Lack of p53 and ras mutations in Helicobacter hepaticus-induced liver tumors in A/JCr mice

Helicobacter hepaticus is a recently discovered bacterium that invades mouse liver causing chronic active hepatitis followed by development of preneoplastic hepatocellular foci, hepatocellular adenomas and carcinomas. This establishes a unique animal model for study of the mechanisms of cancer development due to a chronic bacterial infection. A possible mechanism of bacteria-associated tumorigenesis is mutation of oncogenes or tumor suppressor genes. Since mutations in ras oncogenes have been widely detected in a variety of chemically induced and spontaneous mouse liver tumors and specific mutations in the p53 tumor suppressor gene have been associated with human bladder cancers attributed to chronic schistosomal infection, we studied exons 1 and 2 of the N-, K- and H-ras genes and exons 5-8 of the p53 gene for the presence of point mutations in 25 liver tumors from 10 naturally infected A/JCr mice, ranging in age from 16 to 24 months. The 20 adenomas and five carcinomas varied in size from 0.1 to 2.3 cm and arose in livers characterized by a wide assortment of pathological profiles, including hepatitis, inflammation, hyperplasia, hypertrophy, leukocyte infiltration, necrosis and focal phenotypic alteration. DNA samples extracted from formalin-fixed paraffin-embedded tissues were screened by PCR/SSCP analysis and showed no mutations in the analyzed genes. Complete absence of mutations in ras genes in 25 mouse liver tumors is unusual. Other genes may be targeted or H. hepaticus infection causes liver cancer through other pathways than direct damage to DNA.      

Clinical and endoscopic predictors of histological oesophagitis in infants

Objective: To define the earliest age at which histological changes can be used to diagnose oesophagitis and to determine the relationships between clinical, endoscopic and histological features of oesophagitis in infants.
Methodology: The case records and biopsies of 113 infants aged 2–18 months with clinically significant gastro-oesophageal reflux (GOR), undergoing oesophagoscopy between 1978 and 1994 were retrospectively reviewed. The biopsies were independently evaluated and graded by two pathologists.
Results: Forty-five cases (40%) had histological oesophagitis but only 16 (14%) had abnormal endoscopic findings (excluding erythema). Endoscopy was found to be highly specific (93%) for histological oesophagitis but lacked sensitivity (25%). Irritability was inversely related to the presence of endoscopic abnormalities, and there was poor correlation between symptoms and histological changes with only haematemesis showing a statistically significant association with histological abnormalities ( P = 0.033). Intraepithelial lymphocytes were the earliest of the histological features noted and were present before 4 months of age. The numbers of intraepithelial eosinophils and lymphocytes and the presence of papillary elongation all increased with age.
Conclusions: The presence of oesophagitis is difficult to predict on the basis of symptoms. The presence of intraepithelial lymphocytes is the earliest histological change to be seen in infants with GOR, and can develop before 4 months of age. Oesophagoscopy without biopsy is unreliable in the diagnosis of oesophagitis in infants.     

Trends in the health burden due to urinary tract infection in children in Australia

Objective: To estimate the health burden of urinary tract infection in children less than 15 years of age in Australia and to ascertain whether any significant change has occurred during the past decade. Methodology: The number of children less than 15 years of age who were admitted in New South Wales for urinary tract infection between 1981 and 1994 was ascertained from the Department of Health, and age and sex specific incidence rates were calculated using Australian Bureau of Statistics population data. Costs for inpatient care were calculated using the cost weights from Australia National Disease Related Groups Version 3 for urinary tract infection (DRG 577). The frequency of the four most commonly requested renal tract imaging procedures in children following urinary tract infection and which qualified for Medicare reimbursement were obtained from the Health Insurance Commission for 1984–1994: micturating cystourethrography, intravenous urography, renal ultrasonography, and nuclear medicine renal studies. Results: There were 1203 children who were admitted with urinary tract infection in New South Wales in 1994, at an estimated cost of $A1.6 million. Since 1981, the age standardized annual incidence of urinary tract infection requiring hospitalization has increased from 0.5 to 0.9 per 1000 children, largely because of an increase in the number of young children admitted (from 0.6 to 2.0 per 1000 children less than 5 years of age). In 1994, 46 230 non-inpatient renal imaging procedures were undertaken in children under 15 years of age at a cost of $A5.3 million. Conclusions: Urinary tract infection is an important and increasing health problem for Australian children, particularly for preschool children. Whether this represents a true increase in the incidence of urinary tract infection or improved diagnosis and more intensive management is not possible to establish with this study design. Prospective population based studies are required to assess more completely the frequency with which urinary tract infection occurs in children and any changes that may be occurring.     

The epidemic of SIDS in Norway 1967-93: changing effects of risk factors

Time trends on the association of maternal age, birth order, and marital status with the risk of sudden infant death syndrome (SIDS) and non-SIDS deaths in Norway were analysed: 2356 postperinatal SIDS deaths and 4069 postperinatal non-SIDS deaths were ascertained during 1967-93. The SIDS incidence was 1.25 per 1000 in 1967, reached a peak of 2.69 in 1988, and fell to 1.22 in 1990 after the initiation of an intervention programme to avoid prone sleeping. In the entire period, young maternal age, high birth order, and unmarried motherhood were associated with SIDS. The adverse effects of young maternal age and high birth order increased continuously with time. From 1967-71 to 1990-93, the relative risk for maternal age < 20 years v maternal age 25-29 changed from 2.5 (95% confidence interval 2.0 to 3.2) to 7.0 (95% CI 4.2 to 11.9) (p < 0.0001), and for birth order 4+ nu birth order 1 from 3.2 (95% CI 2.5 to 4.2) to 14.4 (95% CI 8.3 to 24.9) (p < 0.0001). Effects on non-SIDS deaths were far weaker and no secular trends were observed. The strong association of young maternal age, high birth order, and marital status in SIDS, but not in non-SIDS, provides evidence that SIDS is an epidemiological entity. The increasing effects of young maternal age and high birth order, which continued after the sudden drop in the SIDS rate in 1990, suggest that further efforts to prevent SIDS should be aimed particularly at identifying causal mechanisms in high risk groups.     

Association among interleukin-6 gene polymorphism, diabetes and periodontitis in a Chinese population

Objectives:  Diabetics significantly increase risk for periodontitis. Interleukin-6 (IL-6) gene polymorphism may play certain roles in the progression of periodontitis with diabetes. The purpose of this study was to assess the association among IL-6 gene polymorphisms, type 2 diabetes mellitus (T2DM) and chronic periodontitis (CP) in a Chinese population.
Material and methods:  DNA was obtained from 159 patients with CP, 88 patients with T2DM, 110 patients with CP&T2DM and 135 control subjects. The -174/-572/-597 polymorphisms of IL-6 gene were investigated by restriction fragment length polymorphism of polymerase chain reaction products. The results were further confirmed by sequencing. Significance was set at P  < 0.008 after Bonferroni correction.
Results:  Among four groups, CP&T2DM group showed the lowest IL-6-572 CC genotype and C-allele frequencies (54.5% and 74.1%). In this regard, there were significant differences between CP&T2DM group and the control group [ P  = 0.006, odds ratio (OR)  =  0.475, 95% CI: 0.279–0.808 and P  = 0.002, OR = 0.502, 95% CI: 0.319–0.788 respectively]. Logistic regression with adjustment for age, gender, body mass index, smoking and stress showed no significant difference in terms of IL-6-572 genotypes ( P  = 0.058, OR= 0.523, 95% CI: 0.268–1.022).
Conclusions:  The IL-6-572 genotype and allele distributions are unique to subjects with CP&T2DM in a Chinese population.     

Matrix metalloproteinases as mediators of reproductive function

The organs of the adult reproductive system can undergo extensive remodelling, experiencing rapid changes in tissue mass and function. Much of this matrix remodelling is attributed to the action of matrix metalloproteinases. Matrix metalloproteinase family members are expressed in a highly-regulated manner in many reproductive processes, including menstruation, ovulation, implantation, and uterine, breast, and prostate involution. Metalloproteinase concentrations and activity can be regulated by reproductive hormones, as well as by growth factors and cytokines that participate in reproductive events. In addition to playing a role in the loss of connective tissue mass, the metalloproteinases can influence the phenotype of the cellular components of the tissues, altering basic cellular functions such as proliferation, differentiation, and apoptosis. This review focuses on the expression of matrix metalloproteinases in reproductive tissues, and discusses the evidence supporting a role for these enzymes in modulating the structure and function of reproductive organs.      

Nonimmune-mediated phagocytosis by "premedullary" lung macrophages: effects of concanavalin A, tuftsin, and macrophage-inhibitory peptide

Free cells arising in organ-cultured embryonic rat and hamster lungs share ultrastructural, lysosomal enzyme, and cell membrane properties with typical alveolar macrophages, expressing the developmental potential of the earliest-macrophage precursors resident in the lungs. In the lung culture environment cell proliferation is supported and macrophage attributes are developed despite absence of lymphocytes from the system. We have shown previously that among these attributes, the cells respond with increased phagocytosis of erythrocytes if these are opsonized with immunoglobulin G. Attention has now been turned to the question of nonimmune-mediated phagocytosis by the same population. Living macrophages that emerged from lung cultures bound rhodamine-coupled soybean and wheat germ agglutinins to a greater degree than concanavalin A (Con A), which nevertheless promoted lateral translocation of occupied receptors in the cell membrane. Emerged cells also phagocytosed living bacteria and native yeast cells (Y). The percentage of macrophages ingesting 3 or more yeast cells increased 400 (hamsters) to 500% (rats) when yeast was preincubated with Con A (200 micrograms/ml). Pretreatment of macrophages with Tuftsin (100 microM) enhanced uptake of Y by 100 (hamster) to 200% (rat). Pretreatment of macrophages with macrophage-inhibitory peptide (500 microM) appeared to inhibit phagocytosis of Y by 60% in hamsters but had no significant effect on cells from rat lung cultures.     

Mechanisms of cancer chemoprevention in hepatic carcinogenesis: modulation of focal lesion growth in mice

Studies in our laboratory have concentrated on further understanding the mechanism by which chemicals induce cancer and the means to prevent or retard this process. Recent investigations have revolved around the role of oxidative stress and oxidative damage in the induction of cancer by nongenotoxic carcinogens. Hepatocarcinogenic compounds including selective chlorinated hydrocarbons appeared to induce oxidative stress in the liver. This oxidative stress and oxidative damage in turn may be responsible for the tumor-promoting activity of these compounds. Reduction of oxidative damage by antioxidants, or dietary-restriction, results in an ablation of the induction of selective cell growth by these agents. The oxidative stress induced by nongenotoxic agents may influence cell proliferation and/or apoptosis in the preneoplastic cells. Our studies with nongenotoxic hepatic carcinogens showed a dose-dependent increase in oxidative stress and an increase in hepatic focal lesion growth. Antioxidant dietary supplementation or caloric restriction prevented the lesion growth. This appeared to be through an increase in apoptosis in the hepatic lesions.