Clinical activities during a clerkship rotation in emergency medicine.

Clinical log books were completed by the 1995-1996 clinical clerks at Queen's University, Kingston, Ontario, Canada, during their 2-wk rotation in emergency medicine. To determine the clinical activities of the students and assess the educational effectiveness of our clerkship program, the information recorded in these log books was compared with the results of a survey of the emergency department (ED) staff physicians. This survey asked the physicians to identify five essential clinical presentations and procedural skills that they felt the clerks must observe during their rotation in the ED. To our knowledge, this is the first Canadian report using log books as a quality assurance tool for a clerkship program in emergency medicine. This study has highlighted specific weaknesses in the clinical activities of the clerks and will serve as a valuable resource for future assessments of the emergency medicine rotation at our institution.

Alterations in expression of CYP1A1 and NADPH-cytochrome P450 reductase during lung tumor development in SWR/J mice.

We investigated the expression of the cytochrome P450 isozyme, CYP1A1, during the course of tumor development and examined the distribution of the CYP1A1 protein in hyperplastic foci, adenomas and carcinomas. The expression of NADPH-cytochrome P450 reductase, a flavoprotein that mediates the reduction of cytochrome P450, was also determined. Mice were administered urethane (1 mg/g body wt) and were killed at 10, 22 and 52 weeks to coincide with the time at which hyperplastic foci, adenomas and carcinomas were established, respectively. Protein immunoblotting revealed that the antibody for CYP1A1 detected a protein band of approximately M(r) 56,000 in microsomes from mice treated with beta-naphthoflavone. The antibody for NADPH-cytochrome P450 reductase detected a protein band of approximately M(r) 79,000 in microsomes from control mice and mice treated with beta-naphthoflavone. Immunohistochemical studies showed that CYP1A1 was not detected constitutively in the lungs of both non-tumor- and tumor-bearing mice. Treatment with beta-naphthoflavone evoked high induction of CYP1A1 in morphologically normal tissues of all mice, with localization of the protein mainly in endothelial and alveolar type II cells. In contrast, inducibility of CYP1A1 by beta-naphthoflavone was markedly reduced in early hyperplastic foci seen 10 weeks after urethane exposure. At 22 weeks, CYP1A1 was found at low levels in both solid and papillary tumors, whereas at 52 weeks, lung carcinomas were devoid of expression of this protein. However, CYP1A1 inducibility was highly expressed in late hyperplastic foci manifested at 52 weeks. NADPH-cytochrome P450 reductase was expressed in morphologically normal lung tissue of all mice under control conditions and after treatment with beta-naphthoflavone, and was localized mainly in Clara and alveolar type II cells. In contrast, reductase expression in all tumor sites was diminished and closely paralleled that of CYP1A1. These results demonstrated progressive depression of induced CYP1A1 and reductase expression in early hyperplasias, adenomas and carcinomas, suggesting that the co-ordinate regulation of both enzymes is highly conserved during tumor development. Furthermore, these findings suggested diminished capabilities for metabolic activation of potential toxicants and/or carcinogens after neoplastic transformation.

Mammographic screening of women with increased risk of breast cancer.

Five hundred one women from Dallas County, Texas who participated in the American Cancer Society 1987 Texas Breast Screening Project were selected because of a self-reported family history of breast cancer (cases). They were matched with 501 randomly selected women from the same county with no family history (controls). Although there was a statistically significant trend with age for an increasing proportion of women to report having undergone mammography, there was no significant difference when comparing mammographic histories of cases with controls after controlling for age (31.5% versus 35.1%, P = 0.33). Significantly more cases (79%) perceived their risk for breast cancer to be moderate or greater compared with controls (54%, P less than 0.0001), but mammographic histories were not different when controlling for perceived risk. Both cases and controls cited lack of physician referral and cost as their reasons for not having undergone mammography. Women at increased risk for breast cancer (because of their family history) are not undergoing regular mammographic screening despite their self-awareness of the increase in their risk.

Treatment of RAEB-t with intensive chemotherapy and GM-CSF.

A 55-yr old woman with refractory anaemia with excess of blasts in transformation developed prolonged bone marrow hypoplasia following two courses of mitozantrone and cytosine arabinoside. The administration of granulocyte-monocyte colony stimulating factor after two months of pancytopenia led to recovery of normal bone-marrow function, without any morphological evidence of myelodysplasia, which has persisted until the last blood count (6 months +).

The effect of alpha 2-adrenoceptor agonists on the acid secretory responses of rat isolated gastric mucosa to electrical field stimulation.

The effects of clonidine, UK-14,304, noradrenaline, para-aminoclonidine and phenylephrine were examined on the acid secretory response of the rat isolated gastric mucosa preparation to electrical field stimulation. Clonidine, UK-14,304, noradrenaline and para-aminoclonidine but not phenylephrine (10 microM) reduced the response of the gastric mucosa stimulated at 2.5 Hz; gastric mucosae stimulated at higher frequencies were insensitive to the action of these alpha 2-adrenoceptor agonists. The inhibitory effect of the selective alpha 2-adrenoceptor agonist UK-14,304 was antagonized by idazoxan but not by prazosin. These findings indicate that clonidine and other alpha 2-adrenoceptor agents inhibit the acid secretory response of the rat gastric mucosa to electrical field stimulation by an action at alpha 2-adrenoceptors, which are probably located on cholinergic nerve terminals.

Common anionic receptor site hypothesis: its relevance to the antagonist action of naloxone.

Appropriate modification of 14 beta-methoxy- and 14 beta-ethoxycodeinone (prepared by alkylation of 14 beta-hydroxycodeinone) has generated four alkoxy analogues (3a-d) of naloxone and naltrexone. These agents were pure narcotic antagonists in contradiction to the predictions of the common anionic receptor site hypothesis, postulated to be of importance in the enhanced antagonism of naloxone. The molecular change from allyl to cyclopropylmethyl on the N atom increased selectivity of these antagonists for the mu receptor to the same extent as found for naloxone. Increase in the length of the C14 O-substituent had no effect on receptor selectivity, and either formation in most cases did not significantly alter oral/parenteral ratios of durations of action.

Analogues of beta-LPH61-64 possessing selective agonist activity at mu-opiate receptors.

Peptides based in the stabilised tetrapeptide HTyr-D-Ala-Gly-MePheOH have been synthesised and shown to have substantial opioid activity both in vitro and in vivo. The selectivity of these compounds of different receptor populations has been investigated using both isolated tissue assays and binding studies. Results suggest that the compounds are potent agonists at mu-receptors with little or no affinity for the delta-receptor population. One of the compounds, RX783006 (HTyr-D-Ala-Gly-MePhe-NH(CH2)2OH), has been tritiated to high specific radioactivity and may prove to be a useful probe in the elucidation of the function of the heterogenous opiate receptor population.

Effects of changes in the structure of enkephalins and of narcotic analgesic drugs on their interactions with mu- and delta-receptors.

1 The activity pattern of analogues of the enkephalins was determined in four parallel assays, the inhibition of the electrically evoked contraction of the guinea-pig ileum and mouse vas deferens at 36 degrees C and the inhibition of [(3)H]-naltrexone and [(3)H]-leucine-enkephalin binding at 0 to 4 degrees C in homogenates of guinea-pig brain.2 The activity pattern was best characterized by the ratio of the potency in the guinea-pig ileum to that in the mouse vas deferens (G.p.i./M.v.d.) and the ratio of the potency in inhibiting [(3)H]-naltrexone binding to that in inhibiting [(3)H]-leucine-enkephalin binding (Nal/Leu).3 The enkephalins had low G.p.i./M.v.d. (0.02 to 0.09) and low Nal/Leu (0.05 to 0.18) ratios whereas the corresponding values for morphine were 7.0 and 7.5.4 Analogues obtained by substituting D-Ala for Gly(2) and D-Met or D-Leu for L-Met(5) or L-Leu(5) showed only minor changes in G.p.i./M.v.d. (0.01 to 0.11) and in Nal/Leu (0.06 to 0.13) ratios.5 Analogues in which resistance to enzymatic degradation was brought about by amidation of the C-terminal carboxylic group or methylation of the amino group of tyrosine or both modifications, had G.p.i./M.v.d. ratios of 1.2 to 5.5 and Nal/Leu ratios of 0.5 to 21. High values (2.1 and 3.4) were found for the potent antinociceptive analogue of Sandoz, Tyr-D-Ala-Gly-NCH(3)Phe-Met(O)-ol.6 In the mouse vas deferens, some of the analogues with high G.p.i./M.v.d. and Nal/Leu ratios were tested for antagonism by naloxone and found to require less than the high concentration needed for the natural enkephalins. C57/BL mice, which have a lowered sensitivity to morphine but a normal response to peptides with low G.p.i./M.v.d. and Nal/Leu ratios, had a lowered sensitivity to analogues with high ratios.7 In the alkaloid-like series of narcotic analgesic drugs, ketobemidone, levorphanol, methadone, etorphine and the antagonist Mr 2266 had lower Nal/Leu ratios (1.0 to 2.8) than morphine, normorphine, naloxone and naltrexone (8 to 12).8 It would appear that compounds with low G.p.i./M.v.d. and Nal/Leu ratios interact mainly with delta-receptors in the brain and peripheral nervous system while compounds with high ratios interact mainly with mu-receptors. For antinociceptive action mu-receptors may be more important than delta-receptors.

Opioid activities of fragments of beta-endorphin and of its leucine65-analogue. Comparison of the binding properties of methionine- and leucine-enkephalin.

For characterisation in vitro, four parallel assays were used: the guinea-pig ileum and mouse vas deferens as pharmacological models at 36 degrees C and the inhibition of binding of [3H]-naltrexone, [3H]-leucine-enkephalin and [3H]-methione-enkephalin at 0 degrees C. The Leu65-analogue of beta-andorphin and its fragments (61-65, 61-76 and 61-77) have a lower affinity to the [3H]-naltrexone binding site of mu-receptors than the corresponding Met65-peptides wereheas no such difference was found for the [3H]leucine-enkephalin binding sites or delta-receptors. When the binding of [3H]-methionine-enkephalin or [3H]-leucine-enkephalin was inhibited by cold ligands interacting with delta-, mu-, or kappa-receptors, no evidence was obtained for more than one type of delta-binding site.

The relationship between cholinesterase inhibition in the chick biventer cervicis muscle and its sensitivity to exogenous acetylcholine.

The effect of physostigmine has been studied on cholinesterase in homogenates of chick biventer cervicis muscles and on the contractile responses of the intact muscles to acetylcholine and carbachol. The concentration of physostigmine required to produce the maximum increase in sensitivity to acetylcholine almost completely inhibited the cholinesterase in muscle homogenates. This concentration of physostigmine had no effect on muscle contractures elicited by carbachol. By taking account of the combined effects of acetylcholine diffusion and enzymic hydrolysis, a quantitative theoretical relationship has been derived between the level of cholinesterase activity in cylindrical muscles and the fractional occupancy of the acetylcholine receptors in these muscles in the presence of different concentrations of exogenous acetylcholine. This theory attributes the thousand-fold increase in sensitivity to exogenous acetylcholine produced by anticholinesterases in chick biventer cervicis muscles largely to an alteration in acetylcholine concentration gradient within the muscle and accounts satisfactorily for the shift in the dose-response curve for acetylcholine which occurs after treatment of the muscles with various concentrations of physostigmine.

Endogenous opioid peptides: multiple agonists and receptors.

Opioid peptides were assayed by inhibition of 3H-naloxone and 3H-leu-enkephalin binding in brain homogenates and by depression of contractions of the guinea pig ileum and mouse vas deferens. We conclude that the opioid peptidergic system has agonists of different characteristics which interact with more than one type of receptor.