A fostering study of the effects of prenatal cocaine exposure: II. Offspring behavioral measures

The impact of rearing condition was assessed in Sprague-Dawley dams given 40 mg/kg cocaine (C40) or saline (LC control) subcutaneously (SC) from gestational days 8–20 and their offspring. Treated pups reared by their biological dams (LC/LC; C40/C40), treated pups reared by surrogate dams (FOS/LC; FOS/C40), and foster pups raised by treated dams (LC/FOS; C40/FOS) were examined. On postnatal day 7 (P7), pups received either 0 (unpaired) 2, 3, or 4 pairings of an odor and footshock and were tested for their aversion to this odor. Foster and LC pups, regardless of rearing condition, exhibited significant odor aversions following either 2, 3, or 4 training trials. In contrast, C40 pups reared by surrogate dams required 4 trials to acquire the aversion, and C40 pups reared by their own dams did not exhibit conditioning even after 4 trials. At P17, no differences were seen among the groups in the aversion formed to an auditory or an olfactory stimulus that was paired with footshock. At P60, shock-elicited aggression among pairs of siblings was examined. Regardless of prenatal exposure condition, offspring reared by dams given cocaine showed a decreased latency to the first aggressive contact, an effect that was evident without any alteration in shock sensitivity. Together these data suggest that being reared by a dam previously exposed to cocaine has an impact on offspring behavioral function apart from the effects of prenatal cocaine exposure per se. The implications of the data regarding the cognitive performance of pups exposed prenatally to cocaine are also discussed.     

Quinidine inhibits in vivo metabolism of amphetamine in rats: impact upon correlation between GC/MS and immunoassay findings in rat urine

Amphetamine is metabolized by cytochrome P-450 (P450) to p-hydroxyamphetamine and phenylacetone in mammalian species. P450 metabolism is affected by genetic polymorphisms and by xenobiotic interactions in an isozyme-specific fashion. Little is known concerning the isozyme selectivity of amphetamine metabolism. Quinidine selectively inhibits the debrisoquine-specific isozyme (P450db) which displays genetic polymorphism in humans and rats. We now report the effect of quinidine on the metabolism of amphetamine to p-hydroxyamphetamine in vivo. At 0 h male Lewis rats received (po): no treatment (I), 80 mg quinidine/kg in 50% ethanol (II), or 50% ethanol (III), followed at 2 h by 15 mg d-amphetamine sulfate/kg (po). Urine specimens were collected and pooled at 0, 24, and 48 h. Amphetamine and p-hydroxyamphetamine concentrations were determined using a new GC/MS method for simultaneous quantitation. The ethanol vehicle-control (III) had no significant effect on amphetamine metabolism. Quinidine pretreatment (II) resulted in a significant decrease in the excretion of p-hydroxyamphetamine at 24 and 48 h to 7.2 and 24.1% of the vehicle-control levels, respectively, accompanied by a significant increase in amphetamine excretion between 24 and 48 h to 542% of the control. These data show that quinidine inhibits in vivo metabolism of amphetamine in rats and suggest that amphetamine metabolism may, in part, be mediated by an isozyme of P450 which displays genetic polymorphism. The inhibition of amphetamine metabolism results in an increased ratio of parent drug to metabolite concentration (metabolic ratio) in the urine, which mimics the effect of genetic polymorphisms.(ABSTRACT TRUNCATED AT 250 WORDS)     

Calcium-induced contraction and contractile protein of gallbladder smooth muscle after high-cholesterol feeding of prairie dogs

Feeding a high-cholesterol diet to prairie dogs causes a reduction in contractile responses of gallbladder smooth muscle from these animals. In this study, the influence of cholesterol feeding on the contractile response to calcium and on the concentration of the contractile proteins actin and myosin was determined. Strips of gallbladder smooth muscle, at their optimal length for tension development, were stimulated maximally with carbachol. Then the muscle cell membranes were made permeable and strips were exposed to a maximally effective concentration of calcium. Strips from cholesterol fed animals developed less stress than those from control animals under all conditions. The concentration of actin and myosin was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. There were no differences in the concentrations of either protein between the cholesterol-fed and control animals. Our results indicate that the decreased contractile response seen in muscle from cholesterol-fed animals is not due to alterations in membrane excitation, excitation-contraction coupling, or in total contractile proteins.     

Genetic variation in the IGSF6 gene and lack of association with inflammatory bowel disease.

The immunoglobulin superfamily 6 gene (IGSF6) on chromosome 16p11-p12 has been investigated as a positional and functional candidate for inflammatory bowel disease (IBD) susceptibility. Screening of the six exons of IGSF6 for single nucleotide polymorphisms (SNPs) detected four novel SNPs, and validated three of six SNPs listed in the international SNP database (dbSNP). The seven SNPs in IGSF6 formed five distinct linkage disequilibrium groups. There was no evidence for association of the common SNPs with disease in a large cohort of patients with IBD. The novel SNPs and the linkage disequilibrium map will be a useful resource for the analysis of IGSF6 in other immune disorders.     

Saskatchewan’s Joint Chiropractic Professional Review Committee

Saskatchewan’s Joint Chiropractic Professional Review Committee functions to ensure that clinically necessary services are provided to patients. The committee which has both government (payer) and professional representation is created by the Medical Care Insurance Act in Saskatchewan. Examples of committee concerns include frequent visits by individual patients, high number of patients treated per day, poor record keeping, high service per discrete patient value. The article concludes with some suggestions for how to determine if a practitioner’s pattern of practice is unusual and how to respond if contacted by the committee. The strengths of this form of review process include: the committee has a majority of chiropractors, patterns of practice are compared to that of peers, evaluation of patterns of practice uses random sampling of files to be analysed, and guidelines for practice are set by peers using a consensus process.     

Concomitant induction of microsomal epoxide hydrolase and UDP-glucuronosyltransferase activities by dipyridine compounds.

The coordinated response of the major rat hepatic phase II xenobiotic-metabolizing enzymes following 3-day exposure to diaryl compounds was investigated. Four diaryl compounds containing heterocyclic nitrogen atoms elevated microsomal epoxide hydrolase activity from 2- to 4-fold. Equivalent compounds lacking the heteroatom, when given in the same dosing regimen (75 mg/kg, ig, daily for 3 days), did not induce this or any other drug-metabolizing enzyme activity. Epoxide hydrolase activity closely paralleled UDP-glucuronosyltransferase activity toward three aglycones: 4-nitrophenol (r = 0.87), morphine (r = 0.84), and 1-naphthol (r = 0.78). There was less correlation (r = 0.60) between epoxide hydrolase activity and both UDP-glucuronosyltransferase activity toward testosterone and cytosolic glutathione S-transferase activity. There was no correlation between microsomal epoxide hydrolase activity and cytochrome P-450 or the monooxygenase reaction (4-nitrophenol hydroxylase) preferentially induced by pyridine-containing compounds. Induction of rat hepatic microsomal epoxide hydrolase activity by some pyridine-containing compounds appears coordinately regulated with glucuronidation rather than oxidation enzymes.     

The effects of chronic ill health and treatment with sulphasalazine on fertility amongst men and women with inflammatory bowel disease in Leicestershire

The aims of the study were to ascertain whether patients have similar a fertility rate to the background population in Leicestershire and whether they have a similar rate of congenital malformations compared to the background population in Leicestershire. Over 1400 patients were invided to participate with an overall response rate of 81% after three successive mailings. The response rate was similar for both sexes and between the disease groups. The crude infertility rate for the group was 21%. The mean number of children for the whole group was 1.7 ± 1.3 but both men and women with Crohn's disease had significantly less children than would be expected, (men with Crohn's disease 1.5, women with Crohn's disease 1.2). There were 39 children (2% of overall births) with congenital abnormalities reported by patients with inflammatory bowel disease and in 29 cases the parents reported taking sulphasalazine (Table 3). Although this figure compares well with the 1.8% reported congenital abnormality rate for Leicestershire within the patient group in this study congenital malformations were significantly related to sulphasalazine use, z = 4.3, P < 0.0001. In conclusion sulphasalazine not only as causes morphological abnormalities in spermatozoa but may increase the chances of having congenitally abnormal offspring amongst men with IBD. The effects of other 5-aminosalacylic acids have yet to be studied in detail.

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Résumé. Le but de cette étude est de déterminer si les patients ont un taux de fertilité identique à celui du reste de la population du Leicestershire et s'ils développent un taux de malformations congénitales identiques à celui du reste de la population. Mille quatre cents patients ont été invités à l'étude, ce qui a permis d'obtenir un taux global de réponse de 81% après 3 envois postaux successifs du questionnaire. Le taux de réponse est analogue pour les deux sexes et les différents groupes de patients. Le taux d'infertilité brute pour le groupe de patients était de 21%. Le nombre d'enfants moyen pour l'ensemble du groupe était de 1,7 + 1,3 mais à la fois les hommes et les femmes atteints de maladie de Crohn avaient un nombre d'enfants significativement moindre que celui attendu (chez les hommes porteurs de la maladie de Crohn 1,5 et chez les femmes atteintes de la maladie de Crohn 1,2). Dans le groupe de patients atteints de maladies inflammatoires, on relève 39 enfants (2% de l'ensemble des naissances) atteints d'anomalies congénitales; chez 29 de ces derniers, les parents avaient pris de la sulfate salazine (Table 3). Bien que ces données soient analogues au taux de 1,8% d'anomalies congénitales rapportées chez l'ensemble des patients du Leicestershire, le taux d'anomalies congénitales est significativement dépendant de la prise de sulfate salazine (z = 4,3, P < 0,0001). En conclusion, la sulfate salazine entra?ne des anomalies morphologiques des spermatozo?des mais peut également augmenter le risque d'anomalies congénitales chez les descendants de patients porteurs de maladies inflammatoires de l'intestin. Les effets d'autres dérivés d'acide 5-amino-salicylique doit faire l'objet d'études détaillées.

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Accepted: 22 March 1997     

(D-Phe12) bombesin and substance P analogues function as central bombesin receptor antagonists

The potency of synthetic bombesin (BN) analogues with D-Phe12 substitutions and substance P analogues was investigated in the rat CNS. (D-Phe12,Leu14)BN, (D-Phe12)BN and (Tyr4,D-Phe12)BN inhibited binding to rat brain slices with IC50 values of approximately 2 microM. Similarly, spantide inhibited binding to rat brain slices with an IC50 value of 1.5 microM. Spantide inhibited specific (125I-Tyr4)BN binding as a result of decreased rate of association, whereas the rate of dissociation was unaffected. Neither the (D-Phe12)BN analogues nor the substance P analogues inhibited specific binding of 125I-VIP to rat brain slices. Central administration of BN (0.5 micrograms) induced grooming and suppressed feeding and resting. (Tyr4, D-Phe12)BN (5 micrograms) antagonized the behavioral effects of BN. Although spantide (2 micrograms) also antagonized many of the BN effects, it had intrinsic effects and hence the behavioral antagonism was not specific. These data suggest that although both (D-Phe12)BN and substance P analogues may function as central BN receptor antagonists, the (D-Phe12)BN analogues may be functionally the more useful class of antagonists.