BP levels were not different between the groups. At 2, 4, 8, and 12 months of follow-up, there were no statistically significant differences in any BP parameters between groups or increases in any BP parameters in either group A or group B patients compared with baseline. At 12 months, the mean nighttime diastolic BP (DBP) in group A patients was slightly but significantly lower than the mean daytime DBP (daytime DBP 76.6 +/- 1.9 mm Hg vs. nighttime DBP 72.9 +/- 2.1 mm Hg, P < 0.05). The mean daytime and nighttime BPs were not different from each other at two, four, and eight months in group A or at any time in group B, and in both groups, most patients had little diurnal change in BP. CONCLUSION: Correction of hct to normal with epoetin in chronic hemodialysis patients with cardiac disease did not cause increased BP as assessed by interdialytic ABP monitoring or by the measurement of routine predialysis and postdialysis BP. There was little diurnal change in systolic or diastolic BP at baseline or after correction of anemia to normal levels, and although mean nighttime DBP was lower than mean daytime DBP at 12 months in group A, the maintenance of normal hct levels did not affect the abnormal diurnal BP pattern seen at moderately anemic hct levels in most patients.

Influence of excess weight on mortality and hospital stay in 1346 hemodialysis patients.

BACKGROUND: Body mass index (BMI) at its extremes contributes to morbidity and mortality in the general population. Its influence on morbidity and mortality in patients on hemodialysis is not clearly defined. METHODS: The BMI in 1346 patients attending limited-care hemodialysis units across the state of Mississippi was determined, and its relation to one-year mortality and hospital stay was assessed using the Cox proportional hazard model. RESULTS: Of these patients, 89% were black, and 11% were white. Thirty-eight percent of patients were overweight (BMI > 27.5), and 13% were underweight (BMI < 20). The highest (27.60 +/- 0.29, mean +/- SE) and the lowest (24.54 +/- 0.48) BMI were noted in black females and white males, respectively. BMI, race, hematocrit (Hct), and biochemical markers of better nutrition positively influenced the survival, whereas age, serum globulin, and diabetes had a negative influence. In a Cox multivariate analysis, BMI, age, diabetes, prealbumin, and creatinine, but not race, serum albumin, Hct, or serum globulin, retained significant influence on survival. Compared with the normal weight (BMI between 20 and 27.5), the one-year survival rate was significantly higher in the overweight patients and lower in the underweight patients. With a one-unit increase in BMI over 27.5, the relative risk for dying was reduced by 30% (P < 0.04), and with a one-unit decrease in BMI below 20, the relative risk was increased by 1.6-fold (P < 0.01). Furthermore, underweight patients had significantly lower levels of biochemical markers of nutrition and higher frequency and longer duration of hospital stay. CONCLUSION: Adequate dialysis with special attention to proper nutrition aimed to achieve the high end of normal BMI may help to reduce the high mortality and morbidity in hemodialysis patients.

Rehabilitation, aging and chronic renal disease.

Restorative management of the disabled elderly requires knowledge about realistic functional expectations, in addition to knowledge about a patient's particular disease. Health outlook, especially sense of control, should also be assessed because rehabilitation depends on the patient's active participation. A comparison of 349 older end-stage renal disease (ESRD) patients on chronic dialysis and 354 similar-age persons selected as a control group showed that significantly compromised physical function and health outlook were reported by the dialysis patients compared with the control group. Increasing exercise capacity and participation in dialysis self-care activity are recommended ways to improve physical functioning and health outlook among ESRD patients. Individuals who cannot perform strenuous activity can improve in level of fitness; improvements in anemia and muscle strength are key variables. Clinical application of therapeutic and rehabilitative strategies to improve physical function and health outlook in the geriatric renal patient is greatly needed.

Retroperitoneal fibrosis associated with carcinoma of the cervix: review of the literature.

Microinvasive cervical cancer presented in a woman with retroperitoneal fibrosis in remission following steroid therapy. The cervical lesion was treated surgically with good outcome. Review of the literature documenting this association reveals three other cases, one following and two preceding the diagnosis of retroperitoneal fibrosis. The case reports are reviewed and potential difficulties in the management of these patients are discussed.

Leuprolide acetate in the management of ureteral obstruction caused by endometriosis.

Endometriotic ureteral obstruction is a serious event commonly diagnosed late and therefore associated with a major risk of hydronephrotic renal atrophy. The standard therapy is surgical. However, medical treatment has been reported using danazol, progestins, and estrogen-progestin combinations, although solid documentation of the effect of hormonal therapy against ureteral endometriosis is lacking. Gonadotropin-releasing hormone (GnRH) agonist treatment of endometriosis has yielded good results but has not been adequately reported in patients with ureteric involvement. We report three patients treated with a GnRH agonist, leuprolide acetate, for 6-9 months as a preoperative course. One patient had bilateral and two had unilateral obstruction. The preoperative course relieved the obstruction in the patient with bilateral disease and in one with unilateral changes. The failure occurred in a patient with intrinsic ureteric endometriosis. This early experience suggests a place for GnRH agonist therapy for patients with ureteric obstruction due to endometriosis, probably, but not necessarily, in conjunction with a planned surgical procedure. If medical therapy is attempted, close surveillance of renal function is mandatory.

Digital clubbing due to secondary hyperparathyroidism.

Five patients in our dialysis population had digital changes suggestive of clubbing in association with severe secondary hyperparathyroidism. All had parathyroidectomies between June 1986 and December 1987. They represented 0.6% of the patients in our dialysis population and 17.8% of our patients who required operative management of secondary hyperparathyroidism. The clubbing was occasionally painful, and the digits were tender in response to palpation. Parathyroidectomy yielded excessive amounts of hyperplastic parathyroid tissue in each case. Postoperatively, the symptoms were relieved, when present, and the digital changes were stabilized. We believe that these findings are associated with severe secondary hyperparathyroidism and should be looked for in dialysis patients with renal osteodystrophy.