Red cell distribution width as predictor for mortality in critically ill patients.

BACKGROUND: The objective of this study was to evaluate whether the red cell distribution width (RDW) is a significant risk factor for hospital mortality in critically ill patients and to investigate whether RDW is a parameter indicating inflammation, or a risk factor independent of inflammation. METHODS: We studied all patients admitted to a ten-bed mixed intensive care unit in the Netherlands between May 2005 and December 2011 for whom RDW was available, and who had not received a blood transfusion in the preceding three months. Inflammation was measured by C-reactive protein and leucocyte count. Analyses included correlation, logistic regression analysis, and receiveroperating characteristic (ROC) curves. RESULTS: We included 2915 patients, of whom 387 (13.3%) did not survive to hospital discharge. In univariate analysis higher RDW values were associated with increased hospital mortality. In multivariate analysis RDW remained an independent risk factor for mortality after correction for APACHE II score, age, admission type and mechanical ventilation (odds ratio 1.04, 95% confidence interval 1.02-1.06, for each femtolitre of RDW). Adding RDW to APACHE II, however, increased the area under the ROC curve marginally (from 0.845 to 0.849, p<0.001). RDW was not correlated with C-reactive protein and leucocyte count, refuting the hypothesis that the association between RDW and outcome is mediated through inflammation. CONCLUSION: In critically ill patients, the RDW on ICU admission was an independent predictor of mortality. Since RDW was not correlated with inflammation, the underlying mechanism of this association warrants further investigation.

Estimated incidence of sickle-cell disease in Aruba and St. Maarten suggests cost-effectiveness of a universal screening programme for St. Maarten.

OBJECTIVE: To estimate the incidence of Sickle-Cell Disease (SCD) in Aruba and St. Maarten and to determine whether universal screening would be cost-effective according to United Kingdom criteria. METHODS: Consecutive cord blood samples were collected in Aruba and the Dutch part of St. Maarten during 3 and 4 months, respectively. Samples were subjected to High Performance Liquid Chromatography (HPLC) screening of haemoglobin variants. RESULTS: Of the 368 samples (87.6% of all registered births) collected in Aruba, 10 (2.72%; CI 1.3, 4.9%) tested heterozygous for the Sickle-cell gene (HbAS) and 7 (1.90%; CI 0.8, 3.9%) for the haemoglobin C gene (HbAC). Of the 193 samples (83.5%) collected in St. Maarten, 14 (7.25%; CI 4.0, 11.9%) contained HbAS and 10 (5.18%; CI 2.5, 9.3%) HbAC. Hardy-Weinberg equilibrium predicted an incidence of 2.65% for HbAS and 1.86% for HbAC in Aruba and 6.80% for HbAS and 4.86% for HbAC in St. Maarten. These figures imply a newborn rate of about 2 SCD patients per 3 years in Aruba and 2 SCD patients per year in St. Maarten. CONCLUSIONS: Universal screening of newborns for SCD seems cost-effective for St. Maarten.

Plasma levels of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, are elevated in sickle cell disease.

In recent years an important role has been ascribed to a reduced nitric oxide (NO) availability in the pathophysiology of sickle cell disease (SCD). Endogenously produced inhibitors of NO synthase, in particular asymmetric dimethylarginine (ADMA), are currently considered of importance in various vascular disease states characterized by reduced NO availability. We determined ADMA levels in plasma of 12 adult sickle cell patients (eight HbSS and four HbSC), and compared these to plasma levels in race- and age-matched controls. Sickle cell patients were characterized by strongly elevated levels of ADMA [HbSS: median 0.63 micromol/l (interquartile range 0.54-0.85), HbSC: 0.43 micromol/l (0.40-0.46), HbAA: 0.33 micromol/l (0.32-0.35) p<0.001]. ADMA levels were highest in HbSS patients with lowest hemoglobin levels and highest leukocyte counts, and in HbSS patients ADMA levels were positively associated with serum levels of soluble vascular cell adhesion molecule-1. These results suggest an important role of ADMA in limiting NO availability in SCD, and its role in the pathophysiology of SCD should be further investigated.

Curaçao patients with coronary artery disease have a higher prevalence of the HFE C282Y mutation.

Epidemiological studies indicate a positive relation between iron status and coronary artery disease (CAD) risk The HFE C282Y allele is associated with increased iron status and higher CAD risk. We investigated whether HFE C282Ymight be a CAD risk factor in Curaçao in a case-control study design. The patient group comprised 42 men and 10 women. Fifty-four men and 30 women without history of CAD served as age and gender matched controls. HFE C282Y genotypes were established using sequence-specific priming polymerase chain reaction. None of the investigated subjects were homozygous for HFE C282Y, whereas 5/52 (9.6%) CAD patients and 1/84 controls (1.2%) were heterozygous for HFE C282Y (p = 0.03). The HFE C282Y mutation was 8.8 fold (95% CI 1.001, 77.8; p = 0.049) more prevalent in CAD patients than in controls. The HFE C282Y allele frequency in Curaçao is higher than that of African populations, but comparable with that of Jamaica. We conclude that Curaçao CAD patients have somewhat higher frequency of HFE C282Y heterozygosity than controls, and that the HFE C282Y allele frequency in the Curaçao population is higher than might be expected in persons of African descent. The consequences of HFE C282Y heterozygosity as CAD risk factor are as yet uncertain, since there is no proof that iron lowering reduces CAD risk.

Curaçao patients with coronary artery disease have a higher prevalence of the HFE C282Y mutation

Epidemiological studies indicate a positive relation between iron status and coronary artery disease (CAD) risk The HFE C282Y allele is associated with increased iron status and higher CAD risk. We investigated whether HFE C282Ymight be a CAD risk factor in Curaçao in a case-control study design. The patient group comprised 42 men and 10 women. Fifty-four men and 30 women without history of CAD served as age and gender matched controls. HFE C282Y genotypes were established using sequence-specific priming polymerase chain reaction. None of the investigated subjects were homozygous for HFE C282Y, whereas 5/52 (9.6) CAD patients and 1/84 controls (1.2) were heterozygous for HFE C282Y (p = 0.03). The HFE C282Y mutation was 8.8 fold (95 CI 1.001, 77.8; p = 0.049) more prevalent in CAD patients than in controls. The HFE C282Y allele frequency in Curaçao is higher than that of African populations, but comparable with that of Jamaica. We conclude that Curaçao CAD patients have somewhat higher frequency of HFE C282Y heterozygosity than controls, and that the HFE C282Y allele frequency in the Curaçao population is higher than might be expected in persons of African descent. The consequences of HFE C282Y heterozygosity as CAD risk factor are as yet uncertain, since there is no proof that iron lowering reduces CAD risk

Effect of three low-dose fish oil supplements, administered during pregnancy, on neonatal long-chain polyunsaturated fatty acid status at birth.

Adequate long-chain polyunsaturated fatty acid (LCP) status during pregnancy is important. We studied the effect of three low-dose fish oil supplements, administered during uncomplicated pregnancy, on neonatal LCP status at term delivery. Supplements were administered from the second trimester to delivery, either as fish oil capsules ("fish-1": 336 mg LCPomega3, n=15; and "fish-3": 1,008 mg LCPomega3, n=20) or milk-based supplement ("Mum": 528 mg LCPomega3, n=24). Fifty-seven untreated women served as controls. Fatty acids of umbilical veins (UV) and arteries (UA) were measured. The fish-1 group showed no differences, compared to controls. The Mum group had higher 20:5omega3, 22:5omega3, 22:6omega3, LCPomega3 and 22:6omega3/22:5omega6 in UV and UA. The fish-3 group had higher 22:5omega3 and 22:6omega3 (UA), LCPomega3 and 22:6omega3/22:5omega6 (UV and UA) and 20:3omega6 (UV). A 500-1000 mg daily LCPomega3 supplement, taken either as a milk-based supplement or fish oil capsules, effectively increases fetal LCPomega3 status, without affecting LCPomega6 status.

Low adjusted-dose acenocoumarol therapy in sickle cell disease: a pilot study.

Vasoocclusion is a continuous process in sickle cell disease (SCD) and accumulates to significant end organ damage, mostly irrespective of the occurrence of manifest acute vasoocclusive events. As there are indications that reversing the hypercoagulable state may be of clinical benefit in sickle cell patients, we performed a randomized, double blind, placebo-controlled, cross-over pilot study to assess the efficacy and safety of low-adjusted dose acenocoumarol therapy (International Normalized Ratio: 1.6-2.0) in SCD. Treatment consisted of either acenocoumarol or placebo for 14 weeks, after which treatment was discontinued for a period of five weeks. Then, patients initially on acenocoumarol received placebo (and vice versa) for 14 weeks. Therapy efficacy was assessed by comparing the frequency of vasoocclusive complications, the occurrence of bleeding, and clotting activation between acenocoumarol and placebo treatment of each individual patient. Twenty-two patients (14 homozygous [HbSS] and 8 double heterozygous sickle-C [HbSC]; aged 20-59 years) completed the entire study. Acenocoumarol treatment did not result in a significant reduction of acute vasoocclusive events (three painful crises during acenocoumarol, five painful crises during placebo). There was a marked reduction of the hypercoagulable state (depicted by a decrease in plasma levels of prothrombin F1.2 fragments [P = 0.002], thrombin-antithrombin complexes [P = 0.003], and D-dimer fragments [P = 0.001]) without the occurrence of major bleeding. Even though no clinical benefit (pertaining to the frequency of painful crises) was detected in this pilot study, the value of low adjusted-dose acenocoumarol for preventing specific events (such as strokes) and as a long-term treatment of sickle cell patients should be subject of further study.

Optimization of daily folate, vitamin B12 and vitamin B6 supplements in paediatric patients with sickle cell disease

We determined optimal folate, vitamin B12 and vitamin B6 dosages in 21 sickle cell disease (SCD) patients (11 HbSS, 10 HbSC; mean 7 years, range 7-16), using plasma homocysteine (Hcy) as functional marker. They received daily 400 g (0-3 weeks), 700 g (3-6) and 1000 g (6-70) folate; 1 (0-21), 3 (21-45 and 5 RDA (45-70) vitamin B12; and 1 RDA vitamin B6 (0-70). Blood was taken at baseline (P0) and after 3 (PI), 6 (P2), 9 (P3), 21 (P4), 33 (P5), 45 (P6), 57 (P7) and 70 (P8) weeks for measurement of erythrocyte (RBC), serum folate, plasma vitamin B12, whole blood vitamin B6 and plasma Hcy. Vitamin B6 increased from P0 to P1 and P1 to P2; vitamin B12 from P4 to P8; serum folate from P0 to P1 and P1 to P2; RBC folate from P0 to P1, P1 to P2 and P2 to P3. Hcy decreased from P1 to P2 and P4 to P6. Most pronounced Hcy decreases occurred from P0 to P1 (43 percent of patients), P1 to P2 (14 percent) and P4 to P5 (24 percent). Haematological indices did not change. Patients with HbSS had higher RBC folate at P1, P2 and P8. The entire group exhibited inverse relations between RBC folate and haemoglobin on P1, P2, P3, P6, P7 and P8. We conclude that RBC folate is less valuable for folate status assessment in SCD patients. The optimal daily supplement is 700 g folate (3.5-7 RDA vitamin B12 (4.2-6.0 g) and 1 RDA vitamin B6 (1.4-2.0 mg). This combination causes Hcy levels that do not decrease further upon higher dosages and may reduce by simple and relatively inexpensive means their inherently high risk of endothelial damage.(Au)

Predictive value of cord blood hematological indices and hemoglobin Barts for the detection of heterozygous alpha-thalassemia-2 in an African-Caribbean population.

BACKGROUND: Cord blood hemoglobin Barts (HbBarts) and hemocytometric indices may be used for classification of newborns into those without alpha-thalassemia-2 (alphaalpha/alphaalpha) and with heterozygous alpha-thalassemia-2 (-alpha(3.7)/alphaalpha). We investigated by logistic regression analysis whether the combination of HbBarts and hemocytometric indices improves classification compared with classification based on a single analyte. METHODS: HbBarts percentages and hemocytometric indices were determined in cord blood of 208 consecutive newborns in Curaçao (Netherlands Antilles). Of these, 157 had alphaalpha/alphaalpha and 51 had -alpha(3.7)/alphaalpha, as established by DNA analysis. RESULTS: Between-group differences were significant for erythrocytes, mean cell volume, mean cell hemoglobin (MCH), mean cell hemoglobin concentration, platelets, hemoglobin F(0) (HbF(0)), and HbBarts. The Logit equation of the logistic regression model, using MCH (pg) and HbBarts (%), was: 42.7164 + 5.7916(HbBarts) - 1.3110(MCH). A sensitivity of 100% was reached at a Logit value of -3.70. The corresponding specificity was 62.2%, and the predictive value of a positive test (PV+) was 46.3% (95% confidence interval, 37.0-55.7%). The relative information gains were as follows: 88% for the HbBarts-MCH combination, 26% for MCH (not significant), and 0% for HbBarts compared with the 24.6% -alpha(3.7)/alphaalpha prevalence. CONCLUSION: Combined use of cord blood HbBarts and MCH improves classification compared with classification based on single hemocytometric indices.

Umbilical vessels of preeclamptic women have low contents of both n-3 and n-6 long-chain polyunsaturated fatty acids.

BACKGROUND: Preeclampsia is characterized by enhanced platelet aggregation and vasoconstriction and is related to an elevated ratio of thromboxane A2 to prostacyclin I2. OBJECTIVE: We investigated whether altered eicosanoid production in preeclamptic women could be explained by the fatty acid composition of umbilical vessel walls and platelets. DESIGN: The fatty acid composition of maternal and umbilical platelets and of umbilical arteries and veins in 27 preeclamptic women and 24 normotensive women was determined. Between-group differences were analyzed with linear discriminant analysis, the Kruskal-Wallis test, or analysis of covariance with gestational age as the covariate. RESULTS: Platelets of preeclamptic women contained lower amounts of 20:5n-3 and a higher ratio of 20:4n-6 to 20:5n-3 than did platelets of normotensive women. Additionally, linear discriminant analysis revealed higher amounts of 20:4n-6 in platelets of preeclamptic women. Umbilical arteries and veins in preeclamptic women contained lower amounts of long-chain polyunsaturated fatty acids (PUFAs) of the n-3 series, n-6 long-chain PUFAs, and 20:3n-6 than did umbilical arteries and veins of normotensive women. Umbilical arteries also had lower amounts of 20:4n-6, higher amounts of 20:3n-9, and a higher ratio of 20:3n-9 to 20:4n-6. CONCLUSIONS: Low amounts of long-chain n-3 and n-6 PUFAs in umbilical vessels of preeclamptic women with adequate n-6 status may indicate insufficient transplacental transfer of long-chain PUFAs. The low amounts of 20:4n-6, high amounts of 20:3n-9, and high ratio of 20:3n-9 to 20:4n-6 in umbilical arteries may unfavorably affect local prostacyclin production. Low amounts of 20:3n-6 in umbilical arteries and veins and low amounts of 20:5n-3 in maternal platelets may contribute to the dominance of eicosanoids derived from 20:4n-6.

Elevated homocysteine levels indicate suboptimal folate status in pediatric sickle cell patients.

We investigated whether pediatric patients with sickle cell disease (SCD) (9 +/- 4 years; 27 homozygous SCD [HbSS]; 19 sickle-C disease [HbSC]) have different folate status compared with age-, sex-, and race-matched normal hemoglobin (HbAA) controls (n = 20), and whether their folate status can be improved by folate supplementation. The patients were supplemented with vitamins B6 and B12 during one week and with folate during the following week. Circulating folate, homocysteine, vitamin B6 and vitamin B12 levels were measured at baseline (patients and controls), after one week and after two weeks (patients). The patients had similar folate, vitamin B6, and vitamin B12, but higher homocysteine levels compared with HbAA controls (12.7 +/- 4.5 vs. 10.9 +/- 3.5 micromol/l; P = 0.04). Vitamin B6 and B12 supplementation did not change their homocysteine levels, but folate supplementation caused a 53% reduction (to 5.7 +/- 1.6). We conclude that patients with SCD have adequate vitamin B6 and B12 status, but suboptimal folate status, leading to elevated plasma homocysteine levels. They may therefore benefit from folate supplementation to reduce their high risk for endothelial damage.

New concepts in assessing sickle cell disease severity.

Vasoocclusion leads to pain, chronic organ damage, and a decreased life expectancy in patients with sickle cell disease. Therapeutic options for sickle cell disease have usually been evaluated according to their capacity for reducing the frequency of vasoocclusive crises requiring clinical attention. However, the frequency of vasoocclusive crises is not representative for the rate of accumulating organ damage in most sickle cell patients. This implies that the frequency of vasoocclusive crises needn't correlate with disease severity and, although being of importance, cannot solely serve as a parameter of treatment efficacy. Therefore, additional new objective parameters are needed to effectively study the vasoocclusive process in sickle cell disease. Several studies show that intricate adhesive interactions between (red) blood cells, plasma components, and endothelium play a crucial role in the pathophysiology of sickle cell vasoocclusion, offering new potential parameters to effectively assess disease severity as well as new therapeutical targets in the near future. Whether these adhesive mechanisms involve the causes or the effects of vasoocclusion will be determined if their inhibition, by interventive measures, results in therapeutic benefits.

The dietary fatty acids of patients with coronary artery disease and controls in Curaçao. Implications for primary and secondary prevention.

Patients with coronary artery disease are advised to augment their dietary linoleic acid intakes at the expense of saturated fatty acids. We investigated whether the dietary linoleic acid intake of 57 patients with coronary artery disease (47 males, 10 females; ages 61 +/- 10 years) in Curaçao is higher as compared with 77 controls (51 males, 26 females; ages 56 +/- 7 years). For this, we measured plasma cholesterol ester fatty acids, which reflect the dietary fatty acid composition of the preceding weeks. Patients with coronary artery disease and controls had minor differences in cholesterol ester fatty acids. Their cholesterol ester linoleic acid content suggests that the dietary polyunsaturated/saturated fatty acid ratio is far below 1. Comparison with data reported for The Netherlands, Greenland and Crete showed that the dietary fatty acid composition in Curaçao is typically Western with a high intake of saturated fatty acids, a low intake of monounsaturated fatty acids and the consumption of linoleic acid as the predominant polyunsaturated fatty acid. Intake of long chain polyunsaturated fatty acids from fatty fish is low. Reduction of dietary saturated fatty acids, augmentation of fish consumption, and an increase of the alpha-linolenic/linoleic acid ratio are likely to be of benefit to both primary and secondary prevention from coronary artery disease in Curaçao.

The dietary fatty acids of patients with coronary artery disease and control in Curacao: implications for primary and secondary prevention

Patients with coronary artery diseases are advised to augment their dietary linoleic acid intakes at the expense of saturated fatty acids. We investigated whether the dietary linoleic acid intake of 57 patients with coronary artery disease (47 males, 10 females; ages 61 ñ 10 years) in Curacao is higher as compared with 77 controls (51 males, 26 females; ages 56 ñ 7 years). For this, we measured plasma cholesterol ester fatty acids, which reflect the dietary fatty acid composition of the preceeding weeks. Patients with coronary artery disease and controls had minor differences in cholesterol ester fatty acids. Their cholesterol ester linoleic acid content suggests that the dietary polyunsaturated/saturated fatty acid ratio is far below 1. Comparison with data reported for the the Netherlands, Greenland and Crete showed that the dietary fatty acid composition in Curacao is typically Western with a high intake of saturated fatty acids, a low intake of monounsaturated fatty acids and the consumption of linoleic acid as the predominant polyunsaturated fatty acid. Intake of long chain polyunsaturated fatty acids from fatty fish is low. Reduction of dietary saturated fatty acids, augmentation of fish consumption, and an increase of the Ó-linolenic/linoleic acid ratio are likely to be of benefit to both primary and secondary prevention from coronary artery disease in Curaco.

Serum calcium and vitamin D status of patients with sickle cell disease in Curaçao.

We measured parameters of calcium homeostasis and vitamin D status in HbSS patients (median age 8 years, range 3-19; 8 females, 10 males) and matched HbAA controls living in the tropical island of Curaçao. Serum calcium concentration in HbSS patients [2.32(0.07)mmol/L] was lower (ANCOVA, P = 0.002) than that of HbAA controls [2.44(0.14)]. None of the subjects had hypocalcaemia. There were no differences in serum concentrations of phosphate, total protein, albumin, intact parathyroid hormone (PTH), 25-hydroxyvitamin D [87(27) nmol/L in patients, 86(15) nmol/L in controls) and 1,25-dihydroxyvitamin D. There were no significant relations between PTH and 25(OH)D. We conclude that vitamin D status of HbSS patients in Curaçao is adequate.

Hemoglobins S and C: reference values for glycohemoglobin in heterozygous, double-heterozygous and homozygous subjects, as established by 13 methods.

Glycohemoglobin (gly-Hb) reference ranges of non-diabetic adults with HbAA (n = 17), HbAS (n = 37), HbAC (n = 22), HbSC (n = 8), HbSS (n = 6) and HbCC (n = 3) were determined by 13 methods, based on affinity chromatography, HPLC, electrophoresis and immunoassay. Gly-Hb of subjects with HbAS and HbAC can be measured without major difficulties by most methods. Some give rise to absolute gly-Hb differences > or = 1% compared with subjects with HbAA. Measurement of HbA1c/total Hb cannot be recommended. Some HPLC and immunoassay methods cannot measure gly-Hb in subjects with HbSC, HbSS and HbCC, whereas others may suffer from interference. Most methods showed low gly-Hb, reflecting increased erythrocyte turnover. Use of special reference ranges requires previous knowledge of the condition (affinity chromatography and immunoassay) or separation of gly-Hb and its precursor Hb (HPLC and electrophoresis). Interpretation is, however, not recommended because of the numerous factors that determine erythrocyte turnover.