ECG machine QTc intervals are inaccurate in hemodialysis patients.

BACKGROUND: Nephrologists need effective screening tools to identify hemodialysis patients at elevated risk for sudden cardiac death, the leading cause of death in this population. QTc intervals longer than 450 ms in males and 470 ms in females, measured by the gold standard tangent method (trueQTc), are prolonged and increase sudden cardiac death in healthy populations and patients with long QT syndrome. METHODS: We performed a retrospective ECG and chart review of hemodialysis patients. Our first objective was to determine if machine-measured QTc intervals (macQTc) could be used to identify dialysis patients with prolonged trueQTc. Our second objective was to determine at what macQTc could prolonged trueQTc be confidently diagnosed. RESULTS: macQTc differed from the trueQTc by an average of 16.54 ms, and by at least 20 ms in 46.8, 36.1, 53.6, 50.0 and 57.1% of all, short-hours daily hemodialysis, intermittent conventional hemodialysis, frequent nocturnal hemodialysis and intermittent nocturnal hemodialysis patients, respectively. The positive predictive value, negative predictive value, sensitivity and specificity of prolonged macQTc predicting prolonged trueQTc was 57.6, 92.6, 79.1 and 81.8%, respectively. Thus, macQTc is inaccurate at predicting the gold standard trueQTc in hemodialysis patients. macQTc greater than 480 ms in hemodialysis patients predicts trueQTc prolongation with a positive predictive value of 95.2%, but with a low sensitivity of 32.3%. CONCLUSION: In hemodialysis patients, ECG macQTc intervals are insufficiently sensitive or specific to predict prolonged trueQTc intervals, unless >480 ms.

Technical aspects of home hemodialysis.

Home hemodialysis (HHD) has proved to be a useful form of renal replacement therapy. The economic advantage of HHD is well established and interest in it is renewed. Once it has been decided to establish a HHD program, a well developed strategic plan is required. This should address financial and logistical issues and establish policies that will address responsi-bilities of both patients and HD centers. The recruitment of patients is facilitated by ensuring that all incident patients have early access to an education program describing all forms of renal replacement therapy that the regional renal program provides. Patients and members of the pre-dialysis education program should understand the selection process criteria in advance. Once the assessment is completed and the patient agrees to the proceedings, a plan of action should be esta-blished for enrolling the patient into the program and initiating training. Patients' education pro-gram should take into consideration principles of adult learning. When choosing dialysis equip-ment for home use, the needs and preferences of the patients should be respected. As a rule of thumb, the equipment should be simple to use, yet still provide adequate and reliable therapy. De-ciding where to set up and position the HHD equipment is important. Installation of HHD ma-chine at home requires a continuous supply of accessories. Before establishing a HHD program, commitment of the dialysis center to provide and maintain the infrastructure of the program is mandatory. The estimated patients suitable for HHD are less than 15% of all prospective dialysis patients. Generally, those who are have greatly improved quality of life and by using modalities such as nocturnal and daily dialysis can have improved physical well-being with considerable potential cost savings.

Association of intradialytic blood pressure changes with hospitalization and mortality rates in prevalent ESRD patients.

The relationship between blood pressure (BP) and clinical outcomes among hemodialysis patients is complex and incompletely understood. This study sought to assess the relationship between blood pressure changes with hemodialysis and clinical outcomes during a 6-month period. This study is a secondary analysis of the Crit-Line Intradialytic Monitoring Benefit Study, a randomized trial of 443 hemodialysis subjects, designed to determine whether blood volume monitoring reduced hospitalization. Logistic regression was used to estimate the association between BP changes with hemodialysis (Deltasystolic blood pressure=postdialysis-predialysis systoic BP (SBP) and the primary outcome of non-access-related hospitalization and death. Subjects whose systolic blood pressure fell with dialysis were younger, took fewer blood pressure medications, had higher serum creatinine, and higher dry weights. After controlling for baseline characteristics, lab variables, and treatment group, subjects whose SBP remained unchanged with hemodialysis (N=150, DeltaSBP -10 to 10 mm Hg) or whose SBP rose with hemodialysis (N=58, DeltaSBP > or =10 mm Hg) had a higher odds of hospitalization or death compared to subjects whose SBP fell with hemodialysis (N=230, DeltaSBP < or =-10 mm Hg) (odds ratio: 1.85, confidence interval: 1.15-2.98; and odds ratio: 2.17, confidence interval: 1.13-4.15). Subjects whose systolic blood pressure fell with hemodialysis had a significantly decreased risk of hospitalization or death at 6 months, suggesting that hemodynamic responses to dialysis are associated with short-term outcomes among a group of prevalent hemodialysis subjects. Further research should attempt to elucidate the mechanisms behind these findings.

Preserving central blood volume: changes in body fluid compartments during hemodialysis.

The understanding of fluid changes during hemodialysis (HD is essential for reducing complications as well as efficacy of the procedure. Bioimpedance spectroscopy provides a non invasive method of measuring total body water (TBW), the distribution of intra (ICF) and extracellular (ECF) fluids, and their changes during HD. Segmental bioimpedance may be used to measure the same fluid shifts but from different body segments; the technique has previously been shown to com pare well with whole body measures. It is possible that fluid shifts occur differently in different body compartments during HD. Based on previous hemodynamic studies we postulated that during HD ultrafiltration (UF) the body attempts to preserve its central blood volume (cardiopulmonary circula tion plus great vessels), and thus fluid shifts would be greater from the periphery than from central compartments. To test this hypothesis, segmental bioimpedance (Xitron Technolo gies, San Diego, CA) was performed on 11 subjects undergoing HD where ECF and ICF values were obtained from the legs, arms and trunk before and after a period of UF. Blood volume change (ABV%) was also followed using an on-line optical hematocrit (Hct) sensor (Crit-Line monitor, In-Line Diagnostics, UT) where deltaBV% = deltaBV% = (1 - Hct1/Hct0) x 100 (Hct0 = baseline Hct; Hct1 = postultrafiltration Hct) The UF of 2.0 L +/- 0.79 L (M +/- SD) over 75 minutes was associated with a deltaBV% of -9.43% +/- 3.6% (M +/- SD), a significant (Student's paired t-test) reduction in total body (TB) ECF (p < 0.02), a weak correlation in reduction in TBW (p = 0.09) but not in TB ICF. The ECF reductions from the trunk, legs, and arms were all significant (minimum p < 0.02); no ICF changes from these compartments were significant. The amount of ECF reduction was greater from the legs (0.7 L +/- 0.6 L) than the arms (0.12 L +/- 0.08 L) and trunk (0.2 L +/- 0.2 L) (all M +/- SD). Multiple regression analysis showed that TB ECF changes correlated strongly with leg (r = 0.94, p < 0.001) and arm (r = 0.72, p = 0.002) ECF changes but not with trunk changes. deltaBV% correlated weakly with leg (r = 0.45, p = 0.08) and arm (r = 0.42, p = 0.10) ECF changes but not with the trunk. As the deltaBV% represents the net volume change between UF and plasma water refilling, thiss indicates that plasma water is being removed more from the peripheral compartments than from the trunk. These data suggest that plasma refilling during HD to preserve central blood volume is more dynamic from the leg ECF than from elsewhere and may, in turn, explain the frequent occurrence of leg cramps during and after hemodialysis.

Reduced Ia-afferent-mediated Hoffman reflex in streptozotocin-induced diabetic rats.

In addition to reduced nerve conduction velocity, diabetic neuropathic patients often exhibit a reduction in the amplitude of the compound muscle action potential elicited by stimulation of the Ia-afferent-mediated reflex pathway (Hoffman or H wave) that can contribute to diminished or absent tendon reflexes. In contrast to nerve conduction velocity deficits, changes in H-wave amplitudes have not been reproduced in diabetic animal models. Using electrophysiological techniques developed for repeated recordings in individual animals, we report H-wave deficits in streptozotocin (STZ)-treated insulin-dependent diabetic rats. After 4 weeks of diabetes induced by STZ treatment, a 47% reduction in the H-wave amplitude was demonstrated by recording compound muscle action potentials in foot muscles after stimulation of Ia afferents. Interestingly, we also demonstrate that the H-wave amplitude gradually recovers to a 26% deficit after 12 weeks of experimental diabetes. The recovery of the H wave in STZ-treated rats distinguishes this deficit mechanistically from other STZ-induced electrophysiological changes and may model a similar recovery of the H wave reported in diabetic patients.

Hemeral (daily) hemodialysis.

Hemodialysis is generally performed 3 times per week, a treatment prescription not based on optimizing the physiology of the normal kidney that maintains body homeostasis by removing water and waste products continuously and efficiently. Peritoneal dialysis might be continuous but it is not efficient. Daily hemodialysis is both frequent and efficient and theoretically should be superior to other forms of dialysis for renal replacement therapy. There is again a growing interest in daily hemodialysis (it was originally described in 1969), and a number of investigators in North America and Europe are using it. As yet, there have been no randomized prospective studies comparing hard outcomes in patients dialyzed by conventional 3-times-per-week hemodialysis with those treated with daily hemodialysis (either short high-efficiency or long, slow nocturnal). The London, Ontario, study is the first attempt to obtain comparative data. It is a 3-year study to compare daily dialysis patients with cohort controls. To date, the study shows that short daily dialysis does provide more dialysis based on Kt/V than standard therapy. However, predialysis blood urea values are not different because of improved nutrition (increased normalized protein from nitrogen appearance (nPNA) and serum albumin levels). Anemia is improved with less erythropoeitin usage in the study group. Phosphate control is good, but no better than by conventional dialysis and phosphate binders are still required unlike patients receiving nocturnal dialysis. Blood pressure and volume management is better with daily dialysis. So far, the study patients show a trend to less morbidity than their controls, but differences are not (as yet) statistically different. Blood access in daily dialysis dose not cause problems. Quality of life is significantly increased in a number of areas with daily dialysis. The economic impact of daily dialysis is not yet known; the general premise is that the higher dialysis costs attributable to an increment in treatments will be offset by increased wellness and less morbidity with the subsequent beneficial impact on drugs, hospitalizations, and so on. The provision of daily dialysis in the home has attractive economic implications. A considerable growth for this superior form of therapy is expected.

Relationship between effective ionic dialysance and in vivo urea clearance during hemodialysis.

Effective ionic dialysance (EID) can be measured from dialyzer inlet and outlet conductivity changes following two steps of dialysate conductivity. Relationships between EID and in vivo urea clearances were studied four times per hemodialysis treatment in eight patients, each undergoing six hemodialysis treatments (192 data sets). Dialyzer blood flow was varied from 190 to 500 mL/min. Dialysate flow was constant (751 to 771 mL/min), and a standard dialyzer (700 HG; Cobe, Lakewood, CO) was used. Double samples were drawn for arterial, venous, and dialysate urea measurements. Two laboratory values were missing. Twelve unreliable laboratory values indicated by divergent results were excluded. Urea clearances were calculated by formulae converting whole-blood to blood-water urea clearances. EID was measured using Diascan (Gambro-Dasco, Medolla, Italy). Mass balance was checked by comparison of dialysate and blood-water urea clearances. Divergent results between dialysate and blood-water urea clearance values led to the exclusion of an additional three laboratory values. A small error (4.2%) in urea mass balance was found (dialysate greater than blood-water urea clearances). A total of 175 data sets were compared. EID showed excellent correlation with blood-water urea clearances (r = 0.92) over the line of identity, with a mean difference of -3.5 mL/min (-1%), and similarly with dialysate urea clearances (r = 0.92; mean difference, -13.4 mL/min; -5%). For both blood- and dialysate-side comparisons, differences increased with greater clearances. Because EID is an effective clearance and urea clearance is a measure of dialyzer clearance, the curves were corrected for cardiopulmonary recirculation; access recirculation was zero (Transonic monitor; Transonic Systems Inc, Ithaca, NY). For cardiopulmonary recirculation correction, cardiac output and access flows were assumed to be 6.4 L and 1.46 L/min. Corrected data show EID correlates with blood-side urea clearance (r = 0.92), with a mean difference of +7.3 mL/min (3.3%), and is constant over the range of clearances. EID correlated with dialysate urea clearance (r = 0.92) with virtually no difference. The difference on the blood side is consistent with the urea mass balance error found. These data indicate that EID using Diascan can provide an accurate indication of effective urea clearances obtained during hemodialysis and is of value in monitoring dialysis adequacy.

Future directions in dialysis quantification.

The influence of dialysis prescription on outcome is well established, and currently the amount of dialysis prescribed is based on small molecular weight toxin removal as represented by the clearance of urea. The "normalized dose of dialysis" (Kt/V(urea)) concept is well established. Most techniques for dialysis quantification require that blood samples be taken at the beginning and after the completion of dialysis. The postdialysis sample, however, gives cause for concern because of the "rebound phenomenon" due to nonuniform distribution of urea among body compartments. Blood samples give "indirect" measures of dialysis quantification. Thus direct urea concentration measurements in dialysate may be superior in urea kinetic modeling and these may be made "real time" during dialysis. It is with real-time monitoring that future advances in dialysis quantification will take place. These will be of two types. The first will analyze blood water or dialysate samples for urea content multiple times throughout the treatment; the second will assess the on-line clearance of urea using surrogate molecules such as sodium chloride, the clearance being determined by conductivity measurements. On-line urea monitoring is based on the action of urease on urea in a water solution and measurement of the resultant ammonium ions, which are measured directly by a specific electrode or indirectly by conductivity changes. Differences in blood-side versus dialysate-side urea monitors exist which reflect the parameters they can provide, but with both, the standard urea kinetic measurements of Kt/V and nPCR (nPNA) are easily obtainable. A range of additional parameters can be derived from dialysate-side monitoring such as "whole-body Kt/V," "pretreatment urea mass" and "whole-body urea clearance," which are worthy of future studies to determine their roles in adequacy assessment. Conductivity clearance measurements are made by examining the conductivity differences between dialysate inlet and outlet measured at two different dialysate inlet concentrations. This allows for the calculation of the electrolyte (ionic) dialysance, which is equal to the "effective" urea clearance, that is, the clearance that takes into account recirculation effects that reduce hemodialysis efficiency. The continuous reading of effective ionic clearance will allow an average value for K to be obtained for that dialysis, and hence the parameter K x t as an indication of dialysis dose is easily and accurately obtained for every treatment. The conductivity technology is cheap and rugged, and thus expanded use can be expected. Urea monitors have an inherent cost and require maintenance, and perhaps will remain researchers' tools for the present. The methodologies can complement each other; the addition of an accurate and independent value for K to dialysate based urea monitoring is like having simultaneous blood- and dialysate-side monitoring, and allows further increase in measurable parameters.

Selective enhancement of sensitivity to endothelin-1 despite normal endothelium-dependent relaxation in subcutaneous resistance arteries isolated from patients with Type I diabetes.

Type I diabetes mellitus is associated with abnormal vascular function, but few studies have documented its effects on human resistance arteries. This study aimed to determine whether endothelial cell and smooth muscle cell function was impaired in resistance arteries isolated from patients with this condition. Biopsies of subcutaneous gluteal fat were taken from 12 patients with Type I diabetes (age 32.3+/-1.9 years; duration of diabetes 13.9+/-2.5 years) and 12 matched controls (age 31.5+/-2.2 years). Levels of glycosylated haemoglobin were higher (P<0.0001) in patients (9.38+/-0.35%) than in controls (5.48+/-0.11%), but most (11 out of 12) patients showed no evidence of microvascular disease. Small resistance arteries were isolated from the biopsies, and isometric responses to vasoconstrictors and vasodilators were measured in a small-vessel myograph. The magnitude and sensitivity of responses to noradrenaline and potassium were not different in diabetic patients compared with controls. In contrast, the sensitivity (pD(2); negative logarithm of the concentration of the vasoconstrictor required to produce 50% of the maximum effect), but not the magnitude, of contraction in response to endothelin-1 in vessels from patients (8.87+/-0.12) was significantly (P=0.02) greater than in those from controls (8.40+/-0.13). Endothelium-dependent (acetylcholine, bradykinin, A23187) and -independent (3'-morpholinosydnonimine) relaxation responses were unaltered in patients with Type I diabetes. These results suggest a selective alteration in receptor activity in the endothelium, and contrast strikingly with the considerable evidence of impaired endothelium-dependent relaxation in Type I diabetes. The present study indicates, therefore, that endothelial cell function is largely maintained in resistance arteries from patients with well controlled Type I diabetes. The increased response to endothelin-1 supports the possibility that more significant abnormalities would be evident in patients with severe microvascular complications.

Comparison of the timing of acute blood-brain barrier breakdown to rabbit immunoglobulin G in the cerebellum and spinal cord of mice with experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is an animal model for human multiple sclerosis (MS). Similar to MS patients, EAE animals can exhibit chronic or relapsing, remitting paralysis; leukocyte infiltration of the central nervous system (CNS); and breakdown of the blood-brain barrier (BBB), allowing access to serum components. EAE pathology in rodents is generally thought to progress from the spinal cord to the more rostral brain. This common notion is based on numerous reports on the severity and progression of cellular infiltration and BBB breakdown during the course of disease. We studied opening of the BBB in EAE mice immunized to the proteolipid protein (PLP) peptide, PLP 139-151, with or without the use of pertussis toxin. Peripherally injected rabbit immunoglobulin G showed significant penetration through a compromised BBB in EAE mice and was observed throughout the parenchyma as well as intracellularly in multiple neuronal types. Results demonstrate the novel finding that the cerebellar BBB is dramatically and briefly comprised, even before breakdown of the BBB in the thoracolumbar spinal cord and prior to symptomatic disease. The demonstration of susceptibility in the cerebellum provides an important target for studying the factors predisposing certain CNS regions to autoimmune-related compromise of the BBB, such as MS.

High creatinine excretion ratio predicts a good outcome in peritoneal dialysis patients.

The creatinine excretion (CrEx) ratio was first described as a method for detecting noncompliance in peritoneal dialysis (PD) patients. However, a high CrEx ratio is not specific for noncompliance and may also be found in compliant patients with a relatively greater lean body mass (LBM). A cohort of 44 PD patients was followed up for a mean of 13 +/- 8 months after measurement of baseline CrEx ratio to investigate whether greater values were predictive of good or poor clinical outcomes. During this follow-up, 11 patients died, 12 patients transferred to hemodialysis, 4 patients underwent transplantation, 1 patient recovered renal function, and 16 patients continued on PD. The mean CrEx ratio in all patients was 1.14 +/- 0.32. It did not differ between men and women (1.15 versus 1.13, respectively; P = 0.76) but showed a trend toward being less in patients with diabetes (1.03 versus 1.19; P = 0. 19). The mean weekly Kt/V, weekly creatinine clearance, normalized protein equivalent of nitrogen appearance, and serum albumin values were 2.18 +/- 0.57, 73.57 +/- 33.75 L/1.73 m(2), 0.80 +/- 0.22 g/kg/d, and 3.22 +/- 0.59 g/dL, respectively. Technique failure (P < 0.001) and death (P < 0.05) were significantly more common in patients with a CrEx ratio less than 1 compared with those with a CrEx ratio greater than 1. On Cox regression analysis, the CrEx ratio was the only significant predictor of technique failure and was also an independent predictor of death. High CrEx ratio is a predictor of good, rather than poor, outcome in PD patients, perhaps because it is primarily an index of nutrition. This further weakens the argument that it is a reliable or useful marker of noncompliance.

Truncated TrkB mediates the endocytosis and release of BDNF and neurotrophin-4/5 by rat astrocytes and schwann cells in vitro.

Binding and cross-linking studies with radiolabeled neurotrophins demonstrate that cultured rat hippocampal astrocytes lack full-length TrkB, but do express high levels of truncated TrkB (tTrkB). In astrocytes and Schwann cells, tTrkB appears to have the novel function of mediating the endocytosis of neurotrophins into an acid-stable, Triton X-100 resistant intracellular pool that is released back into the medium in a temperature-dependent manner. Chloroquine treatment, trichloroacetic acid solubility, and sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis revealed that when incubated with astrocytes or Schwann cells for at least 48 h neither the intracellular nor the released neurotrophins were significantly degraded. The endocytosis and release of neurotrophins may represent a novel mechanism whereby neuroglia can regulate the local concentration of these neurotrophic factors for extended periods of time.

Linoleic acid metabolism in the spontaneously diabetic rat: delta6-desaturase activity vs. product/precursor ratios.

The activity of delta6-desaturase of linoleic acid, a rate-limiting step in the formation of arachidonic acid, is decreased in animal models of severe, uncontrolled diabetes. The aim of the study was to measure the activity of liver microsomal delta6-desaturase of spontaneously diabetic BioBreeding/Edinburgh rats receiving subcutaneous insulin daily and of genetically related nondiabetic animals. The activity of delta6-desaturase was then compared with indices of activity (plasma lipid fatty acid product/precursor ratios) frequently used in human studies. Diabetic rats treated with insulin had 75 +/- 8% of the activity of microsomal delta6-desaturase of nondiabetic controls (P < 0.05). Insulin withdrawal tended to reduce the activity further (61% of control), although the activity did not differ from insulin-treated diabetic rats. The ratio of plasma phospholipid or cholesteryl ester gamma-linolenic over linoleic acid was not decreased in insulin-treated diabetic rats. By contrast, the ratio of gamma-linolenic over linoleic acid of microsomes was almost three-fold higher in insulin-treated diabetic rats (P < 0.05). The gamma-linolenic over linoleic acid ratio as an index of activity gave inconsistent results in insulin-deprived rats. The ratio of gamma-linolenic over linoleic acid of cholesteryl esters did not differ between control and diabetic rats, nor did it correlate with microsomal delta6-desaturase activity. Furthermore, the index of delta6-desaturase activity, derived from the fatty acid composition of microsomal phospholipids, did not correlate with microsomal delta6-desaturase activity. Diabetes, even when controlled by regular insulin injections, reduces the metabolism of linoleic acid, but the effect is less than previously published. The fatty acid compositions of plasma and liver microsomal lipids are not reliable indices of delta6-desaturase activity in diabetes.

Peptide immunoreactivity in aged rat cortex and hippocampus as a function of memory and BDNF infusion.

Brain-derived neurotrophic factor (BDNF) modulates neuropeptide levels in hippocampus and cortex of young adult rats. Neuropeptide levels are altered in some age-related disorders, such as Alzheimer's and Parkinson's Disease. BDNF may be able to rectify peptide abnormalities but, because plasticity decreases with age, BDNF may not alter peptide levels as readily in aged animals. To determine if BDNF would regulate peptide levels in aged rats, young, aged memory-impaired, and unimpaired rats were infused with BDNF or vehicle into hippocampus and cortex. Cell profile counts, cell profile areas, fiber counts, and/or fiber terminal densities were measured for sections immunostained for neuropeptide Y (NPY), somatostatin (SOM), cholecystokinin-8 (CCK), and dynorphin A(1-8) (DYN). Results showed that BDNF upregulated cortical NPY-immunoreactivity (ir) and SOM-ir, upregulated hippocampal NPY-ir, and downregulated hippocampal DYN-ir in both aged and young rats. In addition, BDNF significantly and selectively normalized the areas of atrophied deep cortical CCK-ir cell profiles in aged-impaired rats. Finally, decreased CCK-ir fiber density was found in the hippocampal formation of aged memory-impaired rats.

Ultrafiltration method for measuring vascular access flow rates during hemodialysis.

BACKGROUND: The vascular access blood flow rate (QA) has been shown to be an important predictor of vascular access failure; therefore, the routine measurement of QA may prove to be a useful clinical method of vascular access assessment. METHODS: We have developed a new ultrafiltration (UF) method for determining QA during HD from changes in arterial hematocrit (H) after abrupt changes in the UF rate with the dialysis blood lines in the normal (DeltaHn) and reverse (DeltaHr) configurations. This method accounts for cardiopulmonary recirculation and requires neither intravenous saline injections nor accurate knowledge of the dialyzer blood flow rate. Clinical studies were conducted in 65 chronic HD patients from three different dialysis programs to compare QA determined by the UF method with that determined by saline dilution using an ultrasound flow sensor. RESULTS: Arterial H increased (P<0.0001) after abrupt increases in the UF rate when the lines were in the normal and reverse configurations. An increase in the UF rate from the minimum setting to 1.8 liter/hr resulted in a DeltaHn of 0.3+/-0.2 (mean +/- SD) H units and a DeltaHr of 1.6+/-1.0 H units. Q(A) values determined by the UF method (1050+/-460 ml/min) were 16+/-25% higher (P<0.001) than those determined by saline dilution (950+/-440 ml/min); the calculated QA values by the UF and saline dilution methods correlated highly with each other (R = 0.92, P<0.0001). The average coefficient of variation for duplicate measurements of QA determined by the UF method in a subset of these patients (N = 21) was approximately 10% when assessed in either the same dialysis session or consecutive sessions. CONCLUSIONS: The results from this study show that changes in arterial H after abrupt changes in the UF rate can be used to assess Q(A).

Brain-derived neurotrophic factor transgenic mice exhibit passive avoidance deficits, increased seizure severity and in vitro hyperexcitability in the hippocampus and entorhinal cortex.

Transgenic mice overexpressing brain-derived neurotrophic factor from the beta-actin promoter were tested for behavioral, gross anatomical and physiological abnormalities. Brain-derived neurotrophic factor messenger RNA overexpression was widespread throughout brain. Overexpression declined with age, such that levels of overexpression decreased sharply by nine months. Brain-derived neurotrophic factor transgenic mice had no gross deformities or behavioral abnormalities. However, they showed a significant passive avoidance deficit. This deficit was dependent on continued overexpression, and resolved with age as brain-derived neurotrophic factor transcripts decreased. In addition, the brain-derived neurotrophic factor transgenic mice showed increased seizure severity in response to kainic acid. Hippocampal slices from brain-derived neurotrophic factor transgenic mice showed hyperexcitability in area CA3 and entorhinal cortex, but not in dentate gyrus. Finally, area CA1 long-term potentiation was disrupted, indicating abnormal plasticity. Our data suggest that overexpression of brain-derived neurotrophic factor in the brain can interfere with normal brain function by causing learning impairments and increased excitability. The results also support the hypothesis that excess brain-derived neurotrophic factor could be pro-convulsant in the limbic system.

Hemodynamic monitoring during hemodialysis.

Intradialytic monitoring of hemodynamic parameters is an active area of research; future developments in this field will decrease intradialytic morbidity and the mortality of end-stage renal disease patients treated by hemodialysis. Recent investigations have been assisted by the development of devices that can continuously and noninvasively measure hematocrit and plasma protein concentration during the treatment. Intradialytic morbidity, fluid overload, and hypertension in chronic hemodialysis patients have been shown to be associated with either large or small intradialytic decreases in blood or plasma volume that can be routinely measured by these devices. The use of intradialytic changes in blood volume as a feedback control parameter to vary the ultrafiltration rate and dialysate sodium concentration, so called profiling, is now possible, but further research in this area is necessary to show how to optimize the control algorithms. Other, more preliminary studies suggest that monitoring of central blood volume, extracellular volume, and cardiac output during hemodialysis may permit improved hemodynamic stability during treatment and better control of blood pressure. Although optimal application of these techniques and devices remains to be shown, their routine use during maintenance hemodialysis therapy will likely be the standard of care in the near future.

Monitoring vascular access flow.

Blood flow in peripheral arterio-venous fistulae and grafts as used for hemodialysis access can be derived from measurements of the amount of access recirculation induced by reversing the dialysis blood lines and a knowledge of dialyzer blood flow rates. Furthermore, low or falling access blood flow rates are predictive of access dysfunction from the development of an intraluminal stenosis, which may be reversible, or of access thrombosis. The monitoring of access blood flow rates in hemodialysis populations is therefore suggested. Technologies including ultrasound dilution, hematocrit dilution (or concentration) differential conductivity, and thermodilution used for such monitoring are described.

Neurotrophins: peripherally and centrally acting modulators of tactile stimulus-induced inflammatory pain hypersensitivity.

Brain-derived neurotrophic factor (BDNF) is expressed in nociceptive sensory neurons and transported anterogradely to the dorsal horn of the spinal cord where it is located in dense core vesicles in C-fiber terminals. Peripheral inflammation substantially up-regulates BDNF mRNA and protein in the dorsal root ganglion (DRG) in a nerve growth factor-dependent fashion and results in novel expression of BDNF by DRG neurons with myelinated axons. C-fiber electrical activity also increases BDNF expression in the DRG, and both inflammation and activity increase full-length TrkB receptor levels in the dorsal horn. Sequestration of endogenous BDNF/neurotrophin 4 by intraspinal TrkB-Fc fusion protein administration does not, in noninflamed animals, change basal pain sensitivity nor the mechanical hypersensitivity induced by peripheral capsaicin administration, a measure of C fiber-mediated central sensitization. TrkB-Fc administration also does not modify basal inflammatory pain hypersensitivity, but does block the progressive hypersensitivity elicited by low-intensity tactile stimulation of inflamed tissue. BDNF, by virtue of its nerve growth factor regulation in sensory neurons including novel expression in A fibers, has a role as a central modulator of tactile stimulus-induced inflammatory pain hypersensitivity.