Effects of proton radiation dose, dose rate and dose fractionation on hematopoietic cells in mice.

The present study evaluated the acute effects of radiation dose, dose rate and fractionation as well as the energy of protons in hematopoietic cells of irradiated mice. The mice were irradiated with a single dose of 51.24 MeV protons at a dose of 2 Gy and a dose rate of 0.05-0.07 Gy/min or 1 GeV protons at doses of 0.1, 0.2, 0.5, 1, 1.5 and 2 Gy delivered in a single dose at dose rates of 0.05 or 0.5 Gy/min or in five daily dose fractions at a dose rate of 0.05 Gy/min. Sham-irradiated animals were used as controls. The results demonstrate a dose-dependent loss of white blood cells (WBCs) and lymphocytes by up to 61% and 72%, respectively, in mice irradiated with protons at doses up to 2 Gy. The results also demonstrate that the dose rate, fractionation pattern and energy of the proton radiation did not have significant effects on WBC and lymphocyte counts in the irradiated animals. These results suggest that the acute effects of proton radiation on WBC and lymphocyte counts are determined mainly by the radiation dose, with very little contribution from the dose rate (over the range of dose rates evaluated), fractionation and energy of the protons.

Work pattern causes bias in self-reported activity duration: a randomised study of mechanisms and implications for exposure assessment and epidemiology.

BACKGROUND: Self-reported activity duration is used to estimate cumulative exposures in epidemiological research. OBJECTIVE: The effects of work pattern, self-reported task dullness (a measure of cognitive task demand), and heart rate ratio and perceived physical exertion (measures of physical task demands) on error in task duration estimation were investigated. METHODS: 24 participants (23-54 years old, 12 males) were randomly assigned to execute three tasks in either a continuous (three periods of 40 continuous minutes, one for each task) or a discontinuous work pattern (40 min tasks each divided into four periods of 4, 8, 12 and 16 min). Heart rate was measured during tasks. After completing the 2 h work session, subjects reported the perceived duration, dullness and physical exertion for each of the three tasks. Multivariate models were fitted to analyse errors and their absolute value to assess the accuracy in task duration estimation and the mediating role of task demands on the observed results. RESULTS: Participants overestimated the time spent shelving boxes (up to 38%) and filing journals (up to 9%), and underestimated the time typing articles (up to -22%). Over- and underestimates and absolute errors were greater in the discontinuous work pattern group. Only the self-reported task dullness mediated the differences in task duration estimation accuracy between work patterns. CONCLUSIONS: Task-related factors can affect self-reported activity duration. Exposure assessment strategies requiring workers to allocate work time to different tasks could result in biased measures of association depending on the demands of the tasks during which the exposure of interest occurs.

Countermeasures against space radiation induced oxidative stress in mice.

Of particular concern for the health of astronauts during space travel is radiation from protons and high atomic number (Z), high energy particles (HZE particles). Space radiation is known to induce oxidative stress in astronauts after extended space flight. In the present study, the total antioxidant status was used as a biomarker to evaluate oxidative stress induced by proton and HZE particle radiation in the plasma of CBA mice and the protective effect of dietary supplement agents. The results indicate that exposure to proton and HZE particle radiation significantly decreased the plasma level of total antioxidants in the irradiated CBA mice. Dietary supplementation with L: -selenomethionine (SeM) or a combination of selected antioxidant agents (which included SeM) could partially or completely prevent the decrease in the total antioxidant status in the plasma of animals exposed to proton or HZE particle radiation. These findings suggest that exposure to space radiation may compromise the capacity of the host antioxidant defense system; this adverse biological effect can be prevented at least partially by dietary supplementation with agents expected to have effects on antioxidant activities.

The protease inhibitor, Bowman-Birk Inhibitor, suppresses experimental autoimmune encephalomyelitis: a potential oral therapy for multiple sclerosis.

Available treatments for multiple sclerosis (MS) require frequent injections and have significant side effects. Proteases generated during inflammation are involved in the induction of tissue damage during inflammatory demyelination in the central nervous system (CNS). The Bowman-Birk Inhibitor (BBI), a soy-derived protease inhibitor with anti-carcinogenic and anti-inflammatory properties, has been shown to be well tolerated in clinical trials for pre-cancerous conditions, such as oral leukoplakia and the inflammatory disease, ulcerative colitis. We hypothesized that BBI may modulate experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The BBI concentrate (BBIC), a soybean extract enriched in BBI, was administered to myelin basic protein (MBP)-immunized Lewis rats by gastric gavage in different treatment regimens, during the induction or the effector phase of disease. BBIC significantly delayed disease onset and suppressed disease severity, clinically and pathologically, in all treatment protocols. Both in vitro and ex vivo, BBIC inhibited MBP-specific proliferation of lymph node cells. BBIC reduced the activity of matrix metalloproteinase (MMP)-2 and -9 in spleen cell supernatants and was detected in the CNS of treated rats. BBIC suppresses EAE, it can be administered orally, and it is safe and relatively inexpensive. It may have a therapeutic role in patients with MS.

The effect of chelation therapy with succimer on neuropsychological development in children exposed to lead.

BACKGROUND: Thousands of children, especially poor children living in deteriorated urban housing, are exposed to enough lead to produce cognitive impairment. It is not known whether treatment to reduce blood lead levels prevents or reduces such impairment. METHODS: We enrolled 780 children with blood lead levels of 20 to 44 microg per deciliter (1.0 to 2.1 micromol per liter) in a randomized, placebo-controlled, double-blind trial of up to three 26-day courses of treatment with succimer, a lead chelator that is administered orally. The children lived in deteriorating inner-city housing and were 12 to 33 months of age at enrollment; 77 percent were black, and 5 percent were Hispanic. Follow-up included tests of cognitive, motor, behavioral, and neuropsychological function over a period of 36 months. RESULTS: During the first six months of the trial, the mean blood lead level in the children given succimer was 4.5 microg per deciliter (0.2 micromol per liter) lower than the mean level in the children given placebo (95 percent confidence interval, 3.7 to 5.3 microg per deciliter [0.2 to 0.3 micromol per liter]). At 36 months of follow-up, the mean IQ score of children given succimer was 1 point lower than that of children given placebo, and the behavior of children given succimer was slightly worse as rated by a parent. However, the children given succimer scored slightly better on the Developmental Neuropsychological Assessment, a battery of tests designed to measure neuropsychological deficits thought to interfere with learning. All these differences were small, and none were statistically significant. CONCLUSIONS: Treatment with succimer lowered blood lead levels but did not improve scores on tests of cognition, behavior, or neuropsychological function in children with blood lead levels below 45 microg per deciliter. Since succimer is as effective as any lead chelator currently available, chelation therapy is not indicated for children with these blood lead levels.

Urinary excretion of Bowman-Birk inhibitor in humans after soy consumption as determined by a monoclonal antibody-based immunoassay.

The Bowman-Birk inhibitor (BBI) found in soybeans is a serine protease inhibitor with anticarcinogenic activity. In the present study, an ELISA for BBI was developed with the use of a monoclonal antibody against a reduced form of BBI. This newly developed ELISA method was used to measure the urinary levels of BBI metabolites in nine human subjects after consumption of 36-oz or 60-oz soymilk (containing 105 or 175 mg of BBI) at two time points 36 h apart. The results demonstrate that urinary BBI excretion rates peaked within 6 h and decreased to baseline levels within 12-24 h after soymilk ingestion. The changes in BBI:creatinine ratios in urine closely paralleled the changes in urinary BBI excretion rates after soymilk consumption. These data suggest that BBI ingested p.o. is absorbed and could be bioavailable for cancer chemoprevention in other organs in addition to those in the gastrointestinal tract.

Treatment with soybean-derived Bowman Birk inhibitor increases serum prostate-specific antigen concentration while suppressing growth of human prostate cancer xenografts in nude mice.

BACKGROUND: Bowman Birk inhibitor (BBI) is an anticarcinogenic serine protease inhibitor that may inhibit the protease activity of prostate-specific antigen (PSA) and the growth of human prostate cancer xenografts in nude mice. METHODS: Human prostate cancer xenografts were established by implanting LNCaP cells into the prostate glands of NCRNU-M athymic nude mice. The animals with established tumors were maintained on a control diet or diets supplemented with 1% BBI or 1%, 2%, or 3% BBI concentrate (BBIC) for 6 weeks. The serum PSA concentrations were determined before and after the BBI or BBIC treatment period. The final tumor loads were determined at autopsy. RESULTS: Treatment with BBI or BBIC decreased the final tumor load and increased the tumor doubling time and PSA density in the nude mice bearing human prostate cancer xenografts. CONCLUSIONS: BBI and/or BBIC could be useful for prostate cancer treatment.

Effects of the Bowman-Birk inhibitor on clonogenic survival and cisplatin- or radiation-induced cytotoxicity in human breast, cervical, and head and neck cancer cells.

Bowman-Birk inhibitor (BBI) is a soybean-derived anticarcinogenic protease inhibitor previously shown to potentiate cisplatin-induced cytoxicity in human lung and ovarian cancer cells. To further assess the potential of BBI as a sensitizing agent for cancer radiotherapy and chemotherapy, we evaluated the effects of BBI and a soybean concentrate enriched in BBI known as BBI concentrate (BBIC) on clonogenic survival and radiation- or cisplatin-induced cell killing in MCF7 human breast carcinoma cells, SCC61 and SQ20B human head and neck carcinoma cells, HeLa, HeLa-R1, and HeLa-R3 human cervical carcinoma cells, MCF10 nontumorigenic human epithelial cells, HTori-3 nontumorigenic human thyroid epithelial cells, and C3H10T1/2 mouse fibroblast cells. BBI and BBIC significantly suppressed the clonogenic survival of MCF7 and SCC61 cells. BBIC also suppressed the survival of SQ20B cells and enhanced radiation-induced cell killing in SCC61 and SQ20B cells and cisplatin-induced cell killing in HeLa, HeLa-R1, and HeLa-R3 cells. In contrast, BBI and/or BBIC did not enhance radiation-induced cell killing in MCF10 cells or cisplatin-induced cell killing in C3H10T1/2 cells. BBI did not significantly affect the survival of SQ20B cells or enhance radiation-induced cell killing in SCC61 and SQ20B cells. The clonogenic survivals of MCF10 and C3H10T1/2 cells were not adversely affected by treatment with BBI or BBIC. The clonogenic survival of HTori-3 cells was only moderately suppressed by treatment with BBIC at > or = 80 micrograms/ml. These results suggest that BBIC could be a useful agent for the potentiation of radiation- and cisplatin-mediated cancer treatment without significant adverse effects on surrounding normal tissues.

Bowman-Birk inhibitor suppresses production of superoxide anion radicals in differentiated HL-60 cells.

The Bowman-Birk protease inhibitor (BBI) is a soybean-derived protease inhibitor with anticarcinogenic and anti-inflammatory properties. BBI has previously been shown to suppress the release of superoxide anion radicals from purified polymorphonuclear leukocytes. In the present study we evaluated the effect of BBI on the production of superoxide anion radicals in differentiated HL-60 cells. HL-60 cells are human lymphocytic cells that acquire neutrophil-like characteristics when treated with dimethyl sulfoxide or tetradecanoyl phorbol acetate. Superoxide anion radical production by differentiated HL-60 cells was measured in the presence of various concentrations of BBI or BBI concentrate, a soybean extract containing high levels of BBI. BBI was observed to suppress superoxide anion radical production by differentiated HL-60 cells in a dose-dependent manner. Extracts of differentiated HL-60 cells were also observed to produce superoxide anion radicals, but this activity was not affected by the presence of BBI. These results suggest that BBI inhibits superoxide anion radical generation in HL-60 cells but does not act as a simple free radical scavenger.

Bowman-Birk inhibitor concentrate reduces colon inflammation in mice with dextran sulfate sodium-induced ulcerative colitis.

Bowman-Birk inhibitor concentrate (BBIC) is a soybean extract enriched in the Bowman-Birk inhibitor, a protein protease inhibitor. The Bowman-Birk inhibitor can inhibit proteases released from inflammation mediating cells and suppress superoxide anion radical secretion from immunocytes. This study investigates the ability of Bowman-Birk inhibitor concentrate to inhibit colon inflammation in the dextran sulfate sodium model of ulcerative colitis, an inflammatory bowel disease. When compared to mice on a standard diet, mice given food supplemented with 0.5% BBIC during and after dextran sulfate sodium treatment showed suppression of three of four scored histopathological inflammation criteria (P < 0.01), total histopathological score (P < 0.01), a 15% lower mortality rate (P < 0.01), and a delayed onset of mortality. We conclude that dietary Bowman-Birk inhibitor concentrate can beneficially affect dextran sulfate sodium-treated mice and may be useful in the treatment of human inflammatory bowel diseases, particularly ulcerative colitis.

Recall of a lead-contaminated vitamin and mineral supplement in a clinical trial.

PURPOSE: The Treatment of Lead-exposed Children (TLC) trial tested whether developmental outcome differed between children treated for lead poisoning with succimer or placebo. On 7 July 1997, TLC was informed that the vitamin and mineral supplements it gave to all children were contaminated with about 35 microg of lead per tablet. METHODS: TLC recalled the contaminated supplements and measured the children's exposure. RESULTS: The families of 96% of the children were contacted with 30 days. Among the 571 children to whom the contaminated supplements were dispensed, the mean increase in blood lead was 0.06+/-0.01 micromol/L (1.2+/-0.2 microg/dL); among 78 children to whom they were not, it was 0.09+/-0.03 micromol/L (1.8+/-0.7 microg/dL). There was no evidence of a dose-response relation between estimated supplement consumption and increase in blood lead concentration. CONCLUSIONS: The children's blood lead concentrations were not detectably affected by the contamination. Since the association of cognitive delay with lead exposure is best described for blood lead, we believe that the trial's inference about the effect of drug therapy on lead induced cognitive delay should be unaffected.

Growth inhibition and cytotoxicity induced by Bowman-Birk inhibitor concentrate in cisplatin-resistant human ovarian cancer cells.

Bowman-Birk inhibitor (BBI) is a soybean-derived anticarcinogenic protease inhibitor that was shown to potentiate the cytotoxicity of cisplatin in our previous studies. To assess the potential of BBI as a sensitizing agent for the chemotherapy of cisplatin-resistant cancers, we evaluated the effects of a soybean concentrate enriched in BBI (known as BBI concentrate or BBIC) on cell growth and clonogenic survival of a human ovarian cancer cell line, A2780, and its cisplatin-resistant sublines, C30, and C200. The presence of BBI and BBIC in the cell culture, medium reduced the clonogenic survival of the A2780, C30, and C200 cells in a dose-dependent manner and enhanced cisplatin-induced growth inhibition and/or cytotoxicity. BBIC alone showed greater inhibitory effects on growth in the cisplatin-resistant cell lines. These results suggest that BBI and BBIC could be useful agents for the treatment of cancers, especially with cisplatin, in tumors resistant to this important anticancer agent.

Soybean Bowman-Birk protease inhibitor is a highly effective inhibitor of human mast cell chymase.

Soybean Bowman-Birk protease inhibitor (BBI) is an inhibitor of serine proteases with two functional inhibitory domains of different specificities: one is specific for chymotrypsin-like proteases, the other for trypsin-like proteases. Chymase and tryptase are serine proteases which are stored in mast cell granules and released upon degranulation. This work investigated the inhibition of human chymase and tryptase by BBI. Active-site titration of human skin chymase by BBI demonstrated that BBI was a highly effective inhibitor of human chymase. Virtually stoichiometric inhibition of chymase by BBI was observed at 10 nM chymase. Kinetic studies of the inhibition reaction yielded an association rate constant of 4.0 x 10(5) M(-1) s(-1) and a dissociation rate constant of 1.7 x 10(-5) s(-1). From these two constants we estimate a K(i) of 50 pM. Chymase/BBI complexes did not dissociate in SDS-PAGE analyses under nonreducing conditions, consistent with the formation of a very tight complex with little tendency to dissociate. In contrast to chymase, human tryptase was not inhibited by BBI. These studies demonstrate that BBI is a good inhibitor of human chymase, exhibiting reaction properties better than physiological inhibitors described to date.

Effects of cigarette smoking on lung function in adolescent boys and girls.

BACKGROUND: Little is known about the sex-specific effects of cigarette smoking on the level and growth of lung function in adolescence, when 71 percent of people in the United States who smoke tried their first cigarette. METHODS: We studied the effects of cigarette smoking on the level and rate of growth of pulmonary function in a cohort of 5158 boys and 4902 girls 10 to 18 years of age, examined annually between 1974 and 1989 in six cities in the United States. RESULTS: We found a dose-response relation between smoking and lower levels of both the ratio of forced expiratory volume in one second to forced vital capacity (FEB1/FVC) and the forced expiratory flow between 25 and 75 percent of FVC (FEF25-75). Each pack per day of smoking was associated with a 3.2 percent reduction in FEF25-75 for girls (P=0.01) and a 3.5 percent reduction in FEF25-75 for boys (P=0.007). Whereas the FVC level was elevated in smokers, the rate of growth of FVC and FEV1 was reduced. Among adolescents of the same sex, smoking five or more cigarettes a day, as compared with never smoking, was associated with 1.09 percent slower growth of FEV1 per year in girls (95 percent confidence interval 0.70 to 1.47) and 0.20 percent slower growth in boys (95 percent confidence interval, -0.16 to 0.56), and with 1.25 percent slower growth of FEF25-75 per year in girls (95 percent confidence interval 0.38 to 2.13) and 0.93 percent slower growth in boys (95 percent confidence interval, 0.21 to 1.65). Whereas girls who did not smoke reached a plateau of lung function at 17 to 18 years of age, girls of the same age who smoked had a decline of FEV1 and FEF25-75. CONCLUSION: Cigarette smoking is associated with evidence of mild airway obstruction and slowed growth of lung function in adolescents. Adolescent girls may be more vulnerable than boys to the effects of smoking on the growth of lung function.