Effects of calcium and plant sterols on serum lipids in obese Zucker rats on a low-fat diet

Ca may interfere with fat and cholesterol metabolism through formation of insoluble soaps with fatty and bile acids in the intestine. In the present study, we examined the effects of different dietary Ca levels on the serum lipid profile and cholesterol metabolism in obese Zucker rats fed a low-fat diet. We also tested whether dietary Ca interfered with the lipid-lowering effects of a pine oil-derived plant sterol mixture. Increase in dietary Ca intake from 0.2 to 0.8%, and further to 2.1% (w/w) dose-dependently decreased serum total cholesterol (r -0.565, P=0.002, n 27), LDL-cholesterol (r -0.538, P=0.006, n 25), and triacylglycerol (r -0.484, P=0.014, n 25) concentrations, and increased HDL-cholesterol (r -0.478, P=0.016, n 25) and HDL: LDL cholesterol (r 0.672, P<0.001, n 25) in rats fed a 1% cholesterol diet. Analysis of serum campesterol: cholesterol and sitosterol: cholesterol suggested that Ca dose-dependently increased intestinal cholesterol absorption (r 0.913, P<0.001, n 18), whereas serum desmosterol: cholesterol and lathosterol: cholesterol indicated that Ca dose-dependently increased endogenous cholesterol synthesis (r 0.691, P=0.003, n 18). Therefore, the decrease of serum LDL-cholesterol appeared to be due to Ca-induced increase in the conversion of cholesterol to bile acids. The increase in Ca intake did not interfere with the beneficial effects of plant sterols on serum total cholesterol, LDL-cholesterol and HDL-cholesterol concentrations. The high-Ca diet with plant sterol supplementation further increased the HDL-cholesterol concentration and HDL: LDL cholesterol. The present findings indicate that the beneficial effects of dietary Ca on the serum lipid profile during a low-fat diet are dose-dependent, and resemble those of bile acid sequestrants. Increased dietary Ca did not impede the lipid-lowering effects of natural plant sterols.     

BDNF regulates the expression of fragile X mental retardation protein mRNA in the hippocampus

Both fragile X mental retardation protein (FMRP) and brain-derived neurotrophic factor (BDNF) are implicated in the maturation of neurons and in the higher cognitive functions. We have investigated whether FMRP and BDNF are reciprocally regulated in neurons. Exposure of cultured hippocampal neurons to BDNF, but not to NT-3, reduced FMR1 mRNA levels to 84.8% of control at 4 h and the levels were back to baseline by 24 h or 4 days. Furthermore, expression of FMR1 mRNA was reduced (82.4% of control) in vivo in the hippocampus of transgenic mice overexpressing TrkB receptors, and a small but significant (5.1%) decrease was also detected in FMRP protein levels. In contrast, the expression patterns of BDNF and TrkB mRNAs were not altered in FMRP-deficient mice compared to wild-type mice. Our data provide evidence that BDNF via TrkB signaling decreases FMRP expression and suggest a role for FMRP in BDNF-induced synaptic plasticity.     

Evidence of benefit from centralised treatment of ovarian cancer: a nationwide population-based survival analysis in Finland

To assess the effect of different hospital types or surgical volume on the survival of ovarian cancer patients, a nationwide and population-based analysis was carried out in Finland. The study included all 3,851 ovarian cancer patients operated from 1983-94. The patients were classified according to the hospital of the first surgery. The hospitals were categorized by type (university, central or other hospital) and, separately, into quartiles by the number of operated patients (surgical volume). The patients operated at university hospitals had better survival than those operated in central hospitals, the 5-year relative survival rates (RSR) being 45% (95% CI = 42-48%) and 37% (34-40%), respectively. RSR in the 'other hospital' category was 45% (42-48%). The RSR for the patients operated in the highest volume hospitals was 47% (43-50%), and by decreasing volume (quartile) the RSR was 40% (36-43%), 40% (36-43%) and 42% (38-45%), respectively. After controlling for potential confounding by stage and age using regression models, the results remained practically the same. The results indicate that further centralizing of operative treatment of ovarian cancer may still improve survival rates on a population level in Finland.     

Socio-economic differences in incidence rates of cancers of the male genital organs in Finland, 1971-95

We studied social class variation in the incidence of cancers of the prostate, testis, penis and scrotum among 1.1 million Finnish men (45-69 years of age) during 1971-95. The incidence of prostate cancer (6,972 cases) was increasing during the study period; the highest at all the times occurred in Social Class I (highest social class), 40-50% higher than in Social Class IV (lowest). The social class gradient was strongest in localized disease but there was some variation in incidence of non-localized prostate cancer. A total of 174 testicular cancer cases were diagnosed during the study period. In the early 1970s, the incidence of testicular cancer in Social Class I was 5-fold compared to Social Classes III and IV. Thereafter, the incidence rate decreased in Social Class I, but increased in the lower classes. The positive social class gradient was similar for seminomas and non-seminomas. For penile cancer (n = 128), the incidence decreased over time and social class variation was small. Only 6 cases of scrotum cancer were observed. In testicular cancer the strong positive social class association in the early 1970s is disappearing along with converging incidence trend slopes in different social classes. The difference diminished to less than 2-fold in the 1990s. Reasons for this observation remain open.     

Uranium and other natural radionuclides in drinking water and risk of leukemia: a case-cohort study in Finland

Objective: We assessed the effect of natural uranium and other radionuclides in drinking water on risk of leukemia. Methods: The subjects (n = 144,627) in the base cohort had lived outside the municipal tapwater system during 1967–1980. A subcohort was formed as a stratified random sample of the base cohort and subjects using drinking water from drilled wells prior to 1981 were identified. A case–cohort design was used comparing exposure among cases with leukemia (n = 35) with a stratified random sample (n = 274) from the subcohort. Activity concentrations of uranium, radium-226, and radon in the drinking water were analyzed using radiochemical and alpha-spectrometric methods. Results: The median activity concentration of uranium in well water was 0.08 Bq/L for the leukemia cases and 0.06 Bq/L for the reference group, radon concentrations 80 and 130 Bq/L, respectively, and radium-226 concentrations 0.01 Bq/L for both groups. The hazard ratio of leukemia for uranium was 0.91 (95% confidence interval 0.73–1.13) per Bq/L, for radon 0.79 per Bq/L (95% CI 0.27–2.29), and for radium-226 0.80 (95% CI 0.46–1.39) per Bq/L. Conclusions: Our results do not indicate an increased risk of leukemia from ingestion of natural uranium or other radionuclides through drinking water at these exposure levels.     

Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease

BACKGROUND: Lung cancer is a frequent cause of death in patients cured of Hodgkin's disease, but the contributions of chemotherapy, radiotherapy, and smoking are not well described. We quantified the risk of treatment-associated lung cancer, taking into account tobacco use. METHODS: Within a population-based cohort of 19 046 Hodgkin's disease patients (diagnosed from 1965 through 1994), a case-control study of lung cancer was conducted. The cumulative amount of cytotoxic drugs, the radiation dose to the specific location in the lung where cancer developed, and tobacco use were compared for 222 patients who developed lung cancer and for 444 matched control patients. All statistical tests were two-sided. RESULTS: Treatment with alkylating agents without radiotherapy was associated with increased lung cancer risk (relative risk [RR] = 4.2; 95% confidence interval [CI] = 2.1 to 8.8), as was radiation dose of 5 Gy or more without alkylating agents (RR = 5.9; 95% CI = 2.7 to 13.5). Risk increased with both increasing number of cycles of alkylating agents and increasing radiation dose (P for trend <.001). Among patients treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), risk increased with cumulative amounts of mechlorethamine and procarbazine (P<.001) when evaluated separately. Statistically significantly elevated risks of lung cancer were apparent within 1-4 years after treatment with alkylating agents, whereas excess risk after radiotherapy began 5 years after treatment and persisted for more than 20 years. Risk after treatment with alkylating agents and radiotherapy together was as expected if individual excess risks were summed. Tobacco use increased lung cancer risk more than 20-fold; risks from smoking appeared to multiply risks from treatment. CONCLUSIONS: Past treatments with alkylating agents and radiation therapy for Hodgkin's disease were associated with an increased risk of lung cancer in a dose-dependent and additive fashion. The precise risk estimates, however, should be interpreted cautiously, given the possible residual and enhancing effects of tobacco.     

Cancer incidence in a cohort of Finnish male smokers.

A total of 29,133 male smokers, aged 50-69 years, were recruited into the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study in 1984-1988. The nationwide Finnish Cancer Registry (FCR) recorded 5944 incident cases of cancer in this cohort through the end of 1999. Compared with the FCR data of the entire Finnish male population of same age the standardized incidence ratio (SIR) of total cancer in the ATBC cohort was 1.55 [95% confidence interval (CI) 1.51-1.59]. There was a significant excess of established smoking-related malignancies, such as lung cancer (SIR 2.45, 95% CI 2.35-2.56), and cancers of the tongue, mouth, pharynx, larynx, oesophagus, pancreas, stomach, liver, urinary bladder and kidney. In addition to these sites, cancers of the prostate and colon were slightly more common in the ATBC cohort than in the total Finnish male population (SIR 1.10, 95% CI 1.04-1.18 and SIR 1.14, 95% CI 1.00-1.30, respectively). In conclusion, the risk of many cancers was significantly higher in the ATBC Study cohort compared with the total Finnish male population of same age. In addition to the well known smoking-related cancers, cigarette smoking may increase slightly the risk of colon and prostate cancer, too.     

The predictive value of bcl-2, bax, bcl-xL, bag-1, fas, and fasL for chemotherapy response in advanced breast cancer.

PURPOSE: The purpose was to evaluate the utility of some bcl-2 family proteins fas and fasL as predictive indicators for chemotherapy response in advanced breast cancer. EXPERIMENTAL DESIGN: Between October 1994 and October 1997, 283 patients with advanced breast cancer were included in a multicenter randomized study comparing docetaxel (D) to sequential methotrexate and 5-fluorouracil (MF) after anthracycline failure. The response rates (complete response + partial response) were 42 and 21% in the D and MF arms, respectively (P < 0.001). In 126 patients, histological blocks of primary tumors were available for immunohistochemical analysis of bax, bcl-2, bcl-xL, bag-1, fas and fasL. RESULTS: Of the investigated factors, bag-1 correlated positively with bax, bcl-2, and fasL, and fasL correlated positively with fas and bax. None of these apoptosis-related factors was associated with a response to chemotherapy either in the whole patient population or in the D or MF arms. Interestingly, low bcl-2 expression was associated with shorter time to progression (P = 0.02) and shorter overall survival (OS; P = 0.001). High fasL expression showed a trend toward shorter OS. In multivariate backwards stepwise Cox analysis, in which histological grade and estrogen receptor status (ER) were also included, bcl-2 (P = 0.01) and fasL (P = 0.005) remained highly significantly associated with OS, whereas histological grade and ER lost their significance. CONCLUSIONS: None of the investigated apoptosis-related factors of primary tumor could predict the later response to either D or MF treatment. However, fasL and bcl-2 were strong prognostic factors. Patients who had tumors with high fasL and low bcl-2 expression had the shortest OS.