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Acacia implexa, Eucalyptus rossii and Exocarpos cupressiformis are native plants of Australia, which were used by the First Peoples for medicinal purposes. In this study, 70% aqueous ethanol crude extracts were prepared from A. implexa bark and leaves, E. rossii leaves and E. cupressiformis leaves, and partitioned via sequential extraction with n -hexane, dichloromethane (DCM), ethyl acetate and ethanol. The crude extracts and fractions were screened for antioxidant activity using a novel, high-throughput lipid-based antioxidant assay, as well as the aqueous ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) assay and the Folin-Ciocalteu test for total phenols. In the lipid-based assay, non-polar n -hexane and DCM fractions showed higher antioxidant activity against the formation of peroxides and thiobarbituric acid reactive substances (TBARS) than the other fractions, whereas the non-polar fractions were not effective in aqueous assays. This illustrates that the high potential of the lipid-soluble n -hexane and DCM fractions as antioxidants would have been missed if only aqueous-based assays were used. In addition, the potent antioxidant compounds were putatively annotated using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-qTOF-MS). Gallic acid, (+)-catechin, (-)-epicatechin and tannins were found in most crude extracts.

Gymnosperms are generally regarded as poor resprouters, especially when compared to angiosperms and particularly following major disturbance. However, is it this clear-cut? This review investigates two main aspects of gymnosperm resprouting: (i) various papers have provided exceptions to the above generalization-how frequent are these exceptions and are there any taxonomic trends?; and (ii) assuming gymnosperms are poor resprouters are there any anatomical or physiological reasons why this is the case? Five of six non-coniferous gymnosperm genera and 24 of 80 conifer genera had at least one species with a well-developed resprouting capability. This was a wider range than would be expected from the usual observation 'gymnosperms are poor resprouters'. All conifer families had at least three resprouting genera, except the monospecific Sciadopityaceae. Apart from the aboveground stem, buds were also recorded arising from more specialised structures (e.g., lignotubers, tubers, burls and underground stems). In some larger genera it appeared that only a relatively small proportion of species were resprouters and often only when young. The poor resprouting performance of mature plants may stem from a high proportion of apparently 'blank' leaf axils. Axillary meristems have been recorded in a wide range of conifer species, but they often did not form an apical dome, leaf primordia or vascular connections. Buds or meristems that did form often abscised at an early stage. While this review has confirmed that conifers do not resprout to the same degree as angiosperms, it was found that a wide diversity of gymnosperm genera can recover vegetatively after substantial disturbance. Further structural studies are needed, especially of: (i) apparently blank leaf axils and the initial development of axillary meristems; (ii) specialised regeneration structures; and (iii) why high variability can occur in the resprouting capacity within species of a single genus and within genera of the same family.

Small diameter branchlets and smooth barked stems and branches of most woody plants have chloroplasts. While the stems of several eucalypt species have been shown to photosynthesise, the distribution of chloroplasts has not been investigated in detail. The distribution of chloroplasts in branchlets (23 species) and larger diameter stems and branches with smooth bark (14 species) was investigated in a wide range of eucalypts (species of Angophora , Corymbia and Eucalyptus ) using fresh hand sections and a combination of bright field and fluorescence microscopy. All species had abundant stem chloroplasts. In both small and large diameter stems, the greatest concentration of chloroplasts was in a narrow band (usually 100-300 μm thick) immediately beneath the epidermis or phellem. Deeper chloroplasts were present but at a lower density due to abundant fibres and sclereids. In general, chloroplasts were found at greater depths in small diameter stems, often being present in the secondary xylem rays and the pith. The cells of the chlorenchyma band were small, rounded and densely packed, and unlike leaf mesophyll. A high density of chloroplasts was found just beneath the phellem of large diameter stems. These trees gave no external indication that green tissues were present just below the phellem. In these species, a thick phellem was not present to protect the inner living bark. Along with the chlorenchyma, the outer bark also had a high density of fibres and sclereids. These sclerenchyma cells probably disrupted a greater abundance and a more organised arrangement of the cells containing chloroplasts. This shows a possible trade-off between photosynthesis and the typical bark functions of protection and mechanical strength.

With an increase in the longevity and thus the proportion of the elderly, especially in developed nations, there is a rise in pathological conditions that accompany ageing, such as neurodegenerative disorders. Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive and memory decline. The pathophysiology of the disease is poorly understood, with several factors contributing to its development, such as oxidative stress, neuroinflammation, cholinergic neuronal apoptotic death, and the accumulation of abnormal proteins in the brain. Current medications are only palliative and cannot stop or reverse the progression of the disease. Recent clinical trials of synthetic compounds for the treatment of AD have failed because of their adverse effects or lack of efficacy. Thus, there is impetus behind the search for drugs from natural origins, in addition to the discovery of novel, conventional therapeutics. Mints have been used traditionally for conditions relevant to the central nervous system. Recent studies showed that mint extracts and/or their phenolic constituents have a neuroprotective potential and can target multiple events of AD. In this review, we provide evidence of the potential role of mint extracts and their derivatives as possible sources of treatments in managing AD. Some of the molecular pathways implicated in the development of AD are reviewed, with focus on apoptosis and some redox pathways, pointing to mechanisms that may be modulated for the treatment of AD, and the need for future research invoking knowledge of these pathways is highlighted.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with an unclear cause. It appears that multiple factors participate in the process of neuronal damage including oxidative stress and accumulation of the protein amyloid β (Aβ) in the brain. The search for a treatment for this disorder is essential as current medications are limited to alleviating symptoms and palliative effects. The aim of this study is to investigate the effects of mint extracts on selected mechanisms implicated in the development of AD. To enable a thorough investigation of mechanisms, including effects on β-secretase (the enzyme that leads to the formation of Aβ), on Aβ aggregation, and on oxidative stress and apoptosis pathways, a neuronal cell model, SH-SY5Y cells, was selected. Six Mentha taxa were investigated for their in vitro β-secretase (BACE) and Aβ-aggregation inhibition activities. Moreover, their neuroprotective effects on H 2 O 2 -induced oxidative stress and apoptosis in SH-SY5Y cells were evaluated through caspase activity. Real-time PCR and Western blot analysis were carried out for the two most promising extracts to determine their effects on signalling pathways in SH-SY5Y cells. All mint extracts had strong BACE inhibition activity. M. requienii extracts showed excellent inhibition of Aβ-aggregation, while other extracts showed moderate inhibition. M. diemenica and M. requienii extracts lowered caspase activity. Exposure of SH-SY5Y cells to M. diemenica extracts resulted in a decrease in the expression of pro-apoptotic protein, Bax, and an elevation in the anti-apoptotic protein, Bcl-xL, potentially mediated by down-regulation of the ASK1-JNK pathway. These results indicate that mint extracts could prevent the formation of Aβ and also could prevent their aggregation if they had already formed. M. diemenica and M. requienii extracts have potential to suppress apoptosis at the cellular level. Hence, mint extracts could provide a source of efficacious compounds for a therapeutic approach for AD.

Premise of the Study: Solanum elaeagnifolium (silverleaf nightshade), having originated in the Americas, is now a serious summer-growing, perennial weed in many countries, including Australia. Most surfaces of the plants have a dense covering of trichomes, giving them a silvery-white appearance, hence the common name. We aimed to identify structural and functional properties of its leaves, especially the trichomes, that may affect the uptake of foliar-applied tracer dyes., Methods: The structure of leaves of Solanum elaeagnifolium was examined by light and scanning electron microscopy. The potential for transport of materials between trichomes and veins was studied with symplastic (carboxyfluorescein diacetate) and apoplastic (lucifer yellow) tracer dyes., Key Results: Mature leaves had a dense covering of complex, stellate trichomes on both surfaces, particularly the abaxial. The basal cells of Solanum elaeagnifolium trichomes penetrated into the underlying palisade mesophyll layers. The innermost lobes of these basal cells sometimes contacted the bundle sheath of the veins, but were not observed to directly contact the xylem or phloem. We found that neither symplastic nor apoplastic dyes were transferred between the basal cells of the trichomes and the vascular tissues. The trichome layer repelled water-based tracer dyes, while one of four adjuvants tested facilitated entry of both symplastic and apoplastic dyes., Conclusions: Our results did not support a transport function for the trichomes. The trichomes may protect the mesophytic leaves from invertebrate herbivory, while also probably decreasing radiation absorbed resulting in cooler leaves in this summer-growing species.

Resprouting as a response to disturbance is now widely recognized as a key functional trait among woody plants and as the basis for the persistence niche. However, the underlying mechanisms that define resprouting responses to disturbance are poorly conceptualized. Resprouting ability is constrained by the interaction of the disturbance regime that depletes the buds and resources needed to fund resprouting, and the environment that drives growth and resource allocation. We develop a buds-protection-resources (BPR) framework for understanding resprouting in fire-prone ecosystems, based on bud bank location, bud protection, and how buds are resourced. Using this framework we go beyond earlier emphases on basal resprouting and highlight the importance of apical, epicormic and below-ground resprouting to the persistence niche. The BPR framework provides insights into: resprouting typologies that include both fire resisters (i.e. survive fire but do not resprout) and fire resprouters; the methods by which buds escape fire effects, such as thick bark; and the predictability of community assembly of resprouting types in relation to site productivity, disturbance regime and competition. Furthermore, predicting the consequences of global change is enhanced by the BPR framework because it potentially forecasts the retention or loss of above-ground biomass., (© 2012 The University of New England. New Phytologist © 2012 New Phytologist Trust.)

Background: The branches of Wollemia nobilis are unbranched; however, it has been noted that new branches can form from the distal end of damaged ones, and branches can grow from axillary structures once a terminal strobilus has fallen. Tomlinson and Huggett (2011, Annals of Botany 107: 909-916) have recently investigated the formation of these reiterative branches and stated in the title of their paper that 'Partial shoot reiteration in Wollemia nobilis (Araucariaceae) does not arise from "axillary meristems"'. They go on to state 'Further research may reveal the presence of these elusive, but still only hypothetical, axillary meristems'., Response: In this Viewpoint, I argue that Tomlinson and Huggett do not refer to previously published information that indicates that axillary meristems are present in Wollemia nobilis branch leaf axils, and that their anatomical methods were probably not optimal for locating and examining these minute structures. Thus, whilst I would agree that the axillary meristems in branch leaf axils of Wollemia nobilis are elusive, I contend that they are not hypothetical.

Fire is a major modifier of communities, but the evolutionary origins of its prevalent role in shaping current biomes are uncertain. Australia is among the most fire-prone continents, with most of the landmass occupied by the fire-dependent sclerophyll and savanna biomes. In contrast to biomes with similar climates in other continents, Australia has a tree flora dominated by a single genus, Eucalyptus, and related Myrtaceae. A unique mechanism in Myrtaceae for enduring and recovering from fire damage likely resulted in this dominance. Here, we find a conserved phylogenetic relationship between post-fire resprouting (epicormic) anatomy and biome evolution, dating from 60 to 62 Ma, in the earliest Palaeogene. Thus, fire-dependent communities likely existed 50 million years earlier than previously thought. We predict that epicormic resprouting could make eucalypt forests and woodlands an excellent long-term carbon bank for reducing atmospheric CO(2) compared with biomes with similar fire regimes in other continents.

Determining the location of buds and bud-forming meristems and hence the level of protection from heat is essential to understanding plant response to fire. Most eucalypts resprout readily from the stem (epicormic resprouting) and the base after felling or high intensity fire. In contrast, Eucalyptus regnans is one of the few eastern Australian fire-sensitive, obligate seeder eucalypts. Some authors have suggested that the relatively weak epicormic resprouting is due to a lack of bud-forming structures. Epicormic strands from the bark and outer xylem of three very large trees and two saplings were examined anatomically. Epicormic bud-forming structures were found in all samples examined. The bud-forming capacity consisted of narrow, radially elongated strips of cells of meristematic appearance. These strips were continuous from the outermost secondary xylem through to the outer bark. Bark was relatively thick at the base of the large trees, but remarkably thin above this basal skirt. Eucalyptus regnans was found to possess the apparently fire-adapted epicormic strands previously described in other eucalypts, thus showing its fire-adapted lineage. However, this fire-sensitive species apparently directs much of its resources to rapid height-growth rates in younger trees, rather than to vegetative fire survival.

Background and Aims: The branch-base xylem structure of the endangered Wollemia nobilis was anatomically investigated. Wollemia nobilis is probably the only extant tree species that produces only first-order branches and where all branches are cleanly abscised. An investigation was carried out to see if these unusual features might influence branch-base xylem structure and water supply to the foliage., Methods: The xylem was sectioned at various distances along the branch bases of 6-year-old saplings. Huber values and relative theoretical hydraulic conductivities were calculated for various regions of the branch base., Key Results: The most proximal branch base featured a pronounced xylem constriction. The constriction had only 14-31 % (average 21 %) of the cross-sectional area and 20-42 % (average 28 %) of the theoretical hydraulic conductivity of the more distal branch xylem. Wollemia nobilis had extremely low Huber values for a conifer., Conclusions: The branch-base xylem constriction would appear to facilitate branch abscission, while the associated Huber values show that W. nobilis supplies a relatively large leaf area through a relatively small diameter 'pipe'. It is tempting to suggest that the pronounced decline of W. nobilis in the Tertiary is related to its unusual branch-base structure but physiological studies of whole plant conductance are still needed.

Intact trees of Wollemia nobilis Jones, Hill and Allen (Araucariaceae) routinely develop multiple coppice shoots as well as orthotropic epicormic shoots that become replacement or additional leaders. As these are unusual architectural features for the Araucariaceae, an investigation was made of the axillary meristems of the main stem and their role in the production of epicormic and possibly coppice shoots. Leaf axils, excised from the apex to the base of 2-m-high W. nobilis plants (seedling origin, ex situ grown), were examined anatomically. Small, endogenous, undifferentiated (no leaf primordia, no vascular or provascular connections) meristems were found in the axils from near the shoot apex. In the more proximal positions about half the meristems sampled did not differentiate further, but became tangentially elongated to compensate for increases in stem diameter. In the remaining axils the meristems slowly developed into bud primordia, although these buds usually developed few leaf primordia and their apical 'domes' were wide and flat. Associated vascular development was generally restricted to provascular dedifferentiation of the cortical parenchyma, with the procambium usually forming a 'closed loop' that did not extend back to the secondary vascular tissues. Development of the meristems was very uneven with adjacent axils often at widely differing stages of development into buds. The study shows that, unlike most conifers, W. nobilis possesses long-lived meristematic potential in most, if not all, leaf axils. Unlike other araucarias that have been investigated, many of the meristems in the orthotropic main stem will slowly develop into bud primordia beneath the bark in intact plants. It appears likely that this slow but continued development provides a ready source of additional or replacement leaders and thus new branches and leaves.

Sixteen Western Whiteface ewes were divided into 2 groups to determine the effects of plant maturity on liver function and weight gains. They were allowed to graze a greater than 95% pure stand of Kochia scoparia for 72 or 55 d. Four additional sheep (controls) were placed on weedy Bermuda grass pasture with the same water supply as the kochia-fed sheep. Body weights were determined on June 5, 1996 and on removal from the kochia pasture. Blood samples were collected at approximately 7-d intervals for serum chemistry profiles. Kochia scoparia plant samples were also randomly collected at 5-6 w intervals, oven dried, identified by date of collection and stored for later nutrient, oxalate, nitrate and sulfate analysis. Liver biopsies were performed pre-, mid- and post-study to assess morphologic changes. An almost exclusive diet (> 95%) of Kochia scoparia resulted in minimal elevations in serum GGT, suggesting mild hepatocellular injury, but was not associated with overt hepatic lesions or clinical disease. Other serum chemistry measurements were within normal ranges. Unlike for other domestic animal species, Kochia scoparia may be a useful grazing forage for sheep, offering little risk of toxicosis.

Although hormone replacement therapy (HRT) appears to protect women from ischaemic heart disease (IHD), its use is associated with increased factor clotting activity (VIIc), an independent risk factor for IHD. The nature of this factor VII rise was therefore examined in a cross-sectional study of 279 women aged between 40 and 65 years. Ninety-four were pre-menopausal, 44 were post-menopausal and taking HRT, whilst 141 were post-menopausal non-users. For those women on oestrogen-only HRT, the mean factor VIIc was 144%, compared to 130% for post-menopausal non-users, and 116% for those on combined HRT. These differences were significant (p = 0.01). Oestrogen-only users also had significantly higher mean levels of factor VIIa (3.3 ng/ml) compared to non-users (2.2 ng/ml) and those on oestrogen-progestogen HRT (2.2 ng/ml-p = 0.015). In contrast for factor VII antigen the mean values of the three groups were similar. Analysis of the age-regression slopes showed a significant age-related rise in factor VIIc of 1.2% per annum (p < 0.01) for post-menopausal non-users. There was a similar increase in factor VII antigen (2.1%) but no rise in factor VIIa. For all HRT users there was no change with age for any of the factor VII measures. Thus the age-related rise in factor VIIc appears to be due to an increase in factor VII zymogen alone, and taking HRT seems to abolish such a rise. In contrast, the increased factor VIIc seen with oestrogen-only HRT appears to be secondary to factor VII activation.

The objective of this study was to assess the performance of chick embryo motoneuron cultures for the study of neurotoxicants. The response of motoneurons to the cytotoxic effects of picrotoxin, strychnine, bulbocapnine, and the naturally occurring excitatory amino acids, N-methyl D-aspartate (NMDA) and L-glutamate was studied by using a colorimetric viability assay using a vital dye. Selective cellular responses other than cell death were evaluated using a spectrofluorometric assay based on the response of an electrochromic styryl dye (Di-4-Anneps) to determine the expression of receptors for glycine, gamma-aminobutyric acid (GABA), NMDA, and L-glutamate by motoneurons in culture. The performance of chick embryo motoneurons (E7) in culture was useful and informative in neurotoxicologic studies. Motoneurons (E7) were found to express receptors for glycine, GABA, NMDA, and dopamine. The presence of the receptors and the inherent characteristics of motoneurons to generate action potential at an early embryonic stage (E4) makes this culture system a reliable model to conduct mechanistic studies as well as for predictive screening tests for agents of pharmacologic and toxicologic potential.

The effect of bacterial infection on antibiotic activity and penetration of parenterally administered ceftiofur into implanted tissue chambers was studied in cattle. Tissue chambers were implanted subcutaneously in the paralumbar fossae of eight calves (256-290 kg body weight). Approximately 80 days after implantation, the two chambers on one side of each animal were inoculated with Pasteurella haemolytica (10(6) CFU/chamber). Eighteen hours after inoculation, ceftiofur sodium was administered intravenously (5 mg/kg) to each of the calves. Non-infected chamber fluid, infected chamber fluid and heparinized blood samples were collected immediately before and at 1, 3, 6, 12 and 24 h after drug administration. Concentrations of ceftiofur and desfuroylceftiofur metabolites and ceftiofur-equivalent microbiological activity were measured by high-pressure liquid chromatography and microbiological assay respectively. Concentrations of ceftiofur and desfuroylceftiofur metabolites and anti-microbial activity in P. haemolytica-infected tissue chambers were significantly higher than those in non-infected tissue chambers at all sampling times, indicating that ceftiofur, regardless of the method used for analysis, localizes at higher concentrations at tissue sites infected with P. haemolytica. Antibiotic activity-concentration ratios were lower in plasma and infected chamber fluid compared with non-infected chamber fluid, suggesting that antibiotic was bound to proteins. However, higher antimicrobial activity in the infected chamber fluid compared with the non-infected chamber fluid, suggests that active drug is reversibly bound to proteins. Protein-bound desfuroylceftiofur may represent a reservoir for release of active drug at the site of infection in the animal.

The pharmacokinetic disposition, urinary excretion and toxicity of tolonium chloride were determined after i.v. administration to sheep. Pretreatment with sodium nitrite significantly decreased the volume of the central compartment, apparent volume of distribution, area under the concentration-time curve, and total body clearance of tolonium chloride. Urinary excretion of tolonium chloride and its metabolite, leucotolonium chloride, together accounted for less than 15% of the administered dose in sheep receiving sodium nitrite and less than 10% of the administered dose in control sheep. The LD50 of tolonium chloride was 10 mg/kg with a 95% confidence interval of 7.35-13.60 mg/kg. Comparison with previously published data describing the pharmacokinetics and toxicity of a related compound, methylene blue, indicated that tolonium chloride has a higher volume of distribution and a narrower therapeutic index.

Six groups of 4 rabbits each were treated as follows: Control; phenobarbital (PB); 3-methylcholanthrene (3MC); proadifen hydrochloride (SKF-525A); Artemisia filifolia and Helenium flexuosum. Prototype P450 inducers (PB and 3MC) increased basal hepatic cytochrome P450 content by 2-3 fold whereas the P450 inhibitor (SKF-525A) had no effect on basal cytochrome P450 content. PB-induction of hepatic microsomes significantly increased the rate of dealkylation of long alkyl chain alkoxyresorufin ethers, benzyloxyresorufin and pentoxyresorufin 47-fold and 17-fold, respectively, but had little or no effect on short alkyl chains. 3MC-induction of microsomes increased dealkylation of all alkoxyresorufin ethers tested, preferentially dealkylating ethers with short alkyl chain in the order: methoxy > ethoxy > propoxy. Artemisia filifolia or Helenium flexuosum had no effect on basal hepatic cytochrome P450 content. However, microsomal dealkylation activity of short alkyl chain alkoxyresorufin ethers (methoxy, ethoxy and propoxy) was inhibited approximately 50%. When these plants are eaten for several days, they may inhibit biotransformation processes in herbivores through the same isoenzymes induced by 3MC.

The objectives of the present experiment were to determine the effects of Artemisia filifolia or Helenium flexuosum ingestion on antipyrine disposition as an indirect index of mixed function oxidase (MFO) activity and to evaluate the rabbit as an animal model for assessing the impact of xenobiotics in food. Twelve adult male New Zealand white rabbits were acclimated and maintained on commercial rabbit pellets for 1 w before treatment commenced. On day 1, all rabbits were given 25 mg antipyrine/kg iv. Beginning on day 14, 6 of the rabbits were fed A filifolia and the other 6 were fed H flexuosum at 250 mg/kg daily for 5 d. Antipyrine injection was repeated in all rabbits on day 19. Serial blood samples were taken following each antipyrine administration and serum concentrations determined and subjected to pharmacokinetic analysis. Administration of H flexuosum significantly increased antipyrine half-life elimination from 99.5 +/- 15 min to 215.5 +/- 28 min, typical of an inhibitory-type effect on MFO. Administration of A filifolia was not accompanied by a significant change in antipyrine disposition. Rabbits appear to be appropriate animal models for evaluating the effect of plant ingestion on hepatic biotransformation.

Phenylbutazone given during the perisurgical period has been reported to increase the intensity and duration of thiamylal anaesthesia in horses. A possible mechanism of competitive plasma protein binding has been suggested. The purpose of the present study was to experimentally reproduce the phenomenon of increased intensity and/or duration of thiamylal anaesthesia and to determine if there is competitive displacement of plasma protein bound thiamylal by phenylbutazone. Six ponies each received one of three treatments, 11 mg/kg intravenous (i.v.) thiamylal; 8.8 mg/kg i.v. phenylbutazone; and 11 mg/kg i.v. thiamylal with 8.8 mg/kg i.v. phenylbutazone given 9 min later. Thirteen blood samples were collected from 0 time through 600 min following drug administration and plasma drug concentrations quantified by high performance liquid chromatography. The pharmacokinetics of thiamylal and phenylbutazone were best described by three- and two-compartment models, respectively. There were no significant differences in pharmacokinetic parameters for thiamylal in the presence of phenylbutazone. However, there were differences in phenylbutazone pharmacokinetics when preceded by thiamylal administration. Unbound phenylbutazone concentrations were increased at 171, 231 and 351 min when given with thiamylal, accompanied by decreases in per cent bound phenylbutazone (P < 0.05). There were also significant (P < 0.05) changes in per cent plasma protein binding of thiamylal and phenylbutazone between 120 and 360 min, when in combination. No changes in intensity or duration of anaesthesia were observed.

Gram-negative bacterial isolates (635) obtained from routine submissions to the Oklahoma Animal Disease Diagnostic Laboratory during 1983-1987 were tested for antimicrobial susceptibility. Minimal inhibitory concentrations (MICs) were determined for the following antimicrobials using commercially prepared microdilution assay materials: ampicillin, cephalothin, chloramphenicol, erythromycin, gentamicin, kanamycin, oxytetracycline, penicillin G, spectinomycin, sulfachlorpyridazine, sulfadimethoxine, and tylosin. Results for isolates from cattle, dogs, horses, and pigs are presented. In only a few instances were differences in MICs apparent among bacterial isolates from different tissues. Aminocyclitol MICs for equine uterine isolates of Klebsiella pneumoniae differed from MICs for isolates from other tissues, and ampicillin, kanamycin, and spectinomycin MICs for bovine fecal isolates of Escherichia coli differed from MICs for isolates obtained from other tissues. In several instances, bimodal distribution of susceptibilities was apparent for ampicillin, kanamycin, and/or oxytetracycline. There was also a bimodal distribution pattern for erythromycin against Pasteurella haemolytica of bovine origin.

A close inter-relationship between raised factor VII clotting activity and elevated blood lipids, particularly serum triglycerides, is well established. A study of factor VII, its activation state and of plasma lipids has been undertaken in two groups of healthy middle-aged males to elucidate this mechanism. A control group with normal factor VII levels were closely matched for age and body-mass index with a second group with elevated levels. Factor VII assays, using rabbit and bovine thromboplastin and a factor VII Ag method, were employed. Triglycerides correlated with the rabbit factor VII thromboplastin assay and factor VII Ag (P < 0.05) but not with the bovine thromboplastin method. Higher HDL-cholesterol and apolipoprotein A-I levels were found in subjects with increased factor VII (P < 0.001) and appeared to be due to differences in alcohol consumption. Cholesterol levels were significantly higher with elevated factor VII. Differential testing suggests that higher factor VII is predominantly mediated through a rise in total VII, rather than an increase in its activity state.

Pasteurella haemolytica serotype A1 isolates were collected from cattle within a feedlot during an outbreak of bovine respiratory disease. Genetic heterogeneity among the isolates was examined by restriction endonuclease analysis (REA), ribotyping, and analysis of plasmid content. The susceptibilities of isolates to several antibiotics were also examined. Five different REA patterns and three different ribotypes were observed among the isolates. Fifty percent of the isolates had an identical REA type, ribotype, and plasmid profile. Examination of the plasmid content of the isolates revealed that most (73%) carry a single plasmid which encodes beta-lactamase, 13.5% carry two plasmids, and 13.5% carry no plasmid. The data reveal the presence of genetic differences among isolates of P. haemolytica A1, associated with shipping fever pneumonia within a closed feedlot, and suggest that a combination of REA, ribotyping, plasmid analysis, and antibiotic susceptibility determination will be useful in analyzing the molecular epidemiology of this disease.

Horses develop severe and often fatal hemolytic anemia after ingesting dried leaves from red maple (Acer rubrum) trees. Toxicosis appears related to an unknown oxidant present in the dried or wilted leaves. This case report describes 2 horses that aborted and developed fatal hemolytic anemia after consuming wilted leaves from red maple (Acer rubrum). While an absolute diagnosis was not confirmed due to lack of proper antemortem and postmortem examinations, red maple toxicosis appeared a reasonable diagnosis based on clinical signs and laboratory findings. Other differentials include equine infectious anemia, autoimmune hemolytic anemia, piroplasmosis, leptospirosis, ehrlichiosis, and other plant or chemical sources of oxidants (onion, garlic, kale, phenothiazines).

Single-dose pharmacokinetic variables of pyrimethamine were studied in horses. Pyrimethamine (1 mg/kg of body weight) was administered IV and orally to 6 adult horses, and plasma samples were obtained at frequent intervals thereafter. Plasma pyrimethamine concentration was assayed by gas chromatography, and concentration-time data were analyzed, using a pharmacokinetic computer program. The IV and oral administration data were best described by 3-compartment and 1-compartment models, respectively. The median volume of distribution at steady state after IV administration was 1,521 ml/kg and the median elimination half-time was 12.06 hours. Mean plasma concentration after oral administration fluctuated between a maximal concentration of 0.18 microgram/ml and 0.09 microgram/ml (24 hours after dosing). Bioavailability after oral administration was 56%.

Pharmacokinetics, CSF penetration, and hematologic effects of oral administration of pyrimethamine were studied after multiple dosing. Pyrimethamine (1 mg/kg of body weight) was administered orally once a day for 10 days to 5 adult horses, and blood samples were collected frequently after the first, fifth, and tenth doses. The CSF samples were obtained by cisternal puncture 4 to 6 hours after administration of the first, third, seventh, and tenth doses. Pyrimethamine concentration in plasma and CSF was quantified by gas chromatography, and plasma concentration-time data were analyzed, using a pharmacokinetic computer program. Repeated daily dosing resulted in accumulation of pyrimethamine in plasma, with steady state being achieved within 5 days, when the mean peak plasma concentration was more than twice that measured after the first dose. Pyrimethamine concentration in CSF was 25 to 50% of corresponding plasma concentration and did not appear to accumulate with successive administration of doses. Blood samples collected during and after the dosing regimen were submitted for hematologic analysis; neutrophil numbers decreased slightly, but remained within normal range for adult horses.

The effects of fasciolosis on drug disposition were studied by administration of antipyrine, erythromycin and oxytetracycline to sheep and cattle. Fasciolosis was produced by administration of 200 or 400 metacercariae (MC) of Fasciola hepatica to sheep and 500 MC to cattle. The disease was subsequently confirmed by determination of plasma glutamate dehydrogenase and gamma-glutamyl transferase and identification and quantitation of mature flukes in the liver at necropsy. Acute or subacute fasciolosis in sheep was accompanied by a significant decrease in the elimination rate constant (beta) and increase in the elimination half-time (t 1/2) for antipyrine and erythromycin when compared with controls or infected sheep which had been treated with the anthelmintic luxabendazole. An increase in apparent volume of distribution (Vd) was seen only for erythromycin in sheep given 400 MC. There were no changes in the disposition of oxytetracycline in sheep with either acute or subacute infection and no effects on disposition of the three test drugs in chronically infected sheep. With early chronic disease in calves, only the disposition of oxytetracycline was affected; not that of antipyrine or erythromycin.

The effects of time and method of administration of rifampin with respect to feeding were evaluated in five mature horses. There was a significant (P less than or equal to 0.05) delay in time of maximum serum concentration and an apparent but not significant decrease in oral absorption when rifampin was given as a top dressing on grain as compared with administration in corn syrup 2 h before or 2 h after feeding. Although there were no differences between administration before or after feeding, administration 2 h prior to feeding was selected as the method of choice for future experiments. The effects of age on rifampin disposition were subsequently examined using this method of administration in six, 1-week old foals. Rifampin (10 mg/kg) was given at increasing age from 1 through 10 weeks and the pharmacokinetic disposition parameters compared. There were significant differences in the slope of the elimination phase (beta) and area under the curve (AUC) at 1 week through 6 weeks compared with 10 weeks or with values in the five mature horses.

A subcutaneous soft tissue infection model in calves was used to study the in vivo response of Pasteurella haemolytica to erythromycin and dexamethasone. Two tissue chambers were implanted SC in each of 12 calves. At 45 days after implantation, all tissue chambers were inoculated with an erythromycin-sensitive strain of P haemolytica. Starting 24 hours after inoculation, calves were allotted to 4 groups of equal size and a 2 x 2-factorial arrangement of treatments was applied: 3 calves were given erythromycin (30 mg/kg of body weight, IM, for 5 days), 3 calves were given dexamethasone (0.05 mg/kg, IM, for 2 days), 3 calves were given erythromycin and dexamethasone, and the remaining calves served as nontreated controls. Chamber fluids were tested daily, and the response to treatment was measured. Neither erythromycin nor dexamethasone affected viability or growth of bacteria within tissue chambers. Dexamethasone had no effect on the influx of neutrophils into infected chambers. Despite repeated administration of a high dose of erythromycin and attainment of adequate concentration in serum, erythromycin concentration in chamber fluids did not exceed the minimal inhibitory concentration established in vitro. These results indicate that the clinical efficacy of erythromycin against P haemolytica sequestered in consolidated pneumonic lesions may not be well correlated with predictions based on serum pharmacokinetic and in vitro susceptibility data.

Practical strategies for developing rational therapeutic regimens based on in vitro sensitivity and pharmacokinetic disposition are presented. Special attention is given to Pasteurella haemolytica, which is regarded as the most frequent cause of bovine bacterial pneumonia. Bacterial-dependent and host-dependent causes of therapeutic failure and potentially valuable novel therapies and drug combinations are considered.

Ten of 100 mature ewes were afflicted with acute oxalate toxicosis within 40 hours after being temporarily penned in a lot that contained considerable growing Rumex crispus (curly dock). Clinical signs of toxicosis included excess salivation, tremors, ataxia, and recumbency. Affected ewes were markedly hypocalcemic and azotemic. Oxalate crystals were not observed in urine. Gross postmortem lesions were minimal and nondiagnostic in 2 ewes that died peracutely, but perirenal edema and renal tubular degeneration were clearly observable in ewes euthanatized on the third day of toxicosis. Diagnosis of oxalate toxicosis was confirmed by histopathologic findings. Samples of Rumex spp contained 6.6 to 11.1% oxalic acid on a dry-weight basis, a concentration comparable with that in other oxalate-containing plants that have caused acute oxalate toxicosis.

Endotoxins are non-protein fragments of the cell wall of Gram-negative bacteria. They must be absorbed into the circulation to produce disease and systemic effects are similar, regardless of bacterial source. Absorption of endotoxins occurs in obstructive bowel disease and may play a significant part in determining the severity of the disease. Many of the responses to experimentally administered endotoxin are identical to those of bowel diseases or the horse and include circulatory, haematological and metabolic alterations. Therapeutic approaches are indirect and include many drugs currently employed in equine practice. The agents are directed toward mediators of the disease rather than the endotoxins themselves and include fluids, corticosteroids, anti-inflammatory drugs, energy sources and vasoactive drugs. The rationale for use and dosages are discussed.

The pharmacokinetics of 3 antibiotics--chloramphenicol, lincomycin, and tylosin--were determined in newborn calves. The kinetic determinations, using 2-compartment open models, were made at increasing ages from 1 day to 42 days and compared with those made from 9-month-old calves. Although all 3 antibiotics require a degree of hepatic metabolism, there were marked differences in the development of elimination processes for the individual drugs. Elimination of tylosin, which was slow in the calves at birth, increased rapidly and was equal to that in older calves by the end of 1 week. Lincomycin elimination was not markedly reduced in calves at birth. Chloramphenicol elimination was slow in calves at birth and only by 4 to 6 weeks attained the rate found in older calves. Dosage adjustments would not be required for the antibiotics tylosin or lincomycin when given to newborn calves, but may be necessary for chloramphenicol given to calves before they are 4 to 6 weeks old.

The mechanism of action of nitrite-thiosulfate (Chen et al., 1933a ,b; Hug , 1933) in the antagonism of the lethal effects of cyanide is much more complex than proposed 50 years ago. Some of the recent findings concerning the mechanism of nitrite action have conceptual theoretical and practical significance, as the development of newer cyanide antagonists are dependent on the elucidation of the basic mechanism of antidotal action. There are preliminary evidence which suggest a vasogenic action rather than methemoglobin formation is the primary action of nitrite, as a cyanide antagonist. Various vasogenic compounds have been uncovered and they may play an important role in the future development of a new class of cyanide antagonists. Also recent development in thiol detoxication of cyanide suggest that rhodanese may play a more complex role. The detoxification of cyanide may be viewed from a considerably more complex perspective with the elucidation of recent mechanisms. It also may provide a newer conceptual basis for a more rational development of future compounds to antagonize the lethal effects of cyanide.

Attempts were made to evaluate the effects of pretreatment with air and oxygen either alone or in various combinations with sodium nitrite and/or sodium thiosulfate on the physiological disposition of 14C-labeled sodium cyanide in mice. The radioactive respiratory excretion was studied by radiorespirometry, and the effects of various combinations of cyanide antagonists were compared. Oxygen either alone or in combination with sodium thiosulfate significantly enhanced the respiratory excretion when compared with air. Sodium thiosulfate accelerated the initial rate, but not the total amount of radioactivity excreted. The cumulative recovery of radioactive gases was significantly greater with groups receiving oxygen either alone or with sodium thiosulfate. When sodium nitrite was employed as an antidote either alone or with sodium thiosulfate, no difference in the respiratory excretion was noted between air and oxygen. The use of the sodium nitrite-sodium thiosulfate combination either with air or oxygen resulted in a marked decrease in the initial rate as well as the total amount of respiratory radioactivity excreted. No significant differences between various experimental groups were noted in the total amount of urinary radioactivity excreted or the total body retention of radioactivity.

The potential for interactions between chloramphenicol, phenylbutazone, acepromazine and thiamylal and chloramphenicol, rifampin, and phenylbutazone were evaluated in two groups of experiments. In the first, five horses were given thiamylal intravenously (iv) (6.6 mg/kg) after pretreatment with acepromazine, and the time of recumbency was determined. Administration of chloramphenicol iv (25 mg/kg) 1 h prior to anaesthesia significantly lengthened the recumbency time from 21.8 +/- 4.8 mins to 36.0 +/- 8.3 mins. There was an apparent but not statistically significant decrease in recumbency time when phenylbutazone (4.4 mg/kg) was administered iv daily for 4 days prior to anaesthesia. In the second series of experiments, phenylbutazone (4.4 mg/kg), chloramphenicol (25 mg/kg) and rifampin (10 mg/kg) were administered in various sequences to five different horses. Chloramphenicol pretreatment produced a significant decrease in the elimination rate and rifampin a significant increase in the elimination rate of phenylbutazone. The half-life of elimination of phenylbutazone alone was about 4 h. Following four days pretreatment with rifampin it was approximately 2.7 h, it was approximately 5.6 h and 9.5 h, respectively, when chloramphenicol was administered in one dose 1 h before or two doses 12 h and 1 h before phenylbutazone.