Plasma Concentrations of Long Chain N-3 Fatty Acids in Early and Mid-Pregnancy and Risk of Early Preterm Birth.

BACKGROUND: Fish oil supplementation has been shown to delay spontaneous delivery, but the levels and clinical significance remain uncertain. We examined the association between plasma fatty acids quantified in pregnancy and subsequent risk of early preterm birth. METHODS: In a case-control design nested in the Danish National Birth Cohort, we identified 376 early preterm cases (<34 gestational weeks, excluding preeclampsia cases) and 348 random controls. Plasma eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA% of total fatty acids), were measured twice in pregnancy, at gestation weeks 9 and 25 (medians). Odds ratios and 95% confidence intervals (CI's) for associations between EPA+DHA and early preterm risk were estimated by logistic regression, adjusted for the woman's age, height, pre-pregnancy BMI, parity, smoking, and socioeconomic factors. Hypotheses and analytical plan were defined and archived a priori. FINDINGS: Analysis using restricted cubic splines of the mean of 1st and 2nd sample measurements showed a strong and significant non-linear association (p < 0.0001) in which the risk of early preterm birth steeply increased when EPA+DHA concentrations were lower than 2% and flattened out at higher levels. Women in the lowest quintile (EPA+DHA < 1.6%) had 10.27 times (95% confidence interval 6.80-15.79, p < 0.0001) increased risk, and women in the second lowest quintile had 2.86 (95% CI 1.79-4.59, p < 0.0001) times increased risk, when compared to women in the three aggregated highest quintiles (EPA+DHA ≥ 1.8%). INTERPRETATION: Low plasma concentration of EPA and DHA during pregnancy is a strong risk factor for subsequent early preterm birth in Danish women.

The prognostic value of lymph node ratio in a national cohort of rectal cancer patients.

OBJECTIVE: To analyze the prognostic implications of the lymph node ratio (LNR) in curative resected rectal cancer. SUMMARY BACKGROUND DATA: It has been proposed that the LNR has a high prognostic impact in colorectal cancer, but the lymph node ratio has not been evaluated exclusively for rectal cancer in a large national cohort study. METHODS: All 6793 patients in Denmark diagnosed with stage I to III adenocarcinoma of the rectum, and so treated in the period from 2003 to 2011, were included in the analysis. The cohort was divided into two groups according to whether or not neo-adjuvant treatment had been given. RESULTS: In a multivariate analysis the pN status, ypN status and lymph node yield were found to be independent prognostic factors for overall survival, irrespective of neo-adjuvant therapy. The LNR was also found to be a significant prognostic factor with a Hazard Ratio ranging from 1.154 (95% CI: 0.930-1.432) (LNR: 0.01-0.08) to 2.974 (95% CI: 2.452-3.606) (LNR > 0.5) in the group of patients who had surgery to begin with and from 1.381 (95% CI: 0.891-2.139) (LNR: 0.01-0.08) to 2.915 (95% CI: 2.244-3.787) (LNR > 0.5) in the group of patients who had neo-adjuvant treatment. CONCLUSIONS: The LNR reflects the influence on survival from N-status and the lymph node yield and since LNR was shown to be a significant prognostic predictor for overall survival in patients with curatively resected stage III rectal cancer irrespective of neo-adjuvant therapy we recommend that the introduction of LNR should be considered for rectal cancer in a revised TNM classification.

Tumour stage and preoperative chemoradiotherapy influence the lymph node yield in stages I-III rectal cancer: results from a prospective nationwide cohort study.

AIM: The study aimed to determine whether the lymph node yield (LNY) in rectal cancer is influenced by patient-related and histopathological factors and the use of preoperative chemoradiotherapy (CRT). METHOD: An analysis was carried out of the LNY in a nationwide Danish cohort of 7950 patients, treated by curative resection of Stage I-III rectal cancer during the period 2001-2011. The impact of year of diagnosis, age, gender, pathological stage of the tumour (pT-stage) and preoperative CRT on LNY was analysed. RESULTS: Twenty-nine per cent of the patients received preoperative CRT. The median LNY was 13 [interquartile range (IQR): 8-19]. A total of 43.4% of the patients had an LNY of < 12. The median LNY increased from 8 (IQR: 5-12) to 20 (IQR: 13-28) LNs over the years of the study period (P < 0.0001). Gender and body mass index (BMI) had no impact on the median LNY. Age had a minor impact, with a range of 12 (IQR: 8-18) to 13 (IQR: 9-20) (P < 0.0001). The LNY ranged from 9 (IQR: 6-14) to 16 (IQR: 10-26), according to pT-stage (pT0-pT4) (P < 0.0001). Median LNY, according to preoperative CRT or no preoperative CRT, was 10 (IQR: 6-16) and 14 (IQR: 8-18), respectively (P < 0.0001). The percentages of patients with an LNY of < 12, according to preoperative CRT or no preoperative CRT, were 58.7% and 37.1%, respectively (P < 0.0001). CONCLUSION: An increase in the LNY over the period of the study was observed, probably reflecting improved quality of surgery and histopathology. A minor significant reduction of LNY was found with increasing age of the patient. LNY was significantly related to pT-stage and to the use of preoperative chemoradiotherapy. For these reasons the minimum harvest of 12 LNs as a surrogate marker for the oncological quality of surgery should be questioned.

The relation between lymph node status and survival in Stage I-III colon cancer: results from a prospective nationwide cohort study.

AIM: This study involved a large nationwide Danish cohort to evaluate the hypothesis that a high lymph node harvest has a positive effect on survival in curative resected Stage I-III colon cancer and a low lymph node ratio has a positive effect on survival in Stage III colon cancer. METHOD: Analysis of overall survival was conducted using a nationwide Danish cohort of patients treated with curative resection of Stage I-III colon cancer. All 8901 patients in Denmark diagnosed with adenocarcinoma of the colon and treated with curative resection in the period 2003-2008 were identified from the Danish Colorectal Cancer Group (DCCG). The impact of lymph node count and lymph node ratio was analysed. RESULTS: Overall 5-year survival was 56.8 and 66.6%, (P < 0.0001) for lymph node counts of fewer than 12 and 12 or more, respectively. The percentages of lymph node positive patients in the two groups were 29.8 and 40.3% (P < 0.0001), respectively. When putting the Stage III patients into four subgroups according to the lymph node ratio (cut-off points 1/12, 1/4 and 1/2) we found an overall 5-year survival rate of 68.1, 57.2, 49.3 and 32.4% (P < 0.0001). Lymph node count and lymph node ratio were independent prognostic factors in multivariate analysis. CONCLUSION: High lymph node count was associated with improved overall survival in colon cancer. Lymph node ratio was superior to N-stage in differentiating overall survival in Stage III colon cancer. Stage migration was observed.

Thrombophilias and adverse pregnancy outcomes: results from the Danish National Birth Cohort.

BACKGROUND: Inherited thrombophilias have inconsistently been linked to adverse pregnancy outcomes. Differences in study design, size and population could explain this heterogeneity. OBJECTIVE: The aim of the present study was to evaluate if factor (F)V Leiden G1691A, prothrombin mutation G20210A (PTM) and methylenetetrahydrofolate reductase C677T (MTHFR) increased the risk of severe preeclampsia, fetal growth restriction, very preterm delivery, placental abruption and a composite of these outcomes also including stillbirth. PATIENTS AND METHODS: In a nested case-cohort study of pregnant women in Denmark, we genotyped 2032 cases and 1851 random controls. Each of the medical records of the cases was validated. We calculated both genomic and allelic models, and present both models. We also performed sensitivity analyses adjusting for parity, age, smoking, body mass index and socioeconomic status. RESULTS: In the allelic models, FV Leiden increased the risk of the composite outcome (odds ratio [OR] 1.4, 95% confidence interval [CI] 1.1-1.8), severe preeclampsia (OR 1.6, 95% CI 1.1-2.4), fetal growth restriction (OR 1.4, 95% CI 1.1-1.8) and placental abruption (OR = 1.7 (95% CI 1.2-2.4). In the sensitivity analyses, adjustment diminished these estimates slightly. PTM was not significantly associated with any of the outcomes, and MTHFR was only significantly associated with severe preeclampsia (OR 1.3, 95% CI 1.1-1.6). CONCLUSION: FV Leiden predisposes to adverse pregnancy outcomes in a setting of Scandinavian women.

Preterm delivery and risk of subsequent cardiovascular morbidity and type-II diabetes in the mother.

OBJECTIVE: Preterm delivery has been shown to be associated with subsequent maternal cardiovascular morbidity. However, the impact of the severity and recurrence of preterm delivery on the risk of specific cardiovascular events and the metabolic syndrome in the mother, have not been investigated. DESIGN: National registry-based retrospective cohort study. SETTING: Women delivering in Denmark from 1978 to 2007. POPULATION: Women with a first singleton delivery (n = 782 287), and with a first and second singleton delivery (n = 536 419). METHODS: Cox proportional hazard models, with the gestational age stratified into four groups as primary exposure. We made adjustments for maternal age, year of delivery, hypertensive pregnancy disorders, fetal growth deviation, placental abruption and stillbirth. MAIN OUTCOME MEASURES: Subsequent maternal hypertension, ischaemic heart diseases, thromboembolism and type-II diabetes. RESULTS: After a first delivery at 32-36 completed weeks of gestation, the adjusted risk of subsequent type-II diabetes increased 1.89-fold (1.69-2.10) and the risk of thromboembolism increased 1.42-fold (1.24-1.62). Women having a preterm delivery in the first pregnancy and a term delivery in the second had a 1.58-fold (1.34-1.86) increased risk of type-II diabetes and a 1.18-fold (0.96-1.44) increased risk of thromboembolism. Women having two preterm deliveries had a 2.30-fold (1.71-3.10) increased risk of type-II diabetes and a 1.80-fold (1.29-2.50) increased risk of thromboembolism. CONCLUSIONS: Preterm delivery is independent of other pregnancy complications associated with subsequent maternal overt type-II diabetes and thromboembolism. The recurrence of preterm delivery will augment these risks.

A combined abnormality in heart rate variation and QT corrected interval is a strong predictor of cardiovascular death in type 1 diabetes.

OBJECTIVE: Long-term diabetes is associated with excess morbidity and mortality, and cardiovascular autonomic neuropathy and QTc interval abnormalities are both predictive of early cardiovascular death in diabetes. We aimed to investigate the effect of these risk factors in a large cohort of type 1 diabetic patients followed prospectively for 10 years. MATERIAL AND METHODS: Three-hundred-and-ninety-one type 1 diabetic mellitus patients (240 M and 151 F, age 41.8 years +/- 9.9 (mean +/-SD), duration of DM 27.3 years +/- 8.2) were followed in an outpatient setting. RESULTS: Patients with decreased heart rate variability had an excess overall mortality that diminished after adjusting for conventional cardiovascular risk factors; hazard ratio 2.5 (0.9-6.8; p = 0.071) compared to patients with normal heart rate variability. Likewise, prolonged QTc interval was associated with premature death with an adjusted hazard ratio of 2.3 (1.3-4.0; p = 0.005). In a combined analysis, patients with abnormal values for heart rate variability and QTc had a poorer prognosis compared to patients with normal test values for both parameters (adjusted hazard ratio 6.7 (1.8-25; p = 0.005)). Of the 34 patients with both test values abnormal, 15 died and 14 of these from cardiovascular causes. CONCLUSIONS: We conclude that combined abnormality in heart rate variability and QTc is a strong predictor of mortality in type 1 diabetes independently of conventional risk factors. These results have implications for future screening and treatment programmes for cardiovascular disease in type 1 diabetes.

Tissue inhibitor of metalloproteinase-1 levels in plasma from tumour arteries and veins of patients with rectal cancer.

OBJECTIVE: Tissue inhibitor of metalloproteinase-1 (TIMP-1) plays a major role in the regulation of tissue growth, including cancer growth. The TIMP-1 protein can be determined in plasma, and increased plasma levels of TIMP-1 are associated with a poor prognosis of colorectal cancer patients. The aim of the present study was to evaluate whether tumour tissue release of the TIMP-1 protein contributes to the increased plasma levels of TIMP-1 observed in patients with colorectal cancer. MATERIAL AND METHODS: Preoperative blood samples from a peripheral vein and intraoperative blood samples from a tumour artery, a tumour vein and from a peripheral vein were drawn from 24 patients undergoing elective, intended curative surgery for primary rectal cancer. TIMP-1 levels were determined concurrently in plasma from all samples using a validated ELISA method. Counts of white blood cells and platelets were also carried out. RESULTS: No significant differences between plasma TIMP-1 levels could be demonstrated in any compartment. In particular, there was no significant difference in TIMP-1 levels in plasma from tumour arteries and tumour veins. However, there was a significant decrease in neutrophil cell counts from tumour arteries to tumour veins (p<0.001). CONCLUSIONS: The present results do not support the current hypothesis that tumour cells contribute substantially to increased plasma TIMP-1 levels observed in patients with colorectal cancer.

Influence of major surgery on the mannan-binding lectin pathway of innate immunity.

The mannan-binding lectin (MBL) pathway of complement activation is important in host defence against pathogens and possibly against cancer. We investigated the effect of major surgery on two central components of the MBL pathway; MBL and the MBL-associated serine protease MASP-2, and for comparison also measured the interleukin (IL)-6 and C-reactive protein (CRP) levels. Serial blood samples were obtained from patients belonging to two different cohorts. Cohort 1 comprised 60 patients undergoing open or laparoscopic colectomy for benign disease (n = 12) or colon cancer (n = 48). Cohort 2 comprised 27 patients undergoing elective, open surgery for colorectal cancer, and was included in order to cover blood sampling between days 2 and 6. As expected, the surgical stress induced a marked acute phase response, as evidenced by a large increase in IL-6 (18-fold) and CRP (13-fold) levels with maximum at 12 h and 2 days, respectively. However, in both cohorts the levels of MBL and MBL-associated serine protease 2 (MASP-2) were largely unaffected, except for a minor but significant increase around day 8 in cohort 1. The preoperative levels of IL-6 and CRP were correlated significantly in both cohorts (r = 0.71, P < 0.0001 and r = 0.65, P = 0.005, respectively). Preoperative MASP-2 correlated with preoperative CRP (r = 0.59, P = 0.001) and IL-6 (r = 0.55, P = 0.02) in cohort 2 only. In contrast to the marked effects on the levels of IL-6 and CRP, the surgery influenced only marginally the two proteins of the MBL pathway.

Toxic encephalopathy and noise-induced hearing loss.

In several laboratory animal studies, it has been documented that the hearing, vision, and brain can be injured due to exposure to organic solvents. This finding formed the background for a pilot study (n=16) aimed at identifying new ways of qualifying diagnostics, treatment, and rehabilitation of patients suffering from brain injury due to exposure to organic solvents, also referred to as toxic encephalopathy. Diagnosing toxic encephalopathy is complicated because the symptoms of this type of diffuse brain injury are non-specific. So, it was initially hypothesised that some of the difficulties involved in diagnosing toxic encephalopathy could be minimized by extending the diagnostic procedure. Apart from clinical interviewing and neuropsychological testing, the diagnosis should include the examination of hearing and vision. This will help in achieving new measures that could improve in diagnosing toxic encephalopathy with more certainty. On the basis of ranking, only one patient in the pilot study was considered to have a normal neuropsychological test profile, which was defined as a test profile without any marked deviations when compared with a normal population. A total of 10 patients were considered to have "discrete problems." These patients had a test profile showing either a few strikingly negative results or an array of results slightly below the expected level when compared with a normal population. A total of four patients were considered to suffer from "moderate problems" and one patient from "severe problems." The patients with "moderate problems" and "severe problems" showed consistent negative results and an unambiguous negative test profile. However, the overall results of all neuropsychological examinations performed revealed a dispersed picture. Quite remarkably, all the 13 patients who had their hearing examined showed a loss of hearing, 7 patients complained about tinnitus, and all patients had a history of exposure to both noise and organic solvents, which had not been observed at the initial examination, but seemed to have serious implications for their prognosis and future life.

Bacterial antigen induced release of soluble vascular endothelial growth factor (VEGF) and VEGFR1 before and after surgery.

OBJECTIVE: The influence of surgery on release of soluble vascular endothelial growth factor (sVEGF) and the soluble inhibitory receptor (sVEGFR1) is unknown. The effect of major and minor surgery on variations in sVEGF and sVEGFR1 concentrations in vivo was studied, and on bacterial antigen-induced release of sVEGF and sVEGFR1 from whole blood in vitro. MATERIAL AND METHODS: Sixty-one patients with abdominal diseases undergoing five different surgical procedures were included in the study. Blood samples were drawn from patients before and after the operation. White blood cells and platelets were counted, and plasma sVEGF and sVEGFR1 were determined. Whole blood from each blood sample was stimulated in vitro with bacteria-derived antigens (lipopolysaccharides or protein A) and sVEGF and sVEGFR1 levels were subsequently determined in the supernatants. RESULTS: Neither sVEGF nor sVEGFR1 concentrations in plasma changed during surgery. In vitro stimulation of blood samples with bacteria-derived antigens resulted in a significant increase in sVEGF (p < 0.0001) and a less pronounced but still significant increase in sVEGFR1 (p < 0.01). Bacterial antigen-induced release of sVEGF correlated significantly with neutrophil cell counts (0.53 < r < 0.78; p < 0.0001). Bacterial antigen-induced sVEGFR1 release did not correlate with cell counts. CONCLUSIONS: Plasma sVEGF and sVEGFR1 concentrations did not change during surgery. In vitro bacterial stimulation led to increased release of sVEGF, which was not compensated for by an equivalent increase in sVEGFR1. There was a positive impact of major abdominal surgery on release of sVEGF. The bacterial antigen-induced changes in sVEGF may be related to the number of circulating neutrophils.

The role of tissue factor in colorectal cancer.

The possible role of tissue factor (TF) in colorectal cancer (CRC) is reviewed. A correlation between TF expression and advanced stages of malignancy, and a correlation between TF expression and overall survival have been suggested in CRC. This is supported by experimental studies indicating that TF plays a key role in growth, invasion and dissemination of tumour cells, and in tumour related angiogenesis as well. In addition, the activation of TF in CRC patients in relation to the surgical trauma, perioperative blood transfusion and development of postoperative bacterial infectious complications are discussed. Finally, future directions for the development of anticancer modalities directed against regulation of TF are considered.

Death and injury caused by land mines in Burma.

One hundred and eighty-eight Burmese refugees in Thailand were interviewed. One hundred and five of those interviewed had knowledge of a total of 313 persons who had been exposed to land mine explosions. Twenty-three of the interviewed were land mine survivors. They were all male, aged between eight and 68 years, and all except one had been injured between 1986 and 1997. Fifteen of the 23 were civilians, eight were guerilla soldiers who were injured either in battle or while deploying or disarming land mines. Those who had stepped on land mines were all crus or femur amputated and had several scars on the lower limbs, abdomen and some also on the forearms. Those who had handled a land mine had lost either fingers or hands and one also lost both eyes. This study shows that the frequency of land mine accidents in Burma has been underestimated and that the mortality is high. The study also supports the general impression that many victims are civilians.

[Spread of methicillin-resistant Staphylococcus aureus. Are our hygienic precautions sufficient?]. / Spredning af meticillinresistente staphylococcus aureus. Er vores hygiejniske forholdsregler tilstraekkelige?

A patient was transferred from Pakistan to a Danish orthopaedic ward. In Denmark he was tested MRSA-positive. Two months after he was discharged, similar MRSA strains were found in another patient. The two patients had been on the same ward for one week. All hygienic precautions had been taken. Staff and other patients on the ward at the relevant time all tested MRSA-negative.

Results of medical examination of refugees from Burma.

OBJECTIVES: To describe exposure to human rights violations among refugees from rural Burma; to compare exposure experienced by an ethnic Burmese minority group, the Shans, with that of the rest of the study population; and to compare exposure of those who had fled Burma recently with that of refugees who had arrived in Thailand earlier. DESIGN: Cross-sectional interview and clinical examination. SETTING: Refugee settlements and refugee camps in Northern Thailand near the border to Burma in November 1997. SUBJECTS: 92 persons (group A) were examined according to the program. Fourty-six were Shans; 34 had migrated within the past five months. A further 96 person (group B), more randomly selected, were interviewed according to an abbreviated interview program; of these, 38 had fled recently. MAIN OUTCOME MEASURES: A score was used to quantify the exposure. Testimonies of exposure to physical violence were validated, assessing the consistency between the reported exposure, reported ensuing symptoms and the result of the clinical examination. RESULTS: Both groups reported massive exposure to the following human rights violations: forced labour (group A: 66%, group B: 35%), porter service (65%, 44%), forced relocation (51%, 51%), killing of family members (36%, 29%). In group A, there were twelve cases of self-reported torture. Moreover, there were reports of rape, disappearances and land mine accidents. In all cases of exposure to physical violence the testimonies were appraised to be valid. CONCLUSION: The violations of human rights in Burma were massive. The Shans were exposed as heavily as the others. Those who had arrived recently were as heavily exposed as the other groups. Apart from the land mine problem, the Burmese army was held responsible for all the reported and documented human rights violations.

Radiation-induced skin injury after percutaneous transluminal coronary angioplasty. Case report.

A 58-year-old man underwent percutaneous transluminal coronary angioplasties in June 1992 and May 1993. Approximately 3 weeks after the last procedure, a cutaneous lesion developed into an ulcer over the right scapular region. The ulcer failed to heal with conservative treatment; therefore, surgical excision was performed. The localization and the course of the development indicated injury caused by radiation, and this was confirmed by the histologic examination. To avoid such injury in interventional procedures with long fluoroscopic time, several precautions should be taken. These include continuous surveillance of the X-ray dosage, the use of different projections to avoid exposure to one skin area throughout the whole procedure, keeping the irradiated area as small as possible, and good planning of the procedure.

A fast, economical and efficient method for DNA purification by use of a homemade bead column.

A fast, efficient and economical method for purification of DNA from various sources by the use of silica particles packed in homemade bead columns is described. The method is a further development of the method devised by Carter and Milton (1), improved by the introduction of a column operated with a vacuum system. The method is highly suitable for multiple sample handling in the preparation of DNA for sequencing and other purposes. Protocols are devised for plasmid minipreparation, gel elution and purification of DNA from solutions e.g. enzyme reactions.