Effects of daily stress or repeated paraoxon exposures on subacute pyridostigmine toxicity in rats

Pyridostigmine (PYR) is a carbamate cholinesterase (ChE) inhibitor used during the Persian Gulf War as a pretreatment against possible chemical nerve agent attack. Because of its quaternary structure, PYR entry into the central nervous system is limited by the blood-brain barrier (BBB). Following reports of unexplained illnesses among Gulf War veterans, however, central nervous system effects of PYR have been postulated through either stress-induced alteration of BBB permeability or via interactions with other neurotoxic agents. We evaluated the effects of daily physical (treadmill running) stress or daily exposure to a subclinical dosage of the organophosphate ChE inhibitor paraoxon (PO) on ChE inhibition in blood, diaphragm and selected brain regions in young adult male Sprague-Dawley rats following subacute PYR exposures. In physical stress studies, rats were placed on a treadmill for 90 min each day for 14 days just prior to PYR (0, 3, or 10 mg/kg per day) administration. In PO–PYR interaction studies, rats were treated with PO (0, 0.05, or 0.1 mg/kg per day) 1 h prior to daily PYR (0 or 3 mg/kg per day) administration for 14 consecutive days. Rats were evaluated daily for signs of cholinergic toxicity and were killed 1 h after the final PYR treatment. Forced running increased plasma corticosterone levels throughout the experiment (on days 1, 3, 7 and 14) when measured immediately after termination of stress. PYR-treated rats in the high dosage (10 mg/kg per day) group exhibited slight signs of toxicity (involuntary movements) for the first 6 days, after which tolerance developed. Interestingly, signs of cholinergic toxicity following PYR were slightly but significantly increased in rats forced to run on the treadmill prior to dosing. ChE activities in whole blood and diaphragm were significantly reduced 1 h after the final PYR challenge, and ChE inhibition in diaphragm was significantly greater in stressed rats than in non-stressed controls following high dose PYR (10 mg/kg per day). No significant effects of treadmill running on PYR-induced ChE inhibition in brain regions were noted, however. Repeated subclinical PO exposure had no apparent effect on functional signs of PYR toxicity. As with repeated treadmill running, whole blood and diaphragm ChE activities were significantly reduced 1 h after the final PYR administration, and ChE inhibition was significantly greater with combined PO and PYR exposures. Brain regional ChE activity was significantly inhibited after daily PO exposure, but no increased inhibition was noted following combined PO and PYR dosing. We conclude that, while some stressors may under some conditions affect functional signs of toxicity following repeated pyridostigmine exposures, these changes are likely to occur via alteration of peripheral cholinergic mechanisms and not through enhanced entry of pyridostigmine into the brain.     

A new simple,highly sensitive and selective spectrofluorimetric method for the speciation of thallium at pico-trace levels in various complex matrices using N-(pyridin-2-yl)-quinoline-2-carbothioamide

A very simple and non-extractive new spectrofluorimetric method for the determination of Tl^I and Tl^III individually and for mixtures of both analytes at pico-trace levels using N-(pyridin-2-yl)-quinoline-2-carbothioamide (PQCTA) has been developed. PQCTA reacts in a slightly acidic (0.0025–0.05 M H₂SO₄) solution with Tl^III in 20% ethanol and is oxidized itself to produce highly fluorescent oxidized product in aqueous solution, which has the excitation and emission wavelengths of λ_ex = 324 nm and λ_em = 379 nm, respectively. The determination of Tl^I is based on the rapid oxidation of this ion by bromine water heating for 15 min with the concomitant formation of fluorescent Tl^III-PQCTA. Fluorescence due to the sum of Tl^I and Tl^III is measured and Tl^I is determined from the difference in fluorescence values. Constant and maximum fluorescence intensities were observed for the period between 2 min and 24 h. Linear calibration graphs were obtained for 0.001–600 μg L⁻¹ of Tl, providing a detection limit of 0.16 ng L⁻¹. The quantification limit of the reaction system was 1.6 ng L⁻¹ and the RSD was 0–2%. A large excess of over 80 cations, anions, and complexing agents (such as chloride, phosphate, azide, tartrate, oxalate, and SCN⁻) do not interfere in the determination. The developed method was successfully used in the determination of thallium in several Standard Reference Materials (SRM) as well as in some environmental waters, biological fluids, soil and food samples, solutions containing both Tl^I and Tl^III, and complex synthetic mixtures. The results of the proposed method for biological samples, vegetables, food, soil, and water analyses were found to be in excellent agreement with those obtained by ICP-OES, AAS, and ICP-MS.

A very simple and non-extractive new spectrofluorimetric method for the determination of Tl^I and Tl^III individually and for mixtures of both analytes at pico-trace levels using N-(pyridin-2-yl)-quinoline-2-carbothioamide (PQCTA) has been developed.     

Economic benefit of leptospirosis prevention in Kelantan,Malaysia: Willingness‐to‐contribute approach

Leptospirosis is an endemic disease in Malaysia. Despite the increasing incidence rate, knowledge on the economic assessment of preventing leptospirosis is still limited. This paper introduces the willingness‐to‐contribute (WTC) method for estimating the economic benefit of preventing leptospirosis. A cross‐sectional study using the WTC method was applied to measure how much time respondents in Kelantan were willing to contribute toward preventing leptospirosis. Study respondents were wet market traders aged 18 years old and above who were fluent in the Malay language. The average WTC value was multiplied by the population of Kelantan to derive the monetary value of preventing leptospirosis. Two hundred and fifty respondents participated in the study. The mean time contribution was 6.68 hours (SD9.01) per month. The average WTC corresponded to a monthly cost savings of US$4.94 per person. Approximately between US$106.7 million to US$315 million per annum can be saved through the prevention of leptospirosis in Kelantan. Preventing leptospirosis is beneficial to Kelantan and would bring major economic savings. The findings are intended to help policy makers in the planning and management of leptospirosis policies and interventions.     

Relationship between methamphetamine exposure and matrix metalloproteinase 9 expression

The involvement of matrix metalloproteinase (MMP) 9 in methamphetamine-induced neurotoxicity was evaluated. Injection of mice with stimulant or toxic doses of methamphetamine upregulated MMP9 gene expression in the brain within 5 min. By 24 h, MMP9 gene expression returned to control levels in the stimulant-treated mice, but remained elevated in animals exposed to toxic doses of methamphetamine. Reductions in striatal dopamine levels, a marker of methamphetamine neurotoxicity, developed 1-7 days after methamphetamine exposure, but were not accompanied by concomitant changes in MMP9 gene expression. In MMP9 knockout mice, methamphetamine retained its ability to elicit neurotoxicity. The data suggest that MMP9 expression does not contribute to methamphetamine-induced neurotoxicity, and may instead be involved in remodeling of the nervous system.     

Lipid lowering effect of antioxidant alpha-lipoic Acid in experimental atherosclerosis

Accumulating data demonstrated that hypercholesterolemia and oxidative stress play an important role in the development of atherosclerosis. In the present study, a protective activity of alpha-lipoic acid; a metabolic antioxidant in hypercholesterolemic-induced animals was investigated. Eighteen adult male New Zealand White (NZW) rabbit were segregated into three groups labelled as group N, HCD and ALA (n = 6). Group N (normal control) was fed with normal chow, the rest (HCD and ALA) were fed with 100 g/head/day of 1% cholesterol rich diet to induce hypercholesterolemia. Four point two mg/body weight of alpha lipoic acid was concomintantly supplemented to the ALA group. Drinking water was given ad-libitum. The study was designed for 10 weeks. Blood sampling was taken from the ear lobe vein at the beginning, week 5 and week 10. Plasma was prepared for lipid profile estimation and microsomal lipid peroxidation index indicated with malondialdehyde (MDA) formation. At the end of the experiment, the animals were sacrificed and the aorta were excised for intimal lesion analysis. The plasma total cholesterol (TC) and low density lipoprotein (LDL) levels were found to be significantly low in ALA group compared to that of the HCD group (p<0.05). Similarly, low level of MDA (p<0.05) in ALA group was observed compared to that of the HCD group showing a significant reduction of lipid peroxidation activity. Histomorphometric intimal lesion analysis of the aorta showing less of atheromatous plaque formation in alpha lipoic acid supplemented group (p<0.05) compared to HCD group. These findings suggested that alpha lipoic acid posses a dual lipid lowering and anti-atherosclerotic properties indicated with low plasma TC and LDL levels and reduction of athero-lesion formation in hypercholesterolemic-induced rabbits.     

Roles and Mechanisms of MicroRNAs in Pancreatic Cancer

Pancreatic cancer (PC) is an aggressive malignancy with poor survival. The discovery of microRNAs (miRNAs) has provided a new opportunity to study the disease. Thus far, altered expression of miRNAs has been reported in a wide range of malignancies, including PC, and some miRNAs are associated with PC cell proliferation, invasion, chemoresistance, and patient survival. This review summarizes recent advances with respect to the roles and mechanisms of miRNAs in PC and discusses potential clinical applications.     

Glycaemic index of four commercially available breads in Malaysia

This study was carried out to determine the blood glucose response and glycaemic index (GI) values of four types of commercially available breads in Malaysia. Twelve healthy volunteers (six men, six women; body mass index, 21.9±1.6 kg/m²; age, 22.9±1.7 years) participated in this study. The breads tested were multi-grains bread (M-Grains), wholemeal bread (WM), wholemeal bread with oatmeal (WM-Oat) and white bread (WB). The subjects were studied on seven different occasions (four tests for the tested breads and three repeated tests of the reference food) after an overnight fast. Capillary blood samples were taken immediately before (0 min) and 15, 30, 45, 60, 90 and 120 min after consumption of the test foods. The blood glucose response was obtained by calculating the incremental area under the curve. The GI values were determined according to the standardized methodology. Our results showed that the M-Grains and WM-Oat could be categorized as intermediate GI while the WM and WB breads were high GI foods, respectively. The GI of M-Grains (56±6.2) and WM-Oat (67±6.9) were significantly lower than the reference food (glucose; GI = 100) (P < 0.05). No significant difference in GI value was seen between the reference food and the GI of WM (85±5.9) and WB (82±6.5) (P > 0.05). Among the tested breads, the GI values of M-Grains and WM-Oat were significantly lower (P < 0.05) than those of WM and WB. There was no relationship between the dietary fibre content of the bread with the incremental area under the curve (r = 0.15, P = 0.15) or their GI values (r = 0.17, P = 0.12), indicating that the GI value of the test breads were unaffected by the fibre content of the breads. The result of this study will provide useful nutritional information for dieticians and the public alike who may prefer low-GI over high-GI foods.