Dendritic cell expression of ADAM23 governs T cell proliferation and cytokine production through the α(v)ß(3) integrin receptor.

ADAM23 is a member of the brain macrophage-derived chemokine family. Structural homology of ADAM proteins suggests their function as integrin receptors. Previous studies have linked ADAM23 as a dominant contributor to brain development and cancer metastasis. The present studies now show that ADAM23 expression on DCs partially governs antigen-presentation capacities to responder CD4+ T cells. With the use of RNAi approaches, knockdown of ADAM23 in murine BMDCs resulted in impaired T cell activation, proliferation, and cytokine production. Knockdown did not alter the maturation profile of DCs (i.e., costimulatory molecule expression or production of proinflammatory cytokines) but markedly impaired cognate T cell responses. There was a significant decrease in antigen-specific clonal expansion coupled with a global decrease in Th cytokine production. Impaired early activation and proliferation did not alter/skew the balance of Th polarization but significantly depressed total levels of IL-2, IFN-γ, IL-4, and IL-17 cytokine production in CD4+ T cells primed by ADAM23 knockdown versus control DCs. Finally, neutralizing antibodies targeting the α(v)ß(3) integrin receptors resulted in similar phenotypes of impaired CD4+ T cell responses. Taken together, these studies show a novel role of ADAM23 in governing DC antigen presentation to cognate CD4+ T cells.

Lipidomic analysis reveals prostanoid profiles in human term pregnant myometrium.

Prostanoids modulate the activity of human pregnant myometrium and their functional role can be appreciated through characterisation of prostanoid receptors and tissue concentration of prostanoids. We have applied a lipidomic approach to elucidate the profile of prostanoids in human non-labouring and labouring myometrium. We have identified a total of nineteen prostanoids including prostacyclin, thromboxanes, prostaglandins and dihydro-prostaglandins. Prostacyclin was the predominant prostanoid in both non-labouring and labouring myometria, with PGD(2) and PGF(2alpha) being the second most abundant. Although the total amount of prostanoids was increased in the labouring tissue, PGE(2) and 13,14-dihydro-15-keto-PGE(2) were the only prostanoids to increase significantly at early and late labour (p< or =0.001). Our data suggest that PGF(2alpha) plays an important role in parturition, whilst the increase in PGE(2) could occur to facilitate cervical dilation and relaxation of the lower myometrium during labour. Although the elevation in TXA(2) was less marked than expected, in terms of translation to function even a relatively small increase in the level of this potent spasmogen may have significant effects.

Investigation into the influence of a high fat diet on antipsychotic-induced weight gain in female rats.

Atypical antipsychotic drug therapy may result in substantial weight gain, increased adiposity and the promotion of metabolic abnormalities. The mechanism(s) which underlie such effects remain unclear. Previous studies in our laboratory have demonstrated significant weight gain in female rats maintained on a standard laboratory diet after sub-chronic administration of olanzapine and risperidone, but not ziprasidone. The aim of this paper is to investigate the effect of antipsychotic drugs on body weight, ingestive behaviour and adiposity in female rats with access to a high fat diet. Adult female rats given free access to a high fat diet received either olanzapine (2 mg/kg), risperidone (0.5 mg/kg), ziprasidone (2.5 mg/kg) or vehicle for 28 days. Body weight, food and water intake in addition to intra-abdominal fat deposition were assessed. Olanzapine initially increased body weight but by the end of the study olanzapine animals appeared to have lost weight compared to the vehicle-treated group. Olanzapine-induced reductions in body weight were accompanied by a significant hypophagia during weeks 3 and 4. Risperidone increased body weight during week 1 only and reduced intake of a high fat diet during weeks 3 and 4. Ziprasidone was without effect on indices of body weight and ingestive behaviour. There were no effects of antipsychotic drugs on intra-abdominal fat deposition. Access to a diet high in fat attenuated weight gain induced by olanzapine and risperidone in female rats.

Oestradiol attenuates the cognitive deficit induced by acute phencyclidine treatment in mature female hooded-Lister rats.

Gender differences in psychiatric research are becoming more widely recognized, and changes in levels of the steroid hormone, oestrogen, over the menstrual or oestrous cycle are becoming increasingly implicated in alterations in cognitive strategies and capacities. The aim of this study is to investigate the interaction between oestrogen, NMDA receptor function and cognitive processing in rats. Forty-five mature female hooded-Lister rats received vehicle, 0.5, 5 or 10 microg/kg of oestradiol benzoate (EB, s.c. in olive oil) 24 h prior to an acute dose of 2 mg/kg phencyclidine (PCP, i.p. in 0.9% w/v saline), or vehicle (0.9% saline). After 30 min following PCP treatment, animals completed the novel object recognition task with a 1 min inter-trial interval to assess object recognition memory. Results show that 5 and 10 microg/kg of EB 24 h prior to 2 mg/kg PCP significantly (P < 0.01 and < 0.001, respectively) protected against the cognitive impairing effect of PCP in contrast to vehicle and 0.5 microg/kg EB plus PCP (not significant). EB may exert a neuromodulatory effect in this animal model leading to attenuation of the PCP-induced impairment in object recognition memory, suggesting an interaction between the gonadal steroids and NMDA receptor-mediated cognitive dysfunction, which is of potential relevance to schizophrenia.

The distinct effects of subchronic antipsychotic drug treatment on macronutrient selection, body weight, adiposity, and metabolism in female rats.

INTRODUCTION: Treatment with some antipsychotic drugs may result in excessive body weight gain which can have detrimental effects on patient compliance, morbidity and mortality. The aim of the present study was to investigate the effect of atypical antipsychotic drugs on dietary macronutrient selection, body weight, body composition and biochemical parameters related to obesity in female rats. MATERIALS AND METHODS: Forty pair-housed, adult female hooded-Lister rats (250 +/- 5 g) were habituated to three diets containing principally protein, fat, or carbohydrate in a home cage self-selection paradigm. Olanzapine (2 mg/kg), risperidone (0.5 mg/kg), ziprasidone (2.5 mg/kg), or vehicle was injected intraperitoneally once daily for 22 days; food selection, water intake, and body weight were recorded daily, while body composition and plasma hormones (insulin, glucose, nonesterified free fatty acid, total cholesterol, glycerol, triacylglycerol, leptin, and prolactin) were analyzed at the end of the study. RESULTS: Only olanzapine significantly increased body weight and food intake. Macronutrient selection was significantly altered after olanzapine and risperidone treatment (increased protein and decreased fat preference). Only olanzapine increased carcass fat content. Locomotor activity was significantly reduced in all treatment groups. Both olanzapine and risperidone significantly increased plasma prolactin. Olanzapine was without effect on any other biochemical parameter measured. Ziprasidone significantly reduced plasma leptin and nonsignificantly reduced NEFA, while risperidone significantly reduced fasting plasma glucose. CONCLUSION: This study supports our previous work demonstrating weight gain and increased feeding behavior induced by olanzapine and could have important implications for enhancing our understanding of the mechanisms by which olanzapine and other atypical antipsychotics induce weight gain in the clinic.

Influence of gender on working and spatial memory in the novel object recognition task in the rat.

Gender differences in many behavioural tasks have been observed in both humans and laboratory animals. The novel object recognition (NOR) task is increasingly used to investigate drug effects on working memory processes, although, the influence of sexually dimorphic behaviours have not yet been evaluated. In addition, the role of natural fluctuations in the sex steroids during the oestrous cycle has received little attention during object recognition tasks. Therefore, the aim of the current study was to investigate the influence of gender and oestrous cycle phase on working and spatial memory using the NOR task. Animals were tested in the NOR task and the spatial NOR task. Male and female rats completed an acquisition trial followed by an inter-trial interval of a specified length, then a final retention trial. Vaginal cytology enabled the influence of oestrous cycle phase to be determined in both the NOR and spatial NOR, each animal was tested during one phase of their regular oestrous cycle only. It was found that female rats performed significantly better than male rats in the standard NOR paradigm (p<0.05 compared to no significance (NS) at 3h, respectively), while male rats showed improved memory in the spatial NOR paradigm compared with female rats (p<0.05 compared to NS at 3h, respectively). There was no influence of phase of oestrous cycle on the NOR task, however, during the spatial NOR there was a significant improvement in ability when oestrogen and progesterone levels have been shown to be at their lowest (i.e. p<0.05 during oestrous compared to NS at other stages). In conclusion, it is clear that gonadal hormones can influence components of memory and gender is an important consideration in experimental design.

Effects of suckling intensity on milk yield and piglet growth from lactation-enhanced gilts.

The effects of suckling intensity on milk yield and piglet growth were determined when lactation capacity of the sow was enhanced through overexpression of a mammary-specific transgene, bovine alpha-lactalbumin. Lactational response to increased suckling stimulation was determined by fostering litters of the same age (d 1) or 7 d older (d 7) than the day of lactation to sows nontransgenic (control) or transgenic (TG) for bovine alpha-lactalbumin. Twenty first-parity gilts were allocated to 4 treatments dependent on gilt genotype and age of litter fostered (control d 1, control d 7, TG d 1, and TG d 7). Litters were standardized to 10 piglets within 24 h postpartum, and nonbirth piglets were fostered to gilts with an equal litter BW within age groups at 36 h postpartum. Milk yield was determined by the weigh-suckle-weigh method on d 6, 9, 12, 15, and 18 of lactation. Mean daily milk yield was greater (P = 0.031) for TG gilts compared with control gilts and tended to be greater (P = 0.056) for all gilts with d-7 piglets compared with those with d-1 piglets. Daily milk yield of TG d 7 gilts increased rapidly to peak at d 9 and was greater than milk yield of all control gilts at d 9 (P < 0.01), 12 (P < 0.02), and 15 (P < 0.02). Mean daily milk yield of TG d 7 gilts was 2.1 kg greater (P = 0.002) than for control d 7 gilts and 2.0 kg greater (P = 0.004) than for TG d 1 gilts. Daily milk yield of control d 1 gilts was not different from that of TG d 1 gilts (P = 0.49) or control d 7 gilts (P = 0.63). Piglet BW gain between d 3 and 6 was greater (P < 0.01) in the TG d 7 group than for all other groups and was greater (P < 0.05) than the control groups between d 6 and 9. No difference was found when comparing accumulated BW gain of the piglets between the day of age at foster (d 1 vs. 7; P = 0.606) or between the control d 1 and control d 7 groups (P = 0.759). Accumulated BW gain of piglets suckling TG d 7 gilts from d 3 through 9 was greater (P < 0.02) than that of the other groups and continued to be greater (P < 0.05) than that of either of the control groups through d 15. However, by d 15, accumulated BW gain of piglets suckling TG d 1 gilts was no longer different (P = 0.40) from that of the TG d 7 group and was greater (P < 0.05) than that of the control d 1 group. The enhanced lactation potential of these TG gilts synergized with suckling intensity to stimulate increased milk production during early lactation, resulting in increased piglet growth.

Effect of the oestrous cycle, pregnancy and uterine region on the responsiveness of the isolated mouse uterus to prostaglandin F(2alpha) and the thromboxane mimetic U46619.

Previous studies in this laboratory have suggested that the isolated uterus from non-pregnant mice has a prostaglandin F and a thromboxane receptor population similar to that found in human myometrium. The aim of this study was to investigate any regional variation in myogenic activity ) and the and responsiveness to prostaglandin F(2alpha) (PGF(2alpha) thromboxane mimetic U46619 in the mouse uterus taken during different stages of the oestrous cycle and during pregnancy. Uterine samples from BKW mice were taken from different anatomical segments along the length of each uterine horn and set up for superfusion at 2 ml/min with Krebs solution (containing 1 microM indometacin) at 37 degrees C, and gassed with 95%O(2)/5%CO(2). Responses (area under the curve) are expressed as a percentage of the final contraction induced by hypotonic shock. Data are expressed as the means +/- s.e.m. of n=5-12 and were analysed using Student's paired t-test or two-way ANOVA with a Bonferroni post hoc test. Regional variation in myogenic activity was observed in all tissues studied except those taken during labour. These tissues displayed significantly greater myogenic activity than tissues taken at late gestation and at all stages of the oestrous cycle. Tissues from pregnant animals were generally more responsive to U46619 and PGF(2alpha) than tissues taken from non-pregnant animals. Tissues taken from the upper segment of the uterine horn were more responsive to both agonists during the oestrous cycle. The findings demonstrated that the hormonal milieu and site of excision are important for myogenic activity and responsiveness.

Identification of Escherichia coli O157:H7 meat processing indicators for fresh meat through comparison of the effects of selected antimicrobial interventions.

Fresh meat products can become contaminated with the pathogen Escherichia coli O157:H7 during the slaughter process; therefore, an E. coli O157:H7 indicator to verify the effectiveness of process controls in slaughter establishments would be extremely useful. The hides of 20 beef cattle were sampled, and 113 bacterial isolates were obtained. Thirteen of these isolates representing four genera, Escherichia, Enterobacter, Providencia, and Serratia, were selected based on growth and biochemical characteristics similar to those of five clinical strains of E. coli O157:H7. The temperature sensitivity was determined for the individual isolates and the five E. coli O157:H7 strains at 55 and 65 degrees C. D65-values for all 13 isolates were not significantly different from D65-values of the E. coli O157:H7 strains. E. coli isolates were the only isolates whose D55-values were not significantly different from those of the E. coli O157:H7 strains. E. coli isolates P3 and P68 were more resistant to the effects of 55 degrees C than were the other E. coli isolates but were not significantly different from E. coli O157:H7 WS 3331 (P > 0.05). The remaining E. coli isolates (P1, P8, and P14) were not significantly different from E. coli O157:H7 strains ATCC 35150, ATCC 43894, ATCC 43895, and WS 3062 (P > 0.05). Prerigor lean and adipose beef carcass tissue was artificially contaminated with stationary-phase cultures of the five E. coli beef cattle isolates or a cocktail of five E. coli O157:H7 strains in a fecal inoculum. Each tissue sample was processed with the following microbial interventions: 90 degrees C water; 90 degrees C water followed by 55 degrees C 2% lactic acid; 90 degrees C water followed by 20 degrees C 2% lactic acid; 20 degrees C water followed by 20 degrees C 2% lactic acid; 20 degrees C water followed by 20 degrees C 20 ppm chlorine; and 20 degrees C water followed by 20 degrees C 10% trisodium phosphate. The appropriateness of the E. coli isolates as potential E. coli O157:H7 indicators was dependent upon the microbial intervention utilized. For all microbial intervention methods applied irrespective of tissue type, the mean log reductions of at least two E. coli isolates were not significantly different from the mean log reduction of the E. coli O157:H7 cocktail (P > 0.05). Because of the frequent employment of multiple microbial interventions in the cattle industry, no single isolate can realistically represent the effectiveness of all microbial interventions for reduction of E. coil O157:H7. Thus, the use of a combination of E. coli isolates may be required to accurately predict the effectiveness of microbial intervention methods on the reduction of E. coli O157:H7 in beef carcass tissue.

Andreev probe of persistent current states in superconducting quantum circuits.

Using the extraordinary sensitivity of Andreev interferometers to the superconducting phase difference associated with currents, we measure the persistent current quantum states in superconducting loops interrupted by Josephson junctions. Straightforward electrical resistance measurements of the interferometers give a continuous readout of the states, allowing us to construct the energy spectrum of the quantum circuit. The probe is estimated to be more precise and faster than previous methods, and can measure the local phase difference in a wide range of superconducting circuits.

Effects of sub-chronic antipsychotic drug treatment on body weight and reproductive function in juvenile female rats.

RATIONALE: Weight gain caused by some antipsychotics is not only confined to adults but can also adversely affect both children and adolescents. Indeed, olanzapine and risperidone have been associated with extreme weight gain in adolescents even greater than that reported in adults. We have recently shown substantial weight gain in adult female rats following treatment with olanzapine and risperidone but not ziprasidone. OBJECTIVES: The aim of the present study was to compare the effects of several antipsychotics on weight gain and reproductive function in juvenile (aged 7 weeks) female hooded Lister rats. METHODS: Olanzapine (4 mg/kg), risperidone (0.5 mg/kg), ziprasidone (2.5 mg/kg), sulpiride (10 mg/kg), haloperidol (0.5 mg/kg) or vehicle was administered i.p. once per day for 21 days. Body weight, food and water intake were measured daily, in addition to the determination of stage of the oestrous cycle. RESULTS: Sub-chronic administration of olanzapine, risperidone, sulpiride and haloperidol, but not ziprasidone, significantly increased body weight compared to vehicle-treated animals during weeks 1-3. Sulpiride significantly increased food and water intake. Significantly increased percentage intra-abdominal fat weight was observed in olanzapine, risperidone, sulpiride and haloperidol, but not ziprasidone-treated animals. Marked disruption of the oestrous cycle was observed in all but the ziprasidone-treated group, which continued to have regular 4-day oestrous cycles. CONCLUSIONS: Weight gain observed in these juvenile animals was 1.5-2 times greater than that previously observed in adult rats. These findings have important implications for the use of antipsychotics in children and adolescent patients.

Investigation into the effects of the novel antipsychotic ziprasidone on weight gain and reproductive function in female rats.

Weight gain and sexual dysfunction are serious side effects of certain antipsychotic drugs. Ziprasidone, a novel antipsychotic with a unique receptor binding profile, is reported to have a low propensity for such side effects. Previous results from this laboratory have demonstrated substantial weight gain following sub-chronic treatment with olanzapine and risperidone. Risperidone induced weight gain and markedly impaired reproductive function while olanzapine induced weight gain, without affecting reproductive function. The aim of this study was to investigate effects of ziprasidone on weight gain and reproductive function in female rats. Ziprasidone (1 and 2.5 mg/kg i.p.) or vehicle was administered once daily for 28 days and body weight, food and water intake measured, in addition to histological examination of vaginal lavage to determine the stage of the oestrous cycle. On day 28, the rats were sacrificed and the uterine weights recorded, intra-abdominal fat weight and plasma prolactin levels measured. Ziprasidone failed to induce significant weight gain during weeks 1-3, however, significant weight gain was observed on day 28 at 2.5 mg/kg (p < 0.05). Ziprasidone had no effect on food intake at any time point. A significant reduction in water intake (p < 0.05) was observed during the first week of treatment with 2.5 mg/kg ziprasidone. Ziprasidone had no effect on intra-abdominal fat weight, wet or dry uterine weight or plasma prolactin levels. All ziprasidone treated animals displayed a normal four-day oestrous cycle. This study is the first to report that ziprasidone is without effect on reproductive function or ingestive behaviour in the rat.

Effects of the classical antipsychotic haloperidol and atypical antipsychotic risperidone on weight gain, the oestrous cycle and uterine weight in female rats.

Antipsychotic drug-induced side effects of weight gain and sexual dysfunction have clinical significance adversely affecting both compliance and morbidity. This study evaluated the effects of haloperidol and the atypical antipsychotic risperidone (0.1-1.0 mg/kg) on weight gain, food and water intake, the oestrous cycle and uterine weight in female hooded Lister rats. Haloperidol and risperidone treated rats displayed marked weight gain, although only risperidone induced significant increases in food consumption over the 21-day period. Neither haloperidol nor risperidone influenced water consumption. Marked disruption of the oestrous cycle was observed in risperidone- and haloperidol-treated animals (0.5 and 1.0 mg/kg), which was supported by significantly reduced uterine weights. The findings presented here suggest that the weight gain and sexual dysfunction induced by antipsychotics may be modelled in rodents. This model may offer insight into the mechanisms involved in mediation of such side effects.

Effects of the atypical antipsychotic olanzapine on reproductive function and weight gain in female rats.

Sexual dysfunction is a major, although poorly understood, side-effect of treatment with antipsychotic drugs. We have recently show marked disruption of reproductive function and weight gain in female rats treated subchronically with risperidone and haloperidol. The aim of the present study was to examine further the potential relationship between reproductive dysfunction and weight gain in female rats treated with olanzapine. The effects of olanzapine on weight gain, food and water intake, intra-abdominal fat, the oestrous cycle and uterine weight were assessed in group-housed adult female hooded-Lister rats. Olanzapine (0.5-4.0 mg/kg i.p.) or vehicle was administered once daily for 21 days and body weight, food and water intake measured, with histological examination of vaginal lavage to determine the stage of the oestrous cycle. On day 22, animals were sacrificed and intra-abdominal fat, wet and dry uterine weights measured. Olanzapine induced significant weight gain with concomitant increases in food and water intake and intra-abdominal fat without an effect on the oestrous cycle, wet and dry uterine weights or plasma prolactin levels. These results confirm the ability of olanzapine to induce weight gain in female rats on unrestricted normal diet with a concomitant increase in food and water intake and increased intra-abdominal fat. These effects of olanzapine were produced in the absence of any apparent impairment in reproductive function, in contrast to the substantial disruption of oestrous and uterine atrophy previously shown in rats treated with risperidone and haloperidol.

Characterisation of kinin receptors on the human isolated umbilical artery.

The aim of this study was to determine the kinin responses on human umbilical artery (HUA) and to characterise the kinin receptors present on this tissue. The HUA was found to constrict in response to both the B2 receptor agonist, bradykinin (BK), and the B1 receptor agonist, des-Arg9-BK. The presence of indomethacin (2.79 microM) was found to have no significant effect on the responses to BK and des-Arg9-BK. The presence of the B2 receptor antagonist, HOE-140 (+2.79 microM indomethacin), resulted in a concentration-related rightward displacement of the concentration-effect curves to BK. The antagonism of the constrictor responses to BK by HOE-140 was found to be competitive (pA2 = 7.5). The responses to BK were not significantly affected by the B1 receptor antagonist des-Arg9(leu8)BK. The presence of des-Arg9(leu8)BK (+2.79 microM indomethacin) resulted in a concentration-related rightward displacement of the concentration-effect curve to des-Arg9-BK. The antagonism of the response to des-Arg9-BK by des-Arg9(leu8)BK was found to be competitive (pA2 = 5.9). The responses to des-Arg9-BK were not significantly affected by HOE-140. The results of the present study suggest that the products of the cyclooxygenase pathway are not involved in the kinin constrictor response on HUA and indicate the presence of B1 and B2 receptors on this tissue.