Use of cytology for canine mammary masses and perceived diagnostic utility in four European countries.

OBJECTIVES: To investigate the use of cytology of canine mammary masses and its perceived diagnostic utility in four European countries. MATERIALS AND METHODS: The link to a web-based questionnaire was sent to veterinarians of Italy, UK, Greece and Spain. The questionnaire contained basic questions regarding the respondents' background, their general use of cytology as a diagnostic tool, the incidence of canine mammary tumours within their clinics and their use of cytology for canine mammary masses. Multiple binary and ordinal logistics models were used to evaluate associations between variables. RESULTS: Four hundred and sixty-five veterinarians completed the survey (Italy: 114; UK: 66; Greece: 55; Spain: 230). Most veterinarians working in each country used cytology as a diagnostic tool, although only 43.0%, 54.6%, 43.6% and 36.5% used cytology for the investigation of CMMs in Italy, UK, Greece and Spain respectively. Supposing the cytology were able to correctly differentiate benign versus malignant canine mammary masses, the percentage of veterinarians using this test would increase in Italy, UK and Greece (Italy: 91.2%; UK: 93.9%; Greece: 96.4%); however, this was not reflected by veterinarians working in Spain (51.7%). CLINICAL SIGNIFICANCE: If cytology of canine mammary masses were able to differentiate between benign and malignant, most veterinarians in Italy, UK and Greece would utilise the technique, justifying further research into the diagnostic accuracy of this test. Spanish veterinarians were significantly different and further research into why these individuals would not value the ability of cytology to differentiate between benign and malignant may be of value.

Disengaging the IL-2 receptor with daclizumab enhances IL-7-mediated proliferation of CD4(+) and CD8(+) T cells.

Allograft rejection is mainly driven by the production of IL-2, which expands T cells by linking the IL-2 receptor (IL-2R) composed of three subunits: CD25, CD122 and CD132. Daclizumab, widely used in immunosuppression, is a humanized anti-CD25 antibody that disrupts IL-2 signaling by binding to CD25 and preventing the assembly of the high-affinity IL-2R. Here we show that Daclizumab, while blocking the T-cell response to IL-2, increases CD4(+) and CD8(+) T-cell proliferative response to the homeostatic cytokine IL-7. The IL-7R shares CD132 with the IL-2R and blocking of CD25 by Daclizumab results in the enhanced formation of the IL-7R that in turn allows IL-7 to bind more efficiently on the cell surface. The consequently increased IL-7R signaling boosts intracellular phosphorylated STAT5 and T-cell proliferation. In addition, treatment with Daclizumab delays the internalization of CD127 upon IL-7 treatment, retaining T-cell sensitivity to IL-7 for a prolonged time. This effect of Daclizumab highlights the redundancy of the cytokine system, which may influence T-cell proliferation in transplanted patients, and provides information to improve future immunosuppressive strategies.

Validation of the Marijuana Effect Expectancy Questionnaire-Brief.

The purpose of this study was to evaluate a brief version of the Marijuana Effect Expectancy Questionnaire (MEEQ; Schafer & Brown, 1991). The original MEEQ was reduced to 6 items (MEEQ-B). Principal component analysis (PCA) was performed and two factors were identified (positive effects and negative effects) accounting for 52.3% of the variance. Internal consistencies (0.42 to 0.60) were slightly lower than those of the original MEEQ. The negative effect expectancy scale correlated with criterion variables that assess marijuana use (p ≤ .05). This measure is a helpful tool for clinicians to use when assessing youth expectancies. Replication across different samples of adjudicated youth is recommended.

Cell size modulation by CDC25 and RAS2 genes in Saccharomyces cerevisiae.

A detailed kinetic analysis of the cell cycle of cdc25-1, RAS2Val-19, or cdc25-1/RAS2Val-19 mutants during exponential growth is presented. At the permissive temperature (24 degrees C), cdc25-1 cells show a longer G1/unbudded phase of the cell cycle and have a smaller critical cell size required for budding without changing the growth rate in comparison to an isogenic wild type. The RAS2Val-19 mutation efficiently suppresses the ts growth defect of the cdc25-1 mutant at 36 degrees C and the increase of G1 phase at 24 degrees C. Moreover, it causes a marked increase of the critical cell mass required to enter into a new cell division cycle compared with that of the wild type. Since the critical cell mass is physiologically modulated by nutritional conditions, we have also studied the behavior of these mutants in different media. The increase in cell size caused by the RAS2Val-19 mutation is evident in all tested growth conditions, while the effect of cdc25-1 is apparently more pronounced in rich culture media. CDC25 and RAS2 gene products have been showed to control cell growth by regulating the cyclic AMP metabolic pathway. Experimental evidence reported herein suggests that the modulation of the critical cell size by CDC25 and RAS2 may involve adenylate cyclase.

Validity and Reliability of the Alcohol Expectancy Questionnaire-Adolescent, Brief.

The purpose of this study was to evaluate a brief version of the Alcohol Expectancy Questionnaire-Adolescent (AEQ-A; Brown, Christiansen, & Goldman, 1987). The original AEQ-A was reduced to seven items (called the AEQ-AB). Principal Components Analysis (PCA) was performed and two factors emerged (General Positive Effects and Potential Negative Effects) accounting for 46% of the variance. Internal consistencies are comparable to those of the original AEQ-A (0.50). Scales correlate with criterion variables such as average drinks per week and average number of drinks per heavy drinking day (p < 0.05). It is concluded that this questionnaire may be useful to clinicians providing brief assessment and intervention. Cross-validation in other samples and other settings is recommended.

N-(2-chloroethyl)-N-nitrosourea tethered to lexitropsin induces minor groove lesions at the p53 cDNA that are more cytotoxic than mutagenic.

Many different N-chloroethyl-N-nitrosourea (CENU) derivatives have been synthesized in an attempt to minimize carcinogenic activity while favoring antineoplastic activity. CENU derivatives linked to the dipeptide lexitropsin (lex) showed significant changes in groove- and sequence-selective DNA alkylation inducing thermolabile N3-alkyladenines (N3-Alkyl-As) at lex equilibrium binding sites. CENU-lex sequence specificity for DNA alkylation was determined using 32P-end-labeled restriction fragments of the p53 cDNA. The adducted sites were converted into single-strand breaks by sequential heating at neutral pH and exposure to piperidine. To establish the mutagenic and lethal properties of CENU-lex-specific lesions, a yeast expression vector harboring a human wild-type p53 cDNA was treated in vitro with CENU-lex and transfected into a yeast strain containing the ADE2 gene regulated by a p53-responsive promoter. p53 mutants were isolated from independent ade- transformants. The results revealed that: (a) CENU-lex preferentially induces N3-Alkyl-A at specific lex equilibrium binding sites, the formations of which are strongly inhibited by distamycin; (b) reactivity toward Gs is still present, albeit to a lesser extent when compared to N-(2-chloroethyl)-N-cyclohexyl-N-nitrosourea and to CENU; (c) 91% of the 49 CENU-lex p53 mutations (45 of 49) were bp substitutions, 29 of which were GC-->AT transitions, mainly at 5' purine G sites; (d) all AT-targeted mutations but one were AT-->TA transversions; (e) the distribution of the CENU-lex mutations along the p53 cDNA was not random, with position 273 (codon 91), where only GC-->AT transitions were observed, being a real (n = 3, P < 0.0002) CENU-lex mutation hot spot; and (f) a shift in DNA alkylation sites between lesion spectra induced by CENU-lex and N-(2-chloroethyl-N-cyclohexyl-N-nitrosourea was associated with an increased lethality and a decreased mutagenicity, whereas no dramatic change in mutational specificity was observed. Hence, it is tempting to conclude that, in this experimental system, N3-Alkyl-A is more lethal than mutagenic, whereas O6-alkylguanine is a common premutational lesion formed at non-lex binding sites. These results suggest that CENU derivatives with virtually absolute specificity for A residues would make targeting of lethal, nonmutagenic lesions at A+T-rich regions possible, and this may represent a new strategy for the development of new chemotherapeutic agents with a higher therapeutic index.

p53 mutants exhibiting enhanced transcriptional activation and altered promoter selectivity are revealed using a sensitive, yeast-based functional assay.

Changes in promoter specificity and binding affinity that may be associated with p53 mutations or post-translational modifications are useful in understanding p53 structure/function relationships and categorizing tumor mutations. We have exploited variable expression of human p53 in yeast to identify mutants with novel phenotypes that would correspond to altered promoter selectivity and affinity. The p53 cDNA regions coding for the DNA binding and tetramerization domains were subjected to random PCR mutagenesis and were cloned directly by recombination in yeast into a vector with a GAL1 promoter whose level of expression could be easily varied. p53 variants exhibiting higher than wild type levels of transactivation (supertrans) for the RGC responsive element were identified at low level of p53 protein expression. All the p53 mutants obtained with this screen were located in the DNA binding domain. Two out of 17 supertrans mutants have been found in tumors. Six mutations were in the L1 loop region between amino acids 115 and 124. The transactivation potential of a panel of supertrans p53 mutants on different promoters was evaluated using the p53 responsive elements, RGC, PIG3, p21 and bax. Although all mutants retained some activity with all promoters, we found different patterns of induction based on strength and promoter specificity. In particular none of the mutants was supertrans for the p21 responsive element. Interestingly, further analysis in yeast showed that the transactivation function could be retained even in the presence of dominant-negative p53 tumor mutations that could inhibit wild type p53. Five mutants were also characterized in human cells in terms of growth suppression and transactivation of various promoters. These novel supertrans p53 mutants may be useful in studies aimed at dissecting p53 downstream pathways, understanding specific interactions between p53 and the DNA, and could replace wild type p53 in cancer gene therapy protocols. The approach may also prove useful in identifying p53 tumor mutations.

Determining mutational fingerprints at the human p53 locus with a yeast functional assay: a new tool for molecular epidemiology.

In order to isolate experimentally induced p53 mutations, a yeast expression vector harbouring a human wild-type p53 cDNA was treated in vitro with the antineoplastic drug chloroethyl-cyclohexyl-nitroso-urea (CCNU) and transfected into a yeast strain containing the ADE2 gene regulated by a p53-responsive promoter. p53 mutations were identified in 32 out of 39 plasmids rescued from independent ade- transformants. Ninety-two percent of CCNU induced mutations were GC-targeted single base pair substitutions, and GC > AT transitions represented 73% of all single base pair substitutions. In 70% of the cases the mutated G was preceded 5' by a purine. The distribution of the mutations along the p53 cDNA was not random: positions 734 and 785 appeared as CCNU mutational hotspots (n=3, P<0.0003) and CCNU induced only GC > AT transitions at those positions. The features of these CCNU-induced mutations are consistent with the hypothesis that O6-alkylguanine is the major causative lesion. One third of the CCNU-induced mutants were absent from a huge collection of 4496 p53 mutations in human tumours and cell lines, thus demonstrating that CCNU has a mutational spectrum which is uniquely different from that of naturally selected mutations. This strategy allows direct comparison of observed natural mutation spectra with experimentally induced mutation spectra and opens the way to a more rigorous approach in the field of molecular epidemiology.

Amifostine (WR2721) restores transcriptional activity of specific p53 mutant proteins in a yeast functional assay.

Many p53 mutants found in human cancer have an altered ability to bind DNA and transactivate gene expression. Re-expression of functional p53 in cells in which the endogenous TP53 gene is inactivated has been demonstrated to restore a non-tumorigenic phenotype. Pharmacological modulation of p53 mutant conformation may therefore represent a mechanism to reactivate p53 function and consequently improve response to radio- and chemotherapy. We have recently reported that the radio- and chemoprotector Amifostine (WR2721, Ethyol) activates wild-type p53 in cultured mammalian cells. In the present study, we have used a yeast functional assay to investigate the effect of WR2721 on the transcriptional activity of p53. WR2721 restored this activity in a temperature-sensitive mutant V272M (valine to methionine at codon 272) expressed at the non-permissive temperature and it also partially restored the transcriptional activity of several other conformationally flexible p53 mutants. The results indicate that the yeast functional assay may be used to identify compounds that modulate p53 activity, with potential therapeutic implications.

p53 mutants can often transactivate promoters containing a p21 but not Bax or PIG3 responsive elements.

The human p53 protein acts mainly as a stress inducible transcription factor transactivating several genes involved in cell cycle arrest (e.g. p21) or apoptosis (e.g. Bax, PIG3). Roughly half of all human tumours contains p53 missense mutations. Virtually all tumour-derived p53 mutants are unable to activate Bax transcription but some retain the ability to activate p21 transcription. Identification of these mutants may have valuable clinical implications. We have determined the transactivation ability of 77 p53 mutants using reporter yeast strains containing a p53-regulated ADE2 gene whose promoter is regulated by p53 responsive elements derived from the regulatory region of the p21, Bax and PIG3 genes. We also assessed the influence of temperature on transactivation. Our results indicate that a significant proportion of mutants [16/77 (21%); 10/64 (16%) considering only tumour-derived mutants] are transcriptionally active, especially with the p21 promoter. Discriminant mutants preferentially affect less conserved (P<0.04, Fisher's exact test), more rarely mutated (P<0.006, Fisher's exact test) amino acids. Temperature sensitivity is frequently observed, but is more common among discriminant than non-discriminant mutants (P<0.003, Fisher's exact test). Finally, we extended the analysis to a group of mutants isolated in BRCA-associated tumours that surprisingly were indistinguishable from wild type in standard transcription, growth suppression and apoptosis assays in human cells, but showed gain of function in transformation assays. The incidence of transcriptionally active mutations among this group was significantly higher than in the panel of mutants studied previously (P<0.001, Fisher's exact test). Since it is not possible to predict the behaviour of a mutant from first principles, we propose that the yeast assay be used to compile a functional p53 database and fill the gap between the biophysical, pharmacological and clinical fields.

Abdominal radiation exposure elicits inflammatory responses and abscopal effects in the lungs of mice.

An inflammatory reaction is a classical feature of radiation exposure and appears to be a key event in the development of the acute radiation syndrome. We have investigated the radiation-induced inflammatory response in C57BL6/J mice after total abdominal or total-body irradiation at a dose of 15 Gy. Our goal was to determine the radiation-induced inflammatory response of the gut and to study the consequences of abdominal irradiation for the intestine and for the lungs as a distant organ. A comparison with total-body irradiation was used to take into account the hematopoietic response in the inflammatory process. For both irradiation regimens, systemic and intestinal responses were evaluated. A systemic inflammatory reaction was found after abdominal and total-body irradiation, concomitant with increased cytokine and chemokine production in the jejunum of irradiated mice. In the lungs, the radiation-induced changes in the production of cytokines and chemokines and in the expression of adhesion molecules after both abdominal and total-body irradiation indicate a possible abscopal effect of radiation in our model. The effects observed in the lungs after irradiation of the abdomino-pelvic region may be caused by circulating inflammatory mediators consequent to the gut inflammatory response.

Comparison of mitotic index and Ki67 index in the prognostication of canine cutaneous mast cell tumours.

Proliferation markers are commonly used for prognostication of mast cell tumours. The aim of the study is to compare the relative abilities of Ki67 and mitotic index to predict survival in the same cohort of dogs with cutaneous MCTs. Histological grade, mitotic index and Ki67 index were performed in all samples and clinical information was obtained by a follow-up questionnaire. Ninety-five dogs were included in the study with a median follow-up of 1145 days. Survival times varied significantly between categories of histological grade, mitotic index and Ki67 index. Multivariable analyses showed that the risk of dying due to MCT was similar in dogs with increased Ki67 index [hazard ratio, HR: 3.0 (95% CI 1.3-6.8)] or increased mitotic index [HR: 2.7 (95% CI 1.1-6.5)]. In conclusion, both mitotic index and Ki67 index were able to independently differentiate MCTs with worse prognosis. This distinction is particularly meaningful in selecting intermediate grade MCTs that may benefit from more aggressive local or systemic treatment.

D-cycloserine to enhance extinction of cue-elicited craving for alcohol: a translational approach.

Cue-elicited craving for alcohol is well established but extinction-based treatment to extinguish this response has generated only modest positive outcomes in clinical trials. Basic and clinical research suggests that D-cycloserine (DCS) enhances extinction to fear cues under certain conditions. However, it remains unclear whether DCS would also accelerate extinction of cue-elicited craving for alcohol. The goal of the current study was to examine whether, compared with placebo (PBO), DCS enhanced extinction of cue-elicited craving among treatment-seeking individuals with alcohol use disorders (AUDs). Participants were administered DCS (50 mg) or PBO 1 h before an alcohol extinction paradigm in a simulated bar environment on two occasions. The extinction procedures occurred 1 week apart and were fully integrated into outpatient treatment. Subjective craving for alcohol was the primary variable of interest. Follow-up cue reactivity sessions were conducted 1 week and 3 weeks later to ascertain persisting DCS effects. Drinking outcomes and tolerability were also examined. DCS was associated with augmented reductions in alcohol craving to alcohol cues during the first extinction session and these effects persisted through all subsequent sessions, suggesting facilitation of extinction. Participants in the DCS condition reported significant short-term reductions in drinking, although these did not persist to follow-up, and found the medication highly tolerable. These findings provide evidence that DCS enhances extinction of cue-elicited craving for alcohol in individuals with AUDs in the context of outpatient treatment. The potential clinical utility of DCS is discussed, including methodological considerations and context-dependent learning.

Depression among cocaine abusers in treatment: relation to cocaine and alcohol use and treatment outcome.

OBJECTIVE: The authors investigated the theoretical and clinical role of depression among cocaine abusers in treatment. METHOD: Eighty-nine cocaine-abusing patients underwent 2 weeks of substance abuse treatment. Posttreatment major depressive disorder, depressive symptoms before and after substance abuse treatment, and alcohol diagnoses were assessed and their relation to pretreatment substance use, cravings in high-risk situations, and 3-month follow-up status was examined. RESULTS: High rates of major depressive disorder were found but were unrelated to pretreatment substance use. The decrease in depressive symptoms during treatment was independent of major depressive disorder or alcohol diagnoses and predicted treatment attrition. Higher levels of depressive symptoms during treatment were associated with greater urge to use cocaine, alcohol, and other drugs in high-risk situations. Concurrent major depressive disorder and depressive symptoms did not predict cocaine use at follow-up. However, patients who had an alcohol relapse episode experienced more depressive symptoms during treatment than did those who abstained. CONCLUSIONS: The results highlight the relationship of depression to alcohol use among cocaine abusers and suggest a need for further studies of the association between depression and substance use disorders.

p53 is frequently mutated in Barrett's metaplasia of the intestinal type.

Barrett's Esophagus (BE) is a complication of gastroesophageal reflux in which the normal squamous epithelium of the lower esophagus is replaced by metaplastic tissue. The clinical significance of this condition is the associated predisposition to adenocarcinomas (ADCs). Three types of BE have been characterized: the gastric fundic (F) type, the gastric cardial (C) type, and the intestinal (I) type. The latter is the most closely associated with the development of ADCs; the causes of this bias remain unknown. To determine whether p53 and/or K-ras gene alterations (a) are present in preneoplastic lesions and (b) are associated with a specific histotype, we performed PCR-based denaturing gradient gel electrophoresis (DGGE) analysis of exon 1 (codons 12-13) of K-ras gene and of exons 5-8 of the p53 gene in biopsies obtained from 30 patients with BE of the I type (9 patients), combined I type (I + C +/- F; 10 patients) and non-I type (C, F, or C + F; 11 patients). None of the cases under study revealed K-ras mutations, whereas biopsies from 12 patients showed at least one p53 DGGE variant. Four patients showed the exact same variants in leukocytes also (polymorphisms), whereas eight cases revealed specific DGGE variants only in biopsies. The molecular characterization of these variants revealed that four of them showed a single base pair substitution, and four showed multiple mutations. Of 17 somatic mutations, all but 1 were base pair substitutions located mainly in exons 7 and 8. The majority of these mutations were GC targeted (13 of 16; 81%), 54% (7 of 13) of which were transitions occurring at CpG sites. All somatic mutations were found in BE with at least one I component. The association with the histotype was statistically significant (P < 0.03; pure I type versus non-I type; P < 0.04, combined I type versus non-I type; Fisher's exact test). Loss of heterozygosity in the vicinity of the p53 locus was evaluated by PCR using a highly polymorphic variable number of tandem repeats marker on 25 out of 30 cases. Ninety-two % of the cases analyzed were informative, and none of them showed LOH. In conclusion, we showed that p53 mutations are frequently observed in specimens from BE patients of the I-type, whereas no involvement of K-ras (exon 1) mutational activation was observed. In light of the key roles that the p53 protein plays in controlling cell cycle and cell diploidy, this result may suggest why this type of metaplasia is the most closely associated to the development of ADCs.

Residual fear of the conditioned stimulus as a function of response prevention after avoidance or classical defensive conditioning in the rat.

Studies employing response prevention (RP) are reviewed. Considering assessment difficulties and conflicting findings, it is questionable whether RP actually reduces fear to a conditioned stimulus (CS). This study measured fear after RP via a conditioned emotional response (CER) paradigm. Hypotheses were that fear of an auditory CS (conditioned in an avoidance paradigm) is reduced during RP, and that fear conditioning would occur to aspects of the conditioning environment per se. Also evaluated was the effectiveness of RP when fear had been learned under two different conditions: (a) avoidance or (b) classical defensive conditioning. Seven groups of 10 experimentally naive female rats were run. Animals were initially trained to bar press for food pellets on a variable interval (VI) 2 schedule. Three groups were then avoidance trained in a two-way shuttle box to a criterion of 10 successive avoidances. Immediately following acquisition, one group received RP (blocking) in the shuttle box (Condition A-B). This consisted of placing a door between the two sides of the box and presenting the 85 dB (A) white noise CS for 15 20-sec periods with a variable 1-min interstimulus interval. One group did not receive RP (nonblocked) and was instead immediately returned to its home cage (Condition A-NBHC). The third group was treated as was A-B except the CS was not presented (Condition A-NBSB). Two other groups were trained in a classical defensive paradigm. These animals were matched to A-B animals in terms of number, order, and duration of CSs and USs. Following conditioning, one group received the same treatment as A-B (Condition CD-B), and the other received the same treatment as A-NBHC (Condition CD-NBHC). Two groups served as controls. A backward control (Condition BC-NBHC) was matched to A-NBHC in terms of number, order, and duration of CSs and USs. A sensitization control (Condition SC-NBHC) was matched to A-NBHC in terms of number, order, and duration of CS presentations. Immediately following conditioning trials, control animals received the same treatment as A-NBHC animals. After differential treatments all animals were immediately returned to the lever box in which they had learned to bar press, a VI 2 schedule was reinstated, and the CER was measured. A-B showed significant suppression initially but significantly less than A-NBHC, suggesting that although RP was effective in reducing fear to the CS, some fear remained. Controls showed essentially no suppression and did not differ. A-B did not differ from A-NBSB, suggesting that conditioning of fear did occur to the environment and that this fear was subsequently reduced in A-NBSB. A-B suppressed significantly more than CD-B, suggesting that RP was more effective when fear was learned in a classical as compared to an avoidance paradigm. Theoretical implications and generalizations to implosive therapy are discussed.

Structural modifications and biological compatibility of doped bio-active glasses.

The Raman laser and infrared spectra of doped bio-active glasses of the 45S5 type are presented and discussed. The spectroscopic results show that the doping agents cause the destruction of the basic glass structure and the consequent formation of SiO4(4-) units in the glass network. When the doped glasses have been immersed in a physiological solution (199 medium), a film of calcite forms on the glass surface and this modification is related to the type of doping agent used, decisive for close linking between metal supports and the glass. The presence of doping agents does not prevent the normal growth of the bone onto the surface of doped bioactive glasses. Histological tests show that tissue response to very fine powders of doped glasses increases up to 15 days more or less according to the structural modifications revealed by spectroscopic measurements.

Olanzapine reduces urge to drink after drinking cues and a priming dose of alcohol.

RATIONALE: Haloperidol, a D2 antagonist, has been shown to moderate the effects of alcohol consumption on craving. OBJECTIVE: The present study was designed to determine whether a single 5-mg dose of olanzapine (a D2/5-HT2 antagonist) would influence responses to alcohol cues or an alcohol challenge. It was hypothesized that olanzapine would attenuate cue-elicited urge to drink, attenuate the effects of alcohol consumption on urge to drink, and reduce the rewarding effects of alcohol. METHODS: To test these hypotheses, 26 heavy social drinkers were randomized to receive either 5 mg olanzapine or placebo approximately 8 h before each of two experimental sessions. Participants consumed a moderate dose of alcohol in one experimental session and a non-alcohol control beverage in another session. RESULTS: Results indicated that mere exposure to alcohol cues and consumption of alcohol increased urge to drink and that olanzapine attenuated these effects. Results also indicated that alcohol increased subjective stimulation and high while olanzapine did not moderate these effects. CONCLUSIONS: These results suggest that olanzapine did not influence the rewarding effects of alcohol but did attenuate the effects of alcohol cues and an alcohol challenge on urge to drink.

Effects of naltrexone with nicotine replacement on smoking cue reactivity: preliminary results.

Although several studies have examined the effects of opioid antagonists on smoking behavior, there have been no reports of the potentially therapeutic combination of naltrexone and nicotine replacement therapy. The primary objective of the present study was to determine whether naltrexone reduced reactivity to smoking cues among abstinent smokers treated with nicotine replacement. Twenty participants were instructed to abstain from smoking cigarettes for 9 h while using nicotine replacement therapy. Participants were subsequently treated with either naltrexone (50 mg) or placebo before being exposed to smoking cues. Results indicated that the smokers who received the placebo responded to smoking cue exposure with increases in urge to smoke and increases in negative affect. Participants who received naltrexone did not show any increase in urge or negative affect and showed a decrease in withdrawal symptoms after exposure to smoking cues. Although preliminary, the findings suggest that naltrexone may work in combination with nicotine replacement therapies to block the effects of smoking stimuli in abstinent smokers.

Whole-body gamma irradiation modifies bile composition in the pig.

The effects of 6 Gy whole-body 60Co gamma irradiation on bile composition in pigs were studied to determine possible alterations in the quality of the bile, which may be a determining factor in diarrhea as well as nutrient malabsorption, which classically occurs after irradiation. The bile duct of pigs was catheterized to allow a total and continuous deviation of bile over several weeks, before and after irradiation. After measurement of the volume and sampling, bile was returned to the animal via a duodenal catheter. Bile samples were then analyzed for cholesterol, phospholipid and total bile acid content. Individual bile acids were quantified by HPLC analysis. Bile flow was significantly decreased during the first 24 h and after the fifth day postirradiation. Whereas cholesterol, phospholipid and total bile acid concentrations were not altered, profiles of individual bile acids were modified significantly as early as the first day postirradiation. Moreover, the change of these profiles with time was specific for each bile acid. Such modifications in bile acid profiles resulted in a change in the properties of the bile acid pool in an increased proportion of dihydroxylated bile acids known to interfere with gut functions, and it is reasonable to suggest that radiation-induced changes in bile acid profiles may be involved in radiation-induced gastrointestinal disorders.