Transplacental carcinogenic effects of nickel(II) acetate in the renal cortex, renal pelvis and adenohypophysis in F344/NCr rats.

Nickel(II) acetate (NiAcet), a soluble nickel salt known to be an effective initiator of renal epithelial tumors in adult rats, was studied for possible transplacental carcinogenicity. Pregnant F344/NCr rats were given NiAcet i.p. either once a day on day 17 (90 mumol/kg body wt; group 1) or twice on days 16 and 18 of gestation (45 mumol/kg body wt/day; group 2). Offspring of these rats were further subdivided into groups 1A and B and 2A and B, respectively. Groups 1A and 2A received ordinary tap water while groups 1B and 2B received drinking water containing 500 p.p.m. sodium barbital (NaBB) during weeks 4-85 of age. Renal cortical epithelial and renal pelvic transitional epithelial tumors occurred in male offspring given NiAcet prenatally followed by NaBB postnatally (group 1B, 15 tumors in 8/15 rats; group 2B, 10 tumors in 7/15), but not in male offspring given NiAcet only (0/32) or in controls given prenatal sodium acetate (NaAcet) only (0/15) and rarely in males given NaAcet followed by the promoter NaBB (1/15). No renal tumors occurred in females. Pituitary tumor incidence was significantly higher in offspring of both sexes given NiAcet prenatally (NaAcet controls, 4/31, both sexes combined; group 1A, 14/33, P = 0.012; group 2A, 14/31, P = 0.008). Pituitary tumors appeared much earlier in rats given NiAcet prenatally, with or without postnatal NaBB, and often were malignant by cytologic and histologic criteria including pleomorphism and invasion of adjacent structures, unlike the well-differentiated adenomas that occurred less frequently in untreated rats. These results are the first evidence that Ni(II) is a potent transplacental initiator of epithelial tumors in fetal rat kidney and a complete transplacental carcinogen for rat pituitary.     

A markedly diminished pleiotropic response to phenobarbital and structurally-related xenobiotics in Zucker rats in comparison with F344/NCr or DA rats.

Phenobarbital (PB) and certain structurally-related compounds induce a variety of hepatic drug-metabolizing enzymes in many strains of rats. Thus, following administration of PB (300, 500 ppm), barbital (BB, 1500 ppm) or 5-ethyl-5-phenylhydantoin (EPH, 500 ppm), CYP2B1-mediated benzyloxyresorufin O-dealkylase activity and epoxide hydrolase activity were profoundly induced in female DA and F344/NCr rats. In contrast, outbred female lean and obese Zucker rats showed markedly reduced CYP2B1 responses (less than 15% and less than 5% of those observed in the female DA or F344/NCr rat) to PB (doses less than or equal to 300 ppm), BB (1500 ppm) or EPH (500 ppm). In parallel studies, profound increases in RNA levels coding for CYP2B1, glutathione S-transferases Ya/Yc (alpha subclass), or epoxide hydrolase were detected in the female F344/NCr rat following treatment with PB (300 ppm), BB (1500 ppm) or EPH (500 ppm). In contrast, lean Zucker rats showed a strong response only to the highest dose of PB (500 ppm), implying that the diminished response in the Zucker rats may occur at some pretranslational level. Similar studies with lower doses of PB, EPH or BB in male lean Zucker rats showed a decreased response, relative to that in male F344/NCr rats. However, this insensitivity was not as profound as that observed in the female Zucker rats. In fact, the response to PB-type inducers in male or female Zucker rats is probably most clearly explained as a shift of the dose-response curve sharply to the right (decreased responsiveness, compared to F344/NCr or DA rats of the same sex). This decreased responsiveness of female lean Zucker rats to induction of CYP2B1, relative to that of F344/NCr rats, was also observed with the structurally-diverse PB-type inducers clonazepam, clotrimazole and 2-hexanone. In contrast, the female Zucker rat (obese or lean) displayed a pronounced response to induction of CYP1A-mediated ethoxyresorufin O-deethylase activity by beta-naphthoflavone, a prototype inducer of CYP1A1 and CYP1A2. The Zucker rat would thus appear to represent a potentially exploitable genetic model for examining the mechanism of enzyme induction by the myriad xenobiotics which induce a PB-type response.     

The family history in family practice: a questionnaire study

OBJECTIVES: Our aims were to investigate family medical history taking in general practice, and to evaluate the value attached to the family medical history as an aid to decision making in general practice. METHOD: A postal questionnaire survey was conducted among all 291 GPs working within the Calderdale and Kirklees Health Authority area. Each questionnaire was followed by a reminder. The main outcome measures were answers to questions on routine and opportunistic family history taking and a question about transmitting knowledge about genetic risk to other members of the family. Questions were also posed about the value attached to the family medical history as an aid to decision making. RESULTS: A total of 193 GPs returned the questionnaire (response rate 66.3%). On registration, 94.3% of GPs indicated that enquiries were made about a family history of coronary heart disease. Breast and colorectal cancer were specifically asked about by 48.4% and 30.7% of GPs, respectively. One-fifth of respondents indicated that they asked a general question about family medical history. A little over one-quarter of respondents indicated that they made opportunistic enquiries about the family history or suggested that the patient should inform other members of the family about possible risks. In the scenarios highlighted in this study, the majority of respondents felt that the family medical history had value as an aid to decision making. This was particularly the case for checking a patient's cholesterol (92.1%) and for initiating referrals in younger patients with possible cancer-related symptoms (three-quarters of respondents). CONCLUSION: GPs value the family medical history as an aid to decision making. Unfortunately, apart from enquiries about coronary heart disease, routine or opportunistic family history taking is not occurring in practice. Mechanisms need to be sought to extract information from the family medical history so that it can be more effectively used by GPs.      

A lipid inhibitor of dengue virus in human colostrum and milk; with a note on the absence of anti-dengue secretory antibody

Neutralizing activity against dengue virus types 1--4 was observed in milk samples from 5 non-immune and 29 dengue immune women. Anti-dengue activity in milk and colostrum was found only in the lipid component. The inhibitory activity is directed against the virus and not cell surfaces. When immunoglobulin types IgM,IgA, IgG were isolated from colostrum from dengue immune women, no antibody activity was found. Anti-dengue activity in human milk did not decrease over a period of ten months after delivery.     

Drug policy in China: pharmaceutical distribution in rural areas

In 1978, China decided to reform its economy and since then has gradually opened up to the world. The economy has grown rapidly at an average of 9.8% per year from 1978 to 1994. Medical expenditure, especially for drugs, has grown even more rapidly. The increase in medical expenditure can be attributed to changing disease patterns, a higher proportion of older people in the population and fee-for-service incentives for hospitals. Due to the changing economic system and higher cost of health care, the Chinese government has reformed its health care system, including its health and drug policy. The drug policy reform has led to more comprehensive policy elements, including registration, production, distribution, utilization and administration. As a part of drug policy reform, the drug distribution network has also been changed, from a centrally controlled supply system (push system) to a market-oriented demand system (pull system). Hospitals can now purchase drugs directly from drug companies, factories and retailers, leading to increased price competition. Patients have easier access to drugs as more drugs are available on the market. At the same time, this has also entailed negative effects. The old drug administrative system is not suitable for the new drug distribution network. It is easy for people to get drugs on the market and this can lead to overuse and misuse. Marketing factors have influenced drug distribution so strongly that there is a risk of fake or low quality drugs being distributed. The government has taken some measures to fight these negative effects. This paper describes the drug policy reform in China, particularly the distribution of drugs to health care facilities.     

Multiorgan transplacental and neonatal carcinogenicity of 3'-azido-3'-deoxythymidine in mice

The anti-HIV drug 3'-azido-3'-deoxythymidine (AZT) is used successfully for reduction of perinatal viral transmission. However toxic side effects including carcinogenesis are possible. To test this, pregnant CD-1 Swiss mice were given 25.0 or 12.5 mg AZT on gestation days 12-18. Previously we reported an increase in lung, liver, and female reproductive system tumors in offspring euthanized at 1 year (Olivero et al., J. Natl. Cancer Inst. 89, 1602-1608, 1997). Findings for all remaining offspring up to 2 years old are reported here. AZT effects were most prominent in female offspring, with a significant threefold increase in lung tumors, a reduction in lymphoblastic and follicle center cell lymphomas, and a significant increase in histiocytic sarcomas (0 in controls, 3% after low-dose AZT, and 8% after high-dose AZT, p = 0.022). Dose-dependent incidences of mammary gland, ovarian, and seminal vesicle tumors were low but significant: 0/106 controls, 3/105 low-dose, and 8/105 high-dose mice presented one of these neoplasms (p = 0.0025). Incidences of females showing any clearly AZT-related neoplasm, in lung, liver, ovary, or mammary gland or histiocytic sarcoma, in the second year, were 12/32 after the low dose and 14/27 after the high dose vs 3/23 controls (p = 0.0045). Also, the sensitivity of neonatal mice was assessed by administration of 25, 50, 100, or 200 mg/kg AZT on postnatal days 1 through 8. The effects at 2 years were similar to those seen after transplacental exposure, with significant increases in lung, liver, and mammary tumors in females. The results confirm that AZT is a moderately effective perinatal carcinogen in mice, targeting several tissue types.     

Proliferative lesions of oviduct and uterus in CD-1 mice exposed prenatally to tamoxifen

Tamoxifen (TAM) is widely used as adjuvant breast cancer therapy after surgery and as a chemopreventive agent in women of child-bearing age. However, TAM therapy has been shown to result in an increased incidence of endometrial carcinoma in women. The present study was designed to investigate the effects of TAM (5 mg/kg and 7.5 mg/kg body wt) given i.g. to pregnant CD-1 mice (1x/day, days 12 through 18 of gestation) on their female offspring. Progressive proliferative hyperplasia of the oviduct was frequently seen in TAM-exposed offspring, reaching 100% incidence by 52 weeks in both treatment groups. These females also developed progressive proliferative uterine lesions, including moderate/severe cystic endometrial hyperplasia (34-50%) and polypoid adenomas (27-30%) between 53 and 78 weeks. Deciduomas (15%) occurred at young ages (12 and 24 weeks) while leiomyomas (14%), a malignant leiomyosarcoma, and ovarian granulosa cell tumors (14%), were found between 72 and 78 weeks. Our findings thus suggest a strong association between transplacental TAM and reproductive tract abnormalities in female CD-1 mice.