Quantitative data on the magnitude of the systemic inflammatory response and its effect on micronutrient status based on plasma measurements.

BACKGROUND: Plasma concentrations of several trace elements and vitamins decrease because of the systemic inflammatory response. Thus, low values do not necessarily indicate deficiency. OBJECTIVE: The magnitude of this effect on plasma micronutrient concentrations was investigated to provide guidance on the interpretation of routine clinical results. DESIGN: Between 2001 and 2011, the results (2217 blood samples from 1303 patients) of routine micronutrient screens (plasma zinc, copper, selenium, and vitamins A, B-6, C, and E) and all vitamin D results (4327 blood samples from 3677 patients) were extracted from the laboratory database. C-reactive protein concentrations were measured as a marker of the severity of inflammation and categorized into 6 groups; for each group, plasma micronutrient concentrations and percentage changes were calculated. RESULTS: Except for copper and vitamin E, all plasma micronutrient concentrations decreased with increasing severities of the acute inflammatory response. For selenium and vitamins B-6 and C, this occurred with only slightly increased C-reactive protein concentrations of 5 to 10 mg/L. For each micronutrient, the change in plasma concentrations varied markedly from patient to patient. The magnitude of the effect was greatest for selenium and vitamins A, B-6, C, and D, for which the median plasma concentrations decreased by >40%. CONCLUSIONS: The clinical interpretation of plasma micronutrients can be made only with knowledge of the degree of inflammatory response. A reliable clinical interpretation can be made only if the C-reactive protein is <20 mg/L (plasma zinc), <10 mg/L (plasma selenium and vitamins A and D), or <5 mg/L (vitamins B-6 and C).

A comparison of inflammation-based prognostic scores in patients with cancer. A Glasgow Inflammation Outcome Study.

INTRODUCTION: Components of the systemic inflammatory response, combined to form inflammation-based prognostic scores (modified Glasgow Prognostic Score (mGPS), Neutrophil Lymphocyte Ratio (NLR), Platelet Lymphocyte Ratio (PLR), Prognostic Index (PI), Prognostic Nutritional Index (PNI)) have been associated with cancer specific survival. The aim of the present study was to compare the prognostic value of these scores. METHODS: Patients (n=27,031) who had an incidental blood sample taken between 2000 and 2007 for C-reactive protein, albumin, white cell, neutrophil, lymphocyte and platelet counts, as well as a diagnosis of cancer (Scottish Cancer Registry) were identified. Of this group 8759 patients who had been sampled within two years following their cancer diagnosis were studied. RESULTS: On follow up, there were 5163 deaths of which 4417 (86%) were cancer deaths. The median time from blood sampling to diagnosis was 1.7 months. An elevated mGPS, NLR, PLR, PI and PNI were predictive of a reduced cancer specific survival independent of age, sex and deprivation and tumour site (all p<0.001). The area under the receiver operator curves was greatest for mGPS and PI. Specifically, in colorectal cancer, an elevated mGPS and PI were predictive of a reduced cancer specific survival independent of age, sex, deprivation and tumour stage (both p<0.001). CONCLUSION: The results of the present study show that systemic inflammation-based scores, in particular the mGPS and PI, have prognostic value in cancer independent of tumour site. Based on the present results and the existing validation literature, the mGPS should be included in the routine assessment of all patients with cancer.

The relation between acute changes in the systemic inflammatory response and plasma 25-hydroxyvitamin D concentrations after elective knee arthroplasty.

BACKGROUND: Studies indicate that low plasma 25-hydroxyvitamin D [25(OH)D] is associated with a range of disease processes, many of which are inflammatory. However, other lipid-soluble vitamins decrease during the systemic inflammatory response, and this response may confound the interpretation of plasma 25(OH)D. OBJECTIVE: The objective was to examine whether plasma 25(OH)D concentrations change during evolution of the systemic inflammatory response. DESIGN: Patients (n = 33) who underwent primary knee arthroplasty had venous blood samples collected preoperatively and postoperatively (beginning 6-12 h after surgery and on each morning for 5 d) for the measurement of 25(OH) D, vitamin D-binding protein, parathyroid hormone (PTH), calcium, C-reactive protein, and albumin. A final sample was collected at 3 mo. RESULTS: Preoperatively, most patients were 25(OH)D deficient (<50 nmol/L) and had secondary hyperparathyroidism (PTH > 5 pmol/L). Age, sex, body mass index, season, medical history, and medication use were not associated with significant differences in preoperative plasma 25(OH)D concentrations. By day 2 there was a large increase in C-reactive protein concentrations (P < 0.001) and a significant decrease in 25(OH)D of ≈40% (P < 0.001). C-reactive protein, 25(OH)D, and calculated free 25(OH)D had not returned to preoperative concentrations by 5 d postoperatively (all P < 0.001). At 3 mo, 25(OH)D and free 25(OH)D remained significantly lower (20% and 30%, respectively; P < 0.01). CONCLUSION: Plasma concentrations of 25(OH)D decrease after an inflammatory insult and therefore are unlikely to be a reliable measure of 25(OH)D status in subjects with evidence of a significant systemic inflammatory response.

Comparison of urinary albumin and urinary total protein as predictors of patient outcomes in CKD.

BACKGROUND: Proteinuria is common and is associated with adverse patient outcomes. The optimal test of proteinuria to identify those at risk is uncertain. This study assessed albuminuria and total proteinuria as predictors of 3 patient outcomes: all-cause mortality, start of renal replacement therapy (RRT), and doubling of serum creatinine level. STUDY DESIGN: Retrospective longitudinal cohort study. SETTING & PARTICIPANTS: Nephrology clinic of a city hospital in Scotland; 5,586 patients with chronic kidney disease (CKD) and proteinuria measured in random urine samples (n = 3,378) or timed urine collections (n = 1,808). PREDICTORS: Baseline measurements of albumin-creatinine ratio (ACR), total protein-creatinine ratio (PCR), 24-hour albuminuria, and total proteinuria. OUTCOMES: All-cause mortality, start of RRT, and doubling of serum creatinine level were assessed using receiver operating characteristic curves and Cox proportional hazards models. MEASUREMENTS: Blood pressure, serum creatinine level, ACR, PCR, date of death, date of starting RRT. RESULTS: Patients were followed up for a median of 3.5 (25th-75th percentile, 2.1-6.0) years. For all outcomes, adjusted HRs were similar for PCR and ACR (derived from random urine samples and timed collections): death, 1.41 (95% CI, 1.31-1.53) vs 1.38 (95% CI, 1.28-1.50); RRT, 1.96 (95% CI, 1.76-2.18) vs 2.33 (95% CI, 2.06-3.01); and doubling of serum creatinine level, 2.03 (95% CI, 1.87-2.19) vs 1.92 (95% CI, 1.78-2.08). Receiver operating characteristic curves showed almost identical performance for ACR and PCR for the 3 outcome measures. Adjusted HRs for ACR and PCR were similar when derived from random urine samples or timed collections and compared with 24-hour total protein and albumin excretion for each outcome measure. LIMITATIONS: This is a retrospective study. CONCLUSIONS: Total proteinuria and albuminuria perform equally as predictors of renal outcomes and mortality in patients with CKD. ACR and PCR were as effective as 24-hour urine samples at predicting outcomes and are more convenient for patients, clinicians, and laboratories. Both ACR and PCR stratify risk in patients with CKD.

Plasma dimethylarginines during the acute inflammatory response.

INTRODUCTION: Asymmetric dimethylarginine (ADMA) concentrations are increased in critically ill patients and may play a role in multiple organ failure. However, plasma ADMA concentrations during the development of the inflammatory response have not been documented. We measured plasma ADMA, as well as urinary excretion of its major metabolite dimethylamine, and nitrate as a marker of nitric oxide synthase (NOS) activity, in a cohort of patients undergoing elective knee arthroplasty that is known to provoke a significant inflammatory response. METHODS: Thirty-eight patients were recruited. Fasting venous blood samples were obtained pre-operatively and at 12h and daily until the fifth post-operative day. ADMA and symmetric dimethylarginine (SDMA) were measured by high-performance liquid chromatography (HPLC). Urinary dimethylamine and nitrate were measured pre-operatively and on each of the post-operative mornings using HPLC and expressed as a ratio to creatinine. RESULTS: Plasma ADMA fell by a median of 31% during the post-operative period, reaching a nadir on day 2, and recovering to baseline by the end of the study. SDMA showed no significant changes. No increase in urinary dimethylamine excretion was noted until day 5 post-op, whereupon it doubled. Urinary nitrate showed a small, but nonsignificant decrease on day 2, suggesting no major activation of NOS activity. CONCLUSIONS: Plasma ADMA concentration decreases rapidly and transiently during the first 48h of acute inflammation. This appears not be caused by increased catabolism and may reflect increased cellular partitioning. This may serve to regulate NOS activity and prevent harmful increases in inducible NOS in situations where it is not appropriate.

Relation between riboflavin, flavin mononucleotide and flavin adenine dinucleotide concentrations in plasma and red cells in patients with critical illness.

BACKGROUND: There is some evidence that the relationship between plasma and red cell vitamin B2 concentrations is perturbed in the critically ill patient. The aim of the present study was to examine the longitudinal interrelationships between riboflavin, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) in plasma and red cells in patients with critical illness. METHODS: Riboflavin, FMN and FAD concentrations were measured, by HPLC, in plasma and red cells in healthy subjects (n=119) and in critically ill patients (n=125) on admission and on follow-up. RESULTS: On admission, compared with the controls, critically ill patients had significantly higher plasma riboflavin and FMN concentrations (p<0.001) and lower median plasma FAD concentrations (p<0.001). In the red cell, FAD concentrations were significantly lower in critically ill patients (p<0.001). In healthy subjects, plasma riboflavin was directly associated with both plasma FMN (r(s)=0.55, p<0.001) and plasma FAD (r(s)=0.49, p<0.001). Red cell riboflavin was directly associated with red cell FMN (r(s)=0.52, p<0.001) but not red cell FAD. In the critically ill patients, plasma riboflavin was not significantly associated with either plasma FMN or FAD. Red cell riboflavin was directly associated with red cell FMN (r(s)=0.79, p<0.001) and red cell FAD (r(s)=0.72, p<0.001). Longitudinal measurements (n=60) were similar. CONCLUSIONS: The relationship between plasma riboflavin, FMN and FAD was significantly perturbed in critical illness. This effect was less pronounced in red cells. Therefore, red cell FAD concentrations are more likely to be a reliable measure of status in the critically ill patient.

Home parenteral nutrition in Scotland: frequency of monitoring, adequacy of review and consequence for complication rates.

BACKGROUND AND AIMS: Home parenteral nutrition (HPN) has been a major advance in the management of patients with gastrointestinal failure. It demands regular monitoring to ensure optimal intake, assess treatment response, and minimize complications. The Scottish Home Parenteral Nutrition Managed Clinical Network (MCN) produced a guideline advising three-monthly monitoring of biochemistry, micronutrients, vitamins, weight, and anthropometry. This study assesses the frequency and adequacy of monitoring of these complex patients and investigates any effect of this on complication rate. METHODS: All patients receiving HPN funded by the National Health Service in Scotland are known to the MCN via the National Contract for provision of HPN. Data are collected in an MS Access database; 2006 data is extracted. RESULTS: There were 141 HPN clinic assessments for 53 patients. Sixteen (30%) were seen every 100 d as recommended by the guideline. Sixty percent of reviews were within 100 d of the previous appointment. Duration of HPN treatment inversely correlated with frequency of review. Bloods were checked at 93% of reviews, weight at 86%, anthropometry at 24%, and vitamins and micronutrients measurement at 62% of clinics. No difference in complication rates was found between those reviewed within the recommended time periods and those reviewed less often. CONCLUSIONS: Less than one-third of patients met the current recommended review frequency. Routine bloods and weight measurements were good, micronutrients less so; anthropometry is poorly monitored. Complication rates were not increased in HPN patients reviewed less often.

Assessing proteinuria in chronic kidney disease: protein-creatinine ratio versus albumin-creatinine ratio.

BACKGROUND: Quantification of proteinuria is important in the assessment of chronic kidney disease (CKD). The aim of this study was to investigate the optimal test to identify significant proteinuria. METHODS: We retrospectively assessed the relationship between total protein:creatinine ratio (TPCR), albumin:creatinine ratio (ACR) and 24-h urine total protein in 6842 patients with CKD focusing on performance at thresholds of 0.5 and 1 g/day of proteinuria. RESULTS: The relationship between ACR and TPCR is non-linear. TPCR is highly correlated with 24-h urine protein (Spearman's rho = 0.91), though ACR also performs well (rho = 0.84). Using receiver-operator characteristic curve analysis, TPCR outperforms ACR at predicting 0.5 g/day [area under the curve (AUC) 0.967 vs 0.951, P < 0.001] and 1 g/day of proteinuria (AUC 0.968 vs 0.947, P = 0.004). A TPCR threshold of 100 mg/mmol had a higher sensitivity (94% vs 79%) but lower specificity (88% vs 95%) than an ACR of 70 mg/mmol to predict 1 g/day of total proteinuria. To achieve comparable sensitivity, the ACR threshold falls to 17.5 mg/mmol, with lower specificity than TPCR (69.8%). Sensitivity of TPCR rose with increasing age, and in females: to achieve 95% sensitivity in a man <49 years, requires a TPCR of 65 mg/mmol, compared to 179 mg/mmol in a woman >79 years. Non-albumin proteinuria was a lower proportion of total proteinuria in patients receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockade than in those who were not (P < 0.001). CONCLUSIONS: TPCR is a more sensitive screening test than ACR to predict clinically relevant proteinuria. The diagnostic performance of both tests varies substantially with age and gender, and should be taken into consideration when interpreting results. Total proteinuria cannot be adequately predicted from ACR, and our results suggest that caution is appropriate before utilizing ACR in patients with non-diabetic CKD.

Assessment of vitamin E status in patients with systemic inflammatory response syndrome: plasma, plasma corrected for lipids or red blood cell measurements?

BACKGROUND: There is some evidence that the plasma vitamin E status is perturbed as part of systemic inflammatory response and correcting this with other plasma markers may not lead to reliable results. The aim of the present study was to examine the longitudinal inter-relationships between plasma and red blood cell vitamin alpha-tocopherol in patients with systemic inflammatory response syndrome. METHODS: alpha-tocopherol concentrations were measured, by HPLC, in plasma and red blood cells in normal subjects (n=67) and in critically ill patients with systemic inflammatory response syndrome (n=82) on admission and on follow-up. RESULTS: Plasma alpha-tocopherol was significantly lower in the critically ill patients compared with the controls (all p<0.001) with 41% of patients having concentrations below the 95% confidence interval. In contrast, when corrected for cholesterol, alpha-tocopherol concentrations were significantly higher in the critically ill patients compared with the control group (p<0.001, 27% above the 95% confidence interval) and when corrected for triglycerides, alpha-tocopherol concentrations were significantly lower in the critically ill patients compared with the control group (p<0.001). Red blood cell alpha-tocopherol corrected for haemoglobin was similar (p=0.852) in the critically ill patients compared with control subjects. The longitudinal measurements (n=53) gave similar results. CONCLUSIONS: These results indicate that there is a discrepancy between vitamin E measurements in plasma, in plasma corrected for lipids and in red blood cells. Although the value of correcting vitamin E concentrations by lipids is well established in population studies, the present study indicates that such correction is unreliable in the presence of systemic inflammatory response syndrome and that vitamin E status should be assessed using red blood cell alpha-tocopherol measurement.

HPLC analysis of asymmetric dimethylarginine (ADMA) and related arginine metabolites in human plasma using a novel non-endogenous internal standard.

BACKGROUND: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthesis which has been implicated in the endothelial dysfunction. Methods for ADMA measurement often yield widely differing results, and few methods simultaneously offer satisfactory accuracy and precision. We describe a fully validated HPLC method for analysis of arginine and its methylated derivatives in human plasma using a novel internal standard. METHODS: Arginine and related metabolites are extracted from plasma by solid phase extraction (SPE), derivatised with ortho-phthaldialdehyde and separated by isocratic reverse phase chromatography. Monoethylarginine (MEA), which is not endogenously present in human plasma was used as internal standard. SPE and chromatographic procedures are optimised and recovery, precision, linearity and sensitivity of the assay established. The suitability and performance of MEA is compared with that of monomethylarginine (MMA), the internal standard most commonly used in HPLC methods. RESULTS: SPE yields high and reproducible recoveries (>90%). The analytes of interest are chromatographically well resolved. The method has high sensitivity (LOD, 0.01 micromol/L for arginine and 0.001 micromol/L for ADMA, SDMA and homoarginine) and good precision (CV, 2.5% for ADMA). The data obtained with the internal standards MEA and MMA is comparable in terms of assay precision and population reference intervals. CONCLUSIONS: We describe an optimised isocratic HPLC method for the simultaneous measurement of arginine and related metabolites in plasma which exhibits satisfactory precision and is suitable for routine use. Its main advantage over other published HPLC methods is the use of the novel internal standard, MEA, which unlike other commonly used internal standards is not inherent in human plasma.

Vitamin antioxidants, lipid peroxidation, tumour stage, the systemic inflammatory response and survival in patients with colorectal cancer.

Both the tumour growth and progression and the systemic inflammatory response have the potential to increase oxidative stress. We therefore examined the relationship between lipid-soluble antioxidant vitamins, lipid peroxidation, the systemic inflammatory response and survival in patients with primary operable (n = 53) and advanced inoperable (n = 53) colorectal cancer. Compared with those patients with primary operable colorectal cancer, patients with unresectable liver disease had significantly lower median concentrations of alpha-tocopherol (p < 0.001), lutein (p < 0.001), lycopene (p < 0.001), alpha-carotene (p < 0.01) and beta-carotene (p < 0.001) and higher malondialdehyde concentrations. An elevated systemic inflammatory response (Glasgow prognostic score, mGPS) was associated with a greater proportion of females (p < 0.05) and more advanced tumour stage (p < 0.05), lower circulating levels of retinol (p < 0.01), lutein (p < 0.01), lycopene (p < 0.01) and alpha- (p < 0.01) and beta-carotene but not MDA (p = 0.633). In the liver metastases group 41 patients died of their cancer and a further 1 patient died of intercurrent disease on follow-up. On univariate survival analysis, mGPS (p < 0.01), retinol (p < 0.001), alpha-tocopherol (p < 0.05) and alpha-carotene (p < 0.05) were associated significantly with cancer-specific survival. On multivariate survival analysis of these significant variables, only mGPS (p < 0.01) and retinol (p < 0.001) were independently associated with cancer-specific survival. The results of the present study showed that the systemic inflammatory response was associated with a reduction of lipid-soluble antioxidant vitamins, whereas advanced tumour stage was associated with increased lipid peroxidation in patients with colorectal cancer. Of the antioxidant vitamins measured, only retinol was independently associated with cancer-specific survival.

Relation between pyridoxal and pyridoxal phosphate concentrations in plasma, red cells, and white cells in patients with critical illness.

BACKGROUND: Evidence suggests that the relation between plasma and red cell vitamin B-6 concentrations is perturbed as part of the systemic inflammatory response in critically ill patients. OBJECTIVE: The aim was to examine the cross-sectional and longitudinal interrelations between pyridoxal (PL) and pyridoxal phosphate (PLP) concentrations in plasma and red and white cells in patients with critical illness. DESIGN: PLP and PL concentrations were measured by HPLC in plasma and red and white cells in normal subjects (n = 126) and critically ill patients (n = 96) on admission and on follow-up. RESULTS: On admission, compared with the controls, median plasma PLP and PL (P < 0.001 and < 0.01, respectively) and red cell PLP and PL (P < 0.001 and < 0.05, respectively) and their ratio (PLP:PL) in plasma and red cells (P < 0.001 and < 0.01, respectively) were significantly lower in the critically ill. In critically ill patients, plasma PLP:PL was significantly lower than red cell PLP:PL (P = 0.001) and white cell PLP:PL (P = 0.008). Plasma PL concentration was directly associated with both red cell PL (r(s) = 0.73, P < 0.001) and white cell PL (r(s) = 0.68, P < 0.001). Red cell PL and white cell PL were directly associated with red cell PLP (r(s) = 0.82, P < 0.001) and white cell PLP (r(s) = 0.68, P < 0.001), respectively. Longitudinal measurements (n = 48) were similar. CONCLUSIONS: The relation between plasma PLP and PL was significantly perturbed in critical illness. This effect was less pronounced in red and white cells. Therefore, these results confirm the hypothesis that intracellular PLP concentrations are more likely to be a reliable measure of status than are plasma measurements in the critically ill patient.

Acute inflammatory response does not affect erythrocyte concentrations of copper, zinc and selenium.

BACKGROUND & AIMS: Measuring the nutritional status of trace elements in plasma is invalidated in the presence of a systemic inflammatory response. We examined the potential of erythrocytes to assess copper, zinc and selenium status in such situations. METHODS: Venous blood samples were withdrawn pre-operatively and at 12, 24, 48, 72 and 168 h post-operatively from 11 patients (6 males and 5 females) who were admitted for elective knee arthroplasty. C-reactive protein, albumin, copper, zinc, selenium and iron were measured in plasma and erythrocytes. RESULTS: Plasma zinc and selenium concentrations fell significantly: 95% confidence intervals (CI)=-32% to -44% and -22% to -36%, respectively. Copper concentrations fell transiently and then increased significantly: CI=12-43%. No significant changes were seen in trace element concentrations in erythrocytes expressed either as a ratio of haemoglobin or iron concentration. Erythrocyte iron levels correlated significantly with haemoglobin (r=0.93). CONCLUSIONS: Plasma concentrations of copper, zinc and selenium are unreliable markers of status in patients with an acute inflammatory response. Erythrocyte concentrations of these trace elements may provide a more reliable measure in long-term studies of patients with a chronic systemic inflammatory response. Iron can be used instead of haemoglobin as the denominator when expressing erythrocyte concentrations of trace elements.

Assessment of dietary intake and trace element status in patients with ileal pouch-anal anastomosis.

PURPOSE: Panproctocolectomy and ileal pouch-anal anastomosis is the operation of choice for patients with ulcerative colitis and familial polyposis. The long-term nutritional consequences after pouch surgery are unknown. We have assessed the nutritional status of the essential trace elements-zinc, copper, manganese, and selenium-in patients several years (median, 10 (range, 2-15) years) after surgery. METHODS: Fifty-five patients with uncomplicated ileal pouch-anal anastomosis and 46 healthy control subjects were studied. A dietary assessment of trace element intake was undertaken by using a semiquantitative food frequency questionnaire. The patients' trace elements status for zinc, copper, manganese, and selenium was assessed by measuring their concentrations in blood. RESULTS: The dietary intake of individual trace elements was similar in both groups (all P values > 0.4). There was no significant difference in the concentrations of plasma copper, zinc, and selenium between patients and healthy control subjects (all P values > 0.07). The concentration of whole blood manganese was significantly higher (P = 0.004) in patients (median, 178.5 nmol/l; range, 59-478 nmol/l) compared with healthy control subjects (median, 140 nmol/l; range, 53-267 nmol/l). Four (7 percent) patients had manganese concentrations more than three standard deviations of the mean of control group (>255 nmol/l). CONCLUSIONS: This study shows that patients who have had uncomplicated pouch surgery have a normal dietary intake of trace elements and do not develop deficiencies in copper, zinc, manganese, and selenium. However, these patients may be at increased risk of manganese toxicity.

HPLC method for plasma vitamin K1: effect of plasma triglyceride and acute-phase response on circulating concentrations.

BACKGROUND: The plasma concentration of vitamin K(1) (phylloquinone) is the most reliable index for assessing vitamin K status. Our aim was to analytically validate an HPLC method for quantifying phylloquinone in plasma and to examine the effect of plasma triglyceride concentration on the phylloquinone reference interval. We also examined the effect of acute-phase response on phylloquinone concentration in plasma. METHODS: Phylloquinone was extracted from fasting plasma samples by deproteinization and C18 solid-phase extraction, separated by reversed-phase HPLC, and detected fluorometrically after postcolumn reduction with a platinum catalyst. We synthesized a novel internal calibrator, docosyl naphthoate. RESULTS: The recovery of phylloquinone was >90%. Between-run imprecision was 8.7%-9.0%, and within-run imprecision was 3.8%-7.0%. The linearity was up to 44.8 nmol/L, limit of detection 0.08 nmol/L, and limit of quantification 0.14 nmol/L. The correlation between plasma phylloquinone and triglyceride concentrations was r = 0.7 in the reference population. The 95% reference interval for the phylloquinone:triglyceride ratio was 0.20 to 2.20 nmol/mmol. Plasma concentrations of C-reactive protein were significantly increased, whereas triglyceride and phylloquinone but not the phylloquinone:triglyceride ratio were transiently decreased >50% after surgery. CONCLUSION: Phylloquinone population reference intervals should be expressed as a ratio of the triglyceride concentration. Phylloquinone concentrations in plasma are decreased in acute-phase response and, unless corrected for plasma triglyceride concentration, are unlikely to be a reliable index of vitamin K status.

Vitamin antioxidants, lipid peroxidation and the systemic inflammatory response in patients with prostate cancer.

The relationship between lipid soluble antioxidant vitamins, lipid peroxidation, disease stage and the systemic inflammatory response were examined in healthy subjects (n = 14), patients with benign prostate hyperplasia BPH (n = 20), localized (n = 40) and metastatic (n = 38) prostate cancer. Prostate cancer patients had higher concentrations of malondialdehyde (p < 0.05) and lower circulating concentrations of lutein (p < 0.05), lycopene (p < 0.001) and beta-carotene (p < 0.05). Patients with metastatic prostate cancer, when compared with patients having localized disease, had a higher Gleason score (p < 0.01) and had more hormonal treatment, but lower concentrations of PSA (p < 0.05), alpha-tocopherol (p < or = 0.05), retinol (p < 0.01), lutein (p < 0.05) and lycopene (p < 0.01). In the prostate cancer patients, PSA was correlated with the concentrations of the lipid peroxidation product, malondialdehyde (rs= 0.353, p = 0.002). C-reactive protein was not correlated with the vitamin antioxidants nor malondialdehyde. In contrast, there was a negative correlation between malondialdehyde concentrations and both lutein (rs= -0.263, p = 0.020) and lycopene (rs= -0.269, p = 0.017). These results indicate that lower concentrations of carotenoids, in particular, lycopene reflect disease progression rather than the systemic inflammatory response in patients with prostate cancer.

Randomized controlled trial of homocysteine-lowering vitamin treatment in elderly patients with vascular disease.

BACKGROUND: Homocysteine is an independent risk factor for vascular disease and is associated with dementia in older people. Potential mechanisms include altered endothelial and hemostatic function. OBJECTIVE: We aimed to determine the effects of folic acid plus vitamin B-12, riboflavin, and vitamin B-6 on homocysteine and cognitive function. DESIGN: This was a factorial 2 x 2 x 2, randomized, placebo-controlled, double-blind study with 3 active treatments: folic acid (2.5 mg) plus vitamin B-12 (500 microg), vitamin B-6 (25 mg), and riboflavin (25 mg). We studied 185 patients aged >or=65 y with ischemic vascular disease. Outcome measures included plasma homocysteine, fibrinogen, and von Willebrand factor at 3 mo and cognitive change (determined with the use of the Letter Digit Coding Test and on the basis of the Telephone Interview of Cognitive Status) after 1 y. RESULTS: The mean (+/-SD) baseline plasma homocysteine concentration was 16.5 +/- 6.4 micromol/L. This value was 5.0 (95% CI: 3.8, 6.2) micromol/L lower in patients given folic acid plus vitamin B-12 than in patients not given folic acid plus vitamin B-12 but did not change significantly with vitamin B-6 or riboflavin treatment. Homocysteine lowering with folic acid plus vitamin B-12 had no significant effect, relative to the 2 other treatments, on fibrinogen, von Willebrand factor, or cognitive performance as measured by the Letter Digit Coding Test (mean change: -1; 95% CI: -2.3, 1.4) and the Telephone Interview of Cognitive Status (-0.7; 95% CI: -1.7, 0.4). CONCLUSION: Oral folic acid plus vitamin B-12 decreased homocysteine concentrations in elderly patients with vascular disease but was not associated with statistically significant beneficial effects on cognitive function over the short or medium term.

The relationship between the acute changes in the systemic inflammatory response, lipid soluble antioxidant vitamins and lipid peroxidation following elective knee arthroplasty.

BACKGROUND AND AIMS: The aim of the present study was to examine the time course of the change in the concentrations of plasma retinol, alpha-tocopherol, lutein, lycopene, alpha-carotene, beta-carotene (antioxidant vitamins) and malondialdehyde (lipid peroxidation) in patients following elective knee arthroplasty. METHODS: Patients (n=20) who underwent an elective knee arthroplasty, had venous blood samples withdrawn pre-operatively and at 12, 24, 48, 72 and 168 h after the start of surgery for the analysis of circulating concentrations of C-reactive protein, albumin, cholesterol, triglycerides and malondialdehyde and also the lipid soluble antioxidants vitamins. RESULTS: Over the study period of 0-168 h there was a significant increase in circulating C-reactive protein concentrations (peak 48 h, P<0.001) and a significant fall in albumin, cholesterol and triglyceride concentrations (trough 48 h, P<0.001). Malondialdehyde concentrations fell by approximately 35% (P<0.001) during the study period. However, they did not alter significantly over the study period when adjusted for triglyceride (P=0.309). The plasma concentrations of retinol, alpha-tocopherol, lutein, lycopene, alpha-carotene and beta-carotene all fell (P0.001). When adjusted for cholesterol, the reductions in plasma concentrations of alpha-tocopherol, lutein, lycopene, and beta-carotene in the post-operative period were no longer statistically significant. CONCLUSIONS: The results of the present study indicate that, in apparently healthy subjects undergoing an acute inflammatory insult, circulating lipid soluble vitamin antioxidants are transiently reduced. However, when corrected for lipids the concentrations were similar to those of baseline. In the absence of an increase in lipid peroxidation such falls in plasma concentrations of lipid soluble vitamins are unlikely to be a reliable measure of status.

Outcomes of pregnancy complicated by thyroid disease.

AIMS: To perform a case note review of pregnancies complicated by thyroid dysfunction to determine management and therapeutic intervention in relation to pregnancy outcome. METHODS: A retrospective case note analysis of 81 ongoing pregnancies in 70 pregnant women with a history of thyroid dysfunction over a period of 5 years at the Glasgow Royal Maternity Hospital (GRMH), Glasgow, Scotland, United Kingdom. The results of thyroid function tests and whether a change in treatment was instituted were recorded. Thyroid function was assessed by standard laboratory reference ranges for free thyroxine (FT4) and thyroid stimulating hormone (TSH) in all trimesters. Other parameters were also noted. RESULTS: Medication levels needed to be increased in the hypothyroid group (45%), and decreased (38%) in the hyperthyroid group. CONCLUSION: Pregnancy outcome was good in majority of cases given appropriate replacement therapy for stated reference values.

Elevated alanine aminotransferase predicts new-onset type 2 diabetes independently of classical risk factors, metabolic syndrome, and C-reactive protein in the west of Scotland coronary prevention study.

We examined the association of serum alanine aminotransferase (ALT) with features of the metabolic syndrome and whether it predicted incident diabetes independently of routinely measured factors in 5,974 men in the West of Scotland Coronary Prevention Study. A total of 139 men developed new diabetes over 4.9 years of follow-up. ALT, but not aspartate aminotransferase, levels increased progressively with the increasing number of metabolic syndrome abnormalities from (means +/- SD) 20.9 +/- 7.6 units/l in those with none to 28.1 +/- 10.1 units/l in those with four or more (P < 0.001). In a univariate analysis, men with ALT in the top quartile (ALT >/=29 units/l) had an elevated risk for diabetes (hazard ratio 3.38 [95% CI 1.99-5.73]) versus those in the bottom quartile (<17 units/l). ALT remained a predictor with adjustment for age, BMI, triglycerides, HDL cholesterol, systolic blood pressure, glucose, and alcohol intake (2.04 [1.16-3.58] for the fourth versus first quartile). In stepwise regression, incorporating ALT and C-reactive protein (CRP) together with metabolic syndrome criteria, elevated ALT (>/=29 units/l), and CRP (>/=3 mg/l) predicted incident diabetes, but low HDL cholesterol and hypertension did not. Thus, elevated ALT levels within the "normal" range predict incident diabetes. The simplicity of ALT measurement and its availability in routine clinical practice suggest that this enzyme activity could be included in future diabetes prediction algorithms.