Comparison of hypoxic cell radiosensitizers,KIN-804, KIN-844, KIN-806 and TX-1877, on brain and liver metabolizing capacities in mice bearing Ehrlich ascites carcinoma

The biochemical effects of the 2-nitroimidazole hypoxic cell radiosensitizers KIN-804, KIN-806, and their analogues KIN-844 and TX-1877 on brain acetylcholinesterase (AChE) and hepatic free radical scavenging systems, such as reduced glutathione (GSH) and glucose-6-phosphate dehydrogenase (G-6-PDH) levels, and hepatic antioxidants, such as superoxide dismutase (SOD) and catalase, were evaluated in Ehrlich ascites carcinoma (EAC)-bearing Swiss albino mice. The assay of brain AChE revealed nonsignificant changes with all drugs examined. To evaluate the hepatic metabolic capacity, groups of mice were divided into control, EAC-inoculated, 10-Gy local gamma-irradiated, and KIN-804, KIN-844, KIN-806, or TX-1877 (50 mg/kg body weight, i.p.) groups, and gamma-irradiation was combined with each drug. EAC inoculation markedly suppressed GSH, G-6-PDH, SOD, and catalase levels. On the other hand, treatment with gamma-irradiation significantly enhanced them. The treatment of EAC-bearing mice with each drug alone in the absence of gamma-irradiation revealed that KIN-806 and its derivative TX-1877 showed antitumor activity through their significant recovery of GSH and SOD levels, respectively, in the EAC-bearing mice group. Similarly, the combined treatment of EAC-bearing mice with gamma-irradiation with each of the drugs tested showed that KIN-806 and TX-1877 significantly increased GSH and SOD, and to a lesser extent G-6-PDH and catalase levels. On the other hand, KIN-804 and KIN-844 had only a nonsignificant effect on all parameters examined. In conclusion, these data reveal that the administration of KIN-806 and TX-1877 with or without subsequent gamma-irradiation, resulted in significant recovery of GSH and SOD activities that were inhibited by EAC inoculation.     

Use of psychoactive substances and sexual risk behavior in adolescents

This study investigated the relationship between the use of illicit drugs and sexual-risk-behavior in a sample of students aged 14 to 21 years at a public high school in S?o Paulo in 1997. A total of 689 useable questionnaires documented the sample in consumption of psychoactive substances and sexual behavior. Sexual behavior of drug users and non-users was compared regarding history of complete sexual intercourse, age at first sexual intercourse, use of condoms, sexual intercourse with sex workers, and prostitution. Drug users (N = 366) presented a higher frequency of complete sexual intercourse (80.8% of users versus 53.5% of non-users), (N = 323, p < .001), a younger age at first sexual intercourse (on average 15.2 years in users versus 15.7 among non-users, p < .005), a trend toward lower use of condoms (56.7% among users versus 65.3% among non-users, p < .1), and more sexual intercourse with sex workers (31.1% among users versus 15% among non-users, p < .001). Sexual-risk-behavior increased with the number of drugs used. Alcohol and marijuana use were associated with the highest sexual-risk-behavior. These data are essential for the development of more specific preventive strategies, focusing on male alcohol and marijuana users.     

Spontaneous sternoclavicular joint infections

Spontaneous sternoclavicular (SC) joint infections are uncommon. Most cases of contained SC joint infections respond well to conservative treatment measures such as intravenous antibiotics and local drainage. However, some cases are more extensive, extending beyond the boundaries of the joint capsule, occasionally involving the anterior chest wall and mediastinum. We report our experience with 3 patients with spontaneous advanced SC joint infections. Radical surgical treatment seemed to provide the best control of this infection.     

Goiter prevalence,urinary iodine excretion,thyroid function and anti-thyroid function and anti-thyroid antibodies after 12 years of salt iodization in Shahriar,Iran

OBJECTIVE: In a previous study in 1983, goiter was found to be endemic in Shahriar, Iran. Iodized salt has been distributed in the region for the past 12 years, and the present study was performed to examine the effect of iodide supplementation on indicators of iodine deficiency (IDD) and thyroid antibodies. DESIGN & METHODS: A total of 3164 people, 58% women and 42% men, were selected by random sampling from the Shahriar area. Goiter was staged according to World Health Organization guidelines. Urinary iodine was measured by a digestion method, and thyroid hormone measurements were done by radioimmunoassay. The results were compared with those of 1983. RESULTS: Goiter prevalence before and after iodine supplementation was 50 and 40% in men, 70 and 51% in women, and 60 and 47% in the whole community, respectively (p < 0.001). A decrease in the prevalence of goiter was observed especially in younger individuals. The mean urinary iodine excretion was 7.6 and 18.5 micrograms/dL, before and after iodine supplementation. In 1983, the urinary iodine in 47.5% of the population studied was between 2 to 5 micrograms/dL, while in 1995, 65% of the population studied had urinary iodine between 10 to 25 micrograms/dL, 12 years after iodine supplementation. Mean serum T4, T3, and thyroid-stimulating hormone (TSH) were normal before and after intervention. There was no significant change in occurrence of positive antibodies, or of hypo- and hyperthyroidism, following iodine supplementation. CONCLUSION: The result of this study shows that the use of iodized salt causes an increase in excreted urinary iodine and a decrease in the prevalence of thyroid goiter, especially in younger age groups. Consumption of iodized salt with 40 parts per million (ppm) iodine has not caused increased prevalence of thyroid dysfunction in this area.     

Combination chemotherapy without cisplatin in the treatment of advanced non-small cell lung cancer

Cisplatin-based combinations are standard regimens in the treatment of advanced non-small cell lung cancer. Survival improvement has been achieved using this therapy. However, the high toxicity induced by cisplatin-based doublets urges the research of alternate treatments. Newest cytotoxic compounds yield a better efficacy-toxicity ratio. Platinum-free doublet regimens based on new drugs are expected to offer the patient an improved survival without decreasing his quality of life. Treatment-allocated time and period with high grade toxicity could be considered as wasted from the patient point of view. QUALY methods based on time without symptoms and toxicity allow the accurate evaluation of this end-point. This brief state-of-the-art deals with methodological statements highlighted by the first publications of randomized studies comparing non-platinum-based doublets with either single-drug chemotherapy or standard cisplatin-based doublets.     

Loss of Brca2 and p53 synergistically promotes genomic instability and deregulation of T-cell apoptosis

BRCA2 is a breast cancer susceptibility gene of which the product is thought to be involved in monitoring genome integrity and cell cycle progression. Brca2-null mice have a defect in embryonic cellular proliferation and die in utero. Here we report the generation of T-cell lineage-specific Brca2-deficient (tBrca2(-/-)) mice using the Cre-loxP system. Mice with a flanked by loxP allele of Brca2 were crossed to transgenic mice bearing Cre recombinase driven by the T cell-specific promoter Lck. Thymic cellularity and distribution of subset populations were normal in tBrca2(-/-) mutants. Thymocytes from tBrca2(-/-) mice underwent normal apoptosis in response to a variety of stimuli, and activated tBrca2(-/-) T cells had normal proliferative capacity. tBrca2(-/-) T cells were more likely than wild-type cells to undergo spontaneous apoptosis, but apoptosed normally in response to restimulation or DNA-damaging stress signals. Examination of metaphase spreads of tBrca2(-/-) T cells revealed that the chromosomes often exhibited aberrations such as breaks and tri-radial structures. The level of chromosomal abnormalities was enhanced in T cells from tBrca2(-/-); p53(-/-) double-mutant mice. However, tBrca2(-/-); p53(-/-) T cells did not show the enhanced level of spontaneous apoptosis demonstrated by tBrca2(-/-) T cells, a difference that likely accounts for an increase in cell number and (3)[H]thymidine incorporation of double-mutant T cells in culture compared with either single mutant. Despite this increased T-cell number, the onset of T-cell lymphomas was only marginally accelerated in tBrca2(-/-); p53(-/-) mice compared with p53(-/-) mice. Our results support a role for Brca2 in repairing spontaneous DNA lesions, and suggest that loss of Brca2 enhances the susceptibility of mouse T-lineage cells to chromosomal aberrations and deregulation of apoptosis in the absence of p53.     

Dunkerque City air pollution particulate matter-induced cytotoxicity, oxidative stress and inflammation in human epithelial lung cells (L132) in culture.

Exposure to urban airborne particulate matter (PM) has been associated with adverse health effects. In this work, we focused our attention on the capacity of air pollution PM to induce cytotoxic, oxidative stress, and inflammatory responses in human epithelial lung cells (L132) in culture. PM were collected in Dunkerque, a French seaside city, and their physical and chemical characteristics were carried out. Their size distribution showed that 92.15% of the PM were equal or smaller than 2.5 and their specific surface area was 1 m2/g. Inorganic (i.e. Fe, Al, Ca, Na, K, Mg, Pb, etc.) and organic (i.e. VOC, PAH, etc.) chemicals were found in PM. Physical and chemical properties of Dunkerque City's PM suggested that much of the collected PM derived from wind-borne dust from the industrial complex and the heavy motor vehicle traffic. Their cytotoxicity, as evaluated by survival rate determination, lactate dehydrogenase activity, and mitochondrial dehydrogenase activity showed concentration and time-dependent effects in L132 cells (LC10 = 18.84 microg PM/ml; LC50 = 75.36 microg PM/ml). Moreover, in PM-exposed L132 cells, there were concentration- and time-dependent changes in lipid peroxidation, superoxide dismutase activity, 8-hydroxy-2'-deoxyguanosine formation, and poly(ADP-ribosyl)ation, on the one hand, and in tumor necrosis factor-alpha secretion, inducible nitric oxide synthase activity, and nitric oxide release, on the other hand. Taken together, these findings suggested that oxidative stress and inflammatory responses proceeded cytotoxicity in PM-exposed L132 cells.     

Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450.

The biotransformation of prasugrel to R-138727 (2-[1-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-mercapto-3-piperidinylidene]acetic acid) involves rapid deesterification to R-95913 (2-[2-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl)ethanone) followed by cytochrome P450 (P450)-mediated formation of R-138727, the metabolite responsible for platelet aggregation. For identification of the P450s responsible for the formation of the active metabolite, the current studies were conducted with R-95913 as the substrate. Incubations required supplementation with reduced glutathione. Hyperbolic kinetics (K(m) 21-30 microM), consistent with a single enzyme predominating, were observed after incubations with human liver microsomes. Correlation analyses revealed a strong relationship between R-138727 formation and CYP3A-mediated midazolam 1'-hydroxylation (r(2) = 0.98; p < 0.001) in a bank of characterized human liver microsomal samples. The human lymphoblast-expressed enzymes capable of forming R-138727, in rank order of rates, were CYP3A4>CYP2B6>CYP2C19 approximately CYP2C9>CYP2D6. A monoclonal antibody to CYP2B6 and the CYP3A inhibitor ketoconazole substantially inhibited R-138727 formation, whereas inhibitors of CYP2C9 (sulfaphenazole) and CYP2C19 (omeprazole) did not. Scaling of in vitro intrinsic clearance values from expressed enzymes to the whole liver using a relative abundance approach indicated that either CYP3A4 alone or CYP3A4 and CYP2B6 are the major contributors to R-138727 formation. R-95913 and R-138727 were also examined for their ability to inhibit metabolism mediated by five P450s. R-138727 did not inhibit the P450s tested. In vitro, R-95913 inhibited CYP2C9, CYP2C19, CYP2D6, and CYP3A, with K(i) values ranging from 7.2 microM to 82 microM, but did not inhibit CYP1A2. These K(i) values exceed circulating concentrations in humans by 3.8- to 43-fold. Therefore, neither R-95913 nor R-138727 is expected to substantially inhibit the P450-mediated metabolism of coadministered drugs.     

Host feeding of mosquitoes (Diptera: Culicidae) associated with the recurrence of Rift Valley fever in Egypt

In 1993, Rift Valley fever (RVF) virus reappeared in Egypt. We determined the prevalence and feeding patterns of mosquitoes in 5 villages where the virus was active. Of 10 species recovered, Aedes caspius (Pallas), Culex pipiens L., Cx. antennatus (Becker), and Cx. perexiguus Theobald constituted 99% of > 35,000 mosquitoes captured in dry ice-baited CDC light traps. Ae. caspius was most prevalent, except at Nag' El Hagar where it was replaced by Cx. perexiguus. Cx. pipiens ranked 2nd, except at Nag' El Ghuneimiya, where it was replaced by Cx. antennatus. Most blood meals analyzed by an enzyme-linked immunosorbent assay reacted to > or = 1 antiserum. Cx. pipiens was mainly anthropophagic, and therefore may have been the main vector of RVF virus among humans. Ae. caspius feeds were chiefly from humans, bovines, and equines. Cx. antennatus and Cx. perexiguus fed generally on bovines. Mixed blood meals from humans and RVF virus susceptible animals were identified in the predominant mosquitoes. Prevalence and host selection, as well as predicted probability for a blood meal being interrupted, indicated that Ae. caspius may have served as a bridge vector between humans and bovines in 4 of the villages. Cx. perexiguus may have played this role at Nag' El Hagar. Because potential vectors are abundant, susceptible domestic animals are associated closely with humans, and surveillance of imported livestock is not systematic, we conclude that RVF virus sporadically will recur in Egypt.