Nickel metabolism in humans investigated with an oral stable isotope.

We report the results of the first complete study of nickel metabolism in human subjects using a stable nickel isotope (62Ni) as tracer. Four healthy adult subjects (two women and two men) fasted overnight before ingesting 10 microg 62Ni/kg body wt. Blood samples were drawn after fixed intervals of time and the total daily output of urine and feces was collected for the first 5 d after dose ingestion. 62Ni in plasma, urine, and feces was determined by isotope-dilution inductively coupled plasma-mass spectrometry with 61Ni. The direct measurement of the fecal excretion of the tracer allowed a reliable assessment of nickel absorption from the gastrointestinal tract and we found no evidence of the excretion of absorbed nickel via the gut. The percentage absorption calculated from the amount of 62Ni excreted in the feces ranged from 29% to 40%. Urinary excretion over 5 d ranged from 51% to 82% of the absorbed dose. Plasma 62Ni peaked between 1.5 and 2.5 h after ingestion and decreased by a factor of > 10 over the next few days. We observed low between-subject variability of nickel absorption and excretion. Confounding factors such as contamination and dietary intake of nickel, which hampered earlier measurements in subjects dosed with naturally abundant nickel, were eliminated by using the tracer isotope 62Ni.

Effect of inflammation on measures of antioxidant status in patients with non-small cell lung cancer.

This study examined the effect of an inflammatory response on measures of antioxidant status in patients with non-small cell lung cancer (NSCLC). In healthy, control subjects (n = 13) and NSCLC patients (n = 22) fasting concentrations of albumin, C-reactive protein, cholesterol, and the antioxidants alpha-tocopherol, retinol, lutein, lycopene, and alpha- and beta-carotene were measured. The two groups were similar in terms of age, sex, and body mass index. However, the cancer group had an inflammatory response as evidenced by significantly increased C-reactive protein concentrations. Concentrations of all the measured antioxidants of the NSCLC group were significantly lower than those of the control group (P < 0.01). The lowest concentrations were those of the carotenoids lycopene and alpha- and beta-carotene. In the cancer group there were significant negative correlations between concentrations of C-reactive protein and retinol (r = -0.682, P < 0.01), alpha-tocopherol (r = -0.464, P < 0.05), and lutein (r = -0.599, P < 0.01). The results of this study have implications for the interpretation of circulating antioxidant concentrations in patients with NSCLC.

Histopathology of early effects of oral cadmium in the rat kidney.

Adult male Wistar rats were given 50 ppm Cd in drinking water over a period of 1-24 weeks. The rats were killed and the cadmium concentration of whole blood, blood plasma red cells, liver and kidneys estimated. The plasma metallothionein concentration was measured by radioimmunoassay. Kidney samples were taken for light, transmission and scanning electron microscopic examination. The accumulation of cadmium in the tissues was shown by a linear increase with time, after exposure for 12 weeks. Plasma Cd concentrations showed a clear increase after 3 weeks and preliminary investigation suggests that most is present as Cd-thionein. Early pathological changes in the rat kidney were seen around the 4-6 week period which coincided with the distinct rise in plasma Cd. At 12 weeks, signs of tubular necrosis, interstitial fibrosis and glomerular epithelial cell hypertrophy were present in small areas of the cortex. By 24 weeks, the renal cortex showed clear evidence of tubulo-interstitial nephritis at a Cd concentration of 60 micrograms Cd/g wet weight.

Neutron activation analysis ofr copper in biological material applied to Wilson's disease.

A method for the neutron activation analysis of copper in biological material is described and applied to the diagnosis and management of four cases of Wilson's disease. Results obtained for serum and urine are in agreement with values obtained by established colorimetric techniques. The method described can estimate 10(-9) g. copper to within 10% and this sensitivity has allowed the determination of copper from biopsy material such as liver, spleen, hair, and nail.

ACP Best Practice No 163. Wilson's disease: acute and presymptomatic laboratory diagnosis and monitoring.

Wilson's disease, the most common inherited disorder of copper metabolism, is a recessive genetic condition. The clinical presentation of Wilson's disease is very variable. It is characterised by low serum copper and caeruloplasmin concentrations coupled with the pathological accumulation of copper in the tissues. However, there are diagnostic difficulties and these are discussed. The current value of DNA diagnosis, both in gene tracking in families or as applied to de novo cases, is examined. Wilson's disease can be treated successfully but treatment must be life long. Patients are best treated by specialist centres with experience and expertise in the condition.

Hypercalciuria related to cadmium exposure.

A work force has been investigated for possible cadmium intoxication. One group who are coppersmiths have an 18.5 per cent prevalence of upper urinary tract stone disease associated with a statistically highly significant hypercalciuria and reduced serum inorganic phosphate. Proof of exposure to cadmium has been confirmed in all workers. The trace element cadmium should be kept in mind when investigating stone formers who exhibit an unexplained hypercalciuria.

Determination of copper in urine by graphite furnace atomic absorption spectrometry.

Two methods are described for the determination of copper in urine by graphite furnace atomic absorption spectrometry. The first, suitable for spectrometers capable of making good background correction at 325 nm, involves a direct determination against simple aqueous standards after 2 X dilution of the sample. The second requires no background correction and can be used when background correction is not available or is inadequate. The copper is extracted from the urine with ammonium tetramethylenedithiocarbamate into methylisobutylketone and the extract is analysed for copper. No significant matrix effect was observed for either method. Analysis of random urine samples from 16 normal subjects gave a mean concentration of 0.42 mumol/l with a range of 0.06--1.04 mumol/l.

Observations on serum iron, zinc, copper and magnesium in intravenously fed patients with chronic sepsis.

In a retrospective study of 176 people who received intravenous nutrition, eight developed a septic episode of at least 12 days duration. We investigated the metabolism of four essential elements (iron, zinc, copper and magnesium) in this group. Plasma concentrations of iron, copper and magnesium followed expected trends; unexpectedly the plasma concentration of zinc was maintained. The implications of these findings in relation to the septic patient are discussed.

Selenium depletion and its correction in a child with homocystinuria.

A child of 10 months with proven homocystinuria was found to be selenium depleted and we report the serial monitoring of replacement therapy. Selenium, as an enriched yeast preparation, equivalent to 50 mug on alternate days was required for maintenance. Indices of selenium status returned to normal in varying times. The child initially demonstrated an abnormality of an in vitro challenge by hydrogen peroxide to her erythrocytes, that returned to within normal limits with selenium therapy alone, the serum vitamin E concentration being normal.

Clinical effects and adequacy of a new all-in-one dextrose-electrolyte-trace element preparation in patients on prolonged TPN.

We have devised a new all-in-one dextrose/electrolyste/trace element mixture (Polyfusor DY) and tested its efficacy in clinical practice. Polyfusor DY was designed to be combined with an amino-acid preparation and to be infused with lipid in a standard total parenteral nutrition (TPN) regimen. This standard regimen was formulated to provide minimum nitrogen, energy, fluid, electrolyte, vitamin and trace element requirements for the stable patient. The adequacy of currently recommended levels of provision of trace elements was tested in patients receiving long periods of intravenous nutrition. Eleven consecutive patients were fed from 13 to 280 days using TPN prescriptions based on this standard regimen. Two patients died but the nutritional state of the remainder improved. Serum concentrations of zinc, copper, chromium and manganese remained largely within or above the reference ranges, however the selenium content of Polyfusor DY (500 nmol/l) was marginally inadequate to maintain normal biochemistry. Pharmacy compounding time for the standard TPN regimen based on Polyfusor DY was 10.6 +/- 0.19 min (mean +/- SEM) compared with 22.5 +/- 0.30 min for non-standard TPN regimens prescribed independently by other clinicians (P < 0.001). A standard TPN regimen based on Polyfusor DY was clinically effective, in particular giving generally adequate trace element provision with a reduction in pharmacy time and costs.

Essential trace element provision to patients receiving home intravenous nutrition in the United Kingdom.

The methods of provision of essential trace elements to patients receiving long-term home intravenous nutrition in the U.K. have been reviewed and their trace element status has been assessed. Over a 2 year period, 57 patients based on 15 hospitals throughout the country were studied. Although biochemical abnormalities of trace element status were frequent, related clinical complications were apparently rare. Zinc provision from commercial preparations generally required further supplementation. Copper requirements were variable. Manganese provision from trace element mixtures and chromium provision from contaminants of other parenteral nutrient solutions were excessive in many cases. Aluminium contamination is not significant in the nutrient solutions currently used in the U.K. The most common depletion state is for selenium which should probably be provided on a routine basis. The clinical consequences of long-term under- or over-provision of trace elements by the intravenous route requires further study.

The effect of environmental temperature on protein and energy changes following burn injury in the rat.

The metabolic response to a standard burn injury in rats (25% of body surface area) was investigated at environmental temperature 20 degrees C and 30 degrees C. With an intake of 15 g diet (20% w/w protein) per day, burned rats at 20 degrees C were found to be in negative energy balance mainly due to increased insensible (evaporative) losses, and they lost weight. Fat was the main endogenous source of energy, although protein was also catabolised from both carcass and pelt. At 30 degrees C, insensible losses of burned rats were still high, but they had lower sensible (mainly radiative) losses leading to a positive energy balance and a gain in weight. This consisted mainly of carcass water, fat and protein. Urine catecholamines were higher in burned rats at 20 degrees C than at 30 degrees C and correlated with heat loss, urine nitrogen and urine 3-methylhistidine, supporting the hypothesis that catecholamines play a central role in mediating the protein and energy changes following burn injury. For the first 4-6 days, urine nitrogen and 3-methylhistidine excretion increased in rats at 30 degrees C, suggesting that this early part of the metabolic response is obligatory. These findings support the use of raised environmental temperatures to reduce the metabolic response to burns.

Mononuclear blood cell magnesium in older subjects: evaluation of its use in clinical practice.

Serum and mononuclear blood cell (MBC) magnesium were measured in 24 healthy community subjects, average age 76 years (67-93), and in 21 ill hospitalized subjects, average age 79 years (65-90). MBC magnesium, expressed as mumol/mg protein, was significantly lower in the in-patient group (P < 0.001), but tended to be higher in the same group when expressed as fmol/cell (not significant). Further samples from community subjects on the same day, and again at 7 days, revealed coefficients of variation for intrasubject analysis of 12% and 22%, respectively (fmol/cell). The equivalent intrasubject values for serum were 2.8% on the same day and 4% at 1 week. MBC magnesium values for inpatients were probably distorted by changes in cell size and cell protein content caused by illness. Biological variability and the effects of illness on the composition and size of cells seem to limit the usefulness of MBC magnesium measurement as a clinical tool for assessment of body magnesium status.

Plasma albumin and haemodilution: the problem of interpretation in sequential studies.

The ability of four formulae (3 based on packed cell volume and one on alpha-2 macroglobulin) to correct for postoperative dilutional changes in plasma albumin was assessed in 4 patients undergoing coronary artery surgery. Cardiopulmonary bypass is a stringent test of the efficacy of the formulae to correct for haemodilution as a large volume of fluid is added to the circulation in a relatively short period of time. Plasma albumin was measured 8 times in the perioperative period in the 4 patients and the clinical situation was mimicked in vitro by adding various volumes of diluent to whole blood. None of the formulae consistently corrected for predicted changes in plasma albumin concentration in vivo; two of the formulae corrected for in vitro changes in plasma albumin but the same formulae produced considerable over-correction when applied in vivo. The problem of correcting for perioperative dilutional changes in plasma albumin is discussed.

Determination of aluminium in serum, dialysate fluid and water by inductively coupled plasma optical emission spectrometry.

Methods for the determination of aluminium in serum, dialysate fluid and water by inductively coupled plasma optical emission spectrometry are described and validated. Aluminium was measured at 167 nm using an argon purged monochromator. Matrix effects in serum and dialysate fluid were overcome by using an yttrium internal standard. Serum was found to have a complicated background in the region of 167 nm: careful selection of the wavelength used for background correction is therefore a pre-requisite for accurate analysis. The method for serum was validated by comparison with electrothermal atomization atomic spectrometry and the limit of agreement determined to be +/- 0.3 mumol/L. Routine performance in a quality assessment scheme has been highly satisfactory for a period of 1 year. The method is ideal for fast and accurate monitoring of patients potentially at risk from aluminium toxicity.

Maintenance of vitamin and trace element status in intravenous nutrition using a complete nutritive mixture.

Complete nutritive mixtures (CNM) of all intravenous nutrients including fat emulsions are being used increasingly because of their convenience. However, this may lead to chemical interactions and reduce the amount of active vitamins and trace elements made available to the patient. We have studied the effects on micronutrient status of provision of all nutrients in one 3-liter bag (CNM: amino acids, dextrose, Intralipid 20%, a nine-element trace metal mixture, and complete fat- and water-soluble vitamin mixtures) in 10 postoperative surgical patients [median intravenous nutrition (IVN) 14.5 days, range 7-38]. A similar group received the fat emulsion plus water- and fat-soluble vitamins as a separate infusion (SI) from a 3-liter bag (median IVN 14.0 days, range 8-28). Serum and urine magnesium, zinc, copper, manganese, chromium, and selenium, serum vitamins A, E, C, folate, and B12, RBC B1, B2 B6, and folate and leukocyte vitamin C were measured at weekly intervals. All patients in both groups maintained or improved their status for all the micronutrients analyzed. No significant differences between the CNM and SI groups were found in blood concentrations of any of the elements or vitamins. Only for urine copper did the CNM lead to increased excretion (1.51 +/- 0.59 mumol/24 hr; copper input 20 mumol/day), compared to SI (1.00 +/- 0.70 mumol/day, p less than 0.001 Mann-Whitney test) suggesting possible interaction. It is concluded that micronutrient status was maintained during short-term IVN with the CNM and that it did not lead to a significantly greater loss of vitamins or essential trace elements than the SI system.

Mg deficiency in chronic inflammatory bowel disease and requirements during intravenous nutrition.

Assessment of magnesium (Mg) status by serum and 24-hr urine estimations has been used to study a group of 17 patients with severe Crohn's disease, 10 of whom have required intravenous (IV) nutrition. Mg depletion was present in 15 (88%) and severe enough to cause symptoms in two. Urine levels were low in most patients and would appear to be a more sensitive indication of Mg depletion than serum levels alone. Serum Mg levels were significantly lower in the Crohn's group than in a group of hospital controls; 5-10 mmol of IV Mg were required daily to prevent Mg depletion during IV nutrition and some patients required higher intakes. Three patients with particularly severe malabsorption required oral Mg supplements in the long-term. The rationale for using our method of assessing Mg status, and the importance of recognizing and treating chronic Mg deficiency are presented.

The effect of oral aluminium therapy on plasma aluminium levels in patients with chronic renal failure in an area with low water aluminium.

In a low water aluminium area ( less than or equal to 0.4 micromoles/1) plasma aluminium levels were normal in 31 non-dialyzed and 7 peritoneally-dialyzed patients unless oral aluminium hydroxide was prescribed. Plasma aluminium levels were above normal in 26 patients on maintenance hemodialysis, but when aluminium hydroxide intake stopped there was a decrease in pre-dialysis plasma aluminium. Poor compliers (indicated by plasma phosphate levels) showed no change. Oral aluminium hydroxide can make a major contribution to plasma aluminium levels in patients with renal failure and should be treated with the same caution as high dialyzate aluminium. Post-dialysis plasma aluminium levels were always higher than pre-dialysis levels both on and off aluminium therapy despite the low dialyzate aluminium concentration. This rise may be due to tissue redistribution.

The effects of intraoperative hypothermia and cardiopulmonary bypass on trace metals and their protein binding ratios.

The ability of intraoperative hypothermia to modify the metabolic response to cardiopulmonary bypass (CPB) was assessed by serial alterations in iron, zinc and copper, and in their molar binding ratios to their respective transport proteins, in 20 male patients under-going elective coronary artery surgery and randomised to an operative blood temperature of 28 degrees C or 20 degrees C. Decreases in serum iron and zinc concentrations, typical of the acute phase response, were preceded by early rises. Significant alterations in the metal: protein molar binding ratios preceded significant changes in the serum concentrations of the metals and occurred earliest in the zinc: albumin binding ratio, which was apparent by the time of skin incision. An intraoperative temperature of 20 degrees C modified iron and zinc concentrations and their protein binding ratios during surgery but not in the post-operative period. These early changes in trace metals and their protein binding ratios are a simple and inexpensive method of quantitating the response to surgical injury and may be useful in assessing new interventions in cardiopulmonary bypass. An awareness of the trace element response to surgical injury is essential to avoid misdiagnoses of iron deficiency anaemia or zinc deficiency.

Arrhythmia prophylaxis after coronary artery surgery. A randomised controlled trial of intravenous magnesium chloride.

One hundred and thirty patients undergoing elective myocardial revascularisation were randomised to receive an intravenous infusion containing either 50 mmol magnesium chloride or placebo during the first 48 h following surgery. Magnesium was given to 66 patients and a placebo infusion to 64 patients. Postoperative serum magnesium concentrations fell in the placebo group (from 0.83 +/- 0.06 to 0.79 +/- 0.11 mmol/l) but were elevated in the magnesium group (from 0.82 +/- 0.05 to 1.2 +/- 0.25 mmol/l). In total, 35 patients (26.9%) had a supraventricular arrhythmia, of which 11 were in the magnesium group (16.7%) and 24 (37.5%) in the placebo group (P = 0.013). Three patients in the magnesium group had an episode of ventricular fibrillation and three patients in the placebo group had frequent ventricular ectopics. There was one death in the magnesium group associated with a perioperative myocardial infarction. This study shows that intravenous magnesium supplements reduce the incidence of supraventricular arrhythmias following coronary artery surgery.