Phytase supplementation effects on amino acid digestibility depend on the protein source in the diet but are not related to InsP6 degradation in broiler chickens.

The objective was to determine phytase effects on prececal amino acid (AA) digestibility and phytate (InsP6) breakdown when different oilseed meals were used in broiler chicken diets. The study included 14 diets: a corn-soybean meal (SBM) basal diet and 6 diets that contained SBM, rapeseed meal (RSM), and sunflower meal (SFM) with 2 inclusion levels at the expense of corn starch (150 and 300 g/kg SBM or SFM, or 100 and 200 g/kg RSM). Each diet was mixed with or without a phytase supplement of 1,500 FTU/kg. Diets were provided to broilers for 5 D. Digesta from the posterior half of the ileum were collected on day 21. The average essential AA digestibility, calculated by a regression approach, without and with phytase was 84 and 85% (SBM), 74 and 77% (SFM), and 66 and 73% (RSM), respectively. In the diets, phytase effects on AA digestibility were lower owing to other protein sources also present in the diet, but significant. Prececal InsP6 disappearance was significantly affected by interactions between oilseed meal, inclusion level, and phytase supplementation. Overall, prececal InsP6 disappearance was higher in SBM diets (52%) than in SFM diets (38%) and intermediate in RSM diets (43%). Across diets, phytase supplementation effects on prececal InsP6 degradation linearly increased with the InsP6 concentration of the diet up to 12 g/kg DM. The only exception from linearity was the diet with the high inclusion of SFM, which contained 15.9 g InsP6/kg DM. In the ileal content, the concentration of myo-inositol was significantly increased by phytase supplementation, and this effect was highest in the diets that contained SBM as the only oilseed meal. Concentrations of lower inositol phosphates were increased by phytase supplementation, and this effect was most remarkable for Ins(1,2,3,4)P4 and inositol tetrakisphosphates. The study showed that phytase effects on AA digestibility varied among the 3 tested oilseed meals, but these differences were not detectable in the diets containing these meals. Although phytase effects on ileal content of InsP6 and its degradation products were substantial, they were not related to the effects on AA digestibility.

Analysis of deaths among children in the period 1996-2008 from closed claims registered by the Danish Patient Insurance Association.

AIM: We investigated the death circumstances among children in the Danish healthcare system by analysing closed claims. METHODS: This retrospective study investigated closed claims with regard to medically related deaths registered by the Danish Patient Insurance Association. RESULTS: From 1996 to 2008, 45 953 claims were made to the Danish Patient Insurance Association (DPIA) covering all medical specialties. Among these claims, a total of 3531 submitted claims were for children younger than 18 years old, and 74 of these children were registered as having died. Forty-one of the 74 deaths were caused by peripartum asphyxia or other birth-related reasons, and 33 children died of causes not related to their birth. Twenty-three of the 33 children died as a result of substandard treatment. This was the ruling of the DPIA or the courts of law on the claim. In these cases, the DPIA, the appeal board or the courts of law settled that an experienced specialist would have acted differently such that the injury could have been avoided. CONCLUSION: Twenty-three of the 33 deaths after the perinatal period could potentially have been avoided if experienced specialists had handled the cases.

Analysis of 136 ureteral injuries in gynecological and obstetrical surgery from completed insurance claims.

OBJECTIVE: Iatrogenic ureteral injury during pelvic surgical procedures is a well-known complication and important cause of morbidity. The authors investigated the circumstances surrounding registered ureteral injuries in order to identify potential opportunities to prevent such injuries. DESIGN: Evaluation of claims concerning ureteral injuries reported to the Danish Patient Insurance Association. SETTING: Danish Patient Insurance Association. SAMPLE: All registered claims for ureteral injuries from 1996 to 2006. METHODS: Retrospective study of medical records and data from Danish Patient Insurance Association. MAIN OUTCOME MEASURES: Preventable ureteral injuries. RESULTS: From 1996 to 2006, 136 submitted claims concerning ureteral injuries were registered. Among these, 73 claims were approved (54%), and compensation paid. In 44 of these, the injury was caused by negligence. Failure to dissect the ureter despite indications for this procedure was the most common type of negligence. Laparotomy procedures were associated with 107 injuries (79%) and 29 injuries (21%) were caused during laparoscopic procedures. Thirty-four patients suffered from chronic renal dysfunction on the affected side. Only 17 of the ureteral injuries were discovered during the procedure. CONCLUSIONS: Forty-four ureteral injuries could potentially have been avoided using established surgical practices, most importantly by exposing the ureter via dissection when indicated. Most of the ureteral injuries were discovered postoperatively.

[Hypoxic brain injuries notified to the Danish Patient Insurance Association during 1992-2004. Secondary publication]. / Asfyksiskader anmeldt til Patientforsikringen i perioden 1992-2004--sekundaerpublikation.

We investigated the files of the Danish Patient Insurance Association for newborns suffering from hypoxic brain injuries. From 1992 to 2004, a total of 127 approved claims concerning peripartum hypoxic injury were registered. Thirty-eight newborns died and the majority of the 89 surviving children suffered major handicaps, primarily cerebral palsy. In 69 of the cases, misinterpretation of or late action in response to an abnormal cardiotocography caused the hypoxic brain injuries. All injuries could potentially have been avoided using established obstetric practice.

Analysis of 127 peripartum hypoxic brain injuries from closed claims registered by the Danish Patient Insurance Association.

BACKGROUND: One of the most feared complications in medicine is hypoxic brain damage to a newborn. The authors investigated the circumstances of registered peripartum hypoxic brain injuries in order to identify potential opportunities to improve patient safety and prevent injuries. METHODS: The authors retrospectively investigated peripartum hypoxic brain injuries registered by the Danish Patient Insurance Association. RESULTS: From 1992 to 2004, 127 approved claims concerning peripartum hypoxic brain injuries were registered and subsequently analysed. Thirty-eight newborns died, and a majority of the 89 surviving children suffered from major handicaps, primarily cerebral palsy. In 69 of the cases, misinterpretation of or late action on an abnormal cardiotocography (CTG) were the reasons for the majority of the hypoxic brain injuries. CONCLUSIONS: All injuries could potentially have been avoided using established obstetric practice. CTGs are often misinterpreted. In the authors' opinion, education and training in CTG interpretation is essential. The use of ST-analysis of the fetus ECG (STAN) could probably reduce the number of these injuries.

Usage of the T1 effect of an iron oxide contrast agent in an animal model to quantify myocardial blood flow by MRI.

BACKGROUND: To present a new method for fully quantitative analysis of myocardial blood flow (MBF) using magnetic resonance imaging. The first pass of an intravascular iron oxide contrast medium can be used to quantify myocardial perfusion. The technique was validated in an animal model using colored microspheres. MATERIALS AND METHODS: In six pigs, a tracking catheter was positioned in the left anterior descending artery (LAD). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed on a 1.5-T scanner using a hybrid gradient-echo/echoplanar imaging (GRE-EPI) sequence. Regional myocardial blood flow (rMBF) was altered by either inducing vasodilatation with adenosine or creating coronary artery obstruction. The T(1) effect of a superparamagnetic iron oxide-based contrast medium (Resovist) administered at a dose of 8 micromol/kg was used. Upslope, time-to-peak and peak intensity were calculated from the signal intensity-time curves and absolute rMBF using the Kety-Schmidt equation; results were compared to those obtained using colored microspheres. RESULTS: The mean rMBF calculated by MRI was 1.49 (+/-6.91, quartile width) ml/min/g versus 3.21 (+/-1.61) ml/min/g measured by means of microspheres under resting conditions. rMBF increased to a mean of 6.21 (+/-2.83) ml/min/g versus 4.22 (+/-1.70) ml/min/g under adenosine and was reduced to zero flow in total occlusion. Linear regression showed the best correlation for upslope (R=0.714), time-to-peak (R=0.626) and the Kety-Schmidt equation (R=0.584). CONCLUSIONS: The T(1) effect of an iron oxide-based contrast medium allows determination of rMBF when using the Kety-Schmidt equation. The results are similar to those obtained with the standard of reference, colored micropheres, but not better than the results of the semiquantitative approach.

The influence of pregnancy on the development of autoimmunity in chronic lymphocytic leukemia.

To examine whether pregnancy influences the development of autoimmunity in chronic lymphocytic leukemia (CLL), we studied 591 consecutive CLL patients (202 post-menopausal women and 389 men). The mean observation time for all patients was 3.8 years, corresponding to approximately 2200 person-years of follow-up. Autoimmune manifestations were analyzed in 194 women with known obstetric history and known number of long-term sexual partners, and in the 389 male CLL patients for comparison. One hundred and fifty-nine of the CLL patients exhibited autoimmune manifestations, 38% in females and 21% in men. In female CLL patients, the frequency of autoimmunity and the number of pregnancies and the number of partners were strongly correlated. Each of the major autoimmune types approximately doubled in frequency for each additional pregnancy. The impact of pregnancy on expressed autoimmunity increased with each additional sexual partner (the odds of autoimmunity increased 11 times with each long-term sexual partner). The average numbers of pregnancies in female CLL patients with and without autoimmunity were 4.92 and 2.24, respectively (P < 0.001). Coombs' positive autoimmune anemia, a gastric ulcer with parietal cell autoantibodies and idiopathic thrombocytopenic purpura were equally common in women and men, whereas autoimmune thyroiditis, Sjögren's syndrome, rheumatoid arthritis and systemic lupus erythematosus were seen in higher rates in women than in men. The spectrum of autoimmunity suggests that pregnancy-related alloimmunization may be involved in the development of autoimmunity in CLL.

Hormone therapy and the impact of estrogen intake on the risk of ovarian cancer.

BACKGROUND: The association between menopausal hormone therapy (HT) and risk of ovarian cancer is as yet equivocal, and the effect of estrogen and estrogen-progestogen therapy, specifically the effect of the cumulative hormone intake, is unclear. METHODS: We conducted a nationwide population-based case-control study in Denmark. Cases were women aged 35 to 79 years with incident ovarian cancer diagnosed between January 1, 1995, and May 30, 1999. Controls were frequency age-matched women from the Danish Central Population Register. The analyses included data on 376 cases who have not undergone hysterectomy and 1111 controls. RESULTS: The risk of ovarian cancer in relation to oral HT increased with the cumulative intake of the estrogen component of HT but not with the duration or the cumulative intake of the progestogen component when the 3 variables were mutually adjusted. A simple trend was found such that each additional gram of estrogen was associated with the same relative increase. The odds ratio was constant throughout the range of cumulative intake. After adjustment for established risk factors, the estimated odds ratio per each additional gram of cumulative estrogen was 1.056 (95% confidence interval, 1.003-1.112), corresponding to an odds ratio of 1.31 (95% confidence interval, 1.01-1.70) per 5 g of estrogen. CONCLUSIONS: Oral HT is associated with risk of ovarian cancer in women who have not undergone hysterectomy. Our results imply that the risk increases with cumulative oral estrogen intake but not with duration of HT, indicating that the increased ovarian cancer risk associated with oral HT may be diminished substantially by minimizing the daily dose of estrogen from oral HT.

The prognostic value of plasma soluble urokinase plasminogen activator receptor (suPAR) levels in stage III ovarian cancer patients.

The level of the urokinase plasminogen activator receptor (uPAR) is elevated in tumor tissue from several forms of cancer. uPAR is shed from the cell surface and the soluble form, soluble urokinase plasminogen activator receptor (suPAR), has been detected in several body fluids. High plasma levels of suPAR in patients with colorectal cancer and high serum levels of suPAR in patients with recurrent metastatic breast cancer have been associated with poor prognosis. In patients with ovarian cancer (OC) it has been shown that the level of suPAR is very high in ascites and cystic fluid and that high serum levels of suPAR were associated with shorter survival of the patients. We evaluated suPAR preoperatively in plasma from primary OC stage III patients and tested for association with prognosis. The prognostic significance of suPAR was also compared to two biochemical markers; cancer antigen 125 (CA125) and tetranectin (TN). No significant differences were found between patients who died of OC compared to patients still alive regarding median plasma suPAR levels (p=0.62) and median serum CA125 levels (p=0.26). In contrast, a significant difference was found between dead and alive OC patients for the median serum TN level (p<0.0001). Dividing the patients into two groups, corresponding to preoperative plasma suPAR levels below or equal to 2.0 ng/ml and higher than 2.0 ng/ml, no significant difference in survival was found between the two groups (p=0.49). When different cut-off levels of plasma suPAR were considered (2.74 ng/ml, 3.25 ng/ml and 4.18 ng/ml), no significant differences in survival could be detected (p=0.58, p=0.68 and p=0.05). Multivariate Cox regression analysis showed that the only independent prognostic factors were radicality after primary surgery (RH=5.34; 95% CI, 2.34-12.20; p<0.0001) and preoperative serum TN (RH=0.69, 95% CI, 0.57-0.82; p<0.0001), whereas plasma suPAR (4.18 ng/ml), age, histological type of tumour and serum CA 125 had no independent prognostic value. In conclusion, preoperative plasma suPAR level was of no prognostic value in this cohort of Danish stage III OC patients.

Loss of heterozygosity on the X chromosome is an independent prognostic factor in ovarian carcinoma: from the Danish "MALOVA" Ovarian Carcinoma Study.

BACKGROUND: Ovarian carcinoma (OC) is the fifth most frequent female cancer type and the fourth most frequent cause of death from cancer among women in Denmark. At the time they are diagnosed with OC, approximately 70% of patients have advanced disease. It is believed that loss of tumor suppressor gene activity plays an important role in the origin and progression of OC and other malignancies. Loss of heterozygosity (LOH) may be detected in individuals heterozygous for an allele and is associated with loss of function of tumor suppressor genes. METHODS: The polymorphic marker regions (TP53, CACNLB1, D18S58, DXS538, and DXS454) were amplified by polymerase chain reaction followed by separation using gel electrophoresis before LOH was identified. In total, 160 women with primary epithelial OC were included in the study. RESULTS: Univariate analyses showed significant differences in survival between patients who had advanced OC with LOH or with retention using the microsatellite markers DXS454 (P = 0.04) and DXS538 (P = 0.01). Multivariate Cox regression analysis that included all patients showed that DXS454 (relative hazard [RH] = 3.5; P = 0.002; 95% confidence interval [95% CI], 1.6-7.8), radicality of primary surgery (RH = 5.5; P < 0.0001; 95% CI, 2.7-11.1), and serum tetranectin level (RH = 0.8; P = 0.009; 95% CI, 0.7-0.9) were independent prognostic factors for survival. Multivariate Cox regression analysis restricted to patients with International Federation of Obstetrics and Gynecology Stage III-IV disease showed that DXS454 (RH = 3.4; P = 0.007; 95% CI, 1.4-8.1), radicality of primary surgery (RH = 5.4; P < 0.0001; 95% CI, 2.2-12.9), and serum tetranectin level (RH = 0.8; P = 0.042; 95% CI, 0.7-1.0) were independent prognostic factors. CONCLUSIONS: LOH at DXS454 (Xq21-q23) appeared to be correlated with reduced survival in patients with OC.

Childhood tumor risk after treatment with ovulation-stimulating drugs.

OBJECTIVE: To assess childhood cancer risk among children conceived following the use of ovulation-stimulating drugs. DESIGN: Record linkage study. SETTING: Infertility patients and their offspring as identified through medical records. PATIENT(S): Cohort of 30,364 Danish women evaluated for infertility beginning in the early 1960s. MAIN OUTCOME MEASURE(S): Standardized incidence ratios (SIRs) compared cancer incidence in the children to the Danish population. Case-cohort techniques calculated rate ratios (RRs) according to prior maternal drug exposures. RESULT(S): A total of 51 cancers were identified among the study children, resulting in an SIR of 1.14 (95% confidence interval [CI] 0.8-1.5). Usage of any fertility drug was associated with an RR of 0.82 (95% CI 0.4-1.6) and clomiphene citrate with an RR of 0.77 (95% CI 0.4-1.6). Tumors occurring early in life and nonhematopoietic malignancies (including neuroblastomas) were not associated with drug usage. Nonsignificant elevations in the risk of cancers occurring later in life, especially childhood hematopoietic malignancies (RR for use of any ovulation-stimulating drugs of 2.30, 95% CI 0.8-6.6), may have been related to underlying reasons for medication usage. CONCLUSION(S): Although the findings of this study are reassuring, additional adequately powered studies should continue monitoring the effects of ovulation-stimulating drugs on specific tumors, including hematopoietic malignancies.

Evaluation of a polymorphism in intron 2 of the p53 gene in ovarian cancer patients. From the Danish "Malova" Ovarian Cancer Study.

BACKGROUND: The p53 gene is frequently mutated in various human tumours. In addition, single nucleotide polymorphisms are often observed in exons and introns of the p53 gene in normal tissues and tumours. MATERIALS AND METHODS: A total of 210 blood and tissue samples from 182 ovarian cancers (OC) and 28 ovarian borderline tumours, in addition to blood samples from 72 healthy women, were analysed. The used analyses were PCR and SSCP. The distinguishable SSCP patterns were confirmed by DNA sequencing. RESULTS: A polymorphism located at position 38 in intron 2 of the p53 gene was studied in blood and tumour tissues from Danish ovarian tumour patients and in blood from controls. Significant differences were found between the distributions of the genotypes in blood samples compared to the corresponding tissue samples (p = 0.0002). A tendency towards a significant difference in survival was observed between OC stage II patients with a shift from one genotype in the blood to another genotype in the tissue and patients with no shift (p = 0.05). In multivariate COX regression analysis restricted to stage III OC patients, the only independent factors found were shift, serum-tetranectin and age. CONCLUSION: A shift from one p53 intron 2 genotype in the blood to another genotype in the tissue may be a prognostic factor in ovarian cancer patients.

Distribution of HER-2 overexpression in ovarian carcinoma tissue and its prognostic value in patients with ovarian carcinoma: from the Danish MALOVA Ovarian Cancer Study.

BACKGROUND: The HER-2 (Human Epidermal Growth factor receptor-2, also known as c-erb-2/neu) protooncogene encodes a transmembrane receptor protein, M(r) 185,000. Studies have shown that the HER-2 oncogene is overexpressed in approximately 25-30% of ovarian carcinoma (OC) cases, but to the authors' knowledge, to date no consensus regarding overexpression and prognosis has been possible. The objective of the current study was first to analyze the presence of HER-2 overexpression in tissue from Danish OC patients and correlate the distribution of HER-2 overexpression with clinical and biochemical data and second to investigate the value of HER-2 overexpression as a prognostic marker in OC and to compare this value with the prognostic value of other biochemical markers. METHODS: The study population was comprised of the first 181 patients diagnosed with epithelial OC who were included in the MALOVA study. The staining procedure for HER-2 overexpression was performed using the p185 antibody. RESULTS: HER-2 overexpression was found in 95 of the 181 investigated cases (52.5%), in which 71 carcinomas (39.2%) were weakly positive (1+) and 24 carcinomas (13.3%) were moderately (2+) to intensely positive (3+). Increased HER-2 expression was found to be correlated with reduced survival. Significant differences in survival between patients with (1+, 2+, and 3+) and those without HER-2 overexpression were found for patients with International Federation of Gynecology and Obstetrics (FIGO) Stage I, Stage III, and Stage III/IV OC (Stage I: P = 0.021; Stage III: P = 0.0078; and Stage III/IV: P = 0.0054). Multivariate survival analyses including all 181 OC patients demonstrated that HER-2 overexpression is a prognostic marker (P = 0.003) together with disease stage, serum tetranectin level, and patient age. For patients with Stage III OC, the only independent prognostic factors detected were HER-2 overexpression (P = 0.009) and serum tetranectin level (P

High plasma YKL-40 level in patients with ovarian cancer stage III is related to shorter survival.

YKL-40 (human cartilage glycoprotein-39) is a member of family 18 glycosyl hydrolases. YKL-40 is a growth factor and is secreted by cancer cells. High serum levels of YKL-40 in patients with colorectal cancer and recurrent metastatic breast cancer have been associated with a poor prognosis. We evaluated the prognostic value of plasma YKL-40 in patients with primary ovarian cancer (OC). YKL-40 was determined by ELISA in plasma obtained preoperatively from 47 women with stage III OC and in plasma from 79 healthy females. The results showed that plasma YKL-40 was elevated compared to healthy females in 57% of the OC patients and was highest in the patients who died during the follow-up compared to the patients still alive (186 vs. 78 micro g/l, p=0.002). Patients with high plasma YKL-40 (>130 micro g/l) had significantly (p=0.0003) shorter survival than patients with normal plasma YKL-40. Multivariate Cox regression analysis showed that plasma YKL-40 (RH=3.95; 95% CI, 1.52-10.27; p=0.005) and radicality after primary surgery (RH=4.03; 95% CI, 1.81-8.97; p=0.001) were independent prognostic factors of survival, whereas age, histological type of tumour and serum CA125 had no independent prognostic value. In conclusion, plasma levels of YKL-40 proved of prognostic value in stage III OC patients.

K-ras alterations in Danish ovarian tumour patients. From the Danish "Malova" Ovarian Cancer study.

OBJECTIVE: Activation of ras oncogenes has been demonstrated in ovarian tumours. All the reported studies are based on a relatively small number of patients and the results therefore remain a subject of debate. METHODS: In this study, we analyzed the presence of mutations at codons 12 and 13 of the K-ras gene in 165 Danish women with ovarian tumours, including 138 invasive ovarian cancers and 27 borderline ovarian tumours, using a restriction fragment length polymorphism-polymerase chain reaction technique and evaluated whether such alterations were associated with the clinicopathological parameters of the patients and survival. RESULTS: K-ras codon 12 gene mutations were found in 8.7% of ovarian cancer patients and in 14.8% of the borderline ovarian tumour patients. A K-ras codon 13 gene mutation was found in 1.5% of ovarian cancer patients. K-ras mutations were found with a significantly higher frequency in mucinous tumours compared to serous tumours (P = 0.011). CONCLUSIONS: Mutation frequency was correlated with the histological type of tumour, but not with stage, radicality of operation, and age. Furthermore, no significant difference in survival was demonstrated between patients with or without K-ras mutation, neither in the univariate nor in the multivariate survival analyses.