Genetics of the low density lipoprotein receptor:

Fibroblast association (plasma membrane binding plus intracellular accumulation) and degradation of radioiodinated low density lipoprotein (125I-LDL) index plasma membrane LDL receptor activity. Cultured fibroblasts from 23 subjects affected with familial hypercholesterolemia (HC) and from 95 subjects without HC (non-HCs) were tested for 125I-LDL association and degradation. Both LDL receptor activity indices were twice as high in non-HC and HC heterozygous cell strains. This is compatible with a major gene effect on LDL receptor activity. However, a considerable overlap between non-HC and HC heterozygous values was found in the 125I-LDL association assay [median (range) 970 (330-2500), and 450 (250-490), respectively] and in the degradation assay [median (range) 810 (280-2020), and 470 (160-790), respectively]. The values are expressed as ng 125I-LDL X mg cell protein-1 X 4.5 h-1. These great overlaps in the LDL receptor activity indices support the view that the influence of LDL receptor activity on the HC phenotype may be smaller than believed previously. Furthermore, for the diagnosis of HC, these LDL receptor activity assays are far more expensive and have less sensitivity and specificity than simple serum cholesterol determination. The LDL receptor-dependent 125I-LDL association values for the HC heterozygous individuals clustered into four groups. Family data supported the hypothesis that this variation could be due to four different LDL receptor variants, each coded for by different alleles at the LDL receptor locus. If confirmed, this finding may have implications for the understanding of the variable expression of HC and also of the genetic impact on lipoprotein metabolism and susceptibility to atherosclerosis in non-HCs.     

Effect of lipid lowering diet on low density lipoprotein receptor activity in freshly isolated peripheral blood mononuclear cells

The effect of lipid lowering diet on low density lipoprotein (LDL) receptor activity has been studied in freshly isolated peripheral blood mononuclear cells (PBMCs) from 16 hypercholesterolemic male subjects during a three weeks' dietary intervention trial. The participants were randomized to an intervention group or to a control group. The subjects in the intervention group had a non-significantly larger increase in LDL receptor activity, determined as degradation of 125I-LDL at 37 degrees C, than the control group (49.7 +/- 18.1 and 35.4 +/- 21.2 ng/mg, respectively). Irrespective of assignment to the intervention group or control group, the eight subjects with the largest reduction in total serum cholesterol had significantly larger absolute and percentage increases in LDL receptor activity than the eight subjects with the smallest reduction in total serum cholesterol (p less than 0.05). Thus, it appears that the cholesterol reduction that can be achieved in humans by dietary intervention results in a small increase in LDL receptor activity in freshly isolated PBMCs.     

Lanzoprazole promotes gastric carcinogenesis in rats with duodenogastric reflux

Background Duodenogastric reflux is known to cause an increased frequency of cancer in the glandular portion of the stomach in rats. Furthermore, it is debated whether inhibition of gastric acid secretion may promote gastric carcinogenesis. In the present study we examined the combined effect of gastroduodenal reflux and acid inhibition with respect to the development of gastric carcinoma in the rat.Methods Following the construction of a gastrojejunostomy in male Wistar rats, half of them were given the proton pump inhibitor lanzoprazole for 1 year. The rats were then killed and the pH in the stomach and gastrin in blood were measured. The stomach was examined macroscopically as well as histologically.Results Gastrin levels at autopsy were significantly increased in treated rats compared to the control group, confirming an effect of lanzoprazole on gastric acid secretion. Body weight was significantly reduced in the treated rats. Thirty of 79 rats developed gastric cancer, and they were all adenocarcinomas of the Lauren intestinal type. Gastric cancers occurred significantly more often in lanzoprazole-treated rats (50%) compared with controls (27%).Conclusion Lanzoprazole given orally enhances the carcinogenic effect of duodenogastric reflux in rats.     

Risk factors for unexplained antepartum fetal death in Norway 1967-1998

OBJECTIVE: To relate unexplained antepartum fetal death with maternal and fetal characteristics in order to identify risk factors. DESIGN: Population-based study based on records of 1,676,160 singleton births with gestational age > or =28 weeks. Unexplained antepartum fetal death was defined as fetal death before labour without known fetal, placental, or maternal pathology. RESULTS: Although unexplained fetal mortality in general declined from 2.4 per 1000 births in 1967-1976 to 1.6 in 1977-1998, the proportion among all fetal deaths increased from 30% to 43% during the same period of observation. Unexplained fetal death occurred later in gestation than explained. From 39 weeks of gestation, the risk increased progressively to 50/10,000 in women aged > or =35 years and <10/10,000 in women <25 years. In birth order > or =5, the risk was particularly high after 39 weeks of gestation. For birth weight percentile 2.5-9.9 and > or =97.5, unexplained fetal death was four and three times more likely to occur, respectively. We found an additive effect of maternal age and birth weight percentile 2.5-9.9. Women with less than 10 years education had higher risk than women with 13 years or more (OR=1.6). Weaker associations were observed with female gender, unmarried mothers, and winter season. CONCLUSIONS: Unexplained antepartum fetal death occurred later in gestation than explained and was associated with high maternal age, multiparity, low education, and moderately low and high birth weight percentile. The increased risk in post-term pregnancies and the additive effect of maternal age and birth weight percentile 2.5-9.9 suggests that older women would benefit from monitoring of fetal growth.     

Unexplained antepartum fetal death in Norway, 1985-97: diagnostic validation and some epidemiologic aspects

OBJECTIVE: To validate the diagnosis of an unexplained antepartum fetal death in the Medical Birth Registry of Norway against data obtained from hospital records, alone and combined with autopsy data. To compare epidemiologic characteristics of an unexplained fetal death based on cases recorded by the three data sources. METHODS: Data on unexplained fetal deaths in the Registry were compared with clinical and autopsy data from 108 457 singletons with a gestational age >or= 28 weeks or a birthweight >or= 1000 g delivered in 1985-97 at Haukeland Hospital in Bergen and Aker Hospital in Oslo. RESULTS: Compared with clinical data, the positive and negative predictive values of a Registry diagnosis of an unexplained fetal death were 88% and 86%, respectively, while the sensitivity and specificity were 76% and 93%, respectively. Compared with clinical and autopsy data combined, the positive and negative predictive values of a Registry diagnosis of an unexplained fetal death were 77% and 89%, respectively, while the sensitivity and specificity were 78% and 88%, respectively. High agreement was observed in comparisons between the data sources of risks according to various independent variables. CONCLUSIONS: The validity of a diagnosis of an unexplained antepartum fetal death based on the Medical Birth Registry of Norway is sufficiently high to justify future large-scale epidemiologic studies based on this database.     

Concentrations of serum proteins and erythrocyte sedimentation rate in patients with different histological types of gastric carcinoma

ESR and serum concentrations of IgG, IgA, IgM, C3, C4, C1-INH and CEA were quantified preoperatively in 195 patients with gastric carcinoma. The values were grouped according to the extent of disease (T1-3N0M0, T2-3N + M0, T4AnyNM0, AnyTAnyNM1) and according to the histological type of tumor (intestinal-type, diffuse and unclassifiable). The data were analysed using a two-way analysis of variance with unequal cell sizes. ESR, C4, C1-INH, IgG and CEA varied with the extent of disease. When the data were adjusted for this variation, we found that the values of ESR, C4 and CEA were different between the various histological types. The values were highest in patients with the intestinal-type tumor and lowest in those with diffuse tumor. The concentrations of IgG and C1-INH were not different between the histological types. Our results are relevant when ESR, C4 and CEA are used in the evaluation of patients with gastric carcinoma.     

Preoperative prediction of extent and prognosis of gastric carcinoma by four serum proteins and erythrocyte sedimentation rate

In 195 patients with gastric carcinoma the preoperative ESR and serum concentrations of IgG, C4, C1-INH and CEA varied significantly with the extent of disease. Extent of disease and prognosis were predicted from these variables by discriminant analysis. The discriminant rules were tested on the same patients in an unbiased way. Metastases or no metastases were correctly predicted in 75% of the patients. By an appropriate prior distribution 93% of the patients without metastases were identified. The disease extent was also predicted in subgroups of patients with and without metastases. Survival was correctly predicted preoperatively in 66% of the patients and 83% of the patients with a fair prognosis were identified. Of the patients preoperatively allocated to the non-survival group 94% did actually die during follow-up. When used in addition to other available information, our discriminant rules will contribute to the quality of the preoperative evaluation of patients with gastric carcinoma.     

The prognostic value of Laurén's histopathological classification system and ABO blood groups in patients with stomach carcinoma

The prognostic value of Laurén's histopathological classification system and the ABO blood group system has been studied in 275 patients with cancer of the stomach. The study disclosed a higher rate of tumours of intestinal type in females aged 70 years or more compared with those under 70 years, but no such relation for males. We found no relation between histopathological classification and blood groups. For patients with blood group A the 5-year survival was 17.5%, compared to 8.4% for blood group O (P less than 0.05). Survival for patients with intestinal and diffuse tumours was 17.7% and 4.8% respectively (P less than 0.01). A multivariate analysis showed that the histopathological classification system, independently, was an important factor with respect to survival (all other factors constant). Blood group might also be of importance as a prognostic factor, but further studies are necessary to confirm this.     

Serum C1-esterase inhibitor, an essential and independent prognosticator of gastric carcinoma

The preoperative concentrations of IgG were lower (P less than 0.002) and the concentrations of C4 and C1-INH higher (P less than 0.01 and P less than 0.001) in 29 patients with recurrence after potentially curative resection of gastric carcinoma, than in 31 patients alive and disease-free 5 years after surgery. These differences between the two groups of patients were consistent within each of six groups of disease extent. In each of the two groups of patients, the preoperative concentrations of IgG, C4 and C1-INH had no significant variation with the extent of disease (P greater than 0.05 or greater). Of our variables, C1-INH was the most potent prognosticator and discriminated between patients with and without recurrence with 80% accuracy. Furthermore, the predictive prognostic value of C1-INH at the time of surgery was superior to the prognostic value of the extent of disease (F values 27.00 and 12.69). Apparently, the preoperative C1-INH concentration is an essential and independent prognostic parameter of gastric carcinoma. We assume that C1-INH reflects an additional prognostic feature appropriate to the tumour or the host. Our finding that the interval between surgery and death from recurrence had an inverse relation to the preoperative C1-INH concentration also supports this assumption.     

Gastric carcinogenesis in rats given hypertonic salt at different times before a single dose ofN-methyl-N′-nitro-N-nitrosoguanidine

A 1-ml dose of 4.5 M NaCl was given intragastrically to male Wistar rats at 10 min, 1 h, 4 h, 12 h, 24 h or 48 h before a single intragastric dose of 250 mg/kgN-methyl-N-nitro-N-nitrosoguanidine (MNNG). After 52 weeks the incidence of forestomach squamous cell carcinoma was 21% in control animals receiving MNNG alone. The cancer incidence in the forestomach varied with the time elapsed between application of NaCl and MNNG, and was significantly increased in animals pretreated with NaCl 4 h (43%), 12 h (54%) and 24 h (41%) before MNNG. These results show that salt has a cocarcinogenic effect on initiation of forestomach carcinogenesis in rats, and that this effect depends on the time interval between pretreatment with NaCl and application of MNNG. Gastric adenocarcinomas occurred more frequently in the antrum (78%) than in the corpus (22%). The incidence of gastric adenocarcinoma in animals pretreated with salt before application of MNNG (11%–22%) was not significantly influenced by the time elapsed between pretreatment with salt and application of MNNG, and did not differ from animals receiving MNNG alone (18%). The lack of a cocarcinogenic effect of NaCl on glandular gastric carcinogenesis might be due to the use of dimethyl/sulfoxide as solvent for MNNG.Abbreviations MNNG N-methyl-N-nitro-N-nitrosoguanidine - DMSO dimethylsulfoxide This work was supported by grants from the Norwegian Cancer Society. Dr Sørbye is a Research Fellow of the Norwegian Cancer Society