P. Choi

Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease

Hepcidin is a critical inhibitor of iron export from macrophages, enterocytes, and hepatocytes. Given that it is filtered and degraded by the kidney, its elevated levels in renal failure have been suggested to play a role in the disordered iron metabolism of uremia, including erythropoietin resistance. Here, we used a novel radioimmunoassay for hepcidin-25, the active form of the hormone, to measure its levels in renal disease. There was a significant diurnal variation of hepcidin and a strong correlation to ferritin levels in normal volunteers. In 44 patients with mild to moderate kidney disease, hepcidin levels were significantly elevated, positively correlated with ferritin but inversely correlated with the estimated glomerular filtration rate. In 94 stable hemodialysis patients, hepcidin levels were also significantly elevated, but this did not correlate with interleukin-6 levels, suggesting that increased hepcidin was not due to a general inflammatory state. Elevated hepcidin was associated with anemia, but, intriguingly, the erythropoietin dose was negatively correlated with hepcidin, suggesting that erythropoietin suppresses hepcidin levels. This was confirmed in 7 patients when hepcidin levels significantly decreased after initiation of erythropoietin treatment. Our results show that hepcidin is elevated in renal disease and suggest that higher hepcidin levels do not predict increased erythropoietin requirements.

Subcutaneous Ghrelin Enhances Acute Food Intake in Malnourished Patients Who Receive Maintenance Peritoneal Dialysis: A Randomized, Placebo-Controlled Trial

Anorexia and malnutrition confer significant morbidity and mortality to patients with end-stage kidney disease but are resistant to therapy. The aim of this study was to determine whether subcutaneous administration of ghrelin, an appetite-stimulating gut hormone, could enhance food intake in patients who are receiving maintenance peritoneal dialysis and have evidence of malnutrition. The principal outcome measure was energy intake during a measured study meal. Secondary outcome measures were BP and heart rate and 3-d food intake after intervention. Nine peritoneal dialysis patients with mild to moderate malnutrition (mean serum albumin 28.6 +/- 5.0 g/L, total cholesterol 4.4 +/- 0.6 mmol/L, subjective global assessment score of 5.7 +/- 1.7) were given subcutaneous ghrelin (3.6 nmol/kg) and saline placebo in a randomized, double-blind, crossover protocol. Administration of subcutaneous ghrelin significantly increased the group mean absolute energy intake, compared with placebo, during the study meal (690 +/- 190 versus 440 +/- 250 kcal; P = 0.0062). When expressed as proportional energy increase for each individual, ghrelin administration resulted in immediate doubling of energy intake (204 +/- 120 versus 100%; P = 0.0319). Administration of ghrelin maintained a nonsignificant increase in energy intake over 24 h after intervention (2009 +/- 669 versus 1579 +/- 330 kcal) and was not followed by subsequent underswing (1790 +/- 370 versus 1670 +/- 530 and 1880 +/- 390 versus 1830 +/- 530 kcal on days 2 and 3, respectively). Ghrelin administration resulted in a significant fall in mean arterial BP (P = 0.0030 by ANOVA). There were no significant adverse events during the study. Subcutaneous ghrelin administration enhances short-term food intake in dialysis patients with mild to moderate malnutrition.

Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidin

Expression of hepcidin, the key hormone governing iron transport, is reduced by anemia in a manner which appears dependent on increased bone marrow activity. The temporal associations between plasma hepcidin and other iron parameters were examined in healthy humans after erythropoietin administration and venesection. Profound hepcidin suppression appeared abruptly 24 hours after subcutaneous erythropoietin (P=0.003), and was near maximal at onset, with peak (mid-afternoon) levels reduced by 73.2%, gradually recovering over the following two weeks. Minor changes in circulating iron, soluble transferrin receptor and growth differentiation factor-15 were observed after the reduction in hepcidin. Similar but more gradual changes in these parameters were observed after reducing hematocrit by removal of 250 mL blood. These human studies confirm the importance of a rapidly responsive marrow–hepcidin axis in regulating iron supply in vivo, and suggest that this axis is regulated by factors other than circulating iron, soluble transferrin receptor or growth differentiation factor-15.

Sustained appetite improvement in malnourished dialysis patients by daily ghrelin treatment

Malnutrition is a common complication in patients on dialysis and is strongly associated with poor prognosis. Effective therapy could substantially improve morbidity and mortality, but neither enteral nor parenteral supplementation provide long-term benefit because of the strong appetite suppression seen in such patients. We performed a double-blinded randomized crossover study of a week-long treatment with daily subcutaneous ghrelin, a gut hormone that regulates hunger through the hypothalamus, in a group of 12 malnourished dialysis patients. Ghrelin administration increased ghrelin levels in circulation, modestly reduced blood pressure for up to 2 h, and immediately and significantly increased appetite, with an increase in energy intake noted at the first study meal. Persistence of this effect throughout the week was confirmed with food diaries and final study meals. Energy expenditure, measured with free-living pulse and motion monitors, was unchanged by ghrelin. Our study shows that daily treatment with ghrelin achieves a sustained positive change in energy balance in malnourished dialysis patients. Direct manipulation of appetite with ghrelin or its analogs represents an attractive and promising therapeutic strategy for this difficult clinical problem.

An Observation of Energetic Electron Beams in Low-Pressure Linear Discharges

Experimental observations of energetic axial electron beams in a linear Z pinch operating in the pseudospark mode are presented. The device is driven from a fast Marx generator and allows reproducible production of electron beams over a wide pressure range. Evidence of the importance of electrons generated in the cathode recess in the formation of the beams is presented. An electron beam of high energy which is not associated with formation of the discharge is identified. A second beam of high current density and lower energy associated with gas breakdown is also observed.

Bacteremia Associated with Tunneled Hemodialysis Catheters: Outcome after Attempted Salvage

BACKGROUND AND OBJECTIVES Treatment without catheter replacement (catheter salvage) has been described for bacteremia associated with tunneled venous catheters in hemodialysis patients, but few data are available on which to base an estimation of the likelihood of treatment success. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In a prospective cohort study, all cases of catheter-associated bacteremia that occurred in a large dialysis center were identified during a 12-mo period. Catheter salvage was attempted according to a standard protocol in all cases in which a favorable early response to antibiotic therapy was seen, and patients were followed for at least 6 mo. Bacteremias, catheter changes, and all major clinical events were recorded. RESULTS During a period covering 252,986 catheter days, 208 episodes were identified involving 133 patients, 74% of which were selected for attempted salvage. Salvage was successful in 66.1% of incident bacteremias with a very low complication risk (0.9%). Some bacteremias, however, recurred as late as 6 mo after the initial infection; salvage was less likely to be successful in treating recurrences. CONCLUSIONS Appropriately used catheter salvage can be successful in approximately two thirds of cases; however, recurrences continue to occur up to 6 mo later and are unlikely to be cured without catheter replacement.

Temporal development of hard and soft x‐ray emission from a gas‐puff Z pinch

Previous time‐ and space‐resolved x‐ray measurements on a small gas‐puff Z pinch indicated the presence of bursts of energetic electron beam and related ‘‘hot spots’’—high‐temperature, high‐density plasma regions. Spectra taken from these hot spots are consistent with a plasma of electron density about 1022–1023 cm−3 and electron temperature of 500 eV. Here we present time correlation of the hard x‐ray emission from the anode with large fluctuations in I and with short bursts of intense soft x rays. These soft x‐ray bursts originating from the hot spots are shown always to be preceded by hard x‐ray emissions. Using suitable apertures, the plasma is shown to be a source of hard x rays, <2.5 A. This is confirmed by x‐ray pinhole photographs. By varying the Z of the anode the electron beam associated with hard x‐ray emission is found to be of low energy (10 keV) agreeing with previous measurements. In particular a plastic, PTFE (Teflon), is shown to be a suitable material for the anode, with superior lifetim...

Plasma formation in a pseudospark discharge

Unique features associated with the hollow cathode recess in a pseudospark discharge have been identified from streak camera observations. A plasma is observed to form in a highly localized region immediately behind the cathode aperture prior to gas breakdown in the main discharge volume. The pointlike plasma expands from an initial diameter of below 0.3 mm to 3 mm, the size of the cathode aperture, in about 20 ns, at which time the main discharge is formed starting from the axis. Numerical modeling based on swarm parameters has been carried out to investigate the plasma formation in the hollow cathode region. Results show that a combination of varying ionization rates due to the field geometry and differing mobilities of electrons and ions leads to the formation of a highly localized space-charge field on the axis behind the hollow cathode. This space-charge field in turn brings about the rapid formation of a highly localized, high density of charge carriers behind the cathode aperture. It is suggested that this pointlike formation of a plasma source is the phenomenon observed in the streak camera observation of the hollow cathode region. >

Experimental investigations of hotspots in a low energy plasma focus operating in hydrogen-argon mixtures

We present experimental results on the investigation of hotspot formation in PFP-I, a small 3.8 kJ plasma focus device operating in hydrogen-argon mixtures, at pressures from below 0.2 torr upward. A combination of multipinhole and slit-wire X-ray photography is used to measure the characteristic size and temperature of the hotspots, over a range of pressure and gas mixing ratios. Filtered p-i-n diodes and a beam-target detector are used to investigate the time evolution of the hotspots. Typical size for the hottest emitting region, at temperatures between 200 and 400 eV, is found to be around 150 /spl mu/m, with a typical duration of the high temperature phase of the order of 10 ns. In general, the temperature in the final phase of the time evolution of the hotspots reaches values which are nearly twice those of the plasma column where they are formed. Characteristic size of the hotspots is about half of that of the initial plasma column.

Breakdown formation in a transient hollow cathode discharge-a statistical study

Discharge formation at low pressure is found to be greatly influenced in the presence of a suitable hollow cathode region. The formation of a moving virtual anode which extends the anode potential to within the hollow cathode region is thought to be responsible for the enhanced ionization growth which subsequently leads to gas breakdown. In this paper, the spatial evolution of the local potential in the discharge region of a pulsed hollow cathode discharge has been measured in a range of pressures with two different cathode apertures. An extensive data set has been collected and analyzed using a statistical technique. From the characteristic of the statistical distribution of the data, unique features associated with the role of hollow cathode at the different stages of discharge formation have been identified. It was found that the influence of the hollow cathode region is strongest in the start of ionization growth and in the final change over to high current breakdown. >