bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of decoctions prepared from Aconitum carmichaeli, Aconitum kusnezoffii and Tripterygium wilfordii on serum lactate dehydrogenase activity and histology of liver, kidney, heart and gonad in mice
Authors: Chan WY , Ng TB , Lu JL , Cao YX , Wang MZ , Liu WK
Published: December 2008

Mature ICR mice were randomly divided into groups and treated with various doses (1 mg, 5 mg or 10 mg herb/25 g body weight) of a decoction of one of three following Chinese medicinal herbs: Aconitum carmichaeli, Aconitum kusnezoffi and Tripterygium wilfordii, once daily for 4 days. Twenty four hours after the last injection the animals were bled and the blood samples were stored at -20°C until assay for liver lactate dehydrogenase (LDH) isozyme activity. The livers, kidneys, hearts and gonads were dissected out, immediately fixed in Bouin's fluid, and subsequently processed for histological examination. It was found that the gonads and hearts of the drug-treated mice were histologically similar to those of control ani mals. After treatment with the lowest dose of the herbs i.e. 1 mg/25 body weight, the liver and kidney did not undergo observable changes. However, the herbs at the doses of 5 mg and 10 mg/25 g body weight produced damaging effects on the liver and kidney, the effects produced by the higher dose being more dramatic. The tissue damage was accom panied by elevations of liver LDH isozyme activity in the serum.
Activation of alpha-human tumour necrosis factor (TNF-α) by human monocytes (THP-1) exposed to 2-chloroethyl ethyl sulphide (H-MG)
Authors: Arroyo Carmen M , Von Tersch Robert L , Broomfield Clarence A
Published: December 2008

Tumour necrosis factor (TNF) is a monokine produced by monocytes and macrophages in response to different stim uli. To determine whether vesicant agents such as half- mustard gas (H-MG; chemical structure: ClCH2CH 2SCH2CH3) may induce the release of TNF-α in human monocytes (THP-1), ELISA experiments were con ducted at different post exposure times. The results indi cate that: (1) Significant increases in the TNF-α (pg mL-1) concentration were observed as a function of time when THP-1 cells were exposed to 100 μL of 2 M H-MG. A spe cific serine-type protease inhibitor, Nα-p-tosyl-L-lysine chloromethyl ketone (TLCK), led to partial but significant inhibition of TNF activation. (2) Furthermore, this labora tory detected the generation of spin adducts of 2-methyl-2- nitrosopropane (MNP) having a resemblance to MNP adducts generated from hydrogen atom abstraction of pro tein constituents.1 The EPR/Spin Trapping data indicate the trapping of by-products of protein degradation after exposure to H-MG. TNF-α may play a role as a biochemi cal marker for pathophysiological changes induced by H- MG or related agents.
Extrapyramidal manifestations complicating organophosphorus insecticide poisoning
Authors: Senanayake N. , Sanmuganathan PS
Published: December 2008

Six patients who developed extrapyramidal manifesta tions following poisoning with the organophosphorus (OP) insecticide fenthion are reported. The extrapyramidal fea tures, in order of frequency, were dystonia, rest tremor, cog-wheel rigidity, and choreo-athetosis. The delay in onset of these signs, following poisoning, varied from 4 to 40 days, and they disappeared spontaneously in about 1 to 4 weeks in those who survived. The human extrapyrami dal system is rich in cholinergic neurons and acetyl cholinesterase (AChE). Inhibition of AChE by fenthion, which has ready access to central neurons on account of its lipid solubility, is postulated as the mechanism under lying the extrapyramidal manifestations.
Fenoverine-induced rhabdomyolysis
Authors: Chariot P. , Ratiney R. , Le Maguet F. , Fourestié V. , Astier A. , Gherardi R.
Published: December 2008

Fenoverine is a spasmolytic drug that inhibits calcium channel currents. We describe the clinicopathologic find ings in two patients with fenoverine-induced rhabdomyo lysis, of whom one died. A transient left-bundle-branch block was observed in both patients. In one case, pre-exist ing hepatic dysfunction may have induced accumulation of the drug. Concurrent treatment by fibrates, as observed in the second patient, may have been a predisposing factor for fenoverine-induced rhabdomyolysis. The incidence of muscular complications of fenoverine therapy could be reduced by avoidance of prescription of the drug in patients with hepatopathy or those being treated with cho lesterol-lowering agents. Physicians should be aware of life-threatening adverse effects of apparently innocuous drugs.
Comparison of toxicity induced by T-2 toxin on human and rat granulo-monocytic progenitors with an in vitro model
Authors: Lautraite S. , Parent-Massin D. , Rio B. , Hoellinger H.
Published: December 2008

T-2 toxin is a trichothecene mycotoxin produced by vari ous species of fungi. Trichothecenes are known as major contaminants of cereals and their derivatives. In man as well as in animals, T-2 toxin has been shown to induce ali mentary intoxication and, among others, haematological symptoms. Granulo-monocytic progenitors from human umbilical cord blood on the one hand and granulo-mono cytic progenitors from rat bone marrow on the other, were cultured in the presence of T-2 toxin (from 10-7 to 10-10 M) for 14 days. A study of concentration and effect relation ships showed a strong and rapid effect of T-2 toxin on rat colony forming unit-granulocyte and macrophage (CFU-GM) between 5.10-9 M and 10-9 M. On the other hand, human CFU-GM were able to grow in the presence of the same T-2 toxin concentrations. IC50 were determined on day 7, 10 and 14. They were, respectively, 1.6.10-9 M; 3.6.10-9 M; 1.4.10-9 M for human cells, and 2.2.10-9 M; 3.3.10-9 M; 2.6.10 -9 M for rat cells. The present study was prompted by the need to define precisely the cytotoxic and inhibitory T-2 toxin concentrations for rat and human CFU-GM. It is particularly relevant for the investigation of cellular T-2 toxin targets and in order to elucidate the mechanism of trichothecene haematotoxicity.
HFA-134a (1 ,1, 1, 2-tetrafluoroethane): lack of oncogenicity in rodents after inhalation
Authors: Alexander DJ , Libretto SE , Chevalier H-J. , Imamura T. , Pappritz G. , Wilson J.
Published: December 2008

1 Groups of 60 male and 60 female B6C3F1 mice or Han- Ibm Wistar rats were exposed to HFA-134a using snout- only inhalation exposure techniques for periods of one hour daily for at least 104 weeks. HFA-134a was deliv ered directly from cylinders at vapour concentrations of 2500, 15 000 and 75 000ppm for mice and from metered-dose inhalers at vapour concentrations of 2500, 10 000 and 50 000ppm for rats.

2 Intended dosages were achieved.

3 Evidence of absorption was found at each dose level and was dose related.

4 Neither species suffered any treatment related effects on survival, clinical signs, body weights, haematology nor on the type, incidence, site or severity of gross lesions.

5 There was no effect of treatment on the type, incidence, site or severity of neoplasms in mice or rats.

6 There were no non-neoplastic findings related to treat ment in mice.

7 HFA-134a was considered not to be oncogenic and to provide a safe alternative to chlorofluorocarbons for use in pharmaceutical metered-dose inhalers.
Life-time exposure to dichlorvos affects behaviour of mature rats
Authors: Schulz H. , Nagymajtényi L. , Dési I.
Published: December 2008

Wistar rats were exposed to dichlorvos [CAS number 62737]. Doses were 1/25; 1/50; 1/75; and 1/100 LD50, that is 3.88; 1.94; 1.46; and 0.97 mg kg-1 DDVP, respectively, throughout gestation (GD1-birth) and during suckling via oral dosing to the dams, and then via the same doses by gavage for the rest of their lives. The offspring were tested in an open field (OF), a multiple T-maze, and in a 'novelty-induced- grooming' test to assess behavioural competence as adults. Dose-related increases in running time and incorrect choices in the maze were observed during the first 2 weeks of a 3-week study at 9-11 weeks of age. Horizontal activity was increased, vertical activity decreased, and defecation decreased in the OF at 9-12 weeks of age; these changes were again dose-related. Sleep was also affected at 12 weeks of age. AChE activity in the brain and in blood at sacrifice was roughly 40% to 65% of control, again reflect ing the doses administered. The significantly changed behavioural profile of DDVP treated rats may serve as a useful biomarker to judge functional damage of CNS prop erties.
Oxidative biotransformation of oxazepam to reactive and nonreactive products in rat, mouse and human microsomes
Authors: Griffin RJ , Burka LT , Demby KB
Published: December 2008

1 The oxidative metabolism of oxazepam by human, B6C3F1 mouse and F344 rat microsomes was examined. The major metabolite in all three species was 6-chloro-4- phenyl-2(1H)-quinazolinecarboxylic acid (CPQ-carboxylic acid). In addition, rat microsomes produced 4'-hydroxyox azepam and oxazepam-dihydrodiol in NADPH-containing incubations.

2 Covalent protein adducts were increased by the addi tion of NADPH to rat and mouse microsomes but not human microsomes. The magnitude of adduct formation was rats > mice > humans.

3 Formation of oxazepam-dihydrodiol was reduced by the addition of cyclohexene oxide and GSH to the incuba tions. Two additional metabolites were produced under these conditions. One of these was tentatively identified as a GSH conjugate. Covalent adduct formation was unaffect ed by GSH or cyclohexene oxide.

4 These results suggest that adduct formation occurred via an unknown reactive product rather than via oxazepam-epoxide, and that the relative rates of oxidative metabolism in vitro parallel that in vivo for the three species examined.
Aluminium deposition in liver and kidney following acute intravenous administration of aluminium chloride or citrate in conscious rats
Authors: Spencer AJ , Wood JA , Saunders HC , Freeman MS , Lote CJ
Published: December 2008

1 Plasma, urinary, liver and kidney cell aluminium (Al) levels were monitored in the rat, 1h after intravenous administration of 29630 nmol (800 μg) Al as either Al chloride or as Al citrate (Al chloride plus excess sodium citrate). Al levels were measured in plasma, urine and liver by atomic absorption spectroscopy (AAS). Liver and kidney Al content was measured at the cellular and subcellular level by electron probe X-ray microanalysis (EPXMA).

2 Urinary excretion of Al was significantly higher ( P < 0.01), when Al was given as the citrate than as the chloride. After 1h, plasma Al levels were significantly lower in the Al citrate group than the Al chloride group (59 ± 3.7 vs 877 ± 214 nmol ml-1, respectively; P< 0.01).

3 Al concentrations were significantly higher in the livers of rats receiving Al chloride (818 ± 252 nmol g-1wet weight; P < 0.05), than in either control or Al citrate groups (122 ± 41 and 107 ± 26 nmol g-1wet weight, respectively). Al concentrations derived from EPXMA measurements were in agreement with AAS values for the three groups, with significantly higher Al concentra tions in the Al chloride group (1.7 ± 0.4 nmol mg-1dry weight; P < 0.05) than in the control or Al citrate groups, where Al was not detectable. EPXMA analysis showed that Al was distributed in all liver organelles analysed (cytoplasm, mitochondria, nucleus, ER) and was not preferentially taken up by any one organelle in Al chloride treated rats.

4 Significant amounts of Al were found in cytoplasm and mitochondria of proximal tubule cells of rats given Al citrate (0.64 ± 0.15 and 0.80 ± 0.11 nmol mg-1dry weight, respectively), but not in nuclei or lysosomes of these cells. Al levels were not detectable in control kid neys, in proximal tubule cells after Al chloride adminis tration or distal tubule cells after either Al treatment.
Effect of urinary alkalinisation and acidification on the tissue distribution of hexachlorophene in rats
Authors: Flanagan RJ , Ruprah M. , Strutt AV , Malarkey P. , Cockburn A.
Published: December 2008

1 Urinary alkalinisation may be helpful in treating acute poisoning with uncouplers of oxidative phosphorylation containing a phenolic hydroxyl (pKa 4-6) or other acidic moiety.

2 We studied the effects of urine alkalinisation and acidi fication on the tissue distribution of hexachlorophene (HCP, pKa 5.7) in male Sprague Dawley rats (10 rats/group).

3 Ammonium chloride (10 mL kg-1, 2% m/v) or sodium bicarbonate (10 mL kg-1, 2% m/v) were administered by gavage on three occasions over 24 h, prior to a single gavage dose of HCP (180 mg kg-1). Controls received aqueous sodium chloride (10 mL kg-1, 0.9% m/v) fol lowed by either HCP (180 mg kg-1) or vehicle alone.

4 Urine pH, body mass and body temperature were moni tored during the study and, at the conclusion of the experiment (12 h post-HCP dose), organ mass (liver, kidney, brain), and plasma, urine and tissue HCP concentrations were measured.

5 No clinical features of toxicity were observed in any group. However, sodium bicarbonate significantly reduced median HCP in liver — median plasma and kidney HCP concentrations were also reduced but not significantly. Conversely, ammonium chloride signifi cantly increased median HCP concentrations in liver and kidney — median plasma HCP was also increased but not significantly.

6 The results provide some support for the hypothesis that blood pH influences the tissue distribution of uncou plers of oxidative phosphorylation containing an acidic moiety. Urinary alkalinisation may be useful in treating acute poisoning with these compounds.
Testing human hair for carbamazepine in epileptic patients: Is hair investigation suitable for drug monitoring?
Authors: Kintz P. , Marescaux C. , Mangin P.
Published: December 2008

Hair samples were obtained from 30 patients who had been taking carbamazepine in fixed daily doses for more than 6 months. Carbamazepine was extracted from the hair by enzymatic hydrolysis and quantified by gas chro matography-mass spectrometry. Concentrations ranged from 1.2 to 57.4 ng mg-1. The concentrations of carba mazepine were significantly correlated (P < 0.0001) with the daily dose and the correlation coefficient was 0.793. Although it had been suggested by several authors that the measurement of carbamazepine in hair might provide a better index of individual dosage history than the plasma level assays, the deviations observed in this study led to the conclusion that hair samples are not suitable for eval uating the quantity of drug consumed. However, hair test ing may be useful for documenting clinical disorders by sectioning the shaft into segments corresponding to 1 month periods.
Review : Neuropsychopathological changes by organophosphorus compounds — a review
Authors: Eyer P.
Published: December 2008

1 Available literature dealing with neuropsychopathologi cal changes after exposure to organophosphate insecti cides is reviewed.

2 Subacute neurological sequelae following acute organophosphate intoxication include the 'intermediate syndrome', probably a myopathy elicited by excess acetylcholine, and the 'organophosphate-induced delayed neuropathy' (OPIDN), which is caused by particularly neurotoxic organophosphates that inhibit neuropathy target esterase.

3 Long-term toxic effects affecting behaviour as well as mental and visual functions are occasionally observed after exposure to high doses of organophosphates with repeated acute, clinically significant intoxications.

4 The available data do not indicate that asymptomatic exposure to organophosphates is connected with an increasing risk of delayed or permanent neuro psychopathological effects.
Immunotoxicity study of repeated small doses of dimethoate and methylparathion administered to rats over three generations
Authors: Institóris L. , Siroki Olga , Dési I.
Published: December 2008

Immunotoxic effects of chronic, equitoxic doses (1/50, 1/75, and 1/100 LD50) of two organophosphorus pesticides dimethoate (DM) and methylparathion (MPT) (14.1, 9.39, and 7.04 mg kg-1DM; and 0.436, 0.291, and 0.218 mg kg-1MPT) were investigated in a three generation study in out- bred Wistar rats. Treatment of the first generation (G1) with these doses began in animals 4 weeks of age; the parental males were dosed until separation of females, and after mating the females were treated until separation of their G2 offspring (at the age of 4 weeks), and the G3 generation was produced in the same way from treated parental G2 animals. Selected 4 week old males from each generation were also treated with DM and MPT for 4 weeks (experimental groups) before determination of certain conventional toxicological (body weight gain, birth weight and number, organ weights), haematological (absolute and differential WBC, RBC, Ht, MCV, nucleated cell content of femoral bone marrow), and immune func tion parameters (IgM-PFC number of spleen, DTH reac tion).

Effects of both substances on immunological variables were detectable at the 1/75 LD50 dose level, but different parameters were affected in the three consecutive genera tions.
Effects of fish oil and sunflower oil supplementations on gentamicin-induced nephrotoxicity in rat
Authors: Abdel-Gayoum AA , Bashir AA , El-Fakhri MM
Published: December 2008

1 Nephrotoxicity was induced in rats by intramuscular administration of gentamicin (80 mg kg-1d-1) for 6 days.

2 Oral supplementation with fish oil (5 ml kg-1d-1), for 2 weeks prior to and during gentamicin exposure, markedly ameliorated the drug-induced nephrotoxici ty. The beneficial effects of oil were evidenced by sig nificantly reduced serum creatinine and urea concen trations, increased renal cortical alkaline phosphatase activity and improved renal tubular histology, com pared with the non oil-treated animals, receiving gen tamicin.

3 Similar supplementation with sunflower oil, rich in ω-6 fatty acids, failed to reverse any of the parameters of nephrotoxicity induced by gentamicin.

4 Hypercholesterolaemia and reduced cortical GSH associated with gentamicin nephrotoxicity were both normalised by supplementation with fish oil, but not by sunflower oil.

5 The beneficial effects of fish oil on gentamicin-induced nephrotoxicity were not related to the extent of uptake and accumulation of the drug by the kidney.
Optimising the removal of inhaled plutonium and americium from the rat by administration of ZnDTPA in drinking water
Authors: Gray SA , Pearce MJ , Stradling GN , Wilson I. , Hodgson A. , Isaacs KR
Published: December 2008

1 The efficacy of ZnDTPA administered in drinking water has been investigated for removing 238 Pu and 241Am from the rat after their simultaneous inhalation as nitrates.

2 The continual administration of ZnDTPA 95 μmol kg-1 d-1 over a 21 d interval commencing 1 h after exposure reduced the 238Pu content of the lungs and total body to 2% and 8% of those in untreated animals; the corresponding values for 241Am were 3% and 5%.

3 The continual intakes of 950 μmol kg-1 d-1, intermittent intakes of 3600 μmol kg-1 d-1 and the repeated injection of 30 μmol kg-1 body weight were considered no more effective. 4 All orally administered concentrations of ZnDTPA, commencing 7 d after exposure, reduced the total body contents of 238Pu and 241Am to 17% and 20% of controls by 28 d.

5 Histopathological examination of the kidneys, liver and gastrointestinal tract showed no apparent effects of these treatment protocols.

6 It is concluded that the oral administration of ZnDTPA could be an effective treatment for the removal of inhaled transportable forms of Pu and Am after human exposure.
Comparison of the efficacy of HI-6 and obidoxime against cyclohexyl methyl phosphonofluoridate (GF) in rats
Authors: Kassa J. , Bajgar J.
Published: December 2008

1 The efficacy of HI-6 and obidoxime in combination with atropine on cyclohexyl methylphosphonofluoridate (GF)- induced cholinergic and stressogenic effects in rats was studied.

2 HI-6 sufficiently reactivated cholinesterase activity in blood as well as acetylcholinesterase activity in brain and diaphragm following GF intoxication, and practically eliminated stressogenic effects of GF (an increase in plas ma corticosterone level and liver tyrosine aminotrans ferase activity).

3 Obidoxime had practically no effect on enzyme activity or stressogenic effects of GF agent.

4 These findings confirm that HI-6 has definite advan tages over obidoxime in the treatment of intoxication with GF.
Renal excretion of aluminium in the rat: effect of citrate infusion
Authors: Lote CJ , Willmott K. , Wood Jeanne A , Thewles A. , Freeman M.
Published: December 2008

When aluminium is administered intravenously to rats, the speciation of the aluminium has a major effect on its renal excretion. Aluminium administered as citrate is much more effectively excreted than that administered as chloride or sulphate. This suggests that citrate could be therapeutically useful in patients who have been exposed to aluminium.

Accordingly, we have performed two series of experi ments in rats, in which a citrate infusion (intravenous), was begun either immediately after, or one hour after, the administration of an intravenous aluminium sulphate bolus. Both protocols led to markedly enhanced alumini um excretion compared to controls in which only 0.7% NaCl was infused. The enhancement of aluminium excre tion was 783% if citrate infusion was begun immediately after aluminium administration, and 335% if the citrate infusion began after an hour delay. The increased excre tion was due to an increase in the freely filterable fraction of aluminium.

In the control experiments, in which aluminium sul phate administration was followed by 0.7% NaCl infusion, aluminium was found to be deposited in the liver. Administration of citrate one hour after the aluminium bolus did not reduce this liver deposition.

The results indicate that a fraction of the plasma alu minium is accessible to the citrate infused and can thereby be converted into a filterable form which can be excreted. It appears that, for maximum therapeutic effect, citrate should be infused as rapidly as possible after an alumini um load, to limit aluminium binding to ligands which allow it to enter cells.
Distribution of nickel in body fluids and organs of rats chronically exposed to nickel sulphate
Authors: Severa J. , Vyskocil A. , Fiala Z. , Cizkova M.
Published: December 2008

1 Male and female rats were given 100 mg Ni L-1 (as nick el sulphate) in drinking water for 6 months.

2 The feeding of nickel was associated with an increased concentration of nickel in body fluids and organs. The highest concentrations of nickel were found in the liver of both male and female rats. In male rats nickel levels decreased in the order: liver > kidney = whole blood = serum > testes > urine. In female rats the decreasing order was similar: liver > kidney = whole blood = serum = plasma > urine > ovaries.

3 No significant differences were found between nickel concentrations in organs (except ovaries), blood and urine of rats exposed for 3 months and those exposed for 6 months indicating the reaching of a steady state of nickel in the rat during long-term exposure.

4 The urinary excretion of the orally administered nickel was only 2% of absorbed dose (supposing 1% Ni absorp tion).
A new route to thyrotoxicosis?
Authors: Thomas Gerry
Published: December 2008

Human thyrocytes were found to synthesise and secrete the selenoenzyme extracellular glutathione peroxidase (E-GPX), a process which was controlled by the Ca2+/phosphoinositol second messenger cas cade. The potential involvement of thyroidal E-GPX in the regulation of thyroid hormone synthesis and in the protection of the thyrocyte from peroxidative damage is discussed.
Bolesatine induces agglutination of rat platelets and human erythrocytes and platelets in vitro
Authors: Gachet C. , Ennamany R. , Kretz O. , Ohlmann P. , Krause C. , Creppy EE , Dirheimer G. , Cazenave JP
Published: December 2008

Bolesatine is a toxic glycoprotein isolated from the mushroom Boletus satanas Lenz, which has been shown to inhibit protein synthesis in cell-free systems and cell culture. It is toxic to rodents, the LD50% 24 h being 1 mg kg-1 (i.p.) and 0.15 mg kg-1 (i.v) in the rat in which it induces hepatic blood stasis.

Bolesatine possesses lectinic properties with in parti cular a sugar binding site for D-galactose and mitogenic activity toward lymphocytes.

Tested for cell agglutination on red blood cells and platelets, bolesatine agglutinates both human and rat platelets from threshold concentrations of 30 and 300 nM respectively.

EDTA and PGI2 (aggregation inhibitors) do not decrease the agglutination induced by bolesatine, indicating that the process does not involve platelet activation. In contrast, fibrinogen decreases platelet agglutination in duced by bolesatine, most likely by masking the binding sites on platelets or by interacting with the toxin.

Bolesatine agglutinates all red blood cells without any blood group specificity in the concentration range of 20 to 40 nM. This haemagglutination cannot be prevented by sugars, including D-galactose at a concentration of 0.5 M.
Some immunological parameters in workers occupationally exposed to n-hexane
Authors: Karakaya A. , Yücesoy B. , Burgaz S. , Sabir HU , Karakaya AE
Published: December 2008

1 To estimate the quantitative relation between exposure to airborne n-hexane and various markers of immune function, 35 male workers were examined and compared with unexposed controls.

2 Urinary 2,5-hexanedione concentrations were signifi cantly higher in the exposed group than in the unexposed.

3 A significant suppression was observed in the serum immunoglobulin (IgG, IgM and IgA) levels between two populations. Also, a significant correlation was found between urinary 2,5-hexanedione concentrations and serum Ig level of the exposed group.

4 No significant difference between white blood cell counts was found in the two groups.
Transplacental passage of [3H]-okadaic acid in pregnant mice measured by radioactivity and high-performance liquid chromatography
Authors: Matias WG , Creppy EE
Published: December 2008

Okadaic acid (OA) is the main toxin produced by dinoflagellates, which can accumulate in the hepatopan creas of mussels and cause diarrhoetic shellfish poisoning in consumers. This toxin is also a tumour promoter and a specific potent inhibitor of protein phosphatases 1 and 2A. The results in this study show for the first time that this marine toxin is able to cross the transplacental barrier.

Foetal tissue contains more okadaic acid than the liver or kidney: 5.60% compared to 1.90 and 2.55% respectively as measured by HPLC and fluorescent detection after derivatization with 9-Anthryldiazomethane (ADAM). In view of its adverse effects, okadaic acid might impair foetal development and promote tumours in neonates.
Influence of age on the passage of paraquat through the blood-brain barrier in rats: A distribution and pathological examination
Authors: Widdowson PS , Farnworth MJ , Simpson MG , Lock EA
Published: December 2008

Experiments were performed to determine the extent of paraquat entry into the brain of neonatal and elderly rats, as compared with adult rats, which may be dependent on the efficacy of the blood-brain barrier. A single, median lethal dose (20 mg/kg s.c.) of paraquat containing [14C]paraquat was administered to neonatal (10 day old), adult (3 month old) and elderly (18 month old) rats. In contrast to the adult and elderly rats where paraquat levels fell over the 24 h post-dosing period to negligible levels, paraquat concentrations in neonatal brains did not decrease with time between 0.5 and 24 h following dosing. The distribution of [14C]paraquat was measured in selective brain regions using quantitative autoradiogra phy in all three age groups of rats, 30 min and 24 h following dosing. Autoradiography demonstrated that brain paraquat distributions were similar in the rat age groups. Most of the paraquat was confined to regions outside the blood-brain barrier and to brain regions that lack a complete blood-brain barrier e.g. dorsal hypotha lamus, area postrema and the anterior olfactory bulb. Between 0.5 h and 24 h following dosing, paraquat concentrations in deeper brain structures, some distance away from the sites of entry, began to slowly increase in all the rat age groups. By 24 h following dosing, a majority of brain regions examined using quantitative autoradiogra phy revealed significantly higher paraquat concentrations in neonatal brains as compared to brain regions of adult and elderly rats. Despite increased paraquat entry into neonatal brain, we could find no evidence for paraquat- induced neuronal cell damage following a detailed histopathological examination of perfused-fixed brains. In conclusion, impaired blood-brain barrier integrity in neonatal brain thus permitting more paraquat to enter than in adult brain, did not result in neuronal damage.
Concentrations of trichloroethylene and its metabolites in blood and urine after acute poisoning by ingestion
Authors: Yoshida M. , Fukabori S. , Hara K. , Yuasa H. , Nakaaki K. , Yamamura Y. , Yoshida K.
Published: December 2008

A 58-year-old man fell into a trichloroethylene reservoir bath head first, during a maintenance degreasing bath and accidentally ingested the solvent. Although he showed deep coma, chemical burns and pneumonia on admission, these symptoms gradually subsided.

The concentrations of trichloroethylene (TRI) and its metabolites, trichloroethanol (TCE) and trichloroacetic acid (TCA) in blood and urine were measured during hospitalization.

Eight hours after the accident, the concentrations ofTRI and its metabolites in serum were 31.4 μ g/ml TRI, 16.5 μg/ ml TCE and 79.5 μg/ml TCA. The serum TRI concentration decreased to 4.3 μg/ml on the following day. Elimination of TCE and TCA from serum occurred biphasically, the estimated half-lives of each metabolites being about 52.6 and 50.4 h in an initial fast phase and 268.3 and 277.2 h in a subsequent slow phase, respectively.

Urinary TRI excretion persisted for the first 2 days. The urinary TCE and TCA excretions were longer than that of TRI with a biphasic decrease and the total amount of TCE excreted during the first 2 days was about two times that of TCA. The half-life of urinary TCE excretion (t½ 25.7 h) was shorter than that of TCA (t½ 52.1 h) in the fast phase but did no difference during the slow phase, with each half-time being about 166.3 h.

The kinetics of TRI metabolites in blood and urine in this case were in slight agreement with the results following inhalation exposure previously reported in the literature.
Fatal acute hepatorenal failure following potassium permanganate ingestion
Authors: Young RJ , Critchley Jajh , Young KK , Freebairn RC , Reynolds AP , Lolin YI
Published: December 2008

Potassium permanganate (KMnO4), a powerful oxidizing agent, is readily available without prescription. Tissue contact produces coagulation necrosis and the lethal consequences of oral ingestion are well described, with most deaths because of airway oedema and obstruction or circulatory collapse. Whilst systemic toxicity is reported, its mechanism is unclear. We describe a case of suicidal ingestion of KMnO4 followed by acute hepatorenal toxicity resulting in the death of the patient. The clinical course bore close resemblance to that of severe paracetamol overdose. We discuss the pathogenesis of the systemic toxicity of KMnO4 and postulate that it is due to oxidative injury from free radicals generated by the absorbed permanganate ion. We recommend that N-acetyl cysteine be given within the first few hours to all patients with potassium permanganate poisoning.
Single fibre electromyographic changes in man after organophosphate exposure
Authors: Baker DJ , Sedgwick E Michael
Published: December 2008

1 Neuromuscular (NM) changes resulting from organo phosphate exposure are known to be complex. After severe acute poisoning recovery from initial depolar isation paralysis may be followed in a limited number of cases by onset of a non-depolarisation paralysis (the Intermediate Syndrome). It is not clear whether this block arises subclinically in all cases of poisoning as a sequel to the initial depolarisation.

2 Single fibre electromyography (SFEMG) is a sensitive clinical neurophysiological technique allowing detec tion of subclinical changes at the neuromuscular junction. In the study reported it has been used to examine changes in NM transmission in the forearm of fit volunteers exposed to a low level of sarin (isopropyl methyl phosphonofluoridate).

3 Small changes in SFEMG were seen at three hours and three days after an exposure sufficient to cause a reduction in red cell acetyl cholinesterase to 60% of normal. The SFEMG changes were not accompanied by any clinical neuromuscular symptoms or signs and returned to normal 2 years after exposure.

4 The results indicate that there are reversible subclini cal changes compatible with the development of non depolarising NM block without frank clinical expres sion. In the small population examined there were individual variations in response which may reflect differences in safety margin at the neuromuscular junction.
The influence of pharmacological pretreatment on efficacy of HI-6 oxime in combination with benactyzine in soman poisoning in rats
Authors: Kassa Jiří , Bajgar Jiří
Published: December 2008

1 The influence of pharmacological pretreatment (pyr idostigmine, benactyzine and trihexyphenidyle), de signated PANPAL, on soman-induced cholinergic and stressogenic effects as well as on the efficacy of antidotal treatment (HI-6 plus obidoxime) in rats was studied.

2 PANPAL prophylaxis significantly decreased soman- induced cholinesterase inhibition in blood, brain and diaphragm as well as stressogenic effects of soman (an increase in plasma corticosterone level and liver tyrosine aminotransferase activity).

3 PANPAL pretreatment did not improve the efficacy of HI-6 in combination with benactyzine on soman- induced anticholinesterase and stressogenic effects.

4 These findings confirm that PANPAL prophylaxis can improve prognosis of soman poisoning especially by protection of cholinesterases.
Cadmium-induced alterations in blood- brain barrier permeability and its possible correlation with decreased microvessel antioxidant potential in rat
Authors: Shukla Arti , Shukla Girja S , Srimal RC
Published: December 2008

1 Male albino rats of 21 days age were exposed to 10 p.p.m. cadmium (CdCl2 salt) in drinking water, ad libitum, for 90 days. It increased the brain cadmium levels by 76% ( P < 0.05) and 165% ( P < 0.001) respec tively at 30 and 90 days of exposure compared to controls.

2 Cadmium increased blood - brain barrier permeability of fluoroscein dye (24%, P < 0.02) and the levels ofbrain microvessel malondialdehyde (31%, P<0.01) at 90 days of exposure. However, these parameters did not alter significantly at 30 days of exposure.

3 Increased activities of microvessel superoxide dismu tase (18%, P<0.02), glutathione peroxidase (20%, P<0.01) and catalase (28%, P<0.01) were observed at 30 days of exposure.

4 The continuation of the Cd treatment for 90 days decreased the levels of superoxide dismutase (30%, P<0.001), glutathione peroxidase (23%, P<0.005), catalase (25%, P < 0.005), glutathione reductase (18%, P < 0.02), vitamin E (20%, P < 0.01), glutathione (26%, P < 0.01), ascorbic acid (18%, P < 0.05) and ceruloplas min (13%, P<0.05) in the microvessal preparation compared to controls.

5 It appears that Cd-induced blood-brian barrier dysfunction may be related to the depletion of microvessel antioxidant substances along with in crease in lipid peroxidation at 90 days of exposure.
Benzene metabolites enhance reactive oxygen species generation in HL60 human leukemia cells
Authors: Shen Y. , Shen H-M. , Shi C-Y. , Ong C-N.
Published: December 2008

Benzene is myelotoxic and leukemogenic in humans. The mechanisms leading to these effects, however have not been fully elucidated. One of the underlying mechanisms is believed to be the oxidative damage caused by its metabolites. A comparative study was undertaken to examine the relationships between reactive oxygen species (ROS) production, lipid peroxidation and subse quent cytotoxicity induced by five major benzene meta bolites. The generation of ROS by benzene metabolites was demonstrated by the significant and dose-dependent increase of intracellular ROS formation in HL60 human promyelocytic leukemia cells in vitro. 1,4-Benzoquinone (BQ) was found to be the most potent metabolite in induction of ROS formation, followed by 1,2,4-benzene triol (BT) and to a lesser extent, phenol (PH) and trans, trans-muconaldehyde (MD). No significant effect was observed when the cells were treated with trans, trans-muconic acid (MA). The enhancement of ROS production by BQ was effectively inhibited by the addition of catalase, deferoxamine (DFO) and dimethyl sulfoxide (DMSO), but unchanged by superoxide dismutase (SOD), suggest that hydrogen peroxide (H2O2) and hydroxyl radicals (OH.) are the two major forms of ROS involved. The results also demonstrate that the ability of benzene metabolites in enhancing ROS generation is closely correlated to their capacity in causing lipid peroxidation and subsequent cytotoxicity. These findings together with earlier parallel observations on DNA damage suggest that ROS play an important role in the mechanism of carcinogenesis induced by benzene metabolites.
Mitigation of nitrofurantoin-induced toxicity in the perfused rat liver
Authors: Wei Shen  , Hoener Betty-ann
Published: December 2008

1 Nitrofurantoin is an antimicrobial agent which pro duces hepatotoxicity caused by the redox cycling of the nitro group and its radical anion. This futile cycling triggers a complex series of events known collectively as oxidative stress.

2 Our goal was to determine treatment strategies which could mitigate nitrofurantoin-induced toxicity in the isolated perfused rat liver. We co-infused various agents which blocked early or late events in the progression to toxicity. Tissue levels of glutathione and protein thiols were measured as indicators of the progression to toxicity and lactate dehydrogenase leakage into the perfusate was used as a marker of irreversible cell death.

3 Five treatments significantly ( P < 0.05) decreased LDH leakage (reported as thousands of units accumulated in perfusate at 300 min, mean ± standard error, n=3- 4) when compared to nitrofurantoin alone (274 ±37). These treatments were adenosine-2'-monophosphate (120 ± 53), penicillamine (90 ± 29), N-(2-mercaptopro pionyl)-glycine (120 ± 49) and bromosulfophthalein with (80 ± 29) or without 5,5'-difluro-1,2-bis(O-amino phenoxy)ethane-N,N,N'N'-tetraacetic acid (101 ± 46). Two other treatments, N-acetylcysteine (183 ± 7) and dithiothreitol (166 ± 59) delayed the onset of toxicity. Finally, calpeptin (319 ± 34) which blocks activation of nonlysosomal proteases was ineffective.

4 We concluded that early intervention on the pathway to toxicity was most effective. The strategies detailed here may prove beneficial in treating hepatotoxicity seen following nitrofurantoin therapy.
Acute effects of the potent lacrimator o-chlorobenzylidene malononitrile (CS) tear gas
Authors: Anderson PJ , Lau Gsn , Taylor Wrj , Critchley Jajh
Published: December 2008

1 The use of tear gas to control civil unrest is accepted practice by government authorities worldwide. It is rarely used in Hong Kong but during a recent riot at a Vietnamese detention centre large quantities were used and this was cause for some concern.

2 All patients presenting to the British Red Cross Clinic after the incident were seen by one of the authors. To establish if exposure to tear gas had serious effects on the health of the detainees, the case records of the 184 patients with symptoms consistent with CS exposure were reviewed 2 months later.

3 The most common complaints were burns (52%), cough (38%), headache (29%), shortness of breath (21%), chest pain (19%), sore throat (15%) and fever (13%). However, the only common findings on examination by a physician were burns (52%) and an inflamed throat (27%). All burns could be categorised as 'minor' according to the American Burns Association classi fication and all were consistent with CS gas exposure.

4 Some patients complained of other symptoms that had not been previously reported in the literature, such as haemoptysis (8%) and haematemesis (4%), but these were only confirmed in one patient.

5 The majority of patients had recovered within 2 weeks of exposure although one asthmatic patient com plained of shortness of breath lasting for 33 days and a sore throat lasting for 38 days after the incident. She had abnormally low peak expiratory flow readings, but had a clinical history of asthma.

6 No serious sequelae were encountered, but the incidence of burns in these patients was higher than would be expected from a review of the literature. However, very little data on the effects of tear gas in a riot situation has been published. There have been reports of high concentrations of CS gas causing reactive airways dysfunction but this was not seen in our group of patients.
Method for the simultaneous quantification of n-hexane metabolites: application to n-hexane metabolism determination
Authors: Soriano T. , Menéndez M. , Sanz P. , Repetto M.
Published: December 2008

1 The described analytical procedure permits the simultaneous determination of the main n-hexane meta bolites in urine. 2-Hexanone, 2-hexanol, 2, 5-hexanediol and 2, 5-hexanedione, were chosen to dose the rats used in this study. All urine samples were collected and analysed on a daily basis, before and after acidic hydrolysis (pH 0.1) by GC/MS. 2-Hexanone, 2, 5-dimethylfurane, γ-valerolac tone and 2, 5-hexanedione were determined before hydro lysis ; 2-hexanol and 2, 5-hexanediol, after hydrolysis; and 5-hydroxy-2-hexanone and 4, 5-dihydroxy-2-hexanone were calculated by the difference between γ-valerolactone and 2, 5-hexanedione with and without hydrolysis, respectively.

2 A metabolic scheme was proposed reflecting the biotransformations undergone by the four compounds assayed. We consider 2, 5-dimethylfurane as a 'true metabolite' because the quantities detected were always greater before hydrolysis.

3 It has been reported that human and rat n-hexane metabolism follow a similar pattern. Therefore, as a practical application and without increasing either sample or time requirements, the simultaneous quantifi cation of the different metabolites and their excretion profile could provide better information about the metabolic situation of exposed workers than the determi nation of 2, 5-hexanedione alone. According to our experimental results, 4, 5-dihydroxy-2-hexanone itself would be a good toxicity indicator.
Vital factors in liver cancer
Authors: Rumsby Paul C
Published: December 2008

The mannose 6-phosphate/insulin-like growth fac tor-II receptor (M6P/IGF2R) functions in the in tracellular trafficking of lysosomal enzymes, the activation to the potent growth inhibitor, transform ing growth factor β, and the degradation of IGF2, a mitogen often overproduced in tumours. We have recently shown that 70% of human hepatocellular tumours have loss of heterozygosity (LOH) at the M6P/IGF2R locus which maps to chromosome 6q26-27. Using a coarse screen, we have now identified point mutations in the remaining allele of 25% of human hepatocellular carcinomas (HCCs) with LOH. These mutations give rise to truncated receptor protein and significant amino substitu tions, and provide evidence that the M6P/IGF2R gene functions as a tumour suppressor in human liver carcinogenesis.
More transformations
Authors: Ryffel Bernhard
Published: December 2008

We have generated transgenic mice overexpressing TGF-β1 in pancreatic β cells. This resulted in massive fibrosis of the pancreas; in adult mice, most of the acini were replaced by fibrotic and adipose tissues. A conspicuous disorganisation of the islets of Langerhans was also observed; how ever, the number of β cells was not decreased and the mice were normoglycemic. Backcrossing to transgenic mice overexpressing TNF-α in their islet β cells (which also remain normoglycemic) 1 yielded double transgenics, most of which became diabetic by the age of 4 months; histological analysis revealed a dramatic decrease in insulin-containing β cells.
Modulation of cisplatin chronotoxicity related to reduced glutathione in mice
Authors: Boughattas NA , Li XM , Filipski J. , Lemaigre G. , Filipski E. , Bouzouita K. , Belhadj O. , Lévi F.
Published: December 2008

Intracellular reduced glutathione (GSH) concentrations were measured according to the tissue sampling-time along the 24 h scale in male B6D2F1 mice. A significant circadian rhythm in GSH content was statistically validated in liver, jejunum, colon and bone-marrow (P≤0.02) but not in kidney. Tissue GSH concentration increased in the dark-activity span and decreased in the light-rest span of mice. The minimum and maximum of tissue GSH content corresponded respectively to the maximum and minimum of cisplatin (CDDP) toxicity. The role of GSH rhythms with regard to CDDP toxicity was investigated, using a specific inhibitor of GSH biosynth esis, buthionine sulfoximine (BSO). Its effects were assessed on both tissue GSH levels and CDDP toxicity at three circadian times. BSO resulted in a 10-fold decrease of the 24 h-mean GSH in kidney. However a moderate GSH decrease characterized liver (-23%) and jejunum (-30%). BSO pretreatment largely enhanced CDDP toxicity which varied according to a circadian rhythm. Although BSO partly and/or totally abolished the tissue GSH rhythms, it did not modify those in CDDP toxicity. We conclude that GSH have an important influence on CDDP toxicity but not in the circadian mechanism of such platinum chronotoxicity.
Metabolism and disposition of difluoromethane (HFC32) in the mouse
Authors: Ellis Martin K , Naylor Jacky L , Collins Michael A , Green Trevor
Published: December 2008

1 Difluoromethane (HFC32) is under development as a replacement for chlorofluorocarbons (CFCs) in some refrigeration applications.

2 The metabolism and disposition of [14C]-difluoro methane ([14C]-HFC32) was determined in male Swiss mice as a consequence of a single 6 h inhalation exposure to atmospheres of 10 000 p.p.m.

3 Of the inhaled dose, about 1-2% was recovered in expired air, urine, faeces and carcass suggesting that systemic absorption of this hydrofluorocarbon from the alveolar air space of the lung into blood is poor. Upon cessation of exposure the majority of the systemically absorbed HFC32 was exhaled within 1 h.

4 Carbon dioxide was a major metabolite of HFC32. Carbon dioxide measured post-exposure accounted for about 0.3% of the inhaled dose. Urinary and faecal excretion of non-volatile metabolites accounted for about 0.34% and 0.07% of the inhaled dose, respec tively.

5 Carbon monoxide could not be detected.

6 Total metabolism, measured as the sum of the radio activity recovered in urine, faeces, as carbon dioxide and that retained in the carcass, amounted to about 0.8% of the inhaled dose, equivalent to 64% of the total radioactivity recovered.

7 Analysis of a range of tissues at 4 days post-exposure showed a relatively uniform distribution of radio activity with the highest concentration in the lung, liver and kidney. There was no evidence of a specific retention in any organ or tissue.