Vitamin B6 catabolism and lung cancer risk: results from the Lung Cancer Cohort Consortium (LC3).

BACKGROUND: Increased vitamin B6 catabolism related to inflammation, as measured by the PAr index (the ratio of 4-pyridoxic acid over the sum of pyridoxal and pyridoxal-5'-phosphate), has been positively associated with lung cancer risk in two prospective European studies. However, the extent to which this association translates to more diverse populations is not known. MATERIALS AND METHODS: For this study, we included 5323 incident lung cancer cases and 5323 controls individually matched by age, sex, and smoking status within each of 20 prospective cohorts from the Lung Cancer Cohort Consortium. Cohort-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between PAr and lung cancer risk were calculated using conditional logistic regression and pooled using random-effects models. RESULTS: PAr was positively associated with lung cancer risk in a dose-response fashion. Comparing the fourth versus first quartiles of PAr resulted in an OR of 1.38 (95% CI: 1.19-1.59) for overall lung cancer risk. The association between PAr and lung cancer risk was most prominent in former smokers (OR: 1.69, 95% CI: 1.36-2.10), men (OR: 1.60, 95% CI: 1.28-2.00), and for cancers diagnosed within 3 years of blood draw (OR: 1.73, 95% CI: 1.34-2.23). CONCLUSION: Based on pre-diagnostic data from 20 cohorts across 4 continents, this study confirms that increased vitamin B6 catabolism related to inflammation and immune activation is associated with a higher risk of developing lung cancer. Moreover, PAr may be a pre-diagnostic marker of lung cancer rather than a causal factor.

Smoking, plasma cotinine and risk of atrial fibrillation: the Hordaland Health Study.

BACKGROUND: Cigarette smoking has been identified as a major modifiable risk factor for coronary heart disease and mortality. However, findings on the relationship between smoking and atrial fibrillation (AF) have been inconsistent. Furthermore, findings from previous studies were based on self-reported smoking. OBJECTIVE: To examine the associations of smoking status and plasma cotinine levels, a marker of nicotine exposure, with risk of incident AF in the Hordaland Health Study. METHODS: We conducted a prospective analysis of 6682 adults aged 46-74 years without known AF at baseline. Participants were followed via linkage to the Cardiovascular Disease in Norway (CVDNOR) project and the Cause of Death Registry. Smoking status was assessed by both questionnaire and plasma cotinine levels. RESULTS: A total of 538 participants developed AF over a median follow-up period of 11 years. Using questionnaire data, current smoking (HR: 1.41, 95% CI: 1.09-1.83), but not former smoking (HR: 1.03, 95% CI: 0.83-1.28), was associated with an increased risk of AF after adjustment for gender, age, body mass index, hypertension, physical activity and education. Using plasma cotinine only, the adjusted HR (95% CI) was 1.40 (1.12-1.75) for participants with cotinine ≥85 nmol L-1 compared to those with cotinine <85 nmol L-1 . However, the risk increased with elevated plasma cotinine levels until 1199 nmol L-1 (HR: 1.55, 95% CI: 1.16-2.05 at the third group vs. the reference group) and plateaued at higher levels. CONCLUSIONS: Current, but not former smokers, had a higher risk of developing AF. Use of plasma cotinine measurement corroborated this finding.

Plasma methionine, choline, betaine, and dimethylglycine in relation to colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC).

BACKGROUND: Disturbances in one carbon metabolism may contribute to carcinogenesis by affecting methylation and synthesis of DNA. Choline and its oxidation product betaine are involved in this metabolism and can serve as alternative methyl group donors when folate status is low. PATIENTS AND METHODS: We conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), to investigate plasma concentrations of the methyl donors methionine, choline, betaine (trimethylglycine), and dimethylglycine (DMG) in relation to colorectal cancer (CRC) risk. Our study included 1367 incident CRC cases (965 colon and 402 rectum) and 2323 controls matched by gender, age group, and study center. Multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for CRC risk were estimated by conditional logistic regression, comparing the fifth to the first quintile of plasma concentrations. RESULTS: Overall, methionine (OR: 0.79, 95% CI: 0.63-0.99, P-trend = 0.05), choline (OR: 0.77, 95% CI: 0.60-0.99, P-trend = 0.07), and betaine (OR: 0.85, 95% CI: 0.66-1.09, P-trend = 0.06) concentrations were inversely associated with CRC risk of borderline significance. In participants with folate concentration below the median of 11.3 nmol/l, high betaine concentration was associated with reduced CRC risk (OR: 0.71, 95% CI: 0.50-1.00, P-trend = 0.02), which was not observed for those having a higher folate status. Among women, but not men, high choline concentration was associated with decreased CRC risk (OR: 0.62, 95% CI: 0.43-0.88, P-trend = 0.01). Plasma DMG was not associated with CRC risk. CONCLUSIONS: Individuals with high plasma concentrations of methionine, choline, and betaine may be at reduced risk of CRC.

Interferon (IFN)-γ-mediated inflammation and the kynurenine pathway in relation to bone mineral density: the Hordaland Health Study.

The risk of osteoporosis increases in inflammatory disorders. In cell-mediated immune activation, interferon (IFN)-γ stimulates macrophage release of neopterin and increases the activity of indoleamine 2,3-dioxygenase (IDO), thereby stimulating tryptophan degradation along the kynurenine pathway. Plasma levels of neopterin and the kynurenine/tryptophan ratio (KTR) are thus markers of IFN-γ-mediated inflammation. Several kynurenine pathway metabolites (kynurenines) possess immunomodulatory properties. The aim of this study was to investigate associations between markers of IFN-γ-mediated inflammation and kynurenines with bone mineral density (BMD). The community-based Hordaland Health Study (HUSK), with middle-aged (46-49 years) and older (71-74 years) participants, was conducted from 1998 to 2000 (n = 5312). Hip BMD in relation to neopterin, KTR and kynurenines were investigated, using linear and logistic regression analyses. In the oldest group, neopterin (P ≤ 0·019) and KTR (P ≤ 0·001) were associated inversely with BMD after multiple adjustment. Comparing the highest to the lowest quartiles, the odds ratios of low BMD (being in the lowest quintile of BMD) in the oldest cohort were for neopterin 2·01 among men and 2·34 among women (P ≤ 0·007) and for KTR 1·80 for men and 2·04 for women (P ≤ 0·022). Xanthurenic acid was associated positively with BMD in all sex and age groups while 3-hydroxyanthranilic acid was associated positively with BMD among women only (P ≤ 0·010). In conclusion, we found an inverse association between BMD and markers of IFN-γ-mediated inflammation in the oldest participants. BMD was also associated with two kynurenines in both age groups. These results may support a role of cell-mediated inflammation in bone metabolism.

A community-based study on determinants of circulating markers of cellular immune activation and kynurenines: the Hordaland Health Study.

Circulating neopterin and kynurenine/tryptophan ratio (KTR) increase during inflammation and serve as markers of cellular immune activation, but data are sparse on other determinants of these markers and metabolites of the kynurenine pathway. We measured neopterin, tryptophan, kynurenine, anthranilic acid, kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and xanthurenic acid in plasma in two age groups, 45-46 years (n = 3723) and 70-72 years (n = 3329). Differences across categories of the potential determinants, including age, gender, renal function, body mass index (BMI), smoking and physical activity, were tested by Mann-Whitney U-test and multiple linear regression including age group, gender, renal function and lifestyle factors. In this multivariate model, neopterin, KTR and most kynurenines were 20-30% higher in the older group, whereas tryptophan was 7% lower. Men had 6-19% higher concentrations of tryptophan and most kynurenines than women of the same age. Compared to the fourth age-specific estimated glomerular filtration rate (eGFR) quartile, the first quartile was associated with higher concentrations of neopterin (25%) and KTR (24%) and 18-36% higher concentrations of kynurenines, except 3-hydroxyanthranilic acid. Additionally, KTR, tryptophan and all kynurenines, except anthranilic acid, were 2-8% higher in overweight and 3-17% higher in obese, than in normal-weight individuals. Heavy smokers had 4-14% lower levels of tryptophan and most kynurenines than non-smokers. Age and renal function were the strongest determinants of plasma neopterin, KTR and most kynurenines. These findings are relevant for the design and interpretation of studies investigating the role of plasma neopterin, KTR and kynurenines in chronic diseases.

Quality of life 2-7 years after major trauma.

BACKGROUND: The aim of the present study was to assess potential long-term reduction in health-related quality of life (HRQOL) in adult trauma patients 2-7 years after discharge from an intensive care unit (ICU), and to study possible determinants of the HRQOL reduction. METHODS: Follow-up study of a cohort of 341 trauma patients admitted to the ICU of a university hospital during 1998-2003. Of the 228 eligible patients, 210 (92%) completed the study. A telephone interview using the EuroQol 5-D (EQ-5D) was conducted. Patients reported their HRQOL both at present and before trauma. RESULTS: Before trauma 88% reported in retrospect no problem in any EQ-5D dimension, compared with 20% at follow-up. After trauma (median 4.0 years) 58% suffered pain/discomfort, 44% reported alterations in usual activities, 40% reduced mobility, 35% anxiety/depression, and 15% limited autonomy. A total of 74% experienced reduction in HRQOL. Severe problems were reported by 16%. Women experienced more anxiety/depression than men. Simplified Acute Physiology Score (SAPS) II and Injury Severity Score (ISS) were significantly associated with impaired HRQOL, while age was not. Patients with severe head injury reported better HRQOL than those without severe head injury. CONCLUSION: More than 2 years post-injury, 74% reported impaired HRQOL but only 16% had severe problems. The majority still suffered pain/discomfort, indicating that pain management is a key factor in improving long-term outcome after severe trauma.

Trauma patients in the intensive care unit: short- and long-term survival and predictors of 30-day mortality.

BACKGROUND: The aims of this cohort study were to assess the survival of trauma patients treated in a general intensive care unit (ICU) and to evaluate the simplified acute physiology score (SAPS) II, maximum sequential organ failure assessment (SOFA) score, injury severity score (ISS), age, sex and severe head injury as predictors of 30-day mortality. METHODS: Three hundred and twenty-five adult patients admitted during 1998-2003 were evaluated retrospectively with update of survival data in January 2005. Kaplan-Meier statistics and Cox proportional hazards regression were used to study survival and to assess predictors of mortality, respectively. RESULTS: The 30-day mortality was 16.9%, ICU mortality 13.8% and hospital mortality 17.8%. Long-term survival (observation time, 1-7 years) was 77.8%. After 3.5 years, mortality was the same as for the background population. Severe head injury was the main cause of death and increased the risk of 30-day mortality 2.4-fold. In addition, SAPS II and an age above 50 years proved to be significant predictors of mortality in a multivariate analysis. Sex was not associated with mortality, and ISS and the maximum SOFA score were significant predictors in univariate analyses only. CONCLUSION: Reduced long-term survival was observed up to 3.5 years after acute injury. The 30-day mortality was strongly related to severe head injury, SAPS II and an age above 50 years. These variables may be useful as predictors of mortality, and may contribute to risk adjustment of this subset of trauma patients when treatment results from different centres are compared.

Quality of life after intensive care in trauma patients.

Published studies and our own preliminary results show that Intensive Care Unit (ICU) patients admitted after severe trauma, all report reduced quality of life (QOL) after discharge. In contrast to other ICU patients, this reduction is decreased by time, but does not seem to reach pre-ICU levels. Interventions to improve this situation have not been documented. This should be a high priority aspect for all health personnel caring for patients surviving severe trauma.

Identification of thoracic intervertebral spaces by means of surface anatomy: a magnetic resonance imaging study.

BACKGROUND: Successful thoracic epidural analgesia depends on the sensory blockage of specific dermatomes following appropriate placement of the epidural catheter. This study aimed to ascertain how accurately anaesthesiologists identify thoracic intervertebral spaces, and whether counting from the prominent vertebra is easier than using the iliac crest as an anatomical landmark. METHODS: Five anaesthesiologists attempted to locate one out of five consecutive intervertebral spaces (Th7-Th8 to Th11-Th12) on patients referred for magnetic resonance imaging of the vertebral column. The intended thoracic interspace and the counting reference point (C7-Th1 or L3-L4) were marked with oil capsules. The body mass index, gender and position of the patient were recorded. The exact capsule positions were determined by a radiologist after the study. RESULTS: In 92 patients, 26.7% of the thoracic interspaces were correctly identified. The counting reference point was the only variable studied with a significant influence on error. The accuracy increased when the iliac crest was used as an anatomical landmark rather than the prominent vertebra (odds ratio, 0.29). The majority (76.4%) of all the incorrectly placed capsules were found cephalad to the intended level. CONCLUSION: We recommend that the caudal of two to three possible interspaces should be used when placing an epidural catheter in the thoracic spine. Because of the inaccurate localization of the thoracic intervertebral spaces, documentation should state the site of puncture as being in the upper or lower thoracic spine instead of claiming to be in an exact interspace.

When is an anesthesiologist needed in a helicopter emergency medical service in northern Norway?

BACKGROUND: A national air ambulance service, including helicopters and airplanes, was implemented in Norway in 1988. The main intention was to offer advanced medical services when needed. All helicopters are manned by anesthesiologists. Catchment areas for the 11 helicopters span from cities to scarcely populated areas, particularly in the north. Our aim was to assess what proportion of ambulance missions carried out by the rescue helicopter in Bodø, northern Norway, delivered advanced medical treatment needing the skills of an anesthesiologist. METHODS: Flight and ambulance records (n = 2078) from 1988 and 1990-98 (10 years) were analyzed retrospectively. Inter-hospital transfers (n = 147) and search- and rescue missions (n = 332) were not included. According to the level of medical treatment given missions were categorized into three groups (A, B and C). Treatment in groups A and B would not require an anesthesiologist. RESULTS: Two thousand and seventy-eight ambulance missions carried 2166 patients (114 per 100 000 per year). Median take-off and on-scene times were 29 and 55 min, respectively. Seven hundred and fifty-five patients (35%) suffered from cardiovascular disease, 495 (23%) were injured and 250 (12%) were parturients. One hundred and seven patients (5.0%) received advanced prehospital emergency treatment requiring an anesthesiologist. Forty-five of the 107 patients survived to discharge from hospital, amongst whom 28 had received intravenous nitroglycerin for angina or suspected myocardial infarction. CONCLUSION: In our rural area, with a widely scattered population, 95% of patients received medical treatment not requiring an anesthesiologist. A selective use of the anesthesiologist seems indicated.

Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians.

BACKGROUND: In India, most people adhere to a vegetarian diet, which may lead to cobalamin deficiency. OBJECTIVE: The objective was to examine indicators of cobalamin status in Asian Indians. DESIGN: The study population included 204 men and women aged 27-55 y from Pune, Maharashtra, India, categorized into 4 groups: patients with cardiovascular disease (CVD) and diabetes, patients with CVD but no diabetes, patients with diabetes but no CVD, and healthy subjects. Data on medical history, lifestyle, and diet were obtained by interviews and questionnaires. Blood samples were collected for measurement of serum or plasma total cobalamin, holotranscobalamin (holoTC), methylmalonic acid (MMA), and total homocysteine (tHcy) and hemetologic indexes. RESULTS: MMA, tHcy, total cobalamin, and holoTC did not differ significantly among the 4 groups; therefore, the data were pooled. Total cobalamin showed a strong inverse correlation with tHcy (r = -0.59) and MMA (r = -0.54). Forty-seven percent of the subjects had cobalamin deficiency (total cobalamin <150 pmol/L), 73% had low holoTC (<35 pmol/L), 77% had hyperhomocysteinemia (tHcy >15 micromol/L), and 73% had elevated serum MMA (>0.26 micromol/L). These indicators of impaired cobalamin status were observed in both vegetarians and nonvegetarians. Folate deficiency was rare and only 2.5% of the subjects were homozygous for the MTHFR 677C-->T polymorphism. CONCLUSIONS: About 75% of the subjects had metabolic signs of cobalamin deficiency, which was only partly explained by the vegetarian diet. If impaired cobalamin status is confirmed in other parts of India, it may have important health implications.

Smoking, folate and methylenetetrahydrofolate reductase status as interactive determinants of adenomatous and hyperplastic polyps of colorectum.

Most studies demonstrate increased risk of colorectal cancer (CRC) and adenomas in folate-deficient subjects or that high folate intake may afford some protection. Smoking increases such risk in some but not all studies. We investigated whether smoking, folate status and methylenetetrahydrofolate reductase (MTHFR) genotype predict the risk of adenomatous and hyperplastic polyps of colorectum. By colonoscopy, the type, number, size and extent of dysplasia of colorectal polyps were assessed in 443 subjects aged 63-72 years. We also determined RBC folate and the C667T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene. Smoking, folate status and the C677T MTHFR polymorphism were strong, interactive determinants of high-risk adenomas (HRAs, defined as adenomas > or =10 mm in diameter, adenomas with villous components or with severe dysplasia). The risk was particularly high in smokers with low folate and the CT/TT genotype (risk category T) and in smokers with high folate and the CC genotype (risk category C). With non-smokers with low folate and the CC genotype as reference, the odds ratios (OR, 95% CI) were 8.7 (2.5-29.7) in category T and 9.9 (2.6-38.4) in category C. Notably, this risk pattern was also observed for hyperplastic polyps. In conclusion, in smokers, high folate status may confer increased or decreased risk for HRAs, depending on the MTHFR genotype. These data demonstrate the strong gene-nutrition interaction involving the C677T MTHFR polymorphism.

Applications of short-chain polydimethylacrylamide as sieving medium for the electrophoretic separation of DNA fragments and mutation analysis in uncoated capillaries.

In capillary electrophoresis (CE), separation of DNA fragments is usually performed in covalently coated capillaries. Recent studies have demonstrated that certain polymers form a dynamic coating on the inner surface of the capillary, thereby suppressing the electroosmotic flow and DNA-capillary wall interactions. We developed a simple method for the synthesis of short-chain polydimethylacrylamide (PDMA) using isopropanol as a chain transfer agent. Capillary (<75 microm internal diameter) filling and replacement of this low-viscosity (14 cP at 4% PDMA) self-coating medium were easily carried out by commercial CE instruments. Using PDMA and uncoated capillaries, we first examined the separation of phi X174 HaeIII DNA digests and observed that the stability of the dynamic coating was markedly better at pH 7.8 than at pH 8.3. At this lower pH and nondenaturing conditions, high resolution of the phi X174 HaeIII DNA digests was obtained for more than 850 injections in the same capillary. We then exploited this sieving medium in CE using multiple approaches for mutation analysis of clinical DNA samples including separation of restriction enzyme cleavage products, analysis of single strand conformation polymorphisms, and simultaneous detection of several mutations using multiplex allele-specific PCR amplification. Our results demonstrate that CE in uncoated capillaries using PDMA as sieving medium is a simple, versatile, and reliable strategy for separation and mutation analysis of clinical DNA samples.

Chemical mismatch cleavage combined with capillary electrophoresis: detection of mutations exon 8 of the cystathionine beta-synthase gene.

Mutation detection by chemical mismatch cleavage (CMC) is based on the chemical modification and cleavage at the site of mismatched C or T in heteroduplexes, using hydroxylamine or osmium tetroxide (OsO4) as chemical probes. In the present study, we evaluated CMC in combination with capillary electrophoresis (CE) by determining the common T833C and G919A mutations in exon 8 of the cystathionine beta-synthase gene in heterozygous and homozygous samples. A 186-bp fragment encompassing exon 8 was amplified by PCR with both primers labeled with 5'-fluorescein. Labeled single strands of 40 and 61 nucleotides (nt) were formed from the coding strand of the T833C sample and non-coding strand from the G919A sample, respectively. These single-stranded DNA (ssDNA) products were analyzed under denaturing conditions by CE with short-chain linear polyacrylamide as the sieving matrix and were detected by laser-induced fluorescence (LIF), using a sensitive, one-channel sheath-flow detector. The CE-LIF format afforded relatively high resolution of ssDNA (down to 1 nt), precise size assessment of CMC products, sensitive detection with small sample requirements, and fast analysis. Thus, CMC combined with CE-LIF is suitable for screening of known mutations, giving expected CMC products, but will also detect unknown mutations, the locations of which are indicated by the fragment sizes.

Long-term outcome of trauma in children: the psychological consequences of a bus accident.

The psychological consequences of trauma on 28 Swedish children were examined 1 year and 3 years after a bus accident in western Norway in 1988. Symptoms were assessed by the Impact of Event Scale (IES), semi-structured interviews, and a questionnaire developed for this study. At the 1-year follow-up, large proportions of the sample had symptoms of Intrusion and Avoidance (IES) and symptoms of general psychological distress, but no clinically significant symptoms were observed at the 3-year follow-up. Girls and children who experienced loss in the accident were characterised by high levels of Intrusion, whereas passenger trauma and age were unrelated to the outcome. A bidirectional relationship was observed between the mothers' and the children's symptoms over time, whereas the fathers' symptoms were unrelated to the children's symptoms. The clinical implications of the study are that symptoms in all children of traumatised families deserve attention during the first year post-trauma, and that objective risk indicators (age, sex, and types of trauma) do not provide sufficient information to identify children at risk.

[Reflexes in brain-dead patients]. / Reflekser hos hjernedød pasient.

We report on a patient who suffered an acute, extensive intracerebral haemorrhage, leading to symptoms of cerebral herniation within a few hours. The clinical diagnosis of brain death was made based on a neurological examination, and an apnoea test eight hours after the haemorrhage. A few hours later the diagnosis was changed, as several reflexes reappeared. After six days mechanical ventilation was withdrawn, as the brain damage was considered so serious as to render further therapy futile. It was considered unethical to sustain therapy for a possible organ donation at a later date. A review of relevant the literature, however, shows that brain-dead patients may exhibit such varying degrees of autonomic and spinal reflexes as to cause confusion, thus delaying the physician in making a diagnosis. Often, an opportunity for organ donation is lost. Based on this review, we believe that our patient was indeed brain dead when the first diagnosis was made, and that a cerebral angiography should have been performed. Because organ donation is an important issue, the diagnosis of brain death must be definitive.

Variability and determinants of total homocysteine concentrations in plasma in an elderly population.

The variability of plasma total homocysteine (tHcy) was examined in 96 individuals over a 1-yr period. Blood tHcy concentrations varied from 7.1 micromol/L in the bottom quintile to 14.5 micromol/L in the top quintile. The mean tHcy was 10.4 micromol/L, the between-person SD was 2.5 micromol/L, and the within-person SD was 0.93 micromol/L. There was little seasonal variation, and the reliability coefficient was 0.88. Mean tHcy concentrations were inversely related to mean plasma folate (r = -0.36) and vitamin B12 (r = -0.35) concentrations. Median tHcy concentrations were approximately 1 micromol/L higher in men than in women and in older (70 to 74 years) than in younger (65 to 69 years) individuals and higher in those with the TT and CT genotypes for the methylenetetrahydrofolate reductase polymorphism than in those with the CC genotype (10.7 and 10.6 vs 9.6 micromol/L). Epidemiological studies based on single tHcy measurements may underestimate the magnitude of any risk associations with disease by 10-15%.

Simultaneous determination of methylenetetrahydrofolate reductase C677T and factor V G1691A genotypes by mutagenically separated PCR and multiple-injection capillary electrophoresis.

The C677T mutation of the methylenetetrahydrofolate reductase gene and the G1691A (Leiden) mutation of the factor V gene are established risk factors for thromboembolic disease. We here present an assay for the simultaneous genotyping of these common genetic variants. The assay involves a strategy based on multiplex mutagenically separated PCR performed in a single tube containing six primers. Separation of the resulting four PCR products (197, 207, 233, and 246 bp) was performed by capillary electrophoresis coupled with laser-induced fluorescence detection. The time for the automated electrophoresis was reduced to 2.5 min per sample by performing the capillary electrophoresis analysis in a multiple-injection mode.