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Background: A woman's nutritional status before conception and during pregnancy is important for maternal health and the health of the foetus. The aim of the study was to compare diet intake in early pregnant women with non-pregnant women., Methods: Between September 2006 and March 2009, 226 women in early pregnancy were consecutively recruited at five antenatal clinics in Northern Sweden. Referent women (n = 211) were randomly selected from a current health screening project running in the same region (the Västerbotten Intervention Program; VIP). We collected diet data with a self-reported validated food frequency questionnaire with 66 food items/food aggregates, and information on portion size, alcohol consumption, and supplement intake. Data were analysed using descriptive, comparative statistics and multivariate partial least square modelling., Results: Intake of folate and vitamin D from foods was generally low for both groups. Intake of folate and vitamin D supplements was generally high in the pregnant group and led to significantly higher total estimated intake of vitamin D and folate in the pregnant group. Iron intake from foods tended to be lower in pregnant women although iron supplement intake evened out the difference with respect to iron intake from foods only. Energy intake was slightly lower in pregnant women but not significant, a reflection of that they reported consuming significantly less of potatoes/rice/pasta, meat/fish, and vegetables (grams/day) than the women in the referent group., Conclusions: In the present study, women in early pregnancy reported less intake of vegetables, potatoes, meat, and alcohol than non-pregnant women. As they also had a low intake (below the Nordic Nutritional Recommendations) of folate, vitamin D, and iron from foods, some of these women and their unborn children are possibly at risk for adverse effects on the pregnancy and birth outcome.

Background: A diet rich in folate is associated with a reduced colorectal cancer risk, whereas the role of circulating levels is less clear. The aim of this study was to relate prediagnostic plasma folate, vitamin B12, and homocysteine concentrations to the risk of colorectal cancer., Methods: This was a prospective case-control study of 331 cases and 662 matched controls nested within the population-based Northern Sweden Health and Disease Study. Median follow-up time from recruitment to diagnosis was 10.8 years., Results: Plasma folate concentrations were positively related to colorectal cancer risk; multivariate odds ratios were 1.62 [95% confidence intervals (CI), 1.08-2.42] and 1.42 (95% CI, 0.94-2.21) for the middle and highest versus lowest tertile, respectively. In subjects with follow-up <10.8 years, a statistically significant doubled risk was observed for the middle and highest versus lowest tertile, whereas findings for longer follow-up times were null. A positive risk relationship was also observed for tumor stage III-IV but not I-II. Plasma vitamin B12 concentrations were inversely associated with rectal cancer risk. Homocysteine was not significantly related to colorectal cancer risk., Conclusions: In this population-based, nested case-control study, low plasma folate concentrations were associated with a reduced colorectal cancer risk. This protective role was mainly observed in subjects with higher tumor stage or shorter follow-up time between recruitment and diagnosis. Low circulating folate status may protect against colorectal cancer or suppress progression of preneoplastic or neoplastic lesions., Impact: These findings may have relevance for the ongoing debate about mandatory folic acid fortification of flour., (©2014 American Association for Cancer Research.)

Background: Elevated total plasma homocysteine (tHcy) in humans is associated with cardiovascular disease but prevention trials have failed to confirm causality. Reported reasons for this association have been that homocysteine and its major genetic determinant methylenetetrahydrofolate reductase (MTHFR) may have an effect on HDL and Apolipoprotein (Apo) A1 levels. We wanted to study if tHcy and its major determinants were correlated with Apo A1 levels in a large population without folate fortification., Methods: This study was a prospective incident nested case-referent study within the Northern Sweden Health and Disease Study Cohort (NSHDSC), including 545 cases with first myocardial infarction and 1054 matched referents, median age at inclusion was 59 years. Univariate and multiple regression analyzes was used to study the associations between apolipoproteins Apo A1 and B, tHcy, folate and vitamin B12 in plasma as well as MTHFR polymorphisms 677C>T and 1298A>C., Results: Apo A1 and Apo B were strongly associated with the risk of a first myocardial infarction. tHcy was not associated with Apo A1 levels. Instead, folate had an independent positive association with Apo A1 levels in univariate and multiple regression models. The associations were seen in all men and women, among referents but not among cases. MTHFR polymorphisms had no clear effect on Apo A1 levels., Conclusions: Analyzing over 1500 subjects we found an independent positive association between plasma folate (major dietary determinant of tHcy) and Apo A1 levels among those who later did not develop a first myocardial infarction. No association was seen between tHcy and Apo A1.

Background: Venous blood specimen collection is a common health care practice that has to follow strict guidelines, non-compliance among sampling staff may compromise patient safety. We evaluated a large-scale 2 h educational intervention that emphasised guideline adherence to assess possible improvements of venous blood specimen collection practices., Methods: Blood specimen haemolysis is usually caused by inadequate venous blood specimen collection and handling, reflecting overall pre-analytical handling. We monitored haemolysis of serum samples with haemolysis index corresponding to ≥ 150 mg/L of free haemoglobin for specimens sent from 11 primary health care centres and analysed on a Vitros 5,1 clinical chemistry analyser before (2008, n = 6652 samples) and after (2010, n = 6121 samples) the intervention., Results: The total percentage of haemolysed specimens was 11.8 % compared to 10.5 % (p = 0.022) before the intervention. As groups, rural primary health care centres demonstrated a significant reduction [Odds ratios (OR) = 0.744] of haemolysed specimens after intervention, whereas urban primary health care centres demonstrated a significant increase (OR = 1.451) of haemolysis., Conclusions: A large-scale 2 h educational intervention to make venous blood specimen collection staff comply with guideline practices had minor effects on collection practices. Educational interventions may be effective in wards/care centres demonstrating venous blood specimen collection practices with larger deviations from guidelines.

Background: High iron levels can increase the formation of noxious oxygen radicals, which are thought to promote carcinogenesis., Objective: The aim of this prospective study was to determine whether iron biomarkers and HFE genotypes, which influence iron regulation, constitute risk factors for colorectal cancer., Design: This is a prospective nested case-referent study., Settings: The study was performed within the population-based Northern Sweden Health and Disease Study., Patients: The study included 226 cases of colorectal cancer and 437 matched referents., Main Outcome Measures: Conditional regression analysis was performed. Adjustments for smoking, smoking and BMI, and HFE C282Y and H63D were performed., Results: The highest quintile of total iron-binding capacity showed significantly higher risk for colorectal cancer, unadjusted OR 2.35 (95% CI 1.38-4.02). When stratified by sex, the findings were only present in women (OR 3.34 (95% CI 1.59-7.02)). Ferritin was associated with reduced risk throughout quintiles 2 to 5 both in univariate and multivariate models., Limitations: Colorectal cancer may influence iron markers because of occult bleeding. Homozygotes for HFE C282Y were too few to make conclusions for this group. The relatively short follow-up time might be insufficient to detect risk of iron biomarkers., Conclusions: High iron levels do not increase the risk of colorectal cancer. HFE genotypes influencing iron uptake had no effect on colorectal cancer risk.

During hemodialysis (HD), blood that passes the dialysis device gets loaded with microbubbles (MB) of air that are returned to the patient without inducing an alarm. The aim with this study was to clarify if these signals are due to microembolies of air, clots, or artifacts, by histopathology of autopsy material of HD patients. These first results are from a patient on chronic HD. Due to pulmonary edema he was ultrafiltered. Within 30 minutes after the start, he suffered from a cardiac arrest and died. Autopsy verified the clinical findings. Microscopic investigation verified microembolies of air that were surrounded by fibrin in the lungs, brain, and heart. The study verified that MBs can enter the blood during HD and are trapped in the lungs. In addition, MBs pass the pulmonary capillaries and enter the arterial part of the body and are dispersed throughout the body. This can contribute to organ damage and be part of the poor prognoses seen in HD patients. Data support the importance to reduce MBs in the dialysis circuit.

Background: The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in stress regulation, and leukocyte telomere length (TL) has been suggested to represent a cumulative measure of stress. Depression is intimately related with stress and frequently exhibits a dysregulated HPA axis. We aimed to study the relationships between TL and biological and psychological facets of stress in recurrent major depressive disorder and controls., Methods: Leukocyte TL was measured in 91 subjects with recurrent major depressive disorder and 451 control subjects. Stress was assessed from both a biological perspective, by assessing HPA axis function with a weight-adjusted very-low-dose dexamethasone suppression test (DST), and a psychological perspective, with self-report questionnaires., Results: TL was shorter among patients compared with control subjects (277 base pairs, p = .001). Overall, short TL was associated with a hypocortisolemic state (low post-DST cortisol and high percentage of cortisol reduction after the DST) among both patients and control subjects but more pronounced among patients. This state, which was overrepresented among patients, was characterized by high familial loading of affective disorders among patients (p = .001) and high C-reactive protein levels among control subjects (p = .040). TL was also inversely associated with stress measured with the Perceived Stress Questionnaire (r(s) = -.258, p = .003)., Conclusions: Short TL is associated with depression and hypocortisolism. Because hypocortisolism has been shown to develop from chronic stress exposure, our findings corroborate the concept of TL as a cumulative measure of stress and provide novel insights into the detrimental role of stress in depressive illness and the general population., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Both leukocyte telomere length and the apolipoprotein ε4 allele have been associated with mortality, cardiovascular disease, cognition, and dementia. The authors investigated whether leukocyte telomere length was associated with APOE genotype or cognitive abilities in the context of APOE genotype. The setting for this cross-sectional study was 427 nondemented individuals aged 41-81 yr. The authors found that ε4 carriers overall exhibited significantly longer telomeres compared with non-carriers (difference of 268 bp, p = 0.001). This difference was greatest at the lower limit of the age span and nonsignificant at the upper limit, which translated into a significantly higher telomere attrition rate (p = 0.049) among ε4 carriers (37 bp/years) compared with non-carriers (21 bp/year). Further, longer telomeres among ε4 carriers significantly predicted worse performance on episodic memory tasks. No significant associations were found on tasks tapping semantic and visuospatial ability, or among ε3/ε3 carriers. In conclusion, APOE ε4 carriers had longer telomeres compared with non-carriers, but higher rate of attrition. Among them, longer telomeres predicted worse performance on episodic memory tasks. These observations suggest that the ε4 allele is associated with abnormal cell turnover of functional and possibly clinical significance., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Telomere length shortens with cellular division, and leukocyte telomere length is used as a marker for systemic telomere length. The hippocampus hosts adult neurogenesis and is an important structure for episodic memory, and carriers of the apolipoprotein E ε4 allele exhibit higher hippocampal atrophy rates and differing telomere dynamics compared with non-carriers. The authors investigated whether leukocyte telomere length was associated with hippocampal volume in 57 cognitively intact subjects (29 ε3/ε3 carriers; 28 ε4 carriers) aged 49-79 yr. Leukocyte telomere length correlated inversely with left (r(s) = -0.465; p = 0.011), right (r(s) = -0.414; p = 0.025), and total hippocampus volume (r(s) = -0.519; p = 0.004) among APOE ε3/ε3 carriers, but not among ε4 carriers. However, the ε4 carriers fit with the general correlation pattern exhibited by the ε3/ε3 carriers, as ε4 carriers on average had longer telomeres and smaller hippocampi compared with ε3/ε3 carriers. The relationship observed can be interpreted as long telomeres representing a history of relatively low cellular proliferation, reflected in smaller hippocampal volumes. The results support the potential of leukocyte telomere length being used as a biomarker for tapping functional and structural processes of the aging brain.

Background: Abnormalities in homocysteine metabolism have been suggested as risk factors for stroke. The aim of this prospective study was to examine whether total plasma homocysteine concentration (tHcy) and its main genetic determinant, methylene tetrahydrofolate reductase (MTHFR) polymorphisms, were associated with first ischemic or hemorrhagic stroke., Methods: This was a nested case-referent study of 321 ischemic and 60 hemorrhagic stroke cases, defined by WHO MONICA criteria and each matched with two event-free referents for sex, age, cohort, recruitment date and geographical area. All subjects were from the population-based Northern Sweden Health and Disease Study cohorts. Odds ratios were determined by conditional logistic regression., Results: The mean follow-up time was 4.2 years. Both tHcy and MTHFR were independent predictors of hemorrhagic stroke in multivariate models including body mass index, hypertension and, for MTHFR, tHcy [OR for the highest vs. lowest tHcy quartile 8.13 (95% CI 1.83-36.1), p(trend)=0.002; OR for MTHFR 677TT vs. 677CC genotype 3.62 (95% CI 0.77-17.0), p(trend)=0.040]. Haplotype analyses confirmed that the MTHFR 677T-1298A haplotype was positively associated with hemorrhagic stroke [OR 1.81 (95% CI 1.09-3.00), p=0.022], whereas the MTHFR 677C-1298C haplotype was not significantly related to either hemorrhagic or ischemic stroke. Neither tHcy nor the MTHFR polymorphisms were significant predictors of ischemic stroke., Conclusion: Both elevated plasma homocysteine levels and the MTHFR 677T allele are indicators of increased risk of hemorrhagic stroke in the northern Swedish population.

Objectives: Our objectives were to study the relationship between iron stores, HFE genotypes and the risk for first-ever myocardial infarction., Methods: First-ever myocardial infarction cases (n=618) and double matched referents from the Northern Sweden Health and Disease Cohort Study were studied in a prospective nested case-referent setting. Plasma iron, total iron binding capacity, transferrin iron saturation and ferritin were analyzed, as well as several confounders. HFE C282Y and H63D genotypes were determined., Results: There was an inverse risk association for myocardial infarction in the highest quartiles of iron (OR 0.68; 95% CI 0.48-0.96) and transferrin iron saturation (OR 0.62; 95% CI 0.42-0.89) in men. This association, however, was lost after adjusting for C-reactive protein. Women homozygous for H63D had a higher risk for myocardial infarction., Conclusions: No risk association between high iron stores and first-ever myocardial infarction was found. The higher risk in female H63D homozygotes is probably not related to iron metabolism., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Viral hemorrhagic fevers (VHF) are considered to be a serious threat to public health worldwide with up to 100 million cases annually. The general hypothesis is that disseminated intravascular coagulation (DIC) is an important part of the pathogenesis. The study objectives were to study the variability of DIC in consecutive patients with acute hemorrhagic fever with renal syndrome (HFRS), and to evaluate if different established DIC-scores can be used as a prognostic marker for a more severe illness., Method and Findings: In a prospective study 2006-2008, data from 106 patients with confirmed HFRS were analyzed and scored for the presence of DIC according to six different templates based on criteria from the International Society on Thrombosis and Haemostasis (ISTH). The DIC-scoring templates with a fibrinogen/CRP-ratio were most predictive, with predictions for moderate/severe illness (p<0.01) and bleeding of moderate/major importance (p<0.05). With these templates, 18.9-28.3% of the patients were diagnosed with DIC., Conclusions: DIC was found in about one fourth of the patients and correlated with a more severe disease. This supports that DIC is an important part of the pathogenesis in HFRS. ISTH-scores including fibrinogen/CRP-ratio outperform models without. The high negative predictive value could be a valuable tool for the clinician. We also believe that our findings could be relevant for other VHFs.

Background: Bilirubin, an effective antioxidant, shows a large variation in levels between individuals and has been positively associated with reduced cardiovascular disease risk. A major reason for the variability is a common promoter polymorphism, UGT1A1*28, which reduces the transcription of the enzyme that conjugates bilirubin, UDP-glucuronosyltransferase 1A1. The aim of the study was to evaluate a possible protective effect of plasma bilirubin and the UGT1A1*28 polymorphism against myocardial infarction in a prospective case-referent setting., Methods and Results: Subjects (n=618) with a first-ever myocardial infarction (median event age, 60.5 years; median lag time, 3.5 years) and 1184 matched referents were studied. Plasma bilirubin was lower in cases versus referents. Despite a strong gene-dosage effect on bilirubin levels in both cases and referents, the UGT1A1*28 polymorphism did not influence the risk of myocardial infarction. Among multiple other variables, serum iron showed one of the strongest associations with bilirubin levels., Conclusions: We found no evidence for a protective effect of the UGT1A1*28 polymorphism against myocardial infarction and consequently neither for bilirubin. The lower bilirubin levels in cases might be caused by decreased production, increased degradation, or increased elimination.

Objective: We related prediagnostic plasma folate, vitamin B12, and total homocysteine concentrations, and the MTHFR 677C>T and 1298A>C polymorphisms, to the risk of colorectal cancer with and without the CpG island methylator phenotype (CIMP)., Methods: This was a nested case-referent study of 190 cases and double, matched referents from the large, population-based Northern Sweden Health and Disease Study. Using archival tumor tissue, promoter methylation in an eight-gene panel was analyzed by MethyLight., Results: A reduced risk of CIMP-low/CIMP-high CRC (> or =1 gene methylated) was observed in subjects with very low plasma folate concentrations [multivariate odds ratio 2.96 (95% CI 1.24-7.08) for quintiles two to five versus one (lowest)]. With the exception of a reduced risk in MTHFR 677 TT-homozygotes, none of the other one-carbon variables were associated with the risk of CIMP-low/CIMP-high CRC. For CIMP-negative CRC, only the MTHFR polymorphisms were statistically significantly related to risk, inversely for 677C>T and positively for 1298A>C, but a tendency toward a reduced risk was observed in subjects with an adequate methyl availability, combining the plasma variables [multivariate odds ratio 0.61 (95% CI 0.32-1.15)]., Conclusion: Though limited by low power, these findings suggest the possibility of different roles for one-carbon metabolism in different pathways of colorectal tumorigenesis.

Background: Bilirubin, an antioxidant, has been associated with reduced cardiovascular disease risk. A major cause of elevated plasma bilirubin is the common UGT1A1*28 promoter polymorphism in the gene of the bilirubin-conjugating enzyme UDP-glucuronosyltransferase 1A1, which reduces transcription by 70%. Earlier studies reporting a protective effect of bilirubin on stroke have not included analysis of UGT1A1*28. The purpose of this study is to investigate if bilirubin and UGT1A1*28 are protective against ischemic stroke in a prospective case-referent setting., Methods: Cases with first-ever ischemic stroke (n = 231; median lag time 4.9 years) and 462 matched referents from the Northern Sweden Health and Disease Study Cohort were included. Plasma bilirubin was measured and UGT1A1*28 was analyzed by fragment analysis., Results: Plasma bilirubin was lower in cases than in referents, but the difference reached significance only for women. The UGT1A1*28 polymorphism (allele frequency 30%) showed a strong gene-dose relationship with bilirubin levels both among cases and referents, but was not associated with risk for stroke. Among multiple other variables analyzed, the strongest correlation with bilirubin was found for plasma iron., Conclusions: There was no evidence for a protective effect of the UGT1A1*28 polymorphism against stroke and consequently neither for bilirubin. The findings suggest that other factors influencing the risk for stroke might also affect bilirubin levels., (Copyright © 2010 S. Karger AG, Basel.)

Purpose: Components of one-carbon metabolism are believed to influence cancer development with suggested mechanisms, including DNA methylation and DNA repair mechanisms. However, few prospective studies have investigated one-carbon metabolism in relation to prostate cancer risk, and the results have been conflicting. The aim of this study was to do a comprehensive investigation of the components of one-carbon metabolism in relation to prostate cancer risk. A panel of seven circulating B vitamins and related metabolites was selected, most of which have not been studied before., Materials and Methods: We analyzed plasma concentrations of betaine, choline, cysteine, methionine, methylmalonic acid (MMA), vitamin B2, and vitamin B6 in 561 cases and 1,034 controls matched for age and recruitment date, nested within the population-based Northern Sweden Health and Disease Cohort. Relative risks of prostate cancer were estimated by conditional logistic regression., Results: Positive associations with prostate cancer risk were observed for choline and vitamin B2, and an inverse association was observed for MMA. The relative risks for a doubling in concentrations were 1.46 [95% confidence interval (95% CI), 1.04-2.05; P(trend) = 0.03] for choline, 1.11 (95% CI, 1.00-1.23; P(trend) = 0.04) for vitamin B2, and 0.78 (95% CI, 0.63-0.97; P(trend) = 0.03) for MMA. Concentrations of betaine, cysteine, methionine, and vitamin B6 were not associated with prostate cancer risk., Conclusion: The results of this large prospective study suggest that elevated plasma concentrations of choline and vitamin B2 may be associated with an increased risk of prostate cancer. These novel findings support a role of one-carbon metabolism in prostate cancer etiology and warrant further investigation.

Background: Haemolysis is usually caused by inadequate specimen collection or preanalytical handling, and is suggested to be a suitable indicator of pre-analytical quality. We investigated the prevalence of detectable haemolysis in all routine venous blood samples to identify differences in preanalytical quality., Methods: Haemolysis index (HI) values were obtained from a Vitros 5,1 in the routine clinical chemistry laboratory for samples collected in primary health care centres (PHCs), nursing homes, and a hospital emergency department (ED). Haemolysis was defined as a HI > or =15 (detection limit)., Results: Samples from the PHC with the highest prevalence of haemolysis were 6.1 times (95% confidence interval (CI) 4.0-9.2) more often haemolysed compared to the centre with the lowest prevalence. Of the samples collected in primary health care, 10.4% were haemolysed compared to 31.1% in the ED (p<0.001). A notable difference in haemolysed samples was found between the ED section staffed by emergency medicine physicians and the section staffed by primary health care physicians (34.8% vs. 11.3%, p<0.001)., Conclusions: The significant variation in haemolysis indices among the investigated units is likely to reflect varying preanalytical conditions. The HI is a valuable tool for estimation and follow-up of preanalytical quality in primary health care.

We conducted a nested case-control study within two prospective cohorts, the New York University Women's Health Study and the Northern Sweden Health and Disease Study, to examine the association between prediagnostic circulating levels of 25-hydroxy vitamin D (25(OH)D) and the risk of subsequent invasive epithelial ovarian cancer (EOC). The 25(OH)D levels were measured in serum or plasma from 170 incident cases of EOC and 373 matched controls. Overall, circulating 25(OH)D levels were not associated with the risk of EOC in combined cohort analysis: adjusted OR for the top tertile versus the reference tertile, 1.09 (95% CI, 0.59-2.01). In addition, there was no evidence of an interaction effect between VDR SNP genotype or haplotype and circulating 25(OH)D levels in relation to ovarian cancer risk, although more complex gene-environment interactions may exist.

In this nested case-referent study, we related plasma concentrations of vitamin B12 to the risk of colorectal cancer, taking into consideration prediagnostic plasma folate and total homocysteine concentrations. Subjects were 226 cases and double matched referents from the population-based Northern Sweden Health and Disease Study. Follow-up times from recruitment to diagnosis ranged from 0.1 to 12.7 years, with a median of 4.2 years. Plasma vitamin B12 concentrations were inversely associated with the risk of rectal cancer: univariate odds ratio for the highest versus lowest quintile 0.34 (95% confidence interval (95% CI) 0.13-0.83), p(trend) = 0.004. Risk estimates were attenuated slightly but remained statistically significant after adjustment for body mass index, current smoking, recreational and occupational physical activity, alcohol intake and prediagnostic plasma folate and total homocysteine concentrations: OR 0.30 (95% CI 0.08-0.99), p(trend) = 0.025. The corresponding univariate and fully adjusted odds ratios for colon cancer were 1.25 (CI 0.66-2.36), p(trend) = 0.185 and 1.42 (CI 0.67-3.05), p(trend) = 0.113, respectively. The observed over-risk was attributable to left-sided colon cancer. Interaction analyses including vitamin B12, folate and homocysteine were in line with the results for vitamin B12 alone. In conclusion, these results suggest that increasing levels of plasma vitamin B12, alone or together with other factors involved in one-carbon metabolism, may reduce the risk of rectal cancer, whereas for colon cancer, the association appears to be less clear., ((c) 2007 Wiley-Liss, Inc.)

Background: Pneumatic tube transport of blood samples reduces turnaround times and labour. However, the preanalytical effects on new clinical chemistry parameters and instruments are not fully known. The aim of this study was to evaluate the effect of pneumatic tube transport on haematology and coagulation parameters, including platelet function with PFA-100, and global coagulation with a thromboelastograph., Methods: Paired venous blood samples from healthy volunteers were obtained before and after 1 week of treatment with acetylsalicylic acid. One sample was transported by pneumatic tube transport, while the other remained in the laboratory., Results: No preanalytical effect of pneumatic tube transport could be seen for most haematology and coagulation parameters, as well as analysis with PFA-100. For the thromboelastographic analysis, time to clot formation was shorter (-16%, p=0.037) in the transported samples. Treatment with acetylsalicylic acid had no effect on the majority of the test results., Conclusions: Pneumatic tube transport does not introduce preanalytical errors when transporting samples for analysis of routine haematology, coagulation parameters and platelet function with the PFA-100. We recommend manual transport of samples for analysis with thromboelastographic techniques.

The methylenetetrahydrafolate reductase (MTHFR) enzyme may influence cancer development by affecting DNA methylation, synthesis and repair. The MTHFR 677C-->T single nucleotide polymorphism (SNP) has been associated with decreased enzyme activity and has therefore been implicated in cancer development. We analyzed the MTHFR 677C-->T SNP in 2,777 incident prostate cancer cases and 1,639 population controls from the CAncer Prostate in Sweden study (CAPS). No significant association was found overall between prostate cancer risk and the 677C-->T SNP (p = 0.27) with heterozygote (CT) and homozygote (TT) allele carriers showing ORs of 1.12 (95% CI: 0.98-1.27) and 1.02 (95% CI: 0.80-1.30), respectively. In the subgroup of low risk prostate cancer, heterozygote-but not homozygote-allele carriers displayed a slight over-risk with an OR of 1.21 (95% CI: 1.03-1.41). Among men under 65 years of age, the 677C-->T SNP was associated with prostate cancer risk (p = 0.007), with odds ratios of 1.33 (95% CI: 1.09-1.63) for heterozygote allele carriers and 0.86 (95% CI: 0.6-1.24) for homozygote allele carriers. However, this association was attributed to a shift in the genotype distribution in the young controls. In conclusion, our results do not provide strong support for the hypothesis that the MTHFR 677C-->T polymorphism is related to prostate cancer risk.

Background: High iron levels can increase the formation of noxious oxygen radicals, which are thought to contribute to cerebrovascular disease. The aim of this prospective study was to determine if iron status and HFE genotypes constitute risk factors for stroke., Methods: First-ever stroke cases (231 ischemic and 42 hemorrhagic) and matched double referents from the population-based Northern Sweden cohorts were studied in a nested case-referent setting., Results: For total iron binding capacity, an increased risk of ischemic stroke was seen in the highest quartile (OR 1.80; 95% CI 1.14-2.83; p for trend 0.012). The highest quartile of transferrin iron saturation showed a decreased risk of ischemic stroke in men (OR 0.44; 95% CI 0.22-0.87; p for trend 0.028), but not in women. There was an increased risk of hemorrhagic stroke in the second (OR 4.07; 95% CI 1.09-15.20) and third quartile (OR 4.22; 95% CI 1.08-16.42) of ferritin. Neither quartiles of plasma iron concentrations nor the HFE C282Y and H63D genotypes were associated with ischemic or hemorrhagic stroke., Conclusions: Iron stores were not positively related to increased risk of ischemic stroke. Furthermore, HFE genotypes did not influence the risk of ischemic or hemorrhagic stroke., ((c) 2007 S. Karger AG, Basel)

It has been proposed that folate and polymorphisms of the enzyme methylenetetrahydrofolate reductase (MTHFR), which regulates influx of folate from DNA synthesis and repair to methylation reactions, are involved in the aetiology of cancer. To relate the MTHFR 677C-->T and 1298A-->C polymorphisms to the risk of prostate cancer, taking into consideration prospective plasma levels of folate, vitamin B12 and homocysteine. The design was a case-control study of 223 prostate cancer cases and 435 matched controls nested within the population-based Northern Sweden Health and Disease Cohort. Neither the MTHFR 677C-->T nor the MTHFR 1298A-->C polymorphism was statistically significantly associated with the risk of prostate cancer in univariate analysis by conditional logistic regression. After adjustment for MTHFR 1298A-->C, plasma folate, vitamin B12, homocysteine, body mass index and smoking, the odds ratios were, for the 677 CT genotype, 1.52 [95% confidence interval (CI) 1.02-2.26], and for TT, 0.91 (95% CI 0.41-2.04). Our previously reported observation of a possible increase in the risk of prostate cancer at high plasma folate levels was attributable in this study to subjects having the MTHFR 677C-->T polymorphism. We found that the MTHFR 677C-->T polymorphism is not likely to have a major role in the development of prostate cancer, although it may possibly increase the risk in combination with high plasma folate levels. Further investigation in larger studies is warranted.

Background: The indications for continuous oral anticoagulant treatment, the target interval and the procedures for withdrawing treatment have changed in the last 10 years., Methods: Patients on continuous oral anticoagulant treatment at the Outpatient Anticoagulant Clinic at Umeå University Hospital in 2002 were included in a descriptive study (n = 900). 263 of those had a mechanical heart valve prosthesis. Only patient records for patients with other indications than mechanical heart valve prosthesis were examined. 582 of those records were found. In the 55 remaining patients some clinical information was retrieved from the computerised warfarin dosage database. These latter, more unsure clinical data, are presented separately. Anticoagulant treatment was discontinued if lack of proper indication or presence of too high risk for hemorrhagic complications were found., Results: The prevalence of continuous oral anticoagulant treatment in the uptake area was 0.65%. The most common target interval was INR 2.1-3.0, but patients with a mechanical heart valve prosthesis were often treated more aggressively, i.e. with a higher INR target interval. Of the patients on continuous treatment, 26.6% of the INR values were outside 2.0-3.0. The most common reasons for oral anticoagulant treatment were atrial fibrillation or mechanical heart valve prosthesis, in contrast to earlier findings in studies of our population in 1987 and 1990. We found 90 patients (10.0%) without proper indication for oral anticoagulant treatment or too high risk, and their treatment was discontinued., Conclusion: In patients on oral anticoagulant therapy, re-evaluation of indications and risks resulted in a substantial number of treatment withdrawals. There have been major changes in treatment indications during the last decade, possibly due to rapid development of knowledge in the field of thrombosis risk factors. Treatment should be re-considered once a year.

The role of folate metabolism in cancer development is a topic of much current interest, with maintenance of adequate folate status tending to show a protective effect. Aberrant methylation, primarily hypermethylation of certain genes including tumor suppressors, has been implicated in prostate cancer development. Folate, vitamin B12 and homocysteine are essential for methyl group metabolism and thus also for DNA methylation. We related plasma levels of these factors to prostate cancer risk in a prospective study of 254 case subjects and 514 matched control subjects. Increasing plasma levels of folate and vitamin B12 were statistically significantly associated with increased prostate cancer risk, with an odds ratio of 1.60 (95% CI = 1.03-2.49; p(trend) = 0.02) for folate and 2.63 (95% CI = 1.61-4.29; p(trend) < 0.001) for vitamin B12 for highest vs. lowest quartile. Increasing plasma homocysteine levels were associated with a reduced risk of borderline significance (OR = 0.67; 95% CI = 0.43-1.04; p(trend) = 0.08). After adjustment for the other 2 plasma variables, body mass index and smoking, a statistically significant increased risk remained only for vitamin B12 (OR = 2.96; 95% CI = 1.58-5.55; p(trend) = 0.001). Adjusted OR for folate and homocysteine were 1.30 (95% CI = 0.74-2.24; p(trend) = 0.17) and 0.91 (95% CI = 0.51-1.58; p(trend) = 0.60), respectively. Our results suggest that factors contributing to folate status are not protective against prostate cancer. On the contrary, vitamin B12, associated with an up to 3-fold increase in risk, and possibly also folate, may even stimulate prostate cancer development. These findings are novel and should be explored further in future studies., ((c) 2004 Wiley-Liss, Inc.)

Analyses of total homocysteine (tHcy) and to some extent methyl malonic acid (MMA) have become increasingly used in Sweden, primarily for investigating folate and cobalamin deficiency. This has led to increasing costs for diagnosis and laboratory testing, since clinicians still order the established tests, cobalamin and folate. The purpose of this study was to compare the profile of test parameters in six Swedish counties, using laboratory statistics from 2003, and to relate these to medical prescriptions for folate and cobalamin in the same counties. We also wanted to evaluate whether or not a laboratory algorithm with tHcy as the primary test-parameter, followed by vitamin analyses only when tHcy is above a certain decision limit, could reduce the expanding cost of diagnosing folate and cobalamin deficiency. For this analysis we used patient results from two counties in Sweden collected during 2003. There is a slight positive correlation between resources spent upon tests and resources spent upon treating these deficiencies, and a laboratory algorithm based upon initial analysis of tHcy, instead of conventional clinical requests for all parameters, could save approximately 30% of laboratory costs. A typical annual saving in one of these counties (ca. 260,000 inhabitants) by implementing this algorithm would be ca 100,000.

Aim: To establish age-adjusted reference intervals of urinary delta-aminolaevulinic acid (U-ALA) and porphobilinogen (U-PBG) in children, and to analyse the frequency and type of clinical manifestations of acute intermittent porphyria (AIP) in childhood., Methods: Concentrations of U-ALA and U-PBG in healthy children aged 3-16y were analysed. In a population-based study in northern Sweden of 61 children aged < 18 y with DNA-verified AIP, the clinical manifestations of AIP in childhood were analysed prospectively (up to 2.5 y). Initially the children underwent a standardized investigation (anamnesis, physical examination, laboratory tests). Instructions were issued to keep a structured diary and to provide urine samples for ALA and PBG analyses in all situations of suspected AIP attacks (prospectively)., Results: Reference intervals for U-ALA and U-PBG showed age-group variations in children. Baseline levels of U-ALA and U-PBG are increased in gene carriers, one-quarter of them exceeding the 90th percentile of age- and gender-matched controls. Baseline levels did not distinguish symptomatic from non-symptomatic children in a short-term perspective. Clinical evidence of AIP attacks was found in 10% of child AIP gene carriers; in all cases the first attack occurred before the age of 15 y., Conclusion: AIP symptoms in children may be vague and of short duration and U-ALA and U-PBG levels are often elevated only slightly or not at all; thus, symptoms and signs may differ from those in adults. Children of AIP gene carriers should be DNA tested, followed up and carefully instructed on preventive measures to avoid developing manifest AIP.

The aim of the study was to elucidate possible sex differences in knowledge, competence and attitudes behind decision-making on cobalamin-associated problems (vitamin B(12)). The study was conducted by postal questionnaires to Swedish physicians in 1996-98. The participants were recruited by random sampling of general practitioners (1996, 1998), and a total sampling of geriatricians (1998). The overall response rate was 71%. The study group comprised 480 female physicians and 526 male physicians. The responses to 24 statements in the questionnaire were measured by means of visual analogue scales. Group differences were evaluated by medians and shapes of distributions. The female doctors appeared to value patient-related symptoms and signs more than male doctors. Conversely, male doctors relied on laboratory tests more than female doctors. As reflected by questionnaire answers, female doctors appeared to be more informed than male doctors on cobalamin-associated clinical problems. Group differences between the sexes were marginal from a numerical point of view. It is suggested that the statistical differences observed should be regarded as negligible until confirmed by further studies.

Background and Purpose: Data from epidemiological and case-control studies suggest that increased total homocysteine (tHcy) levels are associated with increased risk for thromboembolic disease. The mechanisms by which hyperhomocysteinemia contributes to thrombogenesis are incompletely understood. The main objectives of this study of young ischemic stroke patients were (1) to examine fasting and post-methionine load levels of tHcy, (2) to ascertain the genotype frequency of the C677CT mutation in the methylenetetrahydrofolate reductase gene (TT genotype), and (3) to study the possible interaction between plasma tHcy levels and fibrinolytic factors., Methods: This case-control study was based on 80 consecutive patients aged 18 to 44 years admitted between January 1992 and May 1996 as a result of a first-ever ischemic stroke. Forty-one healthy control subjects were recruited. Measurement of fasting tHcy and post-methionine load levels and evaluation of the fibrinolytic system were undertaken at least 3 months (mean, 5.1+/-1. 9 months) after admission. Genotyping of the methylenetetrahydrofolate reductase gene was performed., Results: Although the increase after methionine loading (ie, postload tHcy minus fasting-level tHcy) was significantly higher among patients, there was no difference in fasting and postload tHcy levels. After adjustment for conventional risk factors, elevated postload increase tHcy levels were associated with a 4.8-fold increased risk of ischemic stroke. There was no difference between patients and control subjects in either TT genotype frequency or T allele frequency. Abnormal response to methionine loading was associated with higher tissue plasminogen activator (tPA) mass concentration, higher plasminogen activator inhibitor-1 levels, and lower tPA activity. After adjustment for age, sex, body mass index, serum cholesterol, and triglycerides, an abnormal increase in postload tHcy levels remained significantly associated with tPA mass concentration levels (P=0.03)., Conclusions: A moderately elevated increase in tHcy levels after methionine loading was associated with an increased risk for ischemic stroke in young adults. In contrast, fasting tHcy levels did not differ between patients and controls. A moderately elevated increase in tHcy after methionine loading may provide a additional thrombogenic risk mediated in part by interactions with the fibrinolytic system. In young stroke patients, a methionine loading test to detect hyperhomocysteinemia should always be considered in the convalescent phase of the disease.

Background and Purpose: Elevated fibrinogen levels and abnormalities in the fibrinolytic system are related to the occurrence of cardiovascular events. However, the role of these factors in the evolution of cerebrovascular disease has received less attention, in particular in young stroke patients. The aim of this study was to evaluate possible abnormalities in plasma fibrinogen levels and the state of the fibrinolytic system in young adults with a first-ever ischemic stroke., Methods: This study is based on 102 consecutive patients aged 18 to 44 years admitted between January 1991 and May 1996 as a result of a first ischemic stroke. Forty-one healthy controls were recruited. Evaluations of anthropometric/metabolic variables, plasma fibrinogen levels, and the fibrinolytic system were undertaken >/=3 months (mean, 5.4+/-2.0 months) after admission., Results: Patients had lower tissue plasminogen activator activity and increased plasminogen activator inhibitor type 1 activity at baseline, as well as increased tissue plasminogen activator mass concentration both at baseline and after a venous occlusion test. Overall, there were no significant differences between the main etiologic subgroups regarding plasma fibrinogen levels and fibrinolytic variables. Baseline fibrinolytic variables were strongly correlated with body mass index, serum triglycerides, and cholesterol levels. After adjustments in multivariate models, fibrinogen levels and tissue plasminogen activator mass concentration both at baseline and after venous occlusion test remained significantly increased in patients. Logistic multiple regression analyses indicated that plasma fibrinogen was a strong predictor of ischemic stroke (odds ratio, 11.25; 95% CI, 3.27 to 38. 69)., Conclusions: Increased fibrinogen levels and tissue plasminogen activator mass concentration are independently associated with ischemic stroke in young adults. Metabolic perturbations are closely interrelated with aberrations in tissue plasminogen activator and plasminogen activator inhibitor type 1 activity in these patients, findings consistent with an acquired hypofibrinolysis.