bluuebunny/crossref_metadata_2025 huggingface dataset:
The Relationship Between Total Kidney Cyclosporin A Concentrations, Trough Drug Levels and Renal Function in the Rat Following Withdrawal of Treatment
Authors: Mead John C. , Brown P.A.J. , Whiting P.H.
Published: December 2008

Groups of 6 male rats received cyclosporin A (CsA: 20 mg kg-1 day-1) by gavage for either 4, 7, 10 or 14 days and were sacrificed 24 hours later. CsA nephrotoxicity was characterised functionally by decreased creatinine clearance rates and increased enzymuria. A significant correlation (r2=0.980; P<0.01 ) was observed between the CsA concentration in renal tissue (4.88± 2.16, 13.54± 3.68, 25.71±6.59 and 36.64± 6.797 μg g-1 kidney wet weight, [mean±SD] on days 4, 7, 10 and 14 respectively) and trough whole blood (TWB) CsA concentrations (0.86± 0.18, 1.82± 0.59, 3.35± 0.52 and 3.70± 1.12 μg ml-1, respectively) was observed. Furthermore, an apparent relationship between both renal tissue and TWB CsA concentration, the degree of renal microcalcification (MC) at the cortico-medullary junction and magnitude of the renal dysfunction was observed. In a second experiment, treatment was withdrawn after 14 days at 20 mg kg-1 day-1. Following withdrawal of treatment for 1, 4, 7, 10 or 14 days, renal tissue and whole blood CsA concentrations fell progressively from 32.23± 11.23 and 3.01±0.96 (μg g-1 wet weight and μg ml-1, respectively) to 25.66±9.77 and 2.12± 0.66, 10.42± 0.65 and 0.78± 0.23, 4.35± 1.2 and 0.51± 0.16, 3.98± 3.76 and 0.27± 0.03, and 2.58± 1.56 and Not Detected. However, the severity of MC was maintained over this period and while values for urinary flow rate, glycosuria and NAG were similar to pretreatment values by day 14, those for creatinine clearance rate were not (325± 43 v 421 ± 91 ml h-1 kg-1 body weight [mean±SD], P<0.01). These results suggest that MC, an early feature of chronic CsA toxicity is both irreversible and not related to either TWB or tissue CsA concentrations.
Drug Overdosage and Other Poisoning in Hong Kong - The Prince of Wales Hospital (Shatin) Experience
Authors: Chan Thomas Y.K. , Critchley Julian A.J.H. , Chan Matthew T.V. , Yu C.M.
Published: December 2008

From 1988 to 1991, 732 patients (91.1% Chinese) were admitted to four general medical wards at the Prince of Wales Hospital in Hong Kong with acute poisoning. The patients were predominantly female (68.9%) and relatively young (86.3% below the age of 40). Further analysis of 655 patients indicates that the vast majority of patients (96%) were admitted after self-poisoning with drugs or chemicals while 4% of cases were due to accidental poisoning. The main agents used by the former group included hypnotics/sedatives (33.1 %), household products (15.7%), and analgesics (13.7%). There were nine deaths (1.4%). When compared to other Western countries, two important variations in the pattern of acute poisoning were seen. A substantial proportion of drugs ingested by our patients were not precisely identified. 'Dettol', a household product, was commonly used for self-poisoning in Hong Kong. Territory-wide studies of longer duration are needed to provide the physicians in Hong Kong with much needed information on the incidence and the pattern of acute poisoning.
Toxicity of Cisplatin and Mercuric Chloride in Human Kidney Cortical Slices
Authors: Fisher Robyn L. , Sanuik Jeffery T. , Gandolfi A. Jay , Brendel Klaus
Published: December 2008

1 Organ specific toxicity such as nephrotoxicity is often investigated with the use of in vivo or in vitro animal models.

2 It would be beneficial if these findings could be verified in a human in vitro system which utilizes non-transplantable human kidneys.

3 Non-transplantable human kidneys were decapsulated, cut in half along the long axis, cores made perpendicular to the hemisphere, and precision-cut renal cortical slices produced.

4 These human kidney slices were incubated for 3, 6, 12, 18 and 24 h, viability assessed using intracellular K+ content, protein synthesis and organic ion transport and the potential nephrotoxicity of cisplatin (0.25, 0.5 and 1.0 mM) and mercuric chloride (10, 50 and 100 μm) on these slices were examined.

5 Control human kidney slices were viable for up to 24 h using all viability parameters while a dose-and time-dependent toxic response was seen using both cisplatin and mercuric chloride.

6 Cisplatin was more nephrotoxic in this human in vitro system than in previously investigated in vitro animal systems whereas mercuric chloride was similar in both systems.

7 These results indicate that human renal cortical slices are useful in predicting and verifying potentially nephrotoxic compounds in man.
Suspected Paediatric Pesticide Poisoning in the UK, I - Home Accident Surveillance System 1982-1988
Authors: Casey P.B. , Thompson J.P. , Vale J.A.
Published: December 2008

1 Between 1982 and 1988, 239,350 children under 10 years old attended 20 A & E Departments in England and Wales (22 departments throughout the UK in 1988) as a result of a home accident. 15,144 of 239,350 were suspected cases of poisoning and 514 attendances involved pesticides.

2 501 of 514 children who attended hospital were under 6 years old and 41 % were thought to have ingested a rodenticide, 37% an insecticide or other animal poison, 13% an herbicide or fungicide and 9% other pesticides.

3 Overall 189 of 514 children were admitted to hospital and of these 189 cases 35% were discharged home in less than one day; 94% left hospital within 2 days.

4 Using these data we estimate that over the period of study approximately 1,850 children annually attended an Accident and Emergency Department in the UK with suspected pesticide poisoning and that some 450 were admitted to hospital. However, the morbidity from this cause is low and no deaths from pesticide poisoning have been reported in children in England and Wales for more than two decades.
Suspected Paediatric Pesticide Poisoning in the UK, II — Home Accident Surveillance System 1989-1991
Authors: Thompson J.P. , Casey P.B. , Vale J.A.
Published: December 2008

1 Between 1989 and 1991, 121,708 children less than 10 years old attended 22 Accident and Emergency (A & E) Departments in the UK as a result of an accident at home; 6,478 of these were cases of suspected poisoning.

2 Two hundred and fifty (124 boys and 126 girls) of 6,478 cases involved pesticides. Forty two per cent of these children were thought to have been poisoned by rodenticides, 33% by a different animal poison, 13% by an herbicide or fungicide, 7% by creosote and 5% by mothballs; a pattern similar to that observed in previous years.

3 Fifty-seven of 250 children (23%) were admitted to hospital. The proportion of children admitted to hospital between 1989 and 1991 is smaller than that observed between 1982-1988 (37%). Forty-six per cent of children were discharged home within one day and 95% within 2 days, whereas between 1982 and 1988 only 35% of children were discharged within one day. No child died during the study confirming the low morbidity.

4 Using these data we estimate that between 1989 and 1991 approximately 1,500 children annually attended an A & E Department in the UK with a diagnosis of suspected pesticide poisoning and that some 350 children were admitted each year.
Changes in Debrisoquine Hydroxylation Capacity Following Liver Surgery
Authors: Mitchell S.C. , Shah R.R. , Clements D.G. , Smith R.L.
Published: December 2008

Liver transplantation or the surgical construction of portacaval shunts may radically alter an individual's debrisoquine hydroxylation capacity. Good clinical management should encompass a full awareness of such changing needs and problems in patients who undergo hepatic surgery.
Prevention of Paraquat Toxicity in Suspensions of Alveolar Type II Cells by Paraquat-Specific Antibodies
Authors: Nian Chen  , Bowles Mark R. , Pond Susan M.
Published: December 2008

1 The herbicide, paraquat, is accumulated by the energy-dependent polyamine uptake pathway of alveolar type II cells. There it undergoes redox cycling that results in an amplified production of toxic reactive oxygen species and depletion of NADPH and other reducing equivalents. These processes account for the lung being the major target organ for paraquat toxicity.

2 We postulated that paraquat-specific antibodies would inhibit the uptake of the herbicide by type II cells and prevent its toxicity. Accordingly, we examined the effects of paraquat-specific monoclonal antibodies and Fab fragments on the uptake, efflux and cytotoxicity of 50 μM paraquat in suspensions of alveolar type II cells isolated from the rat.

3 The uptake of paraquat was linear over 40 min. Over this time, the uptake rate was inhibited significantly (% inhibition, 73-89) by IgG (25 or 50 μM) or Fab fragments (50 or 100 μM).

4 The apparent efflux rate of paraquat, studied over 16 h, was increased significantly from 0.12 h-1for the control cells in medium to 0.17 h-1by paraquat-specific Fab fragments but was unaffected by the specific IgG.

5 Cytotoxicity was determined by measuring the release of51Cr from the cells. The cytotoxicity of 50 μM paraquat was decreased significantly (percent decrease, 56-80%) in the presence of specific antibodies.

6 These studies in vitro suggest some potential for immunotherapy in selected cases of paraquat poisoning.
Glutathione Deficiency does not Elevate Susceptibility of Bacteria to the Mutagenicity of Chlorinated Humic Acids
Authors: Ubom G.A. , Chipman J.K. , Hayes M.H.B.
Published: December 2008

1 Rat liver 9,000 g supernatant protected against the mutagenic effect of chlorinated hydrophilic macromolecular humic acids (CHMA) in Salmonella typhimurium strain TA100.

2 Protection against mutagenicity of CHMA was mediated by glutathione and was partially dependent on glutathione S-transferase activity.

3 In contrast to the above findings, CHMA showed lower mutagenicity in Salmonella typhimurium and Escherichia coli strains of bacteria that are deficient in glutathione compared to their mutagenicity in parental (glutathione-rich) bacterial strains.

4 Glutathione-deficient cells do not provide test systems with elevated sensitivity for the detection of mutagenic chlorinated humic substances.
Environmentally friendly bacteria?
Authors: Paine Alan J
Published: December 2008

The decomposition of organic compounds by bacteria has been studied for almost a century, during which time selective enrichment culture has generated microorganisms capable of metabolizing thousands of organic compounds. But attempts to obtain pure cultures of bacteria that can metabolize highly halogenated compounds, a large and important class of pollutants, have been largely unsuccessful. Polyhalogenated compounds are most frequently metabolized by anaerobic bacteria as a result of reductive dehalogenation reactions, the products of which are typically substrates for bacterial oxygenases. Complete metabolism of polyhalogenated compounds therefore necessitates the sequential use of anaerobic and aerobic bacteria. Here we combine seven genes encoding two multi-component oxygenases in a single strain of Pseudomonas which as a result metabolizes polyhalogenated compounds by means of sequential reductive and oxidative reactions to yield non-toxic products. Cytochrome P450 monooxygenase reduces polyhalogenated compounds, which are bound at the camphor-binding site, under subatmospheric oxygen tensions. We find that these reduction products are oxidizable substrates for toluene dioxygenase. Perhalogenated chlorofluorcarbons also act as substrates for the genetically engineered strain.
A hole in our knowledge of ozone toxicity?
Authors: Maynard R.L.
Published: December 2008

Evidence suggests that allergic disease is becoming more common, particularly in industrialized societies. Two studies of schoolchildren from Aberdeen, Scotland aged 8-13 years were undertaken in 1964 and 1989 using identical questionnaires, and found that the reported prevalence of asthma had risen from 4.1% to 11.9% and eczema from 5.3% to 12%. Indication that air pollution may contribute to this increase has come from several studies. In Japan,allergic rhinoconjunctivitis was found to be more prevalent in individuals living near motorways than in cedar forests. Severe asthma also occurs more commonly than mild asthma in children living in polluted areas. Exercise-induced asthma and the use of asthma medication were twice as high in a town near two power stations compared with a non-polluted town. A recent study in Finland showed that admissions to hospital with severe asthma correlated with atmospheric levels of nitrogen dioxide. Deterioration in peak flow recordings in asthmatics and exacerbations of symptoms in hay fever sufferers correlate with ambient levels of ozone. Elucidation of the mechanisms by which exposure to air pollutants may influence the frequency of allergic disease or exacerbate symptoms has come from in vitro and in vivo experiments in animals and man. Animals exposed to ozone, sulphur dioxide, nitrogen dioxide and particles from diesel exhaust, together with allergens, show more ready development of allergic sensitization compared with those exposed to allergen alone. The dose of allergen necessary to produce a 20% fall in FEV, (forced volume in 1 second) in mild-asthmatics is reduced by previous exposure to ozone or a mixture of nitrogen dioxide and sulphur dioxide. It has also been suggested that the allergic potency of pollen grains may be increased when they are coated in pollutants.

Bronchial and nasal lavage studies have shown that air pollutants can induce an influx of inflammatory cells and proinflammatory cytokines into the respiratory tract. Studies on human epithelial cells cultured to confluence in vitro have indicated that exposure to nitrogen dioxide can decrease ciliary beat frequency which would, in theory, reduce allergen clearance and increase the risk of sensitization. Further, exposure of these cells to either ozone or nitrogen dioxide induces the release of inflammatory mediators, such as leukotriene C4, and proinflammatory cytokines, including granulocyte-macrophage colony-stimulating factor, tumour necrosis factor - α and interleukin-8. This effect can be attenuated by the use of anti-inflammatory drugs.
The Clinical Im p lication of Theophylline Intoxication in the Emergency Department
Authors: Tsai Jeffrey , Chern Tzy-Lih , Hu Sheng-Chuan , Lee Chen-Hsen , Wang Rong-bor , Deng Jou-Fang
Published: December 2008

We reviewed the clinical manifestations of 53 episodes of theophylline intoxication in 50 patients over a one year study period, in order to identify the specific features as they presented to the Emergency Department (ED). There was a trend to an increase in the serum theophylline concentration with increased severity of clinical features, but the difference between the mild and the moderate cases was not statistically significant. The most common symptoms and signs were gastrointestinal complaints, sinus tachycardia, and atrial arrhythmias. Mixed atrial and ventricular arrhythmias, which are rarely mentioned as a specific feature of theophylline intoxication, were found in 16% of our patients and accounted for 29% of the cardiovascular manifestations. Four patients developed rhabdomyolysis, which presumably was secondary to a seizure or profound hypokalaemia. Cases of theophylline intoxication presenting to the ED had higher serum concentrations of theophylline and tended to have more severe toxicity than those patients in the non-ED group. Delayed diagnosis may contribute to the severity of the outcome, since severe cases in the ED were usually suspected to have developed intoxication at some point later in the stay in the ED than at the time of presentation, or after admission to the hospital, thus permitting the occurrence of an additional iatrogenic component to the intoxication. They also complained of symptoms not associated with the theophylline toxicity, which may have diverted the physician's attention from recognizing this concurrent problem. The other possible contributory reason for the severe and fatal outcomes was the use of a large dose of theophylline in the ED in the presence of coexisting factors that ordinarily indicate a low dose of theophylline.
Human Polymorphonuclear Leukocyte Chemotaxis as a Tool in Detecting Biological Early Effects in Workers Occupationally Exposed to Low Levels of n-HeXane
Authors: Governa Mario , Valentino Matteo , Visanà Isabella , Monaco Francesca
Published: December 2008

Human polymorphonuclear leukocytes (PMN) were chosen to measure two cellular end points- chemotaxis and respiratory burst - and to verify whether they could function as biomarkers of early effect in detecting occupational exposure to n-hexane of apparently healthy shoe workers, without any electroneuromyographic (ENMG) abnormality.

Chemotaxis, but not respiratory burst, was found to be impaired. A negative linear correlation between chemotaxis of PMN of those workers that had been exposed to n-hexane versus 2,5-hexanedione (2,5-HD) urinary concentrations were found.

This negative trend is consistent with our previous in vitro experimental findings: it was observed that the progressive addition of 2,5-HD to PMN suspensions inhibited chemotaxis in a dose-dependent mode, while chemiluminescence was not modified.

Now we have confirmed in vivo that chemotaxis is more sensitive than the respiratory burst response to 2,5-HD. Such results justify the interest in the behaviour of PMN harvested from workers exposed to n-hexane.

Since significant inhibition of chemotactic activity was observed in some workers whose urinary 2,5-HD levels were lower than 5 mg l-1, which is the biological exposure index suggested by ACGIH, this study suggests that PMN chemotaxis may be proposed as a useful biomarker in detecting occupational exposure to low level of n-hexane.
Accuracy of Admission and Pre-autopsy Clinical Diagnoses in the Light of Autopsy Findings: a Study Conducted in Budapest
Authors: Szende B. , Kendrey G. , Lapis K. , Lee P.N. , Roe F.J.C.
Published: December 2008

Pre- and post-autopsy diagnoses of underlying cause of death were compared in consecutive autopsies on persons aged 30 to 80 years; 1000 from each of two pathology departments in Budapest. Data on admission diagnoses and on contributory causes of death were also analysed. At autopsy, the percentages of deaths by underlying cause were neoplasms (any site) 34.9%, diseases of the circulatory system 40.2%, digestive system 13.8%, endocrine, nutritional, metabolic or immune systems 2.7%, and respiratory system 2.2%.

For these five disease groupings, the percentages of cases diagnosed clinically as the underlying cause of death which were confirmed at autopsy were, respectively, 90.9%, 84.0%, 82.9%, 55.2% and 32.5%. Although, out of 697 cases with an autopsy diagnosis of neoplasia as the underlying cause, there were only 61 (8.8%) where neoplasms were not diagnosed clinically as the underlying cause, this conceals the fact that in 130 (18.7%) the two diagnoses differed as to the site of the primary neoplasm (ICD 3 digit code).

The fact that 43% of post-mortem diagnoses (ICD major category) of underlying cause are missed on admission, and that 19% are missed clinically, indicates that improved clinical diagnostic procedures have not diminished the need for high autopsy rates. Morbid anatomy needs to be better resourced.
Poisoning due to Savlon (Cetrimide) Liquid
Authors: Chan Thomas Y.K.
Published: December 2008

1 Seven adult cases of deliberate oral exposure to 'Savlon' liquid (chlorhexidine gluconate 0.3%, cetrimide 3%) are presented.

2 In six patients, the symptoms were relatively mild including nausea, vomiting, sore throat and abdominal pain.

3 One patient who had concomitantly taken 'Dettol' liquid was comatose and hypotensive at presentation and was complicated by aspiration pneumonia and adult respiratory distress syndrome (ARDS). She was ventilated for a total of 10 days and was hospitalised for 5 weeks.

4 The data from this study suggest that symptoms associated with Savlon poisoning are usually mild. When aspirated, Savlon together with 'Dettol' liquid can cause ARDS.
Viper Bites in France: Clinical and Biological Evaluation; Kinetics of Envenomations
Authors: Audebert Françoise , Sorkine Marc , Robbe-Vincent Annie , Bon Cassian
Published: December 2008

1 A second inquiry was conducted in France to collect more accurate epidemiological, clinical and biological data from patients hospitalized after a viper bite, as well as treatment that they received. Fifty-seven well documented cases were classified in four grades of increasing severity defined according to the clinical signs of envenomation.

2 Local and systemic signs of envenomation appeared during the first 3 h, but the severity of the envenomation was observed to increase during the 12-24 h following bites in 50% of moderate and severe cases. One fatal case was reported. Biological analysis revealed an hyperleukocytosis in patients with moderate and severe envenomations.

3 The average length of hospitalization was of 1.7 ± 1.3 days for patients without signs of envenomation (grade 0) or presenting a minimal envenomation (grade 1), and statistically longer, 6.2 ± 2.9 days, for patients presenting moderate (grade 2) or severe envenomation (grade 3).

4 Levels of venom antigens in serum samples regularly collected during hospitalization were determined by a sandwich ELISA test. The serum venom levels determined during the first 4 h following the bite correlated with the severity of the envenomation when the symptoms were determined at their worst, usually 12-24 h later. In fact, concentrations higher than 20 ng ml-1 predict a moderate or severe clinical evolution.

5 The pharmacokinetics of venom antigens was also investigated during human envenomations. Venom antigens could be detected in the serum of patients as soon as half an hour after the bite, then decreased exponentially during the following hours with an apparent half-life of 8 h, similar in grade 2 and grade 3 patients, indicating that the kinetics of venom antigens in blood is independent of the severity of the envenomation.
Cysteine Esters Protect Cultured Rodent Lung Slices from Sulphur Mustard
Authors: Wilde Paul E. , Upshall David G.
Published: December 2008

1 In previous studies an in vitro rat lung slice system was used to investigate the metabolic and structural changes after exposure to known lung toxicants.

2 In this study, the same system was used to identify the ability of cysteine esters to protect against sulphur mustard toxicity.

3 The cyclopentyl (CCPE), cyclohexyl (CCHE), isopropyl (CIPE), methyl (CME) esters of cysteine, cystine dimethyl ester (CDME), cysteine (CySH) and N-acetyl cysteine (NAc) were all non-toxic to cultured rat lung slices at 5 mM (equivalent cysteine concentration) after a pretreatment time of 30 min.

4 Pretreatment with the isopropyl, cyclohexyl, cyclopentyl and methyl esters of cysteine at concentrations higher than 1 mM protected against an IC50 of sulphur mustard, however, neither cysteine nor N-acetylcysteine protected.

5 We propose that the extent of protection is directly related to increased levels of intracellular cysteine provided by the esters of cysteine.
Fluctuation of Trace Elements During Methylmercury Toxication and Chelation Therapy
Authors: Bapu C. , Purohit R.C. , Sood P.P.
Published: December 2008

The aim of the present investigation was to check the fluctuation in essential elements, such as Na, K, Mg, Mn, Cu, Zn, Cr and Ni in the brain, spinal cord, liver and kidney of mice during methylmercury chloride (MMC) toxication and therapy with monothiols (N-acetyl-DL-homocysteine thiolactone and glutathione) and vitamins (vitamin B complex and E). Mercury deposition and its elimination during chelation therapy were also screened for comparative purposes. The animals were dosed for 7 days with MMC 1 mg/kg/d and some were then kept without treatment for a further 7 days. Other MMC-treated animals were immediately given one of the above antidotes for 7 days. All the animals were sacrificed on the 15th day. There was a decrease in all elements during MMC toxication with few exceptions, for example, copper was increased in the liver as was sodium in the kidney. Treatment with the thiols and vitamins restored the levels of these elements in certain tissues towards normal, but their concentrations remained abnormal in most instances. The fluctuations in the concentration of these elements were attributed to their association with various macromolecules.
Lipid Peroxidation and Cherniluminescence during Naproxen Metabolism in Rat Liver Microsomes
Authors: Yokoyama Hiroyuki , Horie Toshiharu , Awazu Shoji
Published: December 2008

1 Rat liver microsomal suspension containing NADPH and MgCl2 was incubated at 37°C with naproxen, a non-steroidal anti-inflammatory drug. Thiobarbituric acid reactive substances (TBA-RS), high molecular weight protein aggregates and fluorescent substances were formed in the microsomal suspension.

2 Chemiluminescence was produced from the microsomal suspension. This chemiluminescence production was well correlated to the TBA-RS formation, indicating that the chemiluminescence production was closely associated with the lipid peroxidation.

3 The addition of SKF-525A to the microsomal suspension inhibited the production of TBA-RS, chemiluminescence and 6-demethylnaproxen (6-DMN), the oxidative product of naproxen. Further, the antioxidant, α-tocopherol and singlet oxygen quenchers like histidine, dimethylfuran and 1,4-diazabicyclo[2,2,2]octane strikingly inhibited the productions of chemiluminescence and TBA-RS.

4 Neither naproxen nor 6-DMN caused lipid peroxidation in the absence of NADPH. Thus, lipid peroxidation and chemiluminescence during the oxidation of naproxen in liver microsomes was suggested to be provoked by reactive oxygen species and an origin of chemiluminescence was shown to be singlet oxygen.
Altered Urinary Porphyrin Excretion in a Human Po p ulation Chronically Exposed to Arsenic in Mexico
Authors: García-Vargas Gonzalo G. , Del Razo Luz M. , Cebrián Mariano E. , Albores Arnulfo , Ostrosky-Wegman Patricia , Montero Regina , Gonsebatt Maria E. , Lim Chang K. , De Matteis Francesco
Published: December 2008

1 A detailed study of the urinary excretion pattern of porphyrins in humans chronically exposed to As via drinking water was performed using high performance liquid chromatography (HPLC)

2 Thirty-six individuals (15 men and 21 women) were selected from a town which had 0.400 mg L -1 of As in drinking water. The control group consisted of thirty-one individuals (13 men and 18 women) whose As concentration in drinking water was 0.020 mg L-1.

3 The major abnormalities in the urinary porphyrin excretion pattern observed in arsenic-exposed individuals were: (a) significant reductions in coproporphyrin III excretion resulting in decreases in the COPRO III/COPRO I ratio, and (b) significant increases in uroporphyrin excretion. Both alterations were responsible for the decrease in the COPRO/URO ratio.

4 No porphyrinogenic response was found in individuals with urinary As concentrations below 1,000 μg of As g-1 of creatinine, However, as arsenic concentrations exceeded this value, the excretion of porphyrins (except coproporphyrin III) increased proportionally.

5 The prevalence of clinical signs of arsenicism showed a direct relationship to both As concentration in urine and time-weighted exposure to As. A direct relationship between time-weighted exposure and alterations in urinary porphyrin excretion ratios was also observed.

6 The alterations found are compatible with a lower uroporphyrinogen decarboxylase activity in arsenic-exposed individuals. However, the similarities in the urinary porphyrin excretion pattern between As-exposed individuals and Dubin-Johnson syndrome patients suggest that impairments in the excretion of coproporphyrin isomers may also contribute to the pattern observed.
Effects of Polychlorinated Biphenyls (PCBs) and Dioxins on Growth and Development
Authors: Sauer P.J.J. , Huisman M. , Koopman-Esseboom C. , Morse D.C. , Smits-van Prooije A.E. , van de Berg K.J. , Tuinstra L.G.M.Th. , van der Paauw C.G. , Boersma E.R. , Weisglas-Kuperus N. , Lammers J.H.C.M. , Kulig B.M. , Brouwer A.
Published: December 2008

Polychlorinated biphenyls (PCBs) and dioxins are potentially toxic compounds which occur widely in the environment. Their effects on the growth and development of infants at the levels currently found in highly industrialised western countries is not well known. This Dutch multicenter study, combining animal and human studies, tries to answer this question.

Animal studies showed that PCB 169, given once during pregnancy at a dose of 1.8 g kg-1 bodyweight, has an effect on developmental parameters, dopamine regulation and fertility. Effects on thyroid hormones were also found in animals, probably due to both a competitive binding of PCB metabolites to the thyroxine binding protein and increased glucuronidation, Perhaps to compensate for this, an increased diodase activity in the brain was found. Human studies involved 400 mother-infant pairs, half of them being breast-fed, the other half were fed a formula devoid of PCBs and dioxins. PCB levels were measured in serum and dioxin and PCB levels in breastmilk. Levels were found to be as high as previously found in highly industrialised countries. Growth and development were carefully documented, but no data are as yet available. In pregnant women, a significant negative correlation was found between some dioxin and PCB congeners in milk and plasma thyroid hormones, while newborn infants showed higher thyroid stimulating hormone (TSH) at higher levels of dioxin exposure.

In summary, data from this combined multicenter study involving animals and humans increases our insight into the potentially negative effects of PCBs and dioxins on growth and development.
The effect of thyroxine or carbimazole treatment on gentamicin nephrotoxicity in rats
Authors: Ali B.H. , Bashir A.A. , Tanira M.O.M.
Published: December 2008

1 This study examines the effect of treating rats with gen tamicin (80 mg kg-1 day-1 intramuscularly (i.m.), for 6 days) alone or with either L-thyroxine or the anti-thyroid drug carbimazole.

2 Gentamicin produced significant increases in serum creatinine and urea concentrations, and significantly reduced the activity of Na+,K+ATPase in renal cortex. The concentration of serum triiodothyronine (T3) was unaffect ed by graded doses (20, 40 and 80 mg kg-1) of the antibiot ic. Histopathologically, gentamicin produced necrosis of proximal tubules in the renal cortical tissues of treated rats.

3 Treatment of rats with either L-thyroxine or carbima zole alone did not significantly affect any of the biochemi cal variables investigated. Carbimazole alone produced only mild tubular necrosis.

4 Treatment of rats with either L-thyroxine (100 μg kg-1 day-1, subcutaneously) for 10 days, and gentamicin (80 mg kg-1, i.m. daily during the last 6 days of treatment signifi cantly reduced the gentamicin-induced increases in serum creatinine and urea concentrations, and increased the activity of cortical N+,K+ATPase to control levels. Histopathologically, the severity of gentamicin-induced tubular necrosis was reduced by L-thyroxine treatment.

5 Carbimazole (12 mg ml-1 in drinking water for 21 days) and gentamicin (80 mg kg-1 i.m.) daily during the last 6 days of treatment, stimulated the increase in serum urea concentration produced by gentamicin, but did not signifi cantly affect the gentamicin-induced changes in serum creatinine or cortical N+,K+ATPase.
Study of muscular effects of short-term pyridostigmine treatment in resting and exercising rats
Authors: Hubert Michel , Lison Dominique
Published: December 2008

1. Pyridostigmine (PYR) pretreatment is used by the mili tary to obtain 20—30% whole blood acetylcholinesterase (AChE) inhibition in order to enhance the effectiveness of the standard therapeutic regimen for poisoning by an organophosphate anticholinesterase agent. The present study was undertaken to investigate in a rat model the potential muscle damage produced by this pretreatment when given alone or combined with physical exercise.

2. Grip strength and biochemical measurements, i.e. serum creatine phosphokinase (CPK) activity and creatine urinary excretion rate, together with histological studies, were performed in resting animals during a period of 14 days of PYR administration in a dose producing 20-30% whole blood acetylcholinesterase inhibition. No evidence was found of a deleterious effect of this treatment on the skeletal muscle.

3. In contrast, following physical exercise, the same treat ment significantly exacerbated the biochemical changes reflecting a loss of integrity in skeletal muscles, namely, increased CPK and urinary creatine excretion rate. The significance of this observation remains to be clarified.
Prevention of drug absorption in simulated theophylline overdose
Authors: Minton Neil A. , Glucksman Edward , Henry John A.
Published: December 2008

1 The effects of emesis, gastric lavage and oral activated charcoal on theophylline absorption were compared in healthy volunteers.

2 One of four regimes (ipecacuanha-induced emesis, gas tric lavage, oral activated charcoal and no treatment) was randomly chosen one hour after a simulated over dose with sustained-release theophylline on four sepa rate occasions in twelve healthy volunteers.

3 Syrup of ipecacuanha produced emesis in all twelve volunteers but only seven vomited any tablets. Gastric lavage yielded tablets in only one volunteer.

4 The mean systemic availabilities (areas under the con centration-time curves relative to control) of theo phylline for ipecacuanha-induced emesis, gastric lavage and charcoal, were 107.1%, 101.1% and 16.9%, respectively.

5 Oral activated charcoal was thus highly effective, while gastric lavage and emesis were ineffective in pre venting theophylline absorption. Activated charcoal is potentially the most effective first-line treatment for acute overdosage with sustained-release theophylline tablets.
The clinical value of screening for paracetamol in patients with acute poisoning
Authors: Chan Thomas Y.K. , Chan Albert Y.W. , Ho C.S. , Critchley Julian A.J.H.
Published: December 2008

In this retrospective study, we determined the clinical value of screening for paracetamol in 294 Chinese patients with acute poisoning presenting to the general medical wards at the Prince of Wales Hospital between January 1992 and June 1993. Of the 86 patients suspected of having ingested paracetamol, eight had levels above the recom mended 'treatment line'. Of the 208 patients with no sus pected paracetamol ingestion, four were found to have ele vated but non-toxic plasma levels. The incidence of missed, potentially serious paracetamol poisoning in our patients with no suspected paracetamol ingestion is extremely uncommon. Routine screening of all patients with acute poisoning for toxic plasma paracetamol con centrations is therefore not indicated and should never be a substitute for thorough history taking and physical examination.
Continuous intravenous infusion in the unrestrained rat — procedures and results
Authors: Cave Desmond A. , Schoenmakers Ankie C.M. , van Wijk Hans J. , Enninga Ilona C. , van der Hoeven Jan C.M.
Published: December 2008

1 A method of continuous infusion in the unrestrained rat is described, which provides a scientifically accept able and easily maintained rodent model for use in toxicological investigations.

2 Sprague Dawley SPF rats had cannulas implanted into the vena cava via the femoral vein, and were continu ously infused with physiological saline for a total of 28 or 90 days.

3 The results indicate that there was no change in body weight, food consumption, clinical observations or clinical biochemistry of infused rats when compared to non-infused rats. There were small changes in haema tological parameters, however none were toxicological ly significant. Urinary volume was increased and uri nary specific gravity and osmolality were decreased. At macroscopic and microscopic examination there were findings of scar formation associated with the area of surgery and minimal irritation in the area of the vena cava which accommodated the cannula.

4 These results indicate that implantation of a cannula into the vena cava of a rat and subsequent continuous intravenous infusion of physiological saline produces no toxicological adverse effects over a period of 90 days. Consequently, this model can be recommended for the continuous intravenous administration of test substances to rats.
Review : Apoptosis: regulation and relevance to toxicology
Authors: Alison Malcolm R , Sarraf Catherine E
Published: December 2008

1 Apopotosis is a remarkably stereotyped morphological event across all tissues in response to a vast array of dam aging agents.

2 Our very existence depends upon a willing exchange of old life for new: apoptotic cell death is our guardian and saviour from genetic damage.

3 There is a close link between cell proliferation and apoptosis: When a cell picks up the machinery to prolifer ate it also acquires an abort pathway - 'better dead than wrong'.

4 A wide variety of highly conserved genes have been implicated in triggering apoptosis.

5 The release of DNA loops from the nuclear scaffold is a more crucial intracellular event than DNA 'laddering' in apoptotic cells.

6 The manipulation of apoptotic rates in many of the common diseases in man will be a major therapeutic strategy in the future.
Measurement of the respiratory burst and chemotaxis in polymorphonuclear leukocytes from mercury-exposed workers
Authors: Perlingeiro Rcr , Queiroz Mls
Published: December 2008

The chemotactic and nitroblue tetrazolium reducing activ ities of neutrophils from 48 mercury-exposed workers were examined and compared with those of non-exposed, age- and sex-matched individuals. At the time of testing, the exposed population had a mean (± s.d.) urinary mer cury concentration of 24.0 ± 20.1 μg g-1 creatinine and in 44 of these workers urinary mercury levels were below the accepted threshold level (TLV) of 50 μg g-1 creatinine.

The two neutrophil functions were significantly reduced in the mercury-exposed workers compared with the con trols. In 28 of these workers, chemotaxis was re-evaluated 6 months later. During the intervening 6 months, the level of hygiene was improved throughout the plant and uri nary mercury concentrations were determined monthly in each worker. Despite a significant reduction in urinary mercury concentrations, neutrophil migration did not return to within the normal range. These results suggest that 'safe' level mercury exposure may lead to impairment of neutrophil function.
Metal accumulation in human kidney cortex: mutual interrelations and effect of human factors
Authors: López-Artíguez M. , Cameán A. , González G. , Repetto M.
Published: December 2008

1 Different metals were analysed in 77 post mortem samples of human renal cortex.

2 The concentrations of the metallic ions conformed to known distribution frequencies. In abnormal cases calcu lations were based on non parametric techniques.

3 There was no appreciable difference between the val ues found for each element and those described by other authors in other populations.

4 Statistically established correlations indicated that Zn was the element which was most strongly related to the others.

5 The influence of individual factors on metal concentra tions was considered. Significant differences occurred only in Pb between sexes, and in Cd with age. There was no sign that drug abuse influenced the accumulation of metals in renal cortex.
Changes in connective tissue macromolecular components of Yucatan mini-pig skin following application of sulphur mustard vapour
Authors: Lindsay CD , Rice P.
Published: December 2008

1 The aim of this study was to determine the nature of the macromolecular alterations in Yucatan mini-pig skin which occur following application of sulphur mustard vapour, with particular reference to laminin and type IV collagen.

2 The immunostaining of transfer blots from skin extracts run on SDS-PAGE gels revealed no evidence of cross-link ing of type IV collagen or laminin. Laminin was, however, found to be partially degraded as determined by the reso lution of 132 and 143 kDa fragments, possibly by the acti vation of proteases, following the application of sulphur mustard to pig skin. Type IV collagen was not subject to this form of degradation in the skin samples exposed to sulphur mustard.

3 Yucatan mini-pig skin was found to develop microblis ters after exposure to sulphur mustard vapour. The immunohistochemical studies of sulphur mustard exposed skin revealed that separation of the epidermis from the dermis was found to occur within the lamina lucida of the subepidermal basement membrane, supporting the con tention that cleavage of laminin networks occurs following mustard challenge. Immunohistochemical staining with anti-type IV collagen antibodies was restricted to the floor of the micro-blister lesions.

4 The results suggest that laminin may be a target for pro tease activation at the dermo-epidermal junction. This may account for the tendency of certain skin models to develop sulphur mustard-induced blistering. The Yucatan mini-pig may be valuable as a model to determine the effi cacy of prophylactic and therapeutic regimes.
Comparative metabolism and toxicity of dichlorobenzenes in Sprague-Dawley, Fischer-344 and human liver slices
Authors: Fisher Robyn L , Hasal Steven J , Sipes I Glenn , Gandolfi A Jay , Brendel Klaus
Published: December 2008

1 Precision-cut liver slices, prepared from Sprague- Dawley and Fischer-344 rats and donated human liver tis sue, were used to identify differences in 1,2-dichloroben zene (1,2-DCB), 1,3-dichlorobenzene (1,3-DCB) and 1,4- dichlorobenzene (1,4-DCB) metabolism and how it may relate to toxicity.

2 Rat and human liver slices were incubated with 1 mM of either dichlorobenzene to determine metabolism and toxi city, at 2 and 6 h of organ culture.

3 The human liver slices metabolised the dichloroben zenes to a greater extent than those from either of the rat strains. Liver slices from the Fischer-344 strain had a higher metabolic rate than the slices from the Sprague- Dawley rat strain.

4 The metabolic rate of dichlorobenzene isomers did not consistently correlate with its toxicity. For example, human slices did not exhibit any hepatotoxicity, even though they metabolised these compounds to a greater extent than either rat strain.

5 Cross species covalent binding did not correlate with toxicity endpoints measured in this study.

6 The phase two metabolite profiles for each of the iso mers in human and rat slices were similar in that the glu tathione-cysteine conjugate was the major metabolite.

7 The use of an in vitro system which utilises human liver slices might provide an important bridge between animal derived data and the human situation.
The C-S lysis of L-cysteine conjugates by aspartate and alanine aminotransferase enzymes
Authors: Gaskin Peter J , Adcock Harriet J , Buckberry Lorraine D , Teesdale-Spittle Paul H , Shawl P Nicholas
Published: December 2008

One biotransformation pathway which is responsible for the generation of mutagenic and cytotoxic metabolites is that of the C-S lysis (CSL) of L-cysteine conjugates. Thirteen cysteine S-conjugates, synthesised in our labora tories, were incubated with porcine heart aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT), and the C-S lyase activity for each enzyme-sub strate combination was determined. ASAT and ALAT were shown to exhibit CSL activity. It was also demonstrated that this activity was inhibited in the presence of the pyri doxal phosphate (PLP)-dependent enzyme inhibitor amino(oxyacetic acid) (AOAA) confirming the pyridoxal phosphate dependent mechanism by which C-S lysis is known to take place. Since the activities of these enzymes are used as biomarkers for the assessment of organ dam age, the potential interaction of L-cysteine conjugates with them may suppress their activity through direct inhibition.
An outbreak of tetrodotoxin poisoning following gastropod mollusc consumption
Authors: Yang Chen-Chang , Han Koh-Chew , Lin Tzeng-Jih , Tsai Wei-Jen , Deng Jou-Fang
Published: December 2008

Tetrodotoxin, a violent neurotoxin, is present in puffer fish and may occur in a variety of marine animals. Outbreaks of human tetrodotoxin poisoning, following consumption of marine organisms other than puffer fish, has been rare. We here report an outbreak of tetrodotoxin poisoning fol lowing ingestion of gastropod molluscs and its clinical fea tures are discussed.

A 71-year-old woman was admitted with hypertension and other neurological symptoms developing after inges tion of some molluscs. A further 16 cases were also found to have typical symptoms of tetrodotoxication after mol lusc consumption.

Clinical features in these 17 cases were similar to those conventionally found in tetrodotoxin poisoning, except that there was hypertension in eight cases (47%). All except one case had mild poisoning and recovered well. The molluscs consumed comprised two different species: Nassarius castus and Nassarius conoidalis, both of which were shown to contain various amounts of tetrodotoxin.

It is concluded that tetrodotoxin poisoning following mollusc consumption is a possibility. Hypertension, as an unusual feature in tetrodotoxication, is frequent in this outbreak, and should be looked for in future cases. The explanation of hypertension in tetrodotoxication may come either from an exaggerated response to sympathetic stimuli, or due to various responses of the vasomotor centre to a small dose of tetrodotoxin. Further studies are required to answer this question.
Organochlorine compound residues in human milk in the United Kingdom 1989-1991
Authors: Dwarka S. , Harrison DJ , Hoodless RA , Lawn RE , Merson Ghj
Published: December 2008

1 The concentrations of some organochlorine pesticides and polychlorobiphenyls have been determined in 193 samples of human milk collected between July 1989 and July 1991.

2 Comparison of the results with those from previous studies in 1979-80, and earlier, shows a continuing decline in residue levels except for polychlorobiphenyls.

3 The concentrations of organochlorine pesticides and polychlorobiphenyls in human milk samples from resi dents in the United Kingdom compare favourably with data obtained in other countries.
Time-dependent porphyric response in mice subchronically exposed to arsenic
Authors: García-Vargas G. , Cebrián ME , Albores A. , Lim CK , De Matteis Francesco
Published: December 2008

1 A time-course study was carried out in mice subchroni cally exposed to As III (as sodium arsenite) or As V (as sodium arsenate), via drinking water, relating the pattern of urinary porphyrin excretion to the renal and hepatic enzyme activities of porphobilinogen deaminase (PBGD), uroporphyrinogen III synthetase (URO III-S), uropor phyrinogen decarboxylase (URO-D) and coproporphyrino gen oxidase (COPRO-O), as well as to the hepatic por phyrin accumulation in the treated animals.

2 A time-dependent, wave-like porphyric response was found in mice exposed to As V, and the increases seen in total urinary porphyrins (at 3 weeks of exposure) corre sponded to an increased activity of PBGD and Uro III-S in liver.

3 Significant decreases in renal URO-D and hepatic and renal COPRO-O activities were found in treated mice; these inhibitions were more pronounced in animals exposed to As III.

4 The combination of these enzymic effects may explain the time-dependent porphyric response of mice subchroni cally exposed to As. Finally, the relative magnitudes of URO-D and COPRO-O inhibitions may determine the pat tern of porphyrin concentration observed in urine and tis sues.

5 The decrease in renal URO-D activity may help to explain the inversion in the coproporphyrin/uroporphyrin ratio previously reported in humans chronically exposed to As; however, there were differences between the uri nary porphyrin profiles found in both species. The possi ble reasons for the similarities and differences are briefly discussed.