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The final phase of the reionization process can be probed by rest-frame UV absorption spectra of quasars at z>6, shedding light on the properties of the diffuse intergalactic medium within the first Gyr of the Universe. The ESO Large Programme "XQR-30: the ultimate XSHOOTER legacy survey of quasars at z~5.8-6.6" dedicated ~250 hours of observations at the VLT to create a homogeneous and high-quality sample of spectra of 30 luminous quasars at z~6, covering the rest wavelength range from the Lyman limit to beyond the MgII emission. Twelve quasar spectra of similar quality from the XSHOOTER archive were added to form the enlarged XQR-30 sample, corresponding to a total of ~350 hours of on-source exposure time. The median effective resolving power of the 42 spectra is R~11400 and 9800 in the VIS and NIR arm, respectively. The signal-to-noise ratio per 10 km/s pixel ranges from ~11 to 114 at $\lambda \simeq 1285$ \AA rest frame, with a median value of ~29. We describe the observations, data reduction and analysis of the spectra, together with some first results based on the E-XQR-30 sample. New photometry in the H and K bands are provided for the XQR-30 quasars, together with composite spectra whose characteristics reflect the large absolute magnitudes of the sample. The composite and the reduced spectra are released to the community through a public repository, and will enable a range of studies addressing outstanding questions regarding the first Gyr of the Universe., Comment: 21 pages, 10 figures. Final version accepted by MNRAS

The clinical and pathological features of Balkan (endemic) nephropathy are discussed and correlations of incidence with excess late summer and autumn rainfall outlined. Cultures of a strain of Penicillium verrucosum var. cyclopium isolated from maize collected in an endemic area were fed to rats and lesions were produced in the straight third segment of the proximal kidney tubules. Extensive degeneration and nuclear changes were seen and on prolonged feeding further nuclear enlargement (to greater than 6n) and the formation of multinucleate cells occurred. The relevance of these findings to the clinical disease in man, especially the occurrence of urinary tract tumours, and the evidence supporting mycotoxin involvement, are discussed.

This paper is one of several prepared under the project "Food Safety In Europe: Risk Assessment of Chemicals in Food and Diet" (FOSIE), a European Commission Concerted Action Programme, organised by the International Life Sciences Institute, Europe (ILSI). The aim of the FOSIE project is to review the current state of the science of risk assessment of chemicals in food and diet, by consideration of the four stages of risk assessment, that is, hazard identification, hazard characterisation, exposure assessment and risk characterisation. The contribution of animal-based methods in toxicology to hazard identification of chemicals in food and diet is discussed. The importance of first applying existing technical and chemical knowledge to the design of safety testing programs for food chemicals is emphasised. There is consideration of the presently available and commonly used toxicity testing approaches and methodologies, including acute and repeated dose toxicity, reproductive and developmental toxicity, neurotoxicity, genotoxicity, carcinogenicity, immunotoxicity and food allergy. They are considered from the perspective of whether they are appropriate for assessing food chemicals and whether they are adequate to detect currently known or anticipated hazards from food. Gaps in knowledge and future research needs are identified; research on these could lead to improvements in the methods of hazard identification for food chemicals. The potential impact of some emerging techniques and toxicological issues on hazard identification for food chemicals, such as new measurement techniques, the use of transgenic animals, assessment of hormone balance and the possibilities for conducting studies in which common human diseases have been modelled, is also considered.

The bark beetle, Cryphalus trypanus breeds in the bark of branches and trunk of Calophyllum inophyllum var. takamaka. High population densities occur in trees affected by the vascular wilt fungus designated as Verticillium calophylli but now considered to be in the genus Leptographium. In experiments with detached branches from healthy trees, entries by breeding beetles were concentrated around leaf petiole scars but also occurred in the bark at cut ends of larger branches. Some beetles tunnelled within a soft pith central to the leaf-scars, that traversed the xylem to the centre of the branch. Only galleries established in phloem contained eggs. A typical occupied gallery contained up to 30 eggs and a male and female beetle. To establish their role as possible vectors of the wilt fungus, beetles emerging from branches and trunk bark from diseased trees were plated onto a selective agar medium. The fungus was difficult to detect on whole beetles but readily found in homogenised samples. The largest spore loads were found on beetles emerging from trunk bark. Results clearly establish Cryphalus trypanus as the likely vector of the takamaka wilt pathogen in the Seychelles and identify mining within pith of leaf-scars as an unusual and possibly highly effective way of introducing fungal spores into active xylem.

Background A large epidemic of asthma occurred following a thunderstorm in southern and central England on 24/25 June 1994. A collaborative study group was formed. Objectives To describe the epidemic and the meteorological, aerobiological and other environmental characteristics associated with it. Methods Collation of data from the Meteorological Office, the Pollen Research Unit, the Department of the Environment's Automatic Urban Network, from health surveillance by the Department of Health and the National Poisons Unit, from clinical experience in general practice and hospitals, and from an immunological study of some of the affected cases from north east London. Results The thunderstorm was a Mesoscale Convective System, an unusual and large form of storm with several centres and severe wind gusts. It occurred shortly after the peak grass pollen concentration in the London area. A sudden and extensive epidemic occurred within about an hour affecting possibly several thousand patients. Emergency services were stretched but the epidemic did not last long. Cases had high serum levels of IgE antibody to mixed grass pollen. Conclusion This study supports the view that patients with specific IgE to grass pollen are at risk of thunderstorm-related asthma. The details of the causal pathway from storm to asthma attack are not clear. Case-control and time series studies are being carried out.

BACKGROUND: Flow cytometric immunophenotpying (FCI) of cerebrospinal fluid (CSF) and other paucicellular fluids has been demonstrated to have increased sensitivity in detection of lymphoma and leukemia when compared to cytomorphology [(1) de Graaf et al., Cytometry Part B 2011, 80B:271–281; (2) Szamosi et al., CLSI Document H56-A—Body Fluid Analysis for Cellular Composition; Approved Guideline, Wayne, PA: Clinical and Laboratory Standards Institute, 2006; (3) Kraan et al., Flow Cytometric Immunophenotyping of Cerebrospinal Fluid. Current Protocols in Cytometry, Hoboken, NJ: Wiley, 2008]. However, low cellularity has been an historical problem with these samples. Several studies indicate that immediate addition of a stabilization media (e.g., RPMI with fetal calf serum (FCS)) to CSF improves the cell yield for FCI [(1) de Graaf et al.]. Such stabilization medias can, however, significantly increase cost. METHODS: We compared FCI results in CSF stabilized with RPMI 1640 (without additional additives) to results obtained using non-stabilized CSF. Samples were processed according to published CLSI guidelines [(2) Szamosi et al.]. RESULTS: About 98/105 (93%) CSF specimens stabilized with RPMI had adequate numbers of viable cells (>100) for performing FCI. About 65/217 (30%) CSF specimens without stabilization had adequate numbers of viable cells for analysis (70% either quantity not sufficient (QNS) or specimen viability below analytical limits). CONCLUSIONS: Utilizing RMPI without FCS as a stabilization media results in increased cell yield and improved FCI results. We have found FCS is not required to achieve high quality results in FCI of paucicellular CSF specimens.

A marked sex difference in the development of uroporphyria occurred after administration of polychlorinated and polybrominated biphenyls (PCBs and PBBs), as well as hexachlorobenzene (HCB), to F344 rats for 15 weeks. Thus the propensity of female rats to develop uroporphyria appears to be a general response to this class of halogenated chemicals. A heat-stable inhibitor(s) of liver uroporphyrinogen decarboxylase was extractable from uroporphyric livers. Although oxidation of uroporphyrinogen I to uroporphyrin I by hepatic microsomes from rats pretreated with porphyrogenic regimes of HCB and PCBs was induced, there was no correlation with the in vivo sex difference in porphyria development. Levels of total cytochrome P450 and pentoxyresorufin and benzyloxyresorufln dealkylase activities (associated with cytochrome P450IIB1) were greater in microsomes from control, HCB, PCB and PBB treated male rats than females. In contrast, ethoxyresorufin deethylase activity (associated with cytochrome P450IA1) was always significantly greater in females. These findings were confirmed by immunoblotting with polyclonal antibodies to cytochromes P450IA1, IA2 and IIB1. Immunocytochemical studies showed that, even after 30 weeks of HCB exposure, cytochromes P450IA1 and P450IA2 were still more highly induced in female liver, especially in the centrilobular region. The results are consistent with the association of cytochrome P450IA isoenzymes with uroporphyria development, although the sex difference in P450IA levels alone may not be marked enough to provide the complete explanation for the pronounced susceptibility of females to HCB.

The natural reservoirs for the agent of human granulocytic ehrlichiosis (HGE) are suspected to be the small mammals that host immature stages of Ixodes scapularis ticks. To determine if such small mammals are naturally infected, we collected blood and serum samples from small mammal species in rural and suburban areas of Minneapolis and St. Paul, Minn. Samples were collected from white-footed mice (Peromyscus leucopus), eastern chipmunks (Tamias striatus), southern red-backed voles (Clethrionomys gapperi), and insectivorous shrews (Blarina brevicauda and Sorex cinereus). Blood samples were tested by PCR for active infection with the HGE agent, and sera from P. leucopus mice were tested for serologic evidence of infection by indirect immunofluorescence. PCR analyses revealed the presence of HGE agent DNA in 20 of the 190 samples (10.5%) tested. Of the 119 P. leucopus mouse serum samples that were analyzed, 12 (10.1%) contained Ehrlichia equi antibodies. In 3 of 119 (2.5%) P. leucopus mice from which both blood and serum were collected. HGE agent DNA and antibodies against E. equi were present. Animals with evidence of infection with the HGE agent are widely distributed around the Minneapolis-St. Paul area in regions with known I. scapularis tick activity. Small mammals that are frequent hosts for larval I. scapularis ticks and that are found in areas where HGE occurs are likely to be a major reservoir from which infected ticks that bite humans are derived.

This report presents a review of risk characterisation, the final step in risk assessment of exposures to food chemicals. The report is the second publication of the project Food Safety in Europe: Risk Assessment of Chemicals in the Food and Diet (FOSIE). The science underpinning the hazard identification, hazard characterisation and exposure assessment steps has been published in a previous report (Food Safety in Europe, 2002). Risk characterisation is the stage of risk assessment that integrates information from exposure assessment and hazard characterisation into advice suitable for use in decision-making. The focus of this review is primarily on risk characterisation of low molecular weight chemicals, but consideration is also given to micronutrients and nutritional supplements, macronutrients and whole foods. Problem formulation, as discussed here, is a preliminary step in risk assessment that considers whether an assessment is needed, who should be involved in the process and the further risk management, and how the information will provide the necessary support for risk management. In this step an evaluation is made of whether data are available and what level of resources are needed, as well as the timeline for completing the assessment. The report describes good evaluation practice as an organisational process and the necessary condition under which risk assessment of chemicals should be planned, performed, scrutinised and reported. The outcome of risk characterisation may be quantitative estimates of risks, if any, associated with different levels of exposure, or advice on particular levels of exposure that would be without appreciable risk to health, e.g. a guidance value such as an acceptable daily intake (ADI). It should be recognised that risk characterisation often is an iterative and evolving process. Historically, different approaches have been adopted for the risk characterisation of threshold and non-threshold effects. The hazard characterisation for threshold effects involves the derivation of a level of exposure at or below which there would be no appreciable risk to health if the chemical were to be consumed daily throughout life. A guidance value such as the ADI, is derived from the no-observed-adverse-effect-level (NOAEL) or other starting point, such as the benchmark dose (BMD), by the use of an uncertainty or adjustment factor. In contrast, for non-threshold effects a quantitative hazard estimate can be calculated by extrapolation, usually in a linear fashion, from an observed incidence within the experimental dose-response range to a given low incidence at a low dose. This traditional approach is based on the assumption that there may not be a threshold dose for effects involving genotoxicity. Alternatively, for compounds that are genotoxic, advice may be given that the exposure should be reduced to as low as reasonably achievable (ALARA) or practicable (ALARP). When a NOAEL can be derived from a study in humans, this would be utilised in the derivation of guidance values or advice. However, there may be uncertainties related to the possible role of confounders and the precision of both the incidence and exposure data. Individuals may be at an increased risk because of their greater exposure or their greater sensitivity. Risk characterisation should include information not only on the general population, but also on any subpopulation considered to be potentially susceptible.

Equine granulocytic ehrlichiosis (EGE) is caused by infection with Ehrlichia equi. EGE has been reported primarily in northern California, where E equi is transmitted by the tick Ixodes pacificus. Reports of EGE and the emergence of human granulocytic ehrlichia in Minnesota prompted a seroprevalence study of E equi in horses of Minnesota and Wisconsin. Tick (Ixodes scapularis) endemic areas of Minnesota and Wisconsin were compared to nonendemic regions of Minnesota. Indirect fluorescent antibody was used to detect the presence of serum antibodies to E equi. Serum samples from healthy horses, 375 samples from I scapularis endemic counties, and 366 samples from nonendemic counties were screened at a 1:40 dilution. Results demonstrated a seroprevalence of 17.6% in endemic areas versus 3.8% in nonendemic areas. Ehrlichial DNA from 2 samples was successfully amplified by polymerase chain reaction and 919 base pairs were sequenced. The DNA sequence of 1 Minnesota/Wisconsin strain differed from the GenBank strain (M73223) of E equi at positions 84 and 886 and from the MRK strain of E equi at position 84, and was identical to the human granulocytic ehrlichiosis (HGE) agent. The 2nd Minnesota/Wisconsin strain was identical to the 1st with the exception of a substitution of "A" at position 453 that is not present in E phagocytophila, E equi, or HGE agent strain sequences. Based on the results of this study, we concluded that E equi is present and causes infection in horses in Minnesota and Wisconsin. The occurrence of infection is higher in tick endemic regions.

A large epidemic of asthma occurred following a thunderstorm in southern and central England on 24/25 June 1994. A collaborative study group was formed.To describe the epidemic and the meteorological, aerobiological and other environmental characteristics associated with it.Collation of data from the Meteorological Office, the Pollen Research Unit, the Department of the Environment's Automatic Urban Network, from health surveillance by the Department of Health and the National Poisons Unit, from clinical experience in general practice and hospitals, and from an immunological study of some of the affected cases from north east London.The thunderstorm was a Mesoscale Convective System, an unusual and large form of storm with several centres and severe wind gusts. It occurred shortly after the peak grass pollen concentration in the London area. A sudden and extensive epidemic occurred within about an hour affecting possibly several thousand patients. Emergency services were stretched but the epidemic did not last long. Cases had high serum levels of IgE antibody to mixed grass pollen.This study supports the view that patients with specific IgE to grass pollen are at risk of thunderstorm-related asthma. The details of the causal pathway from storm to asthma attack are not clear. Case-control and time series studies are being carried out.

Neospora caninum was identified in a lung aspirate specimen from an adult dog with severe pneumonia. Neosporosis was tentatively diagnosed by cytologic examination of a Wright-Giemsa-stained smear of the aspirate specimen, using light microscopy. The infection was confirmed by immunohistochemical examination of a section of lung tissue obtained at necropsy. Neosporosis is usually a fatal ascending neurologic disease of dogs less than 1 year of age. Neospora caninum infections are uncommon in adult dogs and do not have a consistent clinical course. The disease in the dog of this report was unique because the dog had clinical respiratory tract disease and because preliminary diagnosis was made by cytologic examination.

Air-dried mycelium of Penicillium aurantiogriseum2, grown as a surface culture on yeast extract-sucrose medium, was incorporated into powdered diet and fed to rats and hamsters for different periods up to 28 days. At intervals, animals were anaesthetized and the kidneys fixed in situ by perfusion. In rats, the fungus produced scattered exfoliation of pyknotic cells and an increased frequency of mitotic figures involving the pars recta segment of proximal tubular epithelium. This lesion was detectable as early as three days after beginning of treatment and was well developed by 14 days. No degenerative tubular change or mitogenic effect was observed in hamsters, even after feeding for 35 days; and there was no apparent renal pelvic or interstitial lesion in either species.

Summary 2 congenic strains of mice, B6N.AKN-Ahk and D2N.B6N-Ahb, imported from the USA, were found to be either segregating or fixed for an incorrect allele at a number of biochemical loci. B6N.AKNAh\ supposedly congenic with C57BL/6N, had the wrong genotype at 6 out of 12 biochemical loci; D2N.B6N_Ahb, supposedly congenic with DBA/2N, was segregating at 3 out of 9 loci. There was genetic variation in mandible shape within the 2 strains but no abnormal coat colours were found and no hybrid vigour in breeding performance was detected. Analyses in the USA confirmed these results and showed that 2 other congenic strains, C3N.D2N-Ahd and AKN.B6J-Ah\ were also segregating at a number of loci. Some of the alleles found in the C3N.D2N-Ahd mice must be the result of a genetic contamination. The simplest explanation for this breakdown in the backcrossing programme is genetic contamination with other congenic strains or recombinant inbred lines under development in the same laboratory. These findings emphasize the importance of continual genetic monitoring of all genetic stocks at regular intervals and in particular during the development of congenic and recombinant lines. This paper describes the detection of genetic variation in 2 congenic strains of mice sent to the MRC Laboratory Animals Centre (now known as the MRC Experimental Embryology and Teratology Unit) and the subsequent investigations carried out in the UK and USA. Congenic strains are developed by repeatedly backcrossing a gene on to an inbred background (Bailey, 1981). This particular set were developed to

Treatment of mice of the A2G-hr/+ congenic line with 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in the development of hepatic porphyria over a period of 4 weeks. Female mice responded to a lesser extent than did males. The degree of porphyria in haired heterozygotes (hr/+) was less than in the corresponding hairless homozygotes (hr/hr) and the haired mice had lower resting metabolic rates than hairless mice. Adaptation of mice of either genotype to a 32-33 degrees C environment resulted in a decrease in resting metabolic rate and a reduction in hepatic porphyrin levels. Histologically-demonstrated necrotic changes in livers were accompanied by increased activity of alanine aminotransferase and sorbitol dehydrogenase in the plasma; however, there was no clear temporal trend in plasma enzyme levels. Elevated environmental temperature reduced the plasma alanine aminotransferase activity. The study provided evidence for a pleiotropic effect of variation at the hr locus being expressed in TCDD hepatotoxicity. Suggestions for mechanisms whereby the effect can be mediated through alterations in resting metabolic rate are made.

Water-soluble components of a nephrotoxic isolate of Penicillium aurantiogriseum have been fractionated by sequential ion-exchange, size-exclusion gel filtration, reverse-phase silica chromatography and HPLC. Nephrotoxicity in the rat was confined to a size-exclusion fraction approximating to 1,500 daltons, which also inhibited DNA synthesis in cultured kidney cells. The more sensitive in vitro assay allowed toxicity to be followed to a sub-fraction from gradient-elution HPLC which in further HPLC resolved into a small group of glycopeptides. Recent Yugoslavian P. aurantiogriseum isolates, from a village in which the idiopathic human disease Balkan Nephropathy is hyperendemic, elicited a similar nephropathology and were acutely cytotoxic, reinforcing a need to regard this novel Penicillium nephrotoxin as a potential factor in human nephropathy.

The administration of single oral doses of 200 micrograms kg-1 of 2,3,7,8-tetrachlorodibenzo-p-dioxin to females of the outbred, Lac : P strain of rat results in the formation of hepatic multinucleate cells by cell fusion. Liver cell plasma membranes isolated 6 or 11 days after dosing show two distinct changes. The first is a decrease of the activity of K+-Mg2+-ATPase, which confirms histochemical observations. The second is the formation, in those animals showing a more severe intoxication, of a population of plasma membranes which are less dense than usual and which consist of extended membrane sheets. It is suggested that these alterations are consequent on a disturbance of lipid metabolism in the hepatic cells and that they represent early manifestations of the toxic process which leads to the formation of multinucleate cells.

The biosynthesis in vitro of tetrahymanol (II) from squalene (I) by enzyme preparations of the protozoan Tetrahymena pyriformis is described. The enzyme system involved has been obtained in a soluble, cell-free, lipid-free form, and remains active after freeze-drying. As with the live protozoa, the biosynthesis of tetrahymanol in vitro does not proceed via the intermediacy of 2,3-oxidosqualene; instead a nonoxidative, enzymatic cyclization of squalene occurs. This is an anaerobic process, and has been shown by isotopic labeling experiments with D2O and H218O to result in the acquisition of a hydrogen atom from the medium, presumably at C-3 of tetrahymanol and an oxygen atom from the medium at C-21 of tetrahymanol. The biogenetic implications of these findings are discussed.

(1973). The Toxicity of Polychlorinated Polycyclic Compounds and Related Chemicals. CRC Critical Reviews in Toxicology: Vol. 2, No. 4, pp. 445-498.

Five cases of placenta accreta were reviewed at the Queen of Angels Hospital in Los Angeles, California, for a period beginning January 1, 1950, and two cases were reviewed from Temple Hospital in Los Angeles from 1948 to 1965. During that time, there were 70,966 deliveries at Queen of Angels Hospital and 19,009 at Temple Hospital. There were two cases of partial placenta accreta, one case of placenta percreta, two cases of placenta previa accreta, and two cases of complete placenta accreta.

Porphyria was induced in C57BL/10 mice with iron overload by a single oral dose (100 mg/kg) of hexachlorobenzene (HCB). Within 2 weeks hepatic uroporphyrinogen decarboxylase (EC 4.1.1.37) was inhibited, reaching a maximum (greater than 95%) at 6-8 weeks. There was no recovery by 14 weeks, despite a fall in liver HCB concentrations to only 6% of the day-3 value. The major rise in hepatic porphyrin levels occurred after 4 weeks and secondary inhibition of uroporphyrinogen synthase (EC 4.2.1.75) was inferred from the progressively greater proportion of uroporphyrin I present relative to the III isomer. Plasma alanine aminotransferase (EC 2.6.1.2) activity was also elevated. Although, in further studies, total microsomal cytochrome P-450 content and ethoxyphenoxazone de-ethylase activity reached a peak a few days after dosing and had declined significantly at the time of maximum inhibition of the decarboxylase, additional treatment of HCB-dosed mice with a cytochrome P1-450 inducer, beta-naphthoflavone, enhanced the inhibition, whereas piperonyl butoxide, an inhibitor of cytochrome P-450, partially protected. Uroporphyrinogen decarboxylase was not radiolabelled in vivo by [14C]HCB. There was no major difference in the ability to hydroxylate HCB between hepatic microsomes from induced C57BL/10 mice and those from the insensitive DBA/2 strain. By contrast, lipid peroxidation, in the presence of NADPH, was 8-fold greater in control C57BL/10 microsomes than in DBA/2 microsomes and was stimulated by iron treatment (although not by HCB). The results suggest that the inhibition of hepatic uroporphyrinogen decarboxylase is unlikely to be due to a direct effect of a metabolite of HCB but to another process requiring a specific cytochrome P-450 isoenzyme and an unknown iron species.

Three hexachlorobiphenyl isomers, 2,2′,4,4′,5,5′-hexachlorobiphenyl (I), 2,2′,3,3′,4,4′-hexachlorobiphenyl (II) and 2,2′,3,4,4′,5′-hexachlorobiphenyl (III), have been administered to rats and the effects of these three compounds upon hepatic microsomal drug metabolism and upon hepatic porphyrins have been studied. Comparisons have been made with hexachlorobenzene and a commercial polychlorinated biphenyl mixture, Aroclor 1254. From measurements of activities of microsomal drug oxidations in vitro, the durations of pharmacological actions of certain drugs in vivo and spectral shifts associated with cytochrome P-450 it is shown that the three pure hexachlorobiphenyl isomers initially produce changes in hepatic microsomal activity which resemble those seen after treatment with phenobarbitone (PB). In contrast, following chronic feeding of the isomers, compounds II and III but not I produce a pattern of hepatic microsomal enzyme activity which shows some characteristics of the 3-methylcholanthrene (3-MC) and some characteristics of the phenobarbitone classes of inducer. Also, compounds II and III, but not I, cause accumulation in the liver of porphyrins containing either seven or eight carboxyl groups. These two responses are similar to those observed following hexachlorobenzene treatment and suggest that a relationship may exist between the mixed pattern of enzyme induction and the onset of hepatic porphyrin accumulation.

Anti-thrombin III activity was measured in normal pre- and postmenopausal female controls: during late pregnancy, in young women taking oral contraceptives and in postmenopausal women treated with natural, conjugated estrogens. Both the pregnant patients and women on oral contraceptives had significantly lower anti-thrombin III levels when compared with the normal, untreated control group. Treatment with natural estrogens did not result in any alteration in anti-thrombin III activity. There was no significant difference in the anti-thrombin III values in the pre- and postmenopausal control subjects.

An outline of the development of the NBT test is given. The results of studies in a Black population are given and these conform to the pattern published elsewhere, except that a high degree of positivity was found in pulmonary tuberculosis. The value of the test is discussed, and it is concluded that, except in the rare condition of chronic granulomatous disease, the test is of very limited value in the diagnosis of bacterial infection. The test is positive in many situations of stress and may be mediated through a factor in the 'acute phase'.

Pretreatment of male mice of the inbred strains A2G, BALB/c, C57BL/10, and AKR with iron dextran synergized the action of a single dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 75 micrograms/kg) in causing hepatic porphyria and necrosis 35 days later. There was no effect in DBA/2 mice. Increased porphyrin levels were associated with decreased hepatic activity of uroporphyrinogen decarboxylase. Iron alone had no effect on porphyrin levels or decarboxylase activity. In male BALB/c mice given TCDD alone there was a delay in the onset of porphyria. Female BALB/c, AKR, and AKR X DBA/2 F1 mice were more resistant to the porphyrinogenic effect of TCDD than males. Development of porphyria did not correlate with Ah phenotype of the mice. The inheritance of sensitivity to TCDD in crosses of the AKR and DBA/2 strains, both Ah nonresponsive, was studied by a biometrical genetic analysis. The inheritances of increased porphyrin levels and of increased plasma activity of enzymes indicative of hepatic necrosis were both complex. Segregation of alleles at more than one locus was required to explain the data. A lack of correlation of porphyrins with plasma enzyme levels in the F2 generation suggested that the expression of these traits was determined independently. Genes other than Ah influence the development of TCDD-induced hepatotoxicity in mice.

The clinical and pathological features of Balkan (endemic) nephropathy are discussed and correlations of incidence with excess late summer and autumn rainfall outlined. Cultures of a strain of Penicillium verrucosum var. cyclopium isolated from maize collected in an endemic area were fed to rats and lesions were produced in the straight third segment of the proximal kidney tubules. Extensive degeneration and nuclear changes were seen and on prolonged feeding further nuclear enlargement (to greater than 6n) and the formation of multinucleate cells occurred. The relevance of these findings to the clinical disease in man, especially the occurrence of urinary tract tumours, and the evidence supporting mycotoxin involvement, are discussed.

A single, low-lethality, oral dose of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) (75 μg/kg) induces an hepatic porphyria in C57BL/10 mice of either sex. The hepatic porphyrin levels are maximal 4–6 weeks after dosing and are still elevated 12 weeks after the dose. The activity of hepatic uroporphyrinogen decarboxylase is depressed within one week of the dose and this appears to precede the onset of porphyria. Mice of the DBA/2 strain show no changes of the same magnitude at doses of 1200 μg/kg, for porphyrin levels, or 75 μg/kg, for decarboxylase activity. In both strains there is an increase in hepatic iron content 3 weeks after the 75 μg/kg dose. Female C57BL/10 mice are more resistant than males to the lethal effects of TCDD.

Hexadimethrine bromide was evaluated as a heparin-neutralizing agent in a simple modification of the activated partial thromboplastin time test in canine plasma. Addition of various amounts of heparin in vitro to canine plasma indicated that heparin could be neutralized by adding 0.5 micrograms of hexadimethrine bromide 15 s before CaCl2 was added to the reaction mixture of the activated partial thromboplastin time test. In 8 dogs given (subcutaneous injection) 500 USP units of sodium heparin/kg, marked individual variations in clotting time prolongations were observed over the 12-hour period of study. The hexadimethrine bromide modification effectively neutralized the heparin-related clotting time prolongations to values that were not significantly different from base-line (preheparin) activated partial thromboplastin time values. The modification seems to be useful in confirming the presence of heparin and in monitoring heparin therapy in dogs.

In C57BL/6 mice a single oral dose of 2,3,7,8-tetrachlorodibenzodioxin (LD50 126 mug/kg) results in loss of body weight and death with an enlarged fatty liver after ca. 21 days. A progressive necrotic centrilobular liver lesion is also seen.

The hypothesis that treatment of Gunn rats with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activates an alternative pathway of bilirubin disposal, involving an induced form of cytochrome P-450 [Proc. Natl. Acad. Sci. USA 75:682-685 (1978)], has been investigated by studying the mechanisms of bilirubin oxidation in chemical model systems and in liver microsomal systems in vitro. Hematin, copper sulfate, and the iron chelate of EDTA were all active in promoting degradation of bilirubin in the presence of hydrogen peroxide. Evidence was obtained for a microsomal bilirubin-degrading system that could be induced in the liver by treating either rats or chick embryos with TCDD, beta-naphthoflavone, or 3,4,3',4'-tetrachlorobiphenyl (3,4-TCB) in vivo. The activity of this system required NADPH and oxygen and was markedly stimulated by addition of 3,4-TCB (a planar polyhalogenated biphenyl) and much less markedly by the nonplanar analogue 2,4,2',4'-tetrachlorobiphenyl. These two biphenyls were also inhibitory towards the 7-ethoxyresorufin O-deethylase activity of the induced microsomes and here again the nonplanar analogue was markedly less active. Dose-response experiments for stimulation of bilirubin breakdown and inhibition of 7-ethoxyresorufin O-deethylase activity after addition of 3,4-TCB in vitro showed both effects to be caused by similar concentrations of the biphenyl. These results suggest that a polyhalogenated chemical may interact with TCDD-induced microsomes, inhibit their monooxygenase activity, and stimulate production of a bilirubin-degrading species.

A study was undertaken to assess the effect of natural oestrogen on the coagulation profile of menopausal women. Forty-five postmenopausal women were selected at random and treated with conjugated oestrogen (PREMARIN) FOR ONE YEAR. Blood samples were tested before treatment, at the end of 3 and 9 months' therapy, and 1 month after treatment had been suspended. Parameters studied included: fibrinogen; platelet count and aggregation; single-stage prothrombin time; kaolin partial thromboplastin time; factors v and x assays and euglobulin lysis time. The only statistically significant alteration noted was a depressant effect on the platelet count. The significance of this change is commented upon. For practical purposes, it may be concluded that treatment of a group of menopausal women with conjugated oestraogen for one year had no adverse effect on their coagulation mechanism.

Hepatic uroporphyrinogen decarboxylase activity in male C57BL/10 mice was maintained in regenerated liver after recovery from two-thirds hepatectomy. In contrast, there was little increase in enzyme activity in regenerated liver from animals previously treated with hexachlorobenzene (HCB) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). These chemicals initially cause depression of uroporphyrinogen decarboxylase activity over a time much longer than the period allowed for regeneration. Estimation of HCB levels showed that there was only a small amount of redistribution to the liver during regrowth. The results demonstrate that HCB and TCDD induce either formation of a toxic metabolite or some other inhibitory process and that this can be sustained for a long period which delays recovery to the normal state.