OPTIMAL DISCRIMINANT ANALYSIS FOR ORDINAL RESPONSES

Optimal classification formulation is adapted to the context of discrimination when the response is ordinal. The resulting method, optimal discriminant analysis for ordinal responses (ODAO), is presented and compared with two reference discrimination techniques used in this context (proportional-odds ordinal logistic regression and normal discrimination) using a study of prognosis following burn injuries and simulated data. The ODAO method clearly outperforms both reference methods in terms of classification accuracy (in training and validation samples), robustness to outliers, simplicity of use and applicability in clinical settings. ODAO is a promising method for improving classification performance in discrimination with ordinal responses and merits further investigation. © 1997 by John Wiley & Sons, Ltd.     

4,4'-Methylene-bis(2-chloroaniline) (MOCA): Comparison of Macromolecular Adduct Formation after Oral or Dermal Administration in the Rat

4,4'-Methylene-bis(2-chloroaniline) (MOCA): Comparison of MacromolecularAdduct Formation after Oral or Dermal Administration in theRat. CHEEVER, K. L., RICHARDS, D. E., WEIGEL, W. W., BEGLEY,K. B., DEBORD, D. G., SWEARENGIN, T. F., AND SAVAGE, R. E. JR.(1990). Fundam. Appl. Toxicol. 14, 273–283. The macromolecularbinding of 4,4'-methylene-bis(2-chloroaniline) (MOCA), a suspecthuman carcinogen, was studied in the adult male Sprague-Dawleyrat after both oral and dermal administration. Rats were euthanized1, 3, 7, 10, 14, and 29 days after a single 281 µmol/kgbody wt dose of [¹⁴C]MOCA (oral, 213 µCi/kg; dermal, 904µCi/kg). DNA from various tissues and hemoglobin wereisolated for determination of the time course of MOCA macromolecularbinding. After oral administration adduct formation was rapidwith maximum levels appearing at 24 hr. The 24-hr covalent bindingassociated with the globin was 7.84 pmol/mgglobin (t? = 14.3days). More extensive 24-hr covalent binding was detected forliver DNA with 49.11 pmol/mg DNA (t? = 11.1 days). After dermaladministration of MOCA the major portion of the dose, 86.2%,remained at the application site throughout the study. For theserats the 24-hr covalent binding determined for liver DNA was0.38 pmol/mg DNA (t? = 15.6 days). Although lower levels weredetected after dermal application, similar stability of MOCA-DNAadducts indicates that quantification of such MOCA adducls maybe useful for the long-term industrial biomonitoring of MOCAexposure and for the evaluation of human DNA-MOCA adduct formation,a lesion thought to be associated with the production of cancer.     

Nonclinical Toxicology Studies with Zidovudine: Genetic Toxicity Tests and Carcinogenicity Bioassays in Mice and Rats

Zidovudine (ZDV), an antiviral drug active in the treatmentof acquired immunodeficiency syndrome (recommended human dose,100 mg every 4 hr while awake), was evaluated for mutagenicand carcinogenic potential in a battery of short-term in vitroand in vivo assays and in lifetime studies in mice and rats.In L5178Y mouse lymphoma cells (tk^+/– locus), a weak positiveresult was obtained only at the highest concentrations tested(4000 to 5000 µg/ml) in the absence of metabolic activation.In the presence of metabolic activation, the drug was weaklymutagenic at concentrations of 1000 µg/ml and higher.Following 24 hr treatment in the absence of metabolic activation,ZDV was moderately mutagenic at concentrations up to 600 µg/ml;dose-related structural chromosomal alterations were seen atconcentrations of 3 µg/ml and higher in cultured humanlymphocytes. Such effects were not noted at the two lowest concentrationstested, 0.3 and 1 µg/ml, and BALB/c-3T3 cells were transformedat concentrations of 0.5 µg/ml and higher. No effectswere seen in the Ames Salmonella plate incorporation and preincubationmodification assays (possibly due to bacteriocidal activityof ZDV at low concentrations) at concentrations ranging from0.01 to 10 µg/plate or in a single-dose intravenous bonemarrow cytogenetic assay in CD rats. In multidose micronucleusstudies, increases in micronucleated erythrocytes were seenin mice at doses of 100 to 1000 mg/kg/day. Similar results wereseen in rats and mice after 4 or 7 days of dosing at 500 mg/kg/day.In carcinogenicity bioassays, adjusted doses of 20, 30, or 40mg/kg/day and 80, 220, and 300 mg/kg/day were given to CD-1mice and CD rats, respectively, for up to 22 months in miceand 24 months in rats. ZDV caused a macrocytic, normochromicanemia in both species. No evidence of carcinogenicity was seenin male mice or rats. In female mice, five malignant and twobenign vaginal epithelial neoplasms occurred in animals given40 mg/kg/day. A single benign vaginal epithelial tumor was seenin a mouse given 30 mg/kg/day. In rats, two malignant vaginalepithelial neoplasms were seen in animals given 300 mg/kg/day.In a 7-day study in mice, ZDV was shown to be devoid of estrogenicactivity. In an oral pharmacokinetics study, the AUC was 17and 144 µg/ml hr in female mice and rats given 40 or 300mg/kg of ZDV, respectively. In contrast, the average steady-stateconcentration in humans at the recommended daily dose is 0.62µg/ml. Twenty-four hour urine concentrations were 1245and 4417 µg/ml in female mice and rats given 40 or 300mg/kg of ZDV, respectively. These values were approximately26-and 136-fold higher than the human urine concentration atthe recommended daily dose. In a one- to three-day study withintravenously administered sodium fluoroscein in rats and mice,retrograde flow of urine into the vagina was demonstrated. Ina subsequent lifetime carcinogenicity bioassay in mice in whichZDV was given intravaginally at concentrations of 5 or 20 mgZDV/ml in saline, 13 vaginal squamous cell carcinomas were seenat the highest concentration tested. It was concluded that thevaginal tumors seen in the oral carcinogenicity studies werethe result of chronic local exposure of the vaginal epitheliumto high urine concentrations of ZDV.     

Comparison of nutrition knowledge among health professionals,patients with eating disorders and the general population

Aim: To investigate and compare the level of nutrition knowledge of health professionals, patients with eating disorders and individuals without an eating disorder as controls. Methods: Participants were recruited online through an Australian and New Zealand professional eating disorder organisation and community eating disorder organisations and a university in Australia. Assessment was conducted online using the General Nutrition Knowledge Questionnaire and SCOFF. Demographic data were also collected. Results: Dietitians had greater nutrition knowledge than all other health professionals, except medical doctors. Psychologists and dietitians had similar knowledge for choosing everyday foods. Dietitians had greater nutrition knowledge than eating disorder patients and controls in all areas of nutrition knowledge, while other health professionals had similar knowledge to patients. Patients with eating disorders had greater knowledge of sources of nutrients than controls. Conclusions: Australian health professionals exhibited higher levels of nutrition knowledge than health professionals in previous studies in other countries. However, non‐dietitian health professionals had similar levels of knowledge to individuals with eating disorders. Training and continuing education in nutrition is needed so health professionals can confidently identify when a patient has misleading information about nutrition and either correct the misinformation or refer the patient on to a qualified dietitian.     

ANTINOCICEPTIVE EFFECTS OF THE HYDROPHILIC α2-ADRENOCEPTOR AGONIST ST-91 IN DIFFERENT TEST CIRCUMSTANCES AFTER INTRATHECAL ADMINISTRATION TO WISTAR RATS

The antinociceptive and motor effects of the hydrophilic α₂-adrenoceptor agonist ST-91 were studied after intrathecal administration to male Wistar rats in different heat–pain tests and different test settings. Intrathecal administration of ST-91 caused a dose-dependent increase in hind paw licking latency in the hot-plate test, while in contrast with morphine it had a much lower efficacy in the tail-flick test in freely moving conditions. Sprague–Dawley rats gave similar results to those for Wistar rats in this setting. However, when the tail-flick test was performed under chronic restraint conditions (after a 1-h restraining period), the compound caused a significant antinociception. No signs of motor impairment and no changes in electromyographic activity were detected after ST-91 administration. The results indicate a characteristic analgesic profile for ST-91. In the interpretation of ST-91 data, consideration should be paid both to test model differences and to test conditions.     

Preclinical Toxicology Studies with Acyclovir: Teratologic, Reproductive and Neonatal Tests

Preclinical Toxicology Studies with Acyclovin Teratologic, Reproductiveand Neonatal Tests. Moore, H.L., Jr., Szczech, G.M., Rodwell,D.E., Kapp, R.W., Jr., de Miranda, P. and Tucker, W.E., Jr.(1983).Fundam. Appl Toxicol 3:560–568. Five studies weredone to define the potential of Acyclovir (ACV), a new nucleosideanalog for antiviral chemotherapy, to produce adverse effectson reproduction and development in laboratory animals. ACV producedno adverse effects when given by gavage to F₀ generation miceat 50, 150 and 450 mg/kg/day in a two generation reproduction/fertilitystudy. Some mice were evaluated for teratologic effects andothers for postnatal development, including behavior, with negativeresults. ACV was not embryotoxic and did not increase the incidenceof fetal malformations when given by subcutaneous injectionto pregnant rats and rabbits at dose levels of 12, 25 and 50mg/kg/day during the periods of major organogenesis. A comparativeLD₅₀ study revealed that 3-day-old rats were not more sensitiveto acute toxic effects of ACV than more mature rats. Finally,in a comprehensive multidose toxicity study ACV was given subcutaneouslyto neonatal rats at 5, 20 and 80 mg/kg/day for 19 consecutivedays. There was minimal effect on body weight gain in neonatestreated at 20 mg/kg/day and a significant decrease in body weightgain at 80 mg/kg/day. Minimal renal lesions occurred at 80 mg/kg/ day but no other signs of adverse effects on developingorgan systems were observed. Except for decreased body weightgain in neonatal rats treated at 80 mg/kg/day, ACV did not produceadverse effects on mammalian development when tested in a varietyof preclinical toxicology studies.