Tumor cell cytotoxicity of a novel metal chelator

We have synthesized a novel six-coordinate metal chelator from the triamine cis-1,3,5-triaminocyclohexane by the addition of a 2-pyridylmethyl pendant arm on each nitrogen, which we term tachpyr. The experiments described here were designed to explore whether this compound exhibits potential antitumor activity. When added to MBT2 or T24 cultured bladder cancer cells, tachpyr was profoundly cytotoxic, with an IC50 of approximately 4.6 micromol/L compared with 70 micromol/L for desferioxamine. To explore the mode of action of tachpyr, several metal complexes were prepared, including Fe(II), Ca(II), Mn(II), Mg(II), Cu(II), and Zn(II) tachpyr complexes. Of these, the Zn(II), Cu(II), and Fe(II) complexes were without toxic effect, whereas the Ca(II), Mn(II), and Mg(II) complexes remained cytotoxic. To further probe the role of Zn(II) and Cu(II) chelation in the cytotoxicity of tachpyr, sterically hindered tachpyr derivatives were prepared through N-alkylation of tachpyr. These derivatives were unable to strongly bind Fe(III) or Fe(II) but were able to bind Zn(II) and Cu(II). When added to cells, these sterically hindered tachpyr derivatives were nontoxic, consistent with a role of iron depletion in the cytotoxic mechanism of tachpyr. Further, the addition of tachpyr to proliferating cultures resulted in an early and selective inhibition of ferritin synthesis, an iron storage protein whose translation is critically dependent on intracellular iron pools. Taken together, these experiments suggest that tachpyr is a cytotoxic metal chelator that targets intracellular iron, and that the use of tachpyr in cancer therapy deserves further exploration.     

Pyruvate improves myocardial tolerance to reperfusion injury by acting as an antioxidant: a chemiluminescence study

The utilization of various substrates by sperm from the cauda epididymidis of the tammar was examined because the major naturally occurring sugar in the semen of this species is N-acetyl-D-glucosamine (NAG) and not furctose, as in eutherian mammals. The sperm displayed a high level of endogenous respiration that supported motility for relatively prolonged periods of time in vitro. They also metabolised exogenous 14C-labelled glucose, NAG, sucrose, and acetate through glycolytic and/or oxidative processes to produce lactate and 14CO2 at varying rates. The rate of uptake of NAG by tammar sperm was about four times greater than that of other substrates. Glucose and/or NAG stimulated the rate of oxygen consumption by about 20%, but acetate stimulated oxygen consumption by more than 40%. The most striking findings were that NAG almost completely inhibited the oxidation of glucose and sucrose by the sperm and depressed the uptake of glucose, 3-O-methylglucose, and sucrose. Acetate oxidation also was inhibited by NAG, but only by about 50%. Tammar sperm generated substantial amounts of free glucose during incubation with NAG, but this and the inhibitory effects of NAG on glucose oxidation were not mimicked by rat sperm. It is proposed that tammar sperm fail to oxidise glucose in the presence of NAG because of the rapid cellular uptake of NAG relative to glucose. Also, the intracellular glucose and acetate liberated from NAG would compete with exogenous glucose for processing in the Embden-meyerhof and tricarboxylic acid (TCA) cycle pathways. It is also suggested that tammar sperm oxidise sucrose after extracellular hydrolysis into its glucose and fructose components. The biological implications of these metabolic and transport properties of tammar sperm have as yet to be determined.     

New one-week, low-dose triple therapy for the treatment of duodenal ulcer with Helicobacter pylori infection

BACKGROUND: Antimicrobial therapy is the recommended treatment for duodenal ulcer associated with Helicobacter pylori infection. The eradication of bismuth-based triple therapy with bismuth subcitrate, metronidazole and amoxicillin is limited by low compliance, drug resistance and side-effects. Two-week proton pump inhibitor (PPI)-based triple therapy has a higher eradication rate but is costly. This study was designed to compare the efficacy, patient compliance and cost of short-term PPI-based triple therapy with those of bismuth-based triple therapy. METHODS: Ninety patients with active duodenal ulcer disease and H pylori infection, proven with the 13C-urea breath test and CLO test (Campylobacter-like organism test) were treated randomly in three therapeutic groups: Group A, DeNol 120 mg, amoxicillin 500 mg and metronidazole 250 mg four times a day orally for 14 days; Group B, omeprazole 20 mg plus clarithromycin 500 mg twice a day and amoxicillin 500 mg four times a day for 14 days; Group C, omeprazole 20 mg, clarithromycin 250 mg and metronidazole 500 mg twice a day for seven days. Nizatidine 150 mg twice a day was given continuously following the end of anti-H pylori therapy for each group. Two months later, endoscopy, the CLO test and 13C-urea breath test were repeated to assess the eradication rate of H pylori and the ulcer-healing rate. Drug tolerance was evaluated by patients themselves by daily recording of any side-effects. RESULTS: Eighty-four patients completed the entire course of therapy and evaluation for H pylori infection. The H pylori eradication rates in Groups A, B and C were 75% (21/28), 93% (26/28) and 89% (25/28), respectively (p = 0.466). The ulcer healing rate was 86% (24/28) in Group A and 89% (25/28) in Groups B and C (p = 0.764). A total of 74 patients (88%) were free from symptoms at the end of the triple therapy. Symptom relief was faster in patients with PPI-based triple therapy (Groups B and C) (days 3 and 4) than for patients with bismuth-based triple therapy (day 5). The cost of Group C therapy was lower than that for Groups A and B. There were no major side-effects in any of the patients. CONCLUSIONS: One-week triple therapy with omeprazole, clarithromycin and metronidazole is highly effected for the eradication of H pylori. A therapeutic regime of one week's duration with lower cost, good compliance and mild side-effects may offer a good choice for treatment of duodenal ulcer associated with H pylori infection in clinical practice.     

Induced magnetic fields as evidence for subsurface oceans in Europa and Callisto

The Galileo spacecraft has been orbiting Jupiter since 7 December 1995, and encounters one of the four galilean satellites-Io, Europa, Ganymede and Callisto-on each orbit. Initial results from the spacecraft's magnetometer have indicated that neither Europa nor Callisto have an appreciable internal magnetic field, in contrast to Ganymede and possibly Io. Here we report perturbations of the external magnetic fields (associated with Jupiter's inner magnetosphere) in the vicinity of both Europa and Callisto. We interpret these perturbations as arising from induced magnetic fields, generated by the moons in response to the periodically varying plasma environment. Electromagnetic induction requires eddy currents to flow within the moons, and our calculations show that the most probable explanation is that there are layers of significant electrical conductivity just beneath the surfaces of both moons. We argue that these conducting layers may best be explained by the presence of salty liquid-water oceans, for which there is already indirect geological evidence in the case of Europa.     

Interaction of nonylphenol and hepatic CYP1A in rats

Both estradiol and nonylphenol (NP) inhibited hepatic microsomal 7-ethoxyresorufin O-deethylase (EROD) activity of beta-naphthoflavone-treated rats. Enzyme kinetic analyses (Lineweaver-Burk plots) using different estradiol and NP concentrations with graded increases in the concentrations of the substrate, ethoxyresorufin, showed that the inhibition was of a competitive nature at all concentrations of estradiol or NP used. Thus, the mechanism by which NP inhibits EROD activity is similar to that of estradiol. NP, however, was much less potent than estradiol. Young rats treated in vivo with 80 mg/kg body weight of NP demonstrated a slight but significant decrease in their hepatic microsomal EROD activity and CYP1A protein as measured by western blot analysis. In addition, treatment with NP led to a decrease in the steady-state levels of hepatic CYP1A mRNA in rats, suggesting that NP acted at the pre-translational level. The competitive nature of inhibition by NP on hepatic microsomal EROD activity indirectly suggests that this compound is a possible substrate of the CYP1A enzyme. Furthermore, NP had a moderate modulating effect on the expression of CYP1A in rat liver.     

A generalist herbivore in a specialist mode Metabolic,sequestrative, and defensive consequences

Adults of a generalist herbivore, the lubber grasshopper,Romalea guttata, can be converted to functional specialists by feeding them exclusively on catnip,Nepeta cataria. No obvious adverse effects on adult development resulted from this enforced monophagy. Notwithstanding the fact thatR. guttata has had no coevolutionary relationship with this Eurasian mint, it readily sequesters compounds that are identical to or derived from the terpenoid lactones that are characteristic ofN. cataria. R. guttata appears to both biomagnify minor allelochemicals and to sequester metabolites of theNepeta terpenes in its paired defensive glands. The levels of autogenously produced phenolics are not affected by feeding onN. cataria and the defensive secretions of catnip-fed grasshoppers are more repellent to ants than those of wild-fed acridids. Metabolites of theN. cataria monoterpenes are sequestered in the defensive glands when catnip is added to the natural diet ofR. guttata. The ability of a generalist,R. guttata, to facilely bioaccumulate a potpourri of foreign allelochemicals when feeding in a specialist mode is analyzed in terms of its biochemical, physiological, and functional significance. Sequestration is examined as a response to the enteric effronteries represented by the phytochemicals that can be characteristic of the overload in a monophagous diet.     

Orientation ofMicroplitis croceipes (Hymenoptera: Braconidae) to green leaf volatiles: Dose-response curves

FemaleMicroplitis croceipes wasps were tested in a wind tunnel for their ability to orient to various concentrations of eight different green leaf volatile (GLV) substances [hexanal, (E)-2-hexenal, (E)-2-hexen-1-ol, (Z)-3-hexen-1-ol, (E)-2-hexenyl acetate, (Z)-3-hexenyl acetate, (Z)-3-hexenyl propionate, and (Z)-3-hexenyl butyrate]. Overall, the esters elicited the greatest percentage of successful orientation flights, the alcohols elicited an intermediate response, and the aldehydes elicited a low response. The semilog dose-response curves were generally hill-shaped with high responses at medium release rates and low responses at high or low release rates. For the aldehydes, positive responses occurred at all GLV release rates between 0.01 and 100 nl/min. For some alcohols and esters, positive responses occurred at release rates as low as 1 pl/min and as high as 1μl/min. These data show thatM. croceipes wasps are strongly attracted to GLVs and are capable of orienting to GLV concentrations that would occur in nature when a caterpillar feeds on a green leaf. Hence, in nature, GLVs may be important clues, enablingM. croceipes to locate their hosts.     

Chemical Defense in the Plant Bug Lopidea robiniae (Uhler)

Secretions from the metathoracic glands (MTG) of the black locust bug, Lopidea robiniae (Uhler) (Heteroptera: Miridae) contained six major compounds, including (E)-2-hexenal, (E)-2-hexen-1-ol, (E)-2-octenal, (E)-2-octen-1-ol (E)-2-heptenal, and (Z)-3-octen-1-ol. Males and females did not differ significantly in the relative compositions of identified compounds. In feeding trials, six bird species [robin (Turdus migratorious), blue jay (Cyanocitta cristata), brown thrasher (Toxostoma rufum), killdeer (Charadrius vociferus), starling (Sturnus vulgaris), and house wren (Troglodytes aedon)] demonstrated feeding aversions towards L. robiniae, implying that black locust bugs are chemically defended. Bugs discharged the liquid contents of their MTG when attacked, thereby producing a strong and distinct odor. Some birds immediately ejected bugs out of their mouth after biting them, suggesting that the MTG secretion was a deterrent.     

Symptomatic subclavian steal syndrome four decades after operation for dysphagia lusoria

Congenital abnormalities of the aortic arch may lead to signs and symptoms of tracheal and esophageal obstruction secondary to a restrictive vascular ring. There are many case reports and monographs concerning the surgical management of dysphagia lusoria. This case provides the first example of long-term follow-up of surgical intervention for relief of dysphagia lusoria. A 45-year-old laborer presented with a several year history of episodic bilateral blindness and a more recent onset of "drop attacks." Notably this patient had presented at the age of 18 months with difficulty breathing and eating since birth. The patient also had frequent upper respiratory infections and episodes of pneumonia. Workup revealed a right-sided aortic arch with a left ligamentum arteriosum. When he was first seen in our clinic, history and physical examination revealed claudication and diminished pulses in the left upper extremity. Arteriography and duplex studies confirmed reversal of flow in the patient's left vertebral artery. The arteriogram demonstrated the presence of a right-sided aortic arch and descending aorta along with the proximal stump of the previously ligated left subclavian artery. He underwent left carotid to left axillary artery bypass for the treatment of symptomatic subclavian steal syndrome. His symptoms have resolved with return of antegrade vertebral flow and the presence of normal pulses in the left arm. Congenital aortic abnormalities that lead to tracheal and esophageal compromise are numerous and varied. Surgical management requires a thorough understanding of the person's anatomy and preoperative planning. The life expectancy of patients with dysphagia lusoria necessitates consideration of the long-term consequences of surgical intervention.     

A Multi-Criteria Decision Analysis Technique for Stochastic Task Criticality in Project Management

Inherent in project management is the risk that a project fails to meet planned completion deadlines due to delays experienced in individual tasks. As such, certain critical tasks may be candidates for risk management (e.g., the allocation of additional resources such as labor, materials, and equipment) to prevent delays. A common means to identify such critical tasks is with the critical path method (CPM), which identifies a path of tasks in a project network that, when delayed, result in project delays. This work offers a complementary, stochastic approach to CPM that ranks tasks according to their effect on the project completion time distribution, when the distributions of task completion time are delayed. The new hybrid approach is based on the use of a Monte Carlo simulation and a multi-criteria decision analysis technique. Monte Carlo simulation allows for approximating the cumulative distribution function of the total duration of the project, while the multi-criteria decision analysis technique is used to compare and rank the tasks across percentiles of the resulting project completion time distributions. Doing so allows for different percentile weighting schemes to represent decision maker risk preferences. The suggested approach is applied to two project network examples. The examples illustrate that the proposed approach highlights some tasks as risky, which may not always lie on the critical path as identified by CPM. This is valuable for practicing managers as it allows them to properly consider their risk preferences when determining task criticality based on the distribution of project completion time (e.g., emphasizing median vs. upper tail completion time).