Extravasation reactions associated with the administration of pamidronate: 11 cases (2008-2013).

Pamidronate is a bisphosphonate drug widely utilized in veterinary oncologic practice for the palliation of malignant osteolysis. Pamidronate has not been previously reported to cause tissue injury upon extravasation in dogs. The medical records of 11 client-owned dogs undergoing palliative treatment for primary bone tumors with known or suspected pamidronate extravasation reactions were reviewed. The majority of adverse events were low grade in nature, however in some cases, the reactions were severe and led to euthanasia in one instance. Time to complete resolution of lesions ranged from within several days to greater than one and a half months. Aside from the dog that was euthanized, no long-term sequelae of extravasation were identified. Treatments employed to address the reactions varied widely. Pamidronate extravasation reaction appears to be an uncommon, but potentially serious complication of intravenous administration.

Feline discrete high-grade gastrointestinal lymphoma treated with surgical resection and adjuvant CHOP-based chemotherapy: retrospective study of 20 cases.

The aim of this retrospective study was to evaluate the outcome of cats treated with surgical intervention for a discrete intermediate-/high-grade gastrointestinal lymphoma prior to CHOP-based chemotherapy. Variables including sex, breed, haematocrit, white blood cell count, serum albumin concentration, clinical stage of disease, gastrointestinal obstruction and peritonitis were assessed for their effect on survival. Twenty cats met the inclusion criteria with three cats still alive at the time of data analysis. The overall median survival time (MST) was 417 days (range: 12-2962 days). The disease-free interval (DFI) was 357 days (range: 0-1585 days) with six cats still deemed in remission prior to death. Only clinical stage had a significant effect on both MST and DFI. Cats with discrete intermediate/high-grade gastrointestinal lymphoma that undergo surgical resection followed by adjuvant CHOP chemotherapy may achieve acceptable overall survival times.

Doxorubicin chemotherapy for presumptive cardiac hemangiosarcoma in dogs†.

Sixty-four dogs were treated with single-agent doxorubicin (DOX) for presumptive cardiac hemangiosarcoma (cHSA). The objective response rate (CR + PR) was 41%, and the biologic response rate (CR + PR + SD), or clinical benefit, was 68%. The median progression-free survival (PFS) for treated dogs was 66 days. The median survival time (MST) for this group was 116 days and was significantly improved compared to a MST of 12 days for untreated control dogs (P = 0.0001). Biologic response was significantly associated with improved PFS (P < 0.0001) and OS (P < 0.0001). Univariate analysis identified larger tumour size as a variable negatively associated with PFS. The high rate of clinical benefit and improved MST suggest that DOX has activity in canine cHSA.

Evaluation of histological grade and histologically tumour-free margins as predictors of local recurrence in completely excised canine mast cell tumours.

Completeness of mast cell tumour (MCT) excision is determined by assessment of histologically tumour-free margins (HTFM). The HTFM width necessary to prevent local recurrence (LR), recognized as histologic safety margin (HSM) in human oncology, has not been defined. We hypothesized that HTFM width would correlate with risk for LR and high-grade tumours would require wider HTFM than low-grade tumours. Records of dogs with completely excised MCTs were included. Signalment, two-tier tumour grade, tumour size, HTFM width, recurrence and therapy data was collected. High-grade (n = 39) tumours were more likely to recur than low-grade (n = 51) tumours (35.9% versus 3.9%), P < 0.0001, with no association between HTFM width and LR. Twenty-nine percent of low-grade tumours had HTFM less than 3 mm; none recurred. Narrow (≤3 mm) histologic margins are likely adequate to prevent LR of low-grade tumours. High-grade tumours have significant risk of LR regardless of HTFM width.

Carabidae population dynamics and temporal partitioning: response to coupled neonicotinoid-transgenic technologies in maize.

Insecticidal Bt crops and seed treatments represent additional pest management tools for growers, prompting ecological studies comparing their impact on farm system inputs and effects to nontarget organisms compared with conventional practices. Using high taxonomic and temporal resolution, we contrast the dominance structure of carabids and dynamics of the most abundant species in maize (both sweet and field corn) agroecosystems using pest management tactics determined by the purchase of seed and application of pyrethroid insecticides. In the seed-based treatments, sweet corn contained Cry1Ab/c proteins, whereas field corn contained the coupled technology of Cry3Bb1 proteins for control of corn rootworm and neonicotinoid seed treatments aimed at secondary soil-borne pests. The insecticide treatments involved foliar pyrethroids in sweet corn and at-planting pyrethroids in field corn. The carabid community, comprised of 49 species, was dominated by four species, Scarites quadriceps Chaudoir, Poecilus chalcites Say, Pterostichus melanarius Illiger, and Harpalus pensylvanicus DeGeer, that each occupied a distinct temporal niche during the growing season. Two species, Pt. melanarius and H. pensylvanicus, exhibited differences between treatments over time. Only H. pensylvanicus had consistent results in both years, in which activity densities in field corn were significantly higher in the control in July and/or August. These results, along with laboratory bioassays, led us to hypothesize that lower adult captures resulted from decrease in prey availability or exposure of H. pensylvanicus larvae to soil-directed insecticides-either the neonicotinoid seed treatment in the transgenic field corn or an at-planting soil insecticide in the conventional field corn.

Effects of HIV disease on lipid, glucose and insulin levels: results from a large antiretroviral-naive cohort.

OBJECTIVES: With the use of potent antiretroviral therapy in patients with HIV disease, changes in lipid parameters and glucose homeostasis have been noted. However, these effects have been difficult to interpret because of the varied demographic and treatment characteristics of the cohorts and the complexity of differentiating the effect of HIV disease from that of the drugs used in its treatment. This study was designed to explore these issues. METHODS: Demographic information and fasting blood samples were collected from 419 antiretroviral-naive HIV-1-infected patients. RESULTS: The average age of the participants was 38.2 years, with 21% being female, 60% being African American, and 14% having a history of injection drug use. The mean CD4 lymphocyte count was 216 cells/microL, the mean baseline log10 HIV viral load was 4.98 HIV-1 RNA copies/mL, and 26% of patients had a history of AIDS-defining events. Women and African Americans had significantly higher levels of high-density lipoprotein (HDL) cholesterol, and older age was associated with higher total cholesterol levels. Lower CD4 lymphocyte counts and higher HIV RNA levels were independently associated with lower HDL cholesterol levels. Additionally, higher HIV RNA level was associated with lower levels of low-density lipoprotein (LDL) cholesterol and higher levels of very-low-density lipoprotein (VLDL) cholesterol and triglycerides. A history of AIDS-defining events was associated with higher total cholesterol, VLDL cholesterol and triglyceride concentrations. With respect to glucose homeostasis, a higher CD4 lymphocyte count was associated with less evidence of insulin resistance. However, a higher body mass index was associated with higher lipid levels and with more evidence of insulin resistance. CONCLUSIONS: Both HIV disease and demographic characteristics were found to influence lipid values and glucose homeostasis in the absence of antiretroviral treatment. More advanced HIV disease was associated with less favourable lipid and glucose homeostatic profiles. The independent association between HIV RNA levels and various lipid parameters suggests that viral replication had a direct effect on lipid levels. Interpretation of the effects of various HIV treatment regimen and drugs on metabolic parameters must take into account the stage of HIV disease and the demographic characteristics of the population studied.

IPCS conceptual framework for evaluating a mode of action for chemical carcinogenesis.

The International Programme on Chemical Safety (IPCS) is leading an activity to harmonize approaches to cancer risk assessment as a part of its larger project on the Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals. Through a series of workshops and the evaluation of case studies, a number of key components of risk assessments relating to harmonization were identified: transparency, terminology, weight of evidence, flexibility, and accessibility/communication. A major impediment to harmonization identified in the consideration of weight of evidence was the evaluation of mode of action. To address this need, a conceptual framework was developed, based on the general principles involved in considering the chemical induction of a specific tumor in animals. This is based partly on the Bradford Hill criteria for causality as modified by Faustman et al. (1997) for developmental toxicity. The framework is described in this paper followed by a worked example. It is recognized that the framework addresses only one stage in the overall characterization of hazard to humans of chemical carcinogens. Another important but separate step is the assessment of relevance to humans. This is a priority area for future work in this project.

Lipid, polyamide, and flavonol phagostimulants for adult western corn rootworm from sunflower (Helianthus annuus L.) pollen.

Adult Diabroticites including western corn rootworm (WCR), Diabrotica virgifera virgifera LeConte, consume pollen of corn, squash, sunflower, and other species. Short-chain neutral amino acids in methanol-water extracts of pollen have been previously identified in our laboratory as strong phagostimulants for Diabrotica. Bioassay-driven fractionation was used to characterize the interacting lipid and midpolarity phagostimulants for adult WCR in Giant Gray Stripe sunflower, Helianthus annuus L., pollen. Lipids rich in omega3-linolenic acid including triglycerides, free fatty acids, phosphatidylethanolamines, phosphatidic acids, and phosphatidylcholines were highly phagostimulatory. Other important phagostimulatory components included a hydroxycinnamic acid-polyamine amide, N(1),N(5),N(10)-tri[(E)-p-coumaroyl]spermidine, and a flavonol, quercetin beta-3-O-glucoside. The structural characteristics of these phagoactive compounds and their role in the pollinivory specialization of rootworm beetles are discussed.

Home use of a functional electrical stimulation system for standing and mobility in adolescents with spinal cord injury.

OBJECTIVE: Functional electrical stimulation (FES) is a technology that may allow some patients with spinal cord injury (SCI) to integrate standing and upright mobility with wheelchair mobility. The purpose of this study was to document the patterns of home and community use of a FES system for standing and mobility. DESIGN: A telephone questionnaire was administered every 1 to 4 weeks for a minimum of 1 year. An interview was given at the end of the study to probe the motivators and barriers to home use. SETTING: Training for use of the FES system was performed in an inpatient pediatric rehabilitation setting. Data collection began after the subjects were discharged to home. PARTICIPANTS: Five adolescents with complete, thoracic-level SCI. INTERVENTION: Subjects participated in a program of FES exercise followed by training in basic mobility skills such as standing transfers, maneuvering, level ambulation, one-handed and reaching activities, and stair ascent/descent. MAIN OUTCOME MEASURE: The frequency with which the FES system was used at home and the activities for which it was utilized were documented. Motivators and barriers to FES home use were examined. RESULTS: Subjects donned the FES system on the average once every 3 to 4 days. Between 51% and 84% of the times donned, the system was used for exercise. The remaining times it was used for standing activities, most commonly reaching, one-handed tasks, and standing for exercise. "Motivators" included being able to do things that would otherwise be difficult, perceiving a healthful benefit or a sense of well-being from standing and exercise, and feeling an obligation to stand as a participant in a research study. "Barriers" to FES use included not finding time to use the system, having difficulty seeing opportunities to stand, and being reluctant to wear the FES system all day.

IPCS harmonization of methods for the prediction and quantification of human carcinogenic/mutagenic hazard, and for indicating the probable mechanism of action of carcinogens.

A flow chart is presented as a recommended sequence of tests to predict the carcinogenic hazard, and to predict and quantify the mutagenic hazard to germ cells of chemicals to humans. Ten associated principles of testing for these endpoints are also suggested. These recommendations are the result of a meeting convened under the auspices of the International Programme on Chemical Safety (IPCS), as part of their project on 'Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals'. The meeting was held at Carshalton, Surrey, from 13-17 February 1995.

Desensitization and resensitization to violence against women: effects of exposure to sexually violent films on judgments of domestic violence victims.

An experiment was conducted to examine the effects of repeated exposure to sexually violent films on emotional desensitization and callousness toward domestic abuse victims. Results indicated that emotional response, self-reported physiological arousal, and ratings of the extent to which the films were sexually violent all diminished with repeated film exposure. Three days following exposure to the final film, experimental participants expressed significantly less sympathy for domestic violence victims, and rated their injuries as less severe, than did a no-exposure comparison group. Five days after the final film exposure, their level of sensitivity to the domestic violence victims had rebounded to baseline levels established by the comparison group. Emotional responsiveness at the final film exposure was correlated with levels of sensitivity to the domestic violence victims 3 days later but not at subsequent observation points.

Identification of sensilla involved in taste mediation in adult western corn rootworm (Diabrotica virgifera virgifera LeConte).

A group of sensilla present on the maxillary galea of adult western corn rootworm,Diabrotica virgifera virgifera LeConte (Coleoptera: Chrysomelidae) beetles has been identified morphologically and physiologically to be involved in taste mediation. There are approximately 15 chemosensory hairs on each galea. Bilateral removal of these structures resulted in a significantly reduced consumption of a strongly phagostimulant triterpenoid, cucurbitacin B, and led to increased ingestion of a phagodeterrent alkaloid, strychnine. Electrophysiological responses obtained via tip-recording of galeal chemosensilla with submillimolar concentrations of host and nonhost plant compounds resulted in dose responses overlapping with the effective behavioral ranges. Cucurbitacin B was found to evoke chemosensory responses at levels as low as 0.1µM. Sinceγ-aminobutyric acid (GABA) is an agonist. (-)-ß-hydrastine and strychnine are antagonists, and cucurbitacin B has been proposed to act at a separate modulatory site of classical synaptic GABA and glycine receptor-channel complexes, results reported here raise the possibility that there are peripheral chemosensory receptor sites that may resemble, functionally and structurally, synaptic receptor sites in the central nervous system.

Distribution and antifeedant associations of sesquiterpene lactones in cultivated sunflower (Helianthus annuus L.) on western corn rootworm (Diabrotica virgifera virgifera LeConte).

Seven antifeedant sesquiterpene lactones (STLs), 4,5-dihydroniveusin A, argophyllin B, argophyllin A, 15-hydroxy-3-dehydrodesoxytifruticin, niveusin B, 1,2-anhydridoniveusin A, and an unidentified epoxide, in cultivated sunflower (Helianthus annuus L.) have been quantified by a highperformance thin-layer chromatography and UV-reflectance scanning densitometry analysis. Age-related expression of STL content in sunflower reveals a heretofore undescribed pattern in which nonpolar STLs such as 15-hydroxy-3-dehydrodesoxytifruticin predominate up to an age of three weeks, but are subsequently displaced by polar STLs, especially argophyllin A, through later foliar stages and anthesis. This leaf pattern of STL ontogeny is maintained in three widely differentH. annuus cultivars (Giant Gray Stripe, Royal Hybrid 2141, Hybrid 7111), which in turn had similar total contents of STLs. Antifeedant activity for western corn rootworm was positively correlated with STL content, particularly with argophyllin A and its isomer argophyllin B, in respective tissue extracts. Enhanced amounts of highly antifeedant argophyllins, especially in newly grown leaf and floral tissues yielding sunflower progeny, strongly suggest that these epoxy-STLs are a chemical defense against insect herbivory.

Oocyte production and ovarian steroid concentrations of immature rats in response to some commercial gonadotrophin preparations.

Four commercial gonadotrophin preparations, namely Folligon, F.S.H.-P., Folltropin and Ovagen, were examined for their effects on oocyte production and ovarian steroid concentrations in immature rats. The ratios of the FSH to LH concentrations of the preparations, determined by radioreceptor assays, were Folligon 5, F.S.H.-P. 18, Folltropin 49 and Ovagen 1090. Forty-eight hours after administering each gonadotrophin preparation to immature rats, ovulation was induced by injection of chorionic gonadotrophin. Twenty-four hours later, oocytes were recovered from the oviducts and counted. Oocytes were produced after injection of chorionic gonadotrophin following a single injection of Folligon (10-50 i.u.). However, no oocytes were produced in response to the other gonadotrophin preparations unless they were administered by continuous infusion (30-1000 micrograms day-1). When given by injection (Folligon) or infusion (others), the gonadotrophin preparations all promoted a dose-dependent increase in mean oocyte production, except at the highest doses when mean oocyte numbers either remained unchanged or declined significantly in the cases of Folligon and F.S.H.-P. The highest mean numbers of oocytes produced in response to Folltropin (48 +/- 9 oocytes, mean +/- s.e.m.) and Ovagen (47 +/- 7) were greater than those attained with Folligon (21 +/- 6) or F.S.H.-P. (31 +/- 5). Mean ovarian weights also increased in a dose-dependent fashion in response to each of the gonadotrophin preparations. Measurements of ovarian steroid concentrations 48 h after the onset of gonadotrophin treatment (i.e. immediately prior to ovulation induction with chorionic gonadotrophin) showed that the gonadotrophin preparations markedly influenced the ratios of ovarian oestradiol-17 beta and androgen (androstenedione plus testosterone) concentrations. At low doses the gonadotrophin preparations increased the ratio of oestradiol-17 beta to androgens, but at the highest doses, with the exception of Ovagen, the ratio was reduced relative to peak values. Co-infusion of ovine LH (NIADDK-oLH-25; 10-20 micrograms day-1) with Ovagen (250 micrograms day-1) or ovine FSH (10 micrograms day-1, NIADDK-oFSH-17), both low in LH content, increased the mean number of oocytes produced and also the ovarian oestradiol-17 beta:androgen concentration ratio. However, with 40 micrograms LH day-1, the oestradiol-17 beta:androgen ratio fell due to a continued increase in mean ovarian androgen concentrations and a decrease in mean ovarian oestradiol-17 beta concentration. The mean number of oocytes produced also fell significantly.(ABSTRACT TRUNCATED AT 400 WORDS)

Problems in assessing the risks of mixtures of contaminants in drinking water.

In conducting risk assessments on drinking water contaminants, the U.S. Environmental Protection Agency (EPA) attempts to evaluate all available toxicity data to develop Health Advisory (HA) and Maximum Contaminant Level Goal (MCLG) values. The EPA often has grappled with the issues surrounding the toxicity of chemical mixtures, including radioactive contaminants, nitrate/nitrite, and trihalomethanes (THMs). In evaluating the toxicity of chemical mixtures, the EPA's immediate concern is whether the individual HA values and MCLGs are protecting public health when multiple contaminants are present in drinking water. Potential toxic interactions between drinking water contaminants are difficult to predict because experimental studies are generally performed only at high doses relative to environmental levels. Although the contamination of drinking water involves mixtures of contaminants, drinking water regulations are generally based on an assessment of the risks of individual contaminants. This paper discusses three issues of major concern to the EPA: the synergistic effects of solvent mixtures, vehicle effects in laboratory studies, and setting standards for essential trace nutrients where the absorption and/or toxicity are affected by an individual's nutritional status or other dietary components.

Metallothionein gene expression in mouse tissues by D-penicillamine.

The effect of D-penicillamine on metallothionein mRNA accumulation was examined in mouse tissues by Northern and dot blot analysis. This drug was given as a single intraperitoneal dose of 250 mg/kg body weight and the metallothionein mRNA content of the tissues was measured 1, 4, 8 and 24 hours later. A detectable increase of mRNA was observed after 1 hour and maximal accumulation was seen after 4 hours in the liver, kidneys, lungs, brain and spleen, whereas in the heart the maximum occurred after 8 hours. In the liver metallothionein mRNA was increased 14.5-fold over the control and in the kidneys it was increased by a factor of 9.2. A significant increase was also seen in the lungs, where it was 10 fold. To determine whether the increase is due to new transcription of the metallothionein gene, animals were pretreated with actinomycin D (1.0 mg/kg body weight) before receiving D-penicillamine. Actinomycin D prevented some of the D-penicillamine-induced increase in metallothionein mRNA, indicating that the drug, to some extent, acts at the transcriptional level. Regulation of metallothionein gene expression may play an important role in the molecular mechanisms involved in the clinical action of D-penicillamine in rheumatoid arthritis.

Adaptive relationships of epoxide hydrolase in herbivorous arthropods.

Epoxide hydrolase catalyzes a simple hydrolysis of reactive cyclic ethers that may otherwise alkylate and impair critical proteins and nucleic acids required for life. Although much less studied than the cytochrome P-450 monooxygenases that produce epoxides, differences in subcellular, tissue, pH, substrate, and inhibitor specificities argue for at least three forms of insect epoxide hydrolase. Increasing numbers of epoxides are being identified as plant allelochemicals, antifeedants, and essential hormones or precursors for herbivorous arthropods, and in many cases an associated alkene to diol pathway of metabolism is found. A role for epoxide hydrolase in arthropod-plant interactions is strongly supported by species comparisons and by age-activity and induction studies. Two major limitations for study in biochemical ecology of epoxide hydrolase are the lack of an effective in vivo inhibitor and a range of commercially available radiolabeled substrates for the enzymes.