ICP-MS trace element analysis in serum and whole blood.

Trace elements and minerals are compounds that are essential for the support of a variety of biological functions and play an important role in the formation of and the defense against oxidative stress. Here we describe a technique, allowing sequential detection of the trace elements (K, Zn, Se, Cu, Mn, Fe, Mg) in serum and whole blood by an ICP-MS method using single work-up, which is a simple, quick and robust method for the sequential measurement and quantification of the trace elements Sodium (Na), Potassium (K), Calcium (Ca), Zinc (Zn), Selenium (Se), Copper (Cu), Iron (Fe), Manganese (Mn) and Magnesium (Mg) in whole blood as well as Copper (Cu), Selenium (Se), Zinc (Zn), Iron (Fe), Magnesium (Mg), Manganese (Mn), Chromium (Cr), Nickel (Ni), Gold (Au) and Lithium (Li) in human serum. For analysis, only 100 µl of serum or whole blood is sufficient, which make this method suitable for detecting trace element deficiency or excess in newborns and infants. All samples were processed and analyzed by ICP-MS (Agilent Technologies). The accuracy, precision, linearity and the limit of quantification (LOQ), Limit of Blank (LOB) and the limit of detection (LOD) of the method were assessed. Recovery rates were between 80-130% for most of the analyzed elements; repeatabilities (Cv %) calculated were below 15% for most of the measured elements. The validity of the proposed methodology was assessed by analyzing a certified human serum and whole blood material with known concentrations for all elements; the method described is ready for routine use in biomonitoring studies.

Effect of Excessive Coffee Consumption on the Clinical Course of a Patient With Bipolar Disorder: A Case Report and Literature Review.

OBJECTIVE: The aim of this study was to examine the impact of excessive caffeine consumption on therapeutic outcomes in bipolar disorder. METHODS AND RESULTS: We report on a case of a patient with bipolar disorder whose psychiatric symptoms were ameliorated with the elevation of lithium concentrations after the reduction of excessive daily coffee consumption, and we review the relevant literatures. CONCLUSIONS: Excessive coffee consumption may exacerbate the therapeutic course of bipolar disorder through its effects on the mechanisms underlying bipolar disorder itself, as well as by affecting the blood concentration of lithium.

Impact of experimental hypercalcemia on routine haemostasis testing.

BACKGROUND: The blood to anticoagulant ratio is standardized according to the physiological calcium concentration in blood samples conventionally used for hemostasis testing. Specifically, one fixed volume of 0.109 mmol/L sodium citrate is added to 9 volumes of blood. Since little is known about the impact of hypercalcemia on the calcium-binding capacity of citrate, this study was planned to investigate the effect of experimental hypercalcemia on routine hemostasis testing. METHODS: Fifteen pooled citrated plasmas with matching lithium-heparin pooled plasma from patients with different values of prothrombin time (PT) were divided in three aliquots of 0.6mL each. The first paired aliquots of both citrate and lithium-heparin plasma were supplemented with 60µL of saline, the second paired aliquots with 30µL of saline and 30µL of calcium chloride and the third paired aliquots with 60µL of calcium chloride. Total and ionized calcium was measured in all aliquots of citrate and lithium-heparin plasma, whereas PT, activated partial thromboplastin time (APTT) and fibrinogen were measured in citrate plasma aliquots. RESULTS: Total calcium concentration gradually increased in both lithium-heparin and citrate plasma aliquots 2 and 3 compared to baseline aliquot 1. The concentration of ionized calcium also gradually increased in lithium-heparin plasma aliquots 2 and 3, whereas it remained immeasurable (i.e., <0.10 mmol/L) in all citrate plasma aliquots. No significant differences were observed for values of PT, APTT and fibrinogen in citrate plasma aliquots 2 and 3 compared to the baseline aliquot 1, with a mean bias was always comprised within the desirable quality specifications derived from biological variability data. CONCLUSION: Hypercalcemia, up to severe hypercalcemia does not generate significant bias in results of first-line coagulations tests, so that hypothetical consideration of adjusting citrate-blood ratio is unjustified in hypercalcemic patients.

Lithium Accumulates in Neurogenic Brain Regions as Revealed by High Resolution Ion Imaging.

Lithium (Li) is a potent mood stabilizer and displays neuroprotective and neurogenic properties. Despite extensive investigations, the mechanisms of action have not been fully elucidated, especially in the juvenile, developing brain. Here we characterized lithium distribution in the juvenile mouse brain during 28 days of continuous treatment that result in clinically relevant serum concentrations. By using Time-of-Flight Secondary Ion Mass Spectrometry- (ToF-SIMS) based imaging we were able to delineate temporospatial lithium profile throughout the brain and concurrent distribution of endogenous lipids with high chemical specificity and spatial resolution. We found that Li accumulated in neurogenic regions and investigated the effects on hippocampal neurogenesis. Lithium increased proliferation, as judged by Ki67-immunoreactivity, but did not alter the number of doublecortin-positive neuroblasts at the end of the treatment period. Moreover, ToF-SIMS revealed a steady depletion of sphingomyelin in white matter regions during 28d Li-treatment, particularly in the olfactory bulb. In contrast, cortical levels of cholesterol and choline increased over time in Li-treated mice. This is the first study describing ToF-SIMS imaging for probing the brain-wide accumulation of supplemented Li in situ. The findings demonstrate that this technique is a powerful approach for investigating the distribution and effects of neuroprotective agents in the brain.

Early changes of hypothalamic angiotensin II receptors expression in gestational protein-restricted offspring: effect on water intake, blood pressure and renal sodium handling.

The current study examines changes in the postnatal hypothalamic angiotensin receptors by maternal protein restriction (LP), and its impact on in uteri programming of hypertension in adult life. The data show that LP male pup body weight was significantly reduced when compared to that of control (NP) pups. Also, immunoblotting analysis demonstrated a significantly decreased expression of type 1 AngII receptors (AT1R) in the entire hypothalamic tissue extract of LP rats at 12 days of age compared to age-matched NP offspring. Conversely, the expression of the type 2 AngII (AT2R) receptors in 12-day- and 16-week-old LP hypothalamus was significantly increased. The current data show the influence of central AngII administration on water consumption in a concentration-dependent fashion, but also demonstrate that the water intake response to AngII was strikingly attenuated in 16-week-old LP. These results may be related to decreased brain arginine vasopressin (AVP) expression appearing in maternal protein-restricted offspring. The present investigation shows an early decrease in fractional urinary sodium excretion in maternal protein-restricted offspring. The decreased fractional sodium excretion was accompanied by a fall in proximal sodium excretion and occurred despite unchanged creatinine clearance. These effects were associated with a significant enhancement in arterial blood pressure in the LP group, but the precise mechanism of these phenomena remains unknown.

Differential effects of endogenous lithium on neurobehavioural functioning: a study on auditory evoked potentials.

Lithium occurs naturally in food and water. Low environmental concentrations in drinking water are associated with mental illnesses and behavioural offences, and at therapeutic dosages it is used to treat psychiatric (especially affective) disorders, partly by facilitating serotonergic (5-HT) neurotransmission. As little is known about the psychophysiological role of nutritional lithium in the general population, endogenous lithium concentrations were hypothesised to be associated with measurable effects on emotional liability and the loudness dependence (LD) that is proposed as one of the most valid indicators of 5-HT neurotransmission. Auditory evoked potentials of healthy volunteers [N=36] with high (>2.5 microg/l) or low (<1.5 microg/l) lithium serum concentrations were recorded. Emotional liability was assessed using the Brief Symptom Inventory (BSI). Low-lithium levels correlated with Somatisation while correlations between lithium and LD were not significant. Still, LD correlated positively with Paranoid Ideation, negatively with Anxiety and, in the high-lithium group, inversely with further aspects of emotional liability (Depression, Psychological Distress). In conclusion, the effects of low levels of endogenous lithium are associated with emotional liability, and high levels with some protective effects, although findings remain inconclusive regarding LD. Potential benefits of endogenous lithium on neurobehavioural functioning, especially in high-risk individuals, would have public health implications.

Zinc improves antioxidative enzymes in red blood cells and hematology in lithium-treated rats.

The present study was designed to evaluate the protective role of zinc in attenuating the adverse effects induced by lithium in blood of female Wistar rats. Female Wistar rats received lithium in the form of lithium carbonate in diet at a dose level of 1.1 g/kg diet, zinc alone in the form of zinc sulfate in drinking water at a dose level of 227 mg/L drinking water, or lithium plus zinc treatments in the combined group for a total duration of 2 months. Effects of the treatments were studied on antioxidant defense system, various hematologic parameters, and percentage of (65)Zn-specific activity. Lithium treatment resulted in a significant increase in lipid peroxidation levels but caused a significant decrease in reduced glutathione levels and the activities of catalase, glutathione S-transferase, and superoxide dismutase. Lithium treatment also caused a significant decrease in the activities of aminolevulinic acid dehydratase and Na(+) K(+) adenosine triphosphatase. However, it resulted in a significant increase in total leukocyte counts, neutrophils, and lymphocyte counts as well as zinc protoporphyrin levels, whereas a significant decrease in counts of monocytes, eosinophils, and percentage specific activity of (65)Zn in blood and its various fractions was noticed. Furthermore, lithium treatment caused a significant decrease in serum zinc levels. However, zinc supplementation to lithium-treated rats effectively raised the reduced glutathione levels and also normalized lipid peroxidation and the activities of antioxidative enzymes, which included catalase, glutathione S-transferase, and superoxide dismutase. Moreover, zinc supplementation could raise the activities of the enzymes aminolevulinic acid dehydratase and Na(+) K(+) adenosine triphosphatase as well as the percentage uptake values of (65)Zn in blood and its fractions. The study suggests that zinc, as a nutritional supplement, has the potential in attenuating most of the adverse effects induced by lithium in rat blood.

Appropriateness of therapeutic drug monitoring for lithium.

OBJECTIVE: Evaluate the appropriateness of therapeutic drug monitoring (TDM) for lithium. MATERIAL AND METHOD: A retrospective chart review of all patients who received lithium for treatment of psychiatric disorders between January 2004 and October 2005 was done. The present study was investigated in a psychiatric hospital in Thailand Based on detailed chart review, the appropriateness of TDM utilization comprised of three aspects, i.e., the indication of TDM request, the time of blood sample taking in relation to the medication process, and the clinical applications of the reported serum lithium levels, were evaluated. The Morecambe Bay Shared Care Guideline 2003 was modified and used as criteria for evaluation. Altogether 91 serum lithium samples were measured among 60 patients. RESULT: In 66 (72.5%) of requests, clear indications for lithium TDM were recorded i.e., initiation therapy 41.8%, suspected toxicity 15.4%, patient compliance assessment 5.5%, after regimen changes 5.5%, and therapeutic failure 4.4%. Routine tests without specified indications were found in the remainder (27.5%), all were in-patients, which pointed to potentially redundant use. The time of sample taking was recorded in 37 (40.6%) of blood samples, all were taken from in-patients, after steady state had been reached. These data for out-patients were not recorded, except one noted that blood sample was drawn after the patient had not received lithium for four days. Serum lithium levels were reported in 83 (91.2%) samples. Of these, 37 (44.6%) were out of therapeutic range, and only 12 required dosage alterations. The evaluation demonstrated somewhat inappropriate use of reported lithium levels. Dose changes were done in some patients who required dosage adjustment. Among 14 toxicity-suspected patients, nine actually had serum lithium levels exceeding the therapeutic range. Of these, only one patient was subsequently switched to a reduced dose, three patients were discontinued while five patients were prescribed the pre-TDM doses. Similarly, in five toxicity-suspected patients whose serum lithium levels were below therapeutic range, lithium was discontinued in three patients and no dosage alteration, which was considerably acceptable, in two patients. The doses were increased in three out offour inadequately controlled patients whose serum lithium was lower than the therapeutic range. Overall, in only 33 (36.3%) requests was TDM performed appropriately according to the indication, sampling time and subsequent dose adjustment. CONCLUSION: The findings indicate the need to improve the utilization of TDM for lithium. Education for hospital personnel on appropriateness of serum sample collection, interpretation, and proper use of serum drug levels is encouraged. Development of a request form containing essential data, such as indication for TDM, current drug dosing regimen, time of last dose, patient compliance, test results and interpretations and clinical decision made, can help optimize TDM use and reduce unnecessary costs.

Copper modifies the activity of sodium-transporting systems in erythrocyte membrane in patients with essential hypertension.

The aim of the study was to verify the hypothesis if copper could influence the activity of sodium-transporting systems in erythrocyte membrane that could be related to essential hypertension. The examined group of patients consisted of 15 men with hypertension. The control group was 11 healthy male volunteers. The Na+/H+ exchanger (NHE) activity in erythrocytes was determined according to Orlov et al. The activity of transporting systems (ATP-Na+/K+; co-Na+/K+/Cl-; ex-Na+/Li+; free Na+ and K+ outflow [Na+, K+-outflow]) was determined according to Garay's method. The concentration of copper in plasma was assessed using atomic absorption spectrometry. The activity of ATP-Na+/K+ (micromol/L red blood cells [RBCs]/h) in hypertensive patients was 2231.5 +/- 657.6 vs 1750.5 +/- 291 in the control (p < 0.05), the activity of co-Na+/K+/Cl- (micromol/L RBCs/h) in hypertensives was 171.3 +/- 77.9 vs 150.7 +/- 53.9 in the control (NS). Na+-outflow (micromol/L RBCs/h) in hypertensives was 118.3 +/- 51.6 vs 113.3 +/- 24.4 in the control (NS). The K+-outflow (micromol/L RBCs/h) in hypertensives was 1361.7 +/- 545.4 vs 1035.6 +/- 188.3 in the control (NS). The activity of ex-Na+/Li+ (micromol/L RBCs/h) in hypertensive patients was 266.1 +/- 76.1 vs 204.1 +/- 71.6 in the control (p < 0.05). NHE activity (mmol/L RBCs/h) in hypertensives was 9.7 +/- 2.96 vs 7.7 +/- 1.33 in the control (p < 0.05). In hypertensive patients, negative correlation was found between the activity of Na+/K+/Cl- co-transport and plasma copper concentration (Rs = -0.579, p < 0.05) and between the activity of ex-Na+/Li+ and plasma copper concentration (Rs = -0.508, p < 0.05). Plasma copper concentration significantly influences the activity of sodium transporting systems in erythrocyte membrane. Copper supplementation could be expected to provide therapeutic benefits for hypertensive patients.

Serum lithium as a compliance marker for food and supplement intake.

BACKGROUND: Analyzing 24-h urine for lithium after consumption of lithium-tagged foods or supplements provides a validated compliance marker but is laborious. OBJECTIVE: Most studies involve blood sampling; therefore, we tested whether serum lithium concentration could be used as a compliance marker. DESIGN: We used serum lithium as a compliance marker in a dietary trial and an evaluation study. RESULTS: In the dietary trial, 78 volunteers consumed 500 mL yogurt tagged with lithium (250 micromol/d) for 6 wk. Serum lithium increased from 0.9+/-0.3 to 6.6+/-1.5 micromol/L, which was close to the predicted concentration, indicating that the subjects were highly compliant. However, the interindividual variability in serum lithium concentration was large. To test whether this variability resulted from compliance differences or natural variability, we performed an evaluation study: 12 subjects took a lithium supplement (250 micromol/d) for 13 d under supervision. Serum lithium increased from 0.14+/-0.03 to 3.9+/-0.8 micromol/L (range: 2.6-5.4 micromol/L); thus, there was wide interindividual variation in serum lithium despite 100% compliance. However, within-subject variability was small, with a CV of 7% for serum lithium measured on 4 different days. We checked whether taking half the dose on each of 2 d (125 micromol lithium/d) would significantly lower serum lithium. Indeed, serum lithium dropped in all subjects, by a mean of 1.0 micromol/L on the first day (P<0.0001) and by another 0.3 micromol/L on the second day (P = 0.0004). Thus, changes in serum lithium concentration of > or =1.0 micromol/L suggest altered compliance. CONCLUSION: Serum lithium concentrations after intake of lithium-tagged foods or supplements can be used to assess compliance in dietary trials.

Double-blind and placebo-controlled study of lithium for adolescent bipolar disorders with secondary substance dependency.

OBJECTIVE: To perform a double-blind, placebo-controlled, random assignment, parallel group, pharmacokinetically dosed study of lithium for adolescents with bipolar disorders (BP) and temporally secondary substance dependency disorders (SDD). METHOD: Subjects were 16.3 +/- 1.2 years old and were comprehensively assessed during a 6-week outpatient protocol that included random weekly urine collection for drug assays and random and weekly serum collection for lithium levels. RESULTS: Using both intent-to-treat (N = 25) and completer (n = 21) analyses, there were significant differences on continuous and categorical measures between the active and placebo groups for both psychopathology measures and weekly random urine drug assays. The mean scheduled weekly serum lithium level of active responders was 0.9 mEq/L. Addiction to both alcohol and marijuana was the most frequent category of SDD. Mean age at onset of BP was 9.6 +/- 3.9 years and of SDD was 15.3 +/- 1.3 years. There were multigenerational mood disorders in 96% and multigenerational SDD in 56% of families. CONCLUSIONS: Lithium treatment of BP with secondary SDD in adolescents was an efficacious treatment for both disorders. These results warrant replication with a long-term maintenance phase. The mean 6-year interval between the onset of BP and onset of SDD strongly argues for earliest recognition of BP.

Hypouricemia, abnormal renal tubular urate transport, and plasma natriuretic factor(s) in patients with Alzheimer's disease.

OBJECTIVE: To study tubular urate transport in Alzheimer's disease (AD) and measure sodium and lithium transport rates in rats exposed to AD plasma. DESIGN: Cross-sectional study in three comparison groups. SETTING: Referral private institution involving outpatient and hospitalized patients. PATIENTS: AD, multi-infarct dementia (MID) and non-demented controls (C) were selected and evaluated by a geriatrician and a psychiatrist according to availability and willingness to participate in the study. Demented patients had brain imaging, categorized according to NINCDS-DSM III criteria, and had Mini-mental status examination (MMSE) scores determined. INTERVENTIONS: Injection of 0.5 mL of plasma I.P. followed 120 minutes later by an IV plasma injection of 0.2 mL priming dose and infusion of 1.8 mL of plasma at 0.01 mL/min in Sprague Dawley rats. MEASUREMENTS: Renal clearance studies were performed in subjects and in rats exposed to the plasma of study subjects. We measured serum urate concentration and fractional excretion (FE) of urate in subjects and FE sodium and FE lithium in rats. RESULTS: Serum urate was lower and FE urate higher in 18 AD patients compared with six patients with MID, P < 0.05 and P < 0.005, and 11 C, P < 0.02 and P < 0.005, respectively. Higher FE sodium and FE lithium were noted in rats given plasma from 19 AD patients compared with 12 with MID, P < 0.005 and P < 0.0025, and 14 C, P < 0.0025 and P < 0.0005, respectively. FE sodium and FE lithium decreased progressively after serial dilutions of three AD plasmas and FE lithium was negatively correlated with MMSE scores only in AD, r = -0.71 and P < 0.0005. CONCLUSIONS: In AD there is defective tubular urate transport and a plasma natriuretic factor(s). FE sodium and/or FE lithium in rats exposed to plasma of demented patients may differentiate AD from MID and estimate the severity of AD.

Relaxation times and concentrations of 7Li in the brain of patients receiving lithium therapy.

The present study describes a protocol for the determination of in vivo absolute molar concentrations of Li+ in the human brain using a double tuned 1H/7Li surface coil. The protocol follows the method of Thulborn and Ackerman [J. Mag. Reson. 55, 357-371 (1983)] where the ratio of the signal intensities of 7Li and 1H in the brain is compared to the same ratio in a phantom containing known concentrations of Li+. The 7Li T1 values in the brains of five patients receiving lithium therapy were measured. The average result was T1 = 3.5 +/- 0.25 s. The phantom solution was adjusted to have this T1 value. The protocol was applied for eight bipolar patients receiving lithium therapy. The average ratio of brain to serum lithium molar concentration was found to be 0.59 +/- 0.12.

Effects induced by olive oil-rich diet on erythrocytes membrane lipids and sodium-potassium transports in postmenopausal hypertensive women.

Since we have observed that monounsaturated fatty acids (MUFA) enriched diet modifies red cell membrane lipids and cation transport systems in normotensive subjects, we similarly evaluated a group of hypertensive patients undergoing an analogous dietary modification. In a group of 18 moderately hypertensive women, the diet was supplemented for two months with olive oil (about 45 g/day), which replaced an equal amount of seasoning fats. Before and after this period, red cell fatty acid composition was evaluated by gas-chromatography in order to verify diet compliance: a significant increase in oleic acid was observed, while the content of saturated and polyunsaturated fatty acids remained unchanged. After olive oil, maximal rates of Na-K pump (5580 +/- 329 vs 6995 +/- 390, p less than 0.001) and Na-K cotransport (Na-COT 544 +/- 52 vs 877 +/- 46, p less than 0.001: K-COT 790 +/- 76 vs 1176 +/- 66, p less than 0.001), cell Na content (9.58 +/- 0.4 vs 10.61 +/- 0.6, p less than 0.03) and passive permeability for Na (936 +/- 74 vs 1836 +/- 102, p less than 0.001) rose significantly. Although the reduction in maximal rate of the Li-Na CT after olive oil was not significant, it was the only cation transport parameter being correlated with the variations of membrane lipids, namely negatively with UFA (r = -0.528, p less than 0.05) and positively with SFA (r = 0.482, p less than 0.005). The change in maximal rate of Li-Na CT was also correlated with the variation of systolic and diastolic BP (r = 0.50, p less than 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

The antihypertensive effect of dietary supplementation with a 6-desaturated essential fatty acid concentrate as compared with sunflower seed oil.

There is increasing evidence that the type of fat in the diet may play a role in the control of blood pressure and development of hypertension. The purpose of the present study was to investigate the effect of a concentrated preparation of the 6-desaturated essential fatty acids gamma-linolenic acid (C18:3n-6), eicosapentaenoic acid (C20:5n-3) and docosahexaenoic acid (C22:6n-3) on individuals with raised BP. Eighteen volunteers from our College staff with elevated BP on several occasions but otherwise healthy, were divided into two groups following a two-week baseline period. One group received 4g sunflower seed oil daily and the other 4g of an oil preparation rich in C18:3n-6, C20:5n-3 and C22:6n-3 for six weeks. Major measurements included BP and fatty acids in phospholipids and cholesteryl esters. Dietary intakes and urinary fluid and electrolyte excretion were also monitored during baseline and intervention periods. The subjects' office diastolic BP showed a significantly greater effect of the concentrate over the sunflower seed oil, both overall (P = 0.03) and in interaction with time (P = 0.012). Fatty acids in plasma cholesteryl esters underwent mild alterations following the administration of the concentrate. There were no important changes in nutrient intakes or in sodium, potassium and fluid excretion during the trial period.

Red cell caesium, lithium and selenium in abstinent alcoholics.

Using inductively coupled plasma source mass spectrometry, we have studied the red cell element concentrations of alcoholic subjects with different periods of abstinence before testing. We found consistently elevated red cell caesium concentrations and also reduced red cell selenium concentrations. These may represent persistent abnormalities in oxidation/anti-oxidation mechanisms, and red cell caesium in particular may be a long-term marker of alcohol dependence. Erythrocyte lithium, cerium and boron concentrations were also reduced in the abstinent alcoholic groups.

A possible association between neonatal jaundice and long-term maternal lithium ingestion.

Two newborn infants, who developed moderate-to-severe jaundice, were born to a mother who had been taking lithium throughout both pregnancies. Both infants were treated with phototherapy while the second infant also required an exchange blood transfusion. No specific cause for the jaundice was found, raising the possibility that the maternal lithium intake may have contributed to the infants' hyperbilirubinaemia.

The meaning of serum lithium levels in maintenance therapy of mood disorders: a review of the literature.

Since Cade first described the role of lithium in the treatment of manic-depressive patients 40 years ago, there has not been consistent agreement on the relationship between the serum level of lithium during maintenance therapy and clinical outcome. This is a comprehensive review of literature reporting on lithium dose-response relationships, with particular emphasis on a consideration of serum levels of lithium. Efficacy studies are systematically discussed as are those that consider the relationship between serum level and adverse effects. Even after 40 years of lithium use, the relationship between serum levels of lithium during maintenance therapy and clinical outcome, including the development of side effects, remains obscure.