Aberrant p53 expression in feline vaccine-associated sarcomas and correlation with prognosis.

Eighty spontaneously occurring feline vaccine-associated sarcomas (VAS) were evaluated to determine the immunohistochemical expression of the tumor suppressor gene p53. Sixty-five of 80 VAS (81%) exhibited positive immunoreactivity with Mab240, a murine monoclonal antibody that specifically recognizes mutated p53. Only 44 of 81 tumors (55%) were positive with rabbit polyclonal antibody CM-1. CM-1 often yielded nonspecific staining of nonneoplastic tissues. Nonspecific staining was greatly reduced or absent with Mab240. Cytoplasmic staining for p53 was a consistent pattern of VAS, occurring in 44% of tumors evaluated. Cats with tumors that exhibited cytoplasmic p53 had significantly shorter time to tumor recurrence compared to those cats with tumors that exhibited nuclear p53 staining (P = 0.0284), but no significant difference in survival outcome was observed. Immunohistochemical detection of p53 offers a prognostic tool for VAS, and, because abnormal p53 expression appears to be a common feature of feline VAS, molecular targeting of mutant p53, may offer a promising new therapeutic opportunity for this cancer.

Efficacy and toxicity of paclitaxel (Taxol) for the treatment of canine malignant tumors.

Paclitaxel (Taxol) was administered to 25 dogs with histologically confirmed malignant tumors at a dosage of 165 mg/m2 i.v. over 3-6 hours every 3 weeks. Dogs received premedication with antihistimines and corticosteroids to reduce hypersensitivity reactions. However, 64% of the dogs still experienced allergic reactions. Six dogs (24%) had grade 3 or 4 neutropenia, 6 dogs (24%) required hospitalization and 3 dogs (12%) died of sepsis. Five dogs (20%) had a partial response (osteosarcoma [2 dogs] mammary carcinoma [2 dogs] and malignant histiocytosis [1 dog]) for a median duration of 53 days. The overall toxicity was unacceptable at the 165 mg/m2 dose. Therefore, subsequent evaluations of paclitaxel in tumor-bearing dogs should a starting dose of 132 mg/m2 i.v. every 3 weeks.

Control of nitrogen export from watersheds by headwater streams.

A comparative (15)N-tracer study of nitrogen dynamics in headwater streams from biomes throughout North America demonstrates that streams exert control over nutrient exports to rivers, lakes, and estuaries. The most rapid uptake and transformation of inorganic nitrogen occurred in the smallest streams. Ammonium entering these streams was removed from the water within a few tens to hundreds of meters. Nitrate was also removed from stream water but traveled a distance 5 to 10 times as long, on average, as ammonium. Despite low ammonium concentration in stream water, nitrification rates were high, indicating that small streams are potentially important sources of atmospheric nitrous oxide. During seasons of high biological activity, the reaches of headwater streams typically export downstream less than half of the input of dissolved inorganic nitrogen from their watersheds.

Prognosis for presumed feline vaccine-associated sarcoma after excision: 61 cases (1986-1996).

OBJECTIVE: To evaluate time to first recurrence (TFR) and overall survival in cats with presumed vaccine-associated sarcomas (VAS) treated with excision. DESIGN: Retrospective study. ANIMALS: 61 cats with presumed VAS. PROCEDURE: Medical records of cats that received excision as the only initial treatment for presumed VAS were reviewed to evaluate prognosis. Overall survival curves and TFR were determined. RESULTS: Median TFR was 94 days. Median TFR for tumors treated with excision performed at a referral institution (274 days) was significantly longer than that for tumors excised by a referring veterinarian (66 days). Radical first excision yielded significantly longer median TFR (325 days) than did marginal first excision (79 days). Cats with tumors located on the limbs had longer median TFR (325 days) than cats with tumors located in other sites (66 days). Median overall survival time was 576 days. Significant differences in survival times between groups were not detected. Few cats (13.8%) receiving only surgical treatment had long-term (> 2 years) survival. CONCLUSIONS AND CLINICAL RELEVANCE: Radical first excision of presumed VAS is essential for extended TFR. Current recommendations for vaccination of the distal portions of the extremities are appropriate, because this practice permits radical excision of tumors (amputation) that develop at vaccination sites; however, surgery alone is seldom curative.

Inhalation chemotherapy for macroscopic primary or metastatic lung tumors: proof of principle using dogs with spontaneously occurring tumors as a model.

This study represents part of an effort to determine the safety and efficacy of inhaled antineoplastic drugs, using pet dogs with spontaneously arising primary and metastatic lung cancers (including sarcoma, carcinoma, and malignant melanoma) as a model. Dogs received new formulations of either paclitaxel (PTX) or doxorubicin (DOX) by the inhalation route every 2 weeks using a specially designed aerosol device. Response was assessed radiographically using the indices of tumor nodule number and volume measurement of discrete pulmonary nodules. Dogs experiencing progressive disease after two consecutive treatments were crossed over to receive the alternate compound. In 24 dogs, 6 (25%) responses were noted including 5 partial responses (PR) and 1 complete response. These include 4 (22.2%) of 18 responses to DOX and 2 (13.3%) of 15 responses to PTX. Responses were noted with osteosarcoma (including three dogs with metastatic osteosarcoma that had failed prior systemic chemotherapy), liposarcoma, hemangiosarcoma, and undifferentiated sarcoma. One dog with mammary carcinoma experienced a 47% reduction in volume after PTX inhalation, just shy of PR criteria. One dog with liposarcoma is experiencing a long-term (>12 months) stabilization of disease on PTX. To date, no systemic toxicities have been observed with either PTX or DOX inhalations. Local (pulmonary) toxicity was not observed with PTX; however, changes consistent with pneumonitis/fibrosis were observed in some dogs receiving DOX. Only one of these dogs showed clinical signs, which were responsive to steroid and antitussive therapy. These data represent "proof of principle" for the avoidance of systemic toxicity while delivering efficacious local drug levels by the inhalation route.

Responses of barrel cortex neurons in awake rats and effects of urethane anesthesia.

A "barrel" is an interconnected network of layer IV neurons that is an important component of a functional cortical column in the whisker area of the rodent primary somatosensory cortex. The present study was undertaken in order to resolve apparently conflicting findings from single-unit studies of barrel neurons conducted in rats maintained under different anesthetic conditions. Multiunit responses to controlled deflections of mystacial vibrissae were recorded from the whisker/barrel cortex of awake, undrugged rats, and responses at the same recording site were reexamined after the animal was anesthetized with urethane. In contrast to the awake condition, stimulus-evoked responses under urethane were characterized by a large late component. Such effects were more pronounced for deflections of noncolumnar or "adjacent" whiskers than for the columnar whisker. Latencies to peak responses were virtually identical for the columnar whisker in awake and urethane states (11.9 vs 11.8 ms) but were considerably longer for adjacent whisker deflections in urethane-anesthetized animals (15.5 vs 29.0 ms). The magnitudes of adjacent whisker responses, relative to the response evoked by the columnar whisker, varied with the laminar location of the recording site in awake but not in urethane-anesthetized animals; in awake rats, receptive fields were clearly smallest in the layer IV barrels. Results in the awake condition confirm those of previous studies conducted in unanesthetized or lightly sedated animals, and data obtained with urethane are comparable to others' results in urethane-anesthetized rats. The former have important implications for how barrel cortex processes information in behaving animals.

Tubes and foraging behavior in larval Chironomidae: implications for predator avoidance.

In laboratory experiments, I studied differential susceptibility of four co-occurring species of chironomids to a predatory damselfly. The chironomids differed in foraging behavior and could be ranked according to the amount of time they spent outside of their tubes. In choice experiments, the predator consistently selected the prey which spent more time out of the tube, and time out of tube was a significant predictor of the predation rate coefficient. Electivity indices, calculated from field samples and diet analyses of the predator, supported the laboratory results. The data suggest that exposure to predators in a heterogeneous prey community is largely determined by tubedwelling behavior.

Transformation of a tundra river from heterotrophy to autotrophy by addition of phosphorus.

Continuous enrichment of an arctic river with only 10 parts per billion phosphate-phosphorus caused an immediate growth of attached algae for more than 10 kilometers downstream, showing that phosphorus alone limited photosynthesis. As a result of the increased photosynthesis, there was an increase in bacterial activity in films on rocks on the bottom of the stream. The major source of energy became the photosynthetic carbon fixed in the stream rather than the organic material entering from the surrounding tundra, and the overall metabolism of the stream shifted from heterotrophy to autotrophy. An increase in the size and developmental stage of some of the dominant aquatic insects illustrates the food limitation in this nutrient-poor habitat.

Integrated method for the gas chromatographic determination of antiepileptic drugs in human plasma.

The principles of three independent extraction methods were utilized to develop an integrated extraction scheme for use in routine therapeutic monitoring of seven antiepileptic agents. The final method, in which the three extraction methods were interfaced, permitted routine monitoring in a single 1 ml volume of human plasma of any one or combination of the following drugs: phenytoin (PHT), phenobarbital (PB), primidone (PD), 5-ethyl-5-phenylhydantoin (EPH), ethosuximide (ES), carbamazepine (CBZ), and valproic acid (VPA). An on-column methylation technique was used for simultaneous determination of PHT, PB, PD, EPH, and ES. CBZ and VPA were determined by independent methods as the underivatized compounds. Six appropriate internal standards were employed in the integrated method for quantitation of the drugs.

Gas chromatographic method for the determination of valproic acid in human plasma.

A gas chromatographic method has been developed for the routine monitoring of valproic acid (VPA) in human plasma samples. Two compounds, 2-ethylpentanoic acid (EPA) and 2-propylhexanoic acid (PHA), were synthesized and evaluated as internal standards together with cyclohexane carboxylic acid (CHCA), a commonly employed internal standard. Crystalline barium salts of VPA, EPA, and PHA were prepared, which enabled preparation of standard solutions of high accuracy for use in calibration experiments and in daily intra-laboratory quality control tests. The extraction scheme was designed on the basis of the solvent partitioning properties of VPA. Solvent transfers are required in the extraction scheme, but solvent evaporations are not. Studies were made of the performances of EPA, PHA, and CHCA as internal standards in the VPA assay at different lifetimes of the 10% SP-1000 chromatography column. As judged by these studies, EPA or CHCA is a better choice than PHA as an internal standard, provided that certain guidelines are followed in the use of CHCA.

Effects of dorsomedial thalamic lesions on spatial discrimination reversal in the rat.

Eight rats with lesions of the dorsomedial thalamus and 10 rats with sham operations were compared on acquisition and subsequent reversals of a spatial discrimination. The rats with thalamic damage showed greater perseveration to the incorrect choices (p less than 0.002) and made fewer reversals (p less than 0.05) and more errors (p less than 0.02) during the 100 reversal trials following initial acquisition than did the sham-operated animals. The two groups did not differ on the original acquisition.