Responses of dogs with food allergies to single-ingredient dietary provocation

OBJECTIVE: To characterize specific food ingredients causing allergic reactions in dogs and to assess cross-reactivity between proteins derived from a single animal source or from different plant products. DESIGN: Prospective study. ANIMALS: 25 dogs with histories and cutaneous signs consistent with food-allergic dermatitis. PROCEDURE: Dogs were fed a food-elimination diet until resolution of clinical signs and then challenged with their original diet. A diagnosis of food allergy was made if there was complete return of pruritus within 14 days of challenge exposure. After diagnosis, dogs were fed the food-elimination diet until signs related to dietary challenge abated. The dogs then were fed beef, chicken, chicken eggs, cows' milk, wheat, soy, and corn in single-ingredient provocation trials for 1 week. Any cutaneous reactions to these food ingredients were recorded by their owners. RESULTS: Beef and soy most often caused adverse cutaneous reactions, although all ingredients induced clinical signs in at least 1 dog. Mean number of allergens per dog was 2.4, with 80% reacting to 1 or 2 proteins and 64% reacting to 2 or more of the proteins tested. A significant difference was found between dogs reacting to beef versus cows' milk and between dogs reacting to soy versus wheat; thus, the hypothesis of cross-reactivity to ingredients derived from a single animal source or to different plant products was not supported. Similar differences between chicken meat and eggs were not identified. CLINICAL IMPLICATIONS: Long-term management of dogs with food allergies is facilitated by identification of the most commonly encountered food allergens. Because cross-reactivity cannot be verified, each protein source should be included separately in food-provocation trials.     

Phase I study of a five-day dose schedule of 4-Ipomeanol in patients with non-small cell lung cancer

The mammalian pulmonary toxin 4-ipomeanol (IPO) is activated by the cytochrome P450 system in bronchial Clara cells in animals. The resulting metabolites bind rapidly to macromolecules, producing localized cytotoxicity. IPO has in vitro and in vivo antitumor activity in non-small cell lung cancer (NSCLC) and thus was proposed as a lung cancer-specific antitumor agent. We have completed a directed Phase I trial in patients with NSCLC. Forty-four patients (34 men and 10 women) with NSCLC were treated with IPO. All but two patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. They received 91 courses of therapy with i.v. IPO; 82 courses were administered daily for five days, and 9 were single bolus doses. The dose-limiting toxicity of elevated serum transaminases was observed in three of seven patients at 922 mg/m2/day. The maximum tolerated dose was 693 mg/m2/day on 5 consecutive days every 3 weeks. One patient developed grade 4 pulmonary toxicity at 167 mg/m2/day. There was no significant hematological or renal toxicity. No objective antitumor responses were observed. Pharmacokinetic analysis of 39 patients from day 1 of IPO administration showed biexponential elimination with mean half-lives of 8.6 (alpha half-life) and 76 min (beta half-life). There was a linear relationship between the area under the plasma drug concentration-time curve and the dose of IPO. There was no significant difference between the pharmacokinetic parameters measured on day 1 and day 5. Using a 4-day in vitro cytotoxicity assay, two tumor cell lines established from patients treated at 693 mg/m2/day had IC50s of approximately 6 mM, a concentration more than 75-fold higher than the plasma levels measured in these patients. Thus, although the total amount of drug administered per cycle on a daily times five dose schedule is more than 2.5-fold higher than the recommended single daily dose, IPO is unlikely to be a useful drug for patients with lung cancer.     

A parametric confidence interval for a moment-based scaled criterion for individual bioequivalence

Confidence intervals of proposed individual bioequivalence metrics are difficult to determine in closed form because their stochastic distributions are unknown. In this article, it is shown that, with slightly modified weights, the Relative Individual Risks (RIR) moment-based scaled statistic for individual bioequivalence that was presented by Schall and Williams has an exact noncentral Fisher's F distribution with noncentrality parameter give by a scaled squared difference in formulations means. This can be approximated by a central F with adjusted degrees of freedom from which it follows that an upper (1-alpha) confidence bound for RIR is given by [formula: see text] where [formula: see text] is the least square estimate of RIR; dfER is the degrees of freedom associated with the reference intrasubject variance estimate, v is the subject-by-formulation degrees of freedom adjusted for noncentrality and alpha is the significance level. Individual bioequivalence is concluded if UL does not exceed the regulatory limit. The performance of this confidence interval was investigated by comparing its experimental bioequivalence rate to that of the unweighted metric under known parameter situations through simulations of two formulations in a fully replicated study design. Results showed that the proposed metric is slightly less biased and more precise than the unweighted metric.     

Inhibition of hypoxic pulmonary vasoconstriction by dipyridamole is not platelet mediated

Dipyridamole, which is known to alter platelet function, has also been shown to reduce hypoxic pulmonary vasoconstriction. This latter effect could result from dipyridamole either acting on a platelet-mediated system, or acting directly on pulmonary vascular smooth muscle. To investigate these two possibilities, normal dogs were compared with dogs rendered thrombocytopenic by a platelet antiserum. Compared with the hypoxic pressor response before drug treatment, the hypoxic response following dipyridamole was only 32% as great in the normal dogs and only 38% as great in the thrombocytopenic dogs. Thus, dipyridamole was no less effective in reducing the hypoxic pressor response in the virtual absence of platelets. This supports a direct effect of dipyridamole on pulmonary vascular smooth muscle, which could be mediated by an increase in adenosine levels.     

Overexpression of cyclin D1 and cdk4 in tumorigenesis of sporadic hepatoblastomas

We have shown previously that normal B cells share, with Epstein-Barr virus-transformed and malignant B cells, the ability to activate the alternative pathway (AP) of complement in vitro, resulting in the deposition of C3 fragments on the cell surface. Complement receptor type 2 (CR2, CD21) has been implicated directly as the site for formation of an AP convertase, which provides nascent C3b for deposition at secondary sites on the B-cell surface. In the present study, we have examined C3 fragment deposition in vitro in more detail by (1) assessing the importance of locally generated C3b for the deposition process, (2) investigating whether CR2 is the sole requirement for conferring AP activation capacity on a cell, and (3) determining whether CR2's function, as an AP activator, has different structural requirements from ligand binding. Increasing the availability of native C3, by increasing the serum (NHS) concentration, resulted in enhanced C3 fragment deposition on the B cells, whereas use of factor 1-depleted NHS, which showed massive fluid phase C3 conversion during the incubation, diminished the deposition. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting of untreated and hydroxylamine-treated lysates from B cells, after in vitro activation, revealed that the majority of C3 fragments (primarily iC3b and C3dg) had been covalently bound to the cell surface. Transfection of COS cells with wild-type CR2 or a deletion mutant lacking 11 of the molecule's 15 homologous domains, but retaining the ligand-binding site, revealed that expression of intact CR2 conferred a 12-fold increase in AP-activating capacity on these cells, while no increase in AP activity was apparent on cells transfected with the mutant CR2.     

Telephone administration of the SF-36 health survey: validation studies and population norms for adults in Queensland

The Rand Corporation medical outcomes short-form 36 health survey (SF-36) is a multidimensional measure of self-perceived general health status, which has been validated in adult populations in the United States and Great Britain, and, more recently, in an Australian population. The SF-36 is increasingly being used in health outcomes research internationally, mainly as a self-administered tool, and clearly has potential for use in Australia. This study aimed to assess the acceptability, reliability and validity of telephone administration of the instrument in the Queensland adult population, and to provide reliable population norms. We report the results of a telephone survey in which we interviewed 12,793 adults. It was the first large-scale, statewide application of the SF-36 in Australia. A response rate of 82 per cent was achieved, and the SF-36 satisfied psychometric criteria for reliability and construct validity. Population norms broken down by age and sex are provided. They will be important for the interpretation of future studies using the SF-36 in particular population or patient groups.