Multigroup invariance of the DAS across a random and an internet-sourced sample.

It is well established that angry and, subsequently, aggressive drivers pose a problem for road safety. Over recent years, there has been an increase in the number of published studies examining driver anger, particularly using the Driving Anger Scale (DAS). The DAS measures six broad types of situations likely to provoke anger while driving (i.e., police presence, illegal driving, discourtesy, traffic obstructions, slower drivers, and hostile gestures). The majority of the recent studies have moved away from traditional paper-and-pencil methodologies, using the internet to collect data, for reasons of convenience. However, it is not yet completely clear whether data obtained from this methodology differs from more traditional methods. While research outside of the driving arena has not found substantial differences, it is important to establish whether this also applies to driving-related research and measures, such as the DAS. The present study used Multigroup Confirmatory Factor Analysis (MGCFA) to investigate the invariance of the DAS across a random sample from the electoral roll (n = 1,081: males = 45%) and an internet sourced sample (n = 627; males = 55%). The MGCFA showed the same six-factor solution was supported in both datasets. The relationships between the DAS factors and age, sex, trait anger, and annual mileage were broadly similar, although more significant differences were identified in the internet sample. This research demonstrates that driving measures administered over the internet produce similar results to those obtained using more traditional methods.

The effect of ozone fumigation on the biogenic volatile organic compounds (BVOCs) emitted from Brassica napus above- and below-ground.

The emissions of BVOCs from oilseed rape (Brassica napus), both when the plant is exposed to clean air and when it is fumigated with ozone at environmentally-relevant mixing ratios (ca. 135 ppbv), were measured under controlled laboratory conditions. Emissions of BVOCs were recorded from combined leaf and root chambers using a recently developed Selective Reagent Ionisation-Time of Flight-Mass Spectrometer (SRI-ToF-MS) enabling BVOC detection with high time and mass resolution, together with the ability to identify certain molecular functionality. Emissions of BVOCs from below-ground were found to be dominated by sulfur compounds including methanethiol, dimethyl disulfide and dimethyl sulfide, and these emissions did not change following fumigation of the plant with ozone. Emissions from above-ground plant organs exposed to clean air were dominated by methanol, monoterpenes, 4-oxopentanal and methanethiol. Ozone fumigation of the plants caused a rapid decrease in monoterpene and sesquiterpene concentrations in the leaf chamber and increased concentrations of ca. 20 oxygenated species, almost doubling the total carbon lost by the plant leaves as volatiles. The drop in sesquiterpenes concentrations was attributed to ozonolysis occurring to a major extent on the leaf surface. The drop in monoterpene concentrations was attributed to gas phase reactions with OH radicals deriving from ozonolysis reactions. As plant-emitted terpenoids have been shown to play a role in plant-plant and plant-insect signalling, the rapid loss of these species in the air surrounding the plants during photochemical pollution episodes may have a significant impact on plant-plant and plant-insect communications.

Addressing prescription discrepancies in renal patients: a prospective audit.

Background Management of chronic renal failure requires complex medication regimens to manage hypertension, hyperlipidaemia, diabetes, phosphate, anaemia and acidosis. Patient engagement in medicine management is essential to avoid potential harm. Methods We prospectively audited the rate of discrepancies between our hospital record of patient medications and their current prescription. We investigated whether changes to appointment letters reduced the number of discrepancies. Results The proportion of patients attending renal outpatient clinics failing to bring a list or unable to recall their medications fell over a 3-year period following changes to appointment letters (median proportion: 0.45 in 2014, 0.36 in 2015, 0.30 in 2016, Chi-sq = 46.94, p < 0.001); percentage of patients forgetting to bring a list with significant prescription discrepancies fell from 10.9% in 2014 to 3.9% in 2016). Conclusion Changes to appointment letters can potentially improve prescribing safety in an outpatient setting.

Joint attention for stimuli on the hands: ownership matters.

The visual system treats the space near the hands with unique, action-related priorities. For example, attention orients slowly to stimuli on the hands (Taylor and Witt, 2014). In this article, we asked whether jointly attended hands are attended in the same way. Specifically, we examined whether ownership over the hand mattered: do we attend to our hands and the hands of others in the same way? Pairs of participants performed a spatial cueing task with stimuli that could be projected onto one partner's hands or on a control surface. Results show delayed orienting of attention to targets appearing on the hands, but only for the owner of the hands. For an observer, others' hands are like any other surface. This result emphasizes the importance of ownership for hand-based effects on vision, and in doing so, is inconsistent with some expectations of the joint action literature.

Fungal pathogens of Proteaceae.

Species of Leucadendron, Leucospermum and Protea (Proteaceae) are in high demand for the international floriculture market due to their brightly coloured and textured flowers or bracts. Fungal pathogens, however, create a serious problem in cultivating flawless blooms. The aim of the present study was to characterise several of these pathogens using morphology, culture characteristics, and DNA sequence data of the rRNA-ITS and LSU genes. In some cases additional genes such as TEF 1-α and CHS were also sequenced. Based on the results of this study, several novel species and genera are described. Brunneosphaerella leaf blight is shown to be caused by three species, namely B. jonkershoekensis on Protea repens, B. nitidae sp. nov. on Protea nitida and B. protearum on a wide host range of Protea spp. (South Africa). Coniothyrium-like species associated with Coniothyrium leaf spot are allocated to other genera, namely Curreya grandicipis on Protea grandiceps, and Microsphaeropsis proteae on P. nitida (South Africa). Diaporthe leucospermi is described on Leucospermum sp. (Australia), and Diplodina microsperma newly reported on Protea sp. (New Zealand). Pyrenophora blight is caused by a novel species, Pyrenophora leucospermi, and not Drechslera biseptata or D. dematoidea as previously reported. Fusicladium proteae is described on Protea sp. (South Africa), Pestalotiopsis protearum on Leucospermum cuneiforme (Zimbabwe), Ramularia vizellae and R. stellenboschensis on Protea spp. (South Africa), and Teratosphaeria capensis on Protea spp. (Portugal, South Africa). Aureobasidium leaf spot is shown to be caused by two species, namely A. proteae comb. nov. on Protea spp. (South Africa), and A. leucospermi sp. nov. on Leucospermum spp. (Indonesia, Portugal, South Africa). Novel genera and species elucidated in this study include Gordonomyces mucovaginatus and Pseudopassalora gouriqua (hyphomycetes), and Xenoconiothyrium catenata (coelomycete), all on Protea spp. (South Africa).

Discovery and characterization of taspoglutide, a novel analogue of human glucagon-like peptide-1, engineered for sustained therapeutic activity in type 2 diabetes.

AIM: Glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of type 2 diabetes are administered by daily injection because of short plasma half-lives, which result partly from the biochemical instability of these peptides. There is a medical need for GLP-1 analogues that can be administered less frequently for patient convenience. METHODS: We synthesized a series of human GLP-1 (hGLP-1(7-36)NH(2) ) derivatives containing α-aminoisobutyric acid (Aib) substitutions, analysed their enzymatic stabilities and evaluated their secondary structures using circular dichroism (CD) and nuclear magnetic resonance (NMR). RESULTS: Plasma stability experiments showed that only the analogue containing Aib substitutions in both the N-terminus (position 8) and the C-terminus (position 35), [Aib8(,)³5]hGLP-1(7-36)NH2 (BIM-51077), was fully resistant to enzymatic cleavage. Incubation with human plasma kallikrein or plasmin confirmed that the Aib substitution at position 35 prevented protease cleavage around this residue, which contributes to the significantly enhanced plasma stability and increased plasma half-life. CD revealed increased C-terminal α-helicity in Aib³5-substituted analogues compared with both hGLP-1(7-36)NH2 and analogues containing only Aib8 substitutions. Based on NMR studies, the secondary structure of BIM-51077 is similar to hGLP-1(7-36)NH2 with a slight increase in α-helicity in the C-terminus. Compared with hGLP-1(7-36)NH2, BIM-51077 had similar binding affinity for the human GLP-1 receptor and activated this receptor with similar potency. CONCLUSIONS: We have discovered an Aib8(,)³5-substituted analogue of native hGLP-1(7-36)NH2 (BIM-51077) that retains the structure of the native peptide, and has similar activity and enhanced stability. A sustained-release formulation of this molecule (taspoglutide) is in phase-3 clinical development.

Shear rheology of molten crumb chocolate.

The shear rheology of fresh molten chocolate produced from crumb was studied over 5 decades of shear rate using controlled stress devices. The Carreau model was found to be a more accurate description than the traditional Casson model, especially at shear rates between 0.1 and 1 s(-1). At shear rates around 0.1 s(-1) (shear stress approximately 7 Pa) the material exhibited a transition to a solid regime, similar to the behavior reported by Coussot (2005) for other granular suspensions. The nature of the suspension was explored by investigating the effect of solids concentration (0.20 < phi < 0.75) and the nature of the particles. The rheology of the chocolate was then compared with the rheology of (1) a synthetic chocolate, which contained sunflower oil in place of cocoa butter, and (2) a suspension of sugar of a similar size distribution (volume mean 15 mum) in cocoa butter and emulsifier. The chocolate and synthetic chocolate showed very similar rheological profiles under both steady shear and oscillatory shear. The chocolate and the sugar suspension showed similar Krieger-Dougherty dependency on volume fraction, and a noticeable transition to a stiff state at solids volume fractions above approximately 0.5. Similar behavior has been reported by Citerne and others (2001) for a smooth peanut butter, which had a similar particle size distribution and solids loading to chocolate. The results indicate that the melt rheology of the chocolate is dominated by hydrodynamic interactions, although at high solids volume fractions the emulsifier may contribute to the departure of the apparent viscosity from the predicted trend.

Effects of selective somatostatin analogs and cortistatin on cell viability in cultured human non-functioning pituitary adenomas.

Clinically "non-functioning" human pituitary adenomas (NFPA) constitute about 35% of pituitary adenomas. Somatostatin receptors (SSTR) expression in these adenomas has previously been described both in vitro and in vivo, without evidence for a correlation with tumor volume or the therapeutic efficacy of somatostatin analogs. This study was performed on 13 surgically removed pituitary macroadenomas, diagnosed before surgery as "non-functioning". In addition, 3 growth hormone (GH)-secreting adenomas served as controls. A specimen from each tumor was dispersed and digested to isolate and culture the tumor cells, and the in vitro effects of SSTR2 and SSTR5 selective analogs and Cortistatin (CST) (100nM) on cell viability were studied. The quantity of viable cells was estimated using the XTT method. RNA purification of tumor samples and subsequent RT-PCR studies for SSTR2 and SSTR5 expression were performed. Somatostatin analog with high affinity for SSTR2 reduced cell viability by 20-80% in 8 of 13 NFPAs studied, all expressing the SSTR2. The inhibitory effect on cell viability of SSTR5-selective analog was 15-80% in 10 of 13 NFPAs studied, all but three expressing the SSTR5. CST, however, effectively reduced cell viability in only 6 NFPAs. Cell viability was inhibited by all peptides studied in 2 out of 3 GH-secreting adenomas, expressing both receptors. The third adenoma responded to SSTR2 analog and expressed only SSTR2. These results suggest the involvement of SSTR2 and SSTR5 in the anti-proliferative effects of somatostatin; however, CST is less potent in reducing cell viability in these tumors.

In vitro antiangiogenic activity of selective somatostatin subtype-1 receptor agonists.

BACKGROUND: Endothelial cells of human blood vessels (arteries and veins) show high levels of somatostatin subtype-1 receptor (sst(1)). The aim of the present study is to investigate the inhibitory effects of novel somatostatin analogs, highly selective for human sst(1), on in vitro angiogenesis and their modulation of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR-2) expression. MATERIALS AND METHODS: Somatostatin analogs BIM-23745 and BIM-23926 were tested for their ability to prevent proliferation and migration of human endothelial HMEC-1 cells, to modulate VEGF and VEGFR-2 expression and to inhibit sprouting of microvessels from cultured human placental vessel explants in fibrin matrix for 28 days. RESULTS: The somatostatin sst(1 )receptor-selective agonists, BIM-23745 and BIM-23926 showed a suppression of endothelial proliferation (e.g. 10(-6) M BIM-23475, 40.0 +/- 2.1% vs. 100% of controls; 10(-7) M BIM-23926, 55.3 +/- 3.3% vs. 100% of controls), migration (e.g. 10(-7) M BIM-23475, 35.0 +/- 1.56% vs. 100% of controls; 10(-7) M BIM-23926, 53.7 +/- 1.77% vs. 100% of controls) and microvessel sprouting (e.g. 10(-8) M BIM-23475, 42.8 +/- 5.6% vs. 100% of controls; 10(-7) M BIM-23926, 17.2 +/- 11.8% vs. 100% of controls). A small but significant percentage of cells exposed to BIM-23745 and BIM-23926 for 24 h and for 72 h presented typical apoptotic morphology. Moreover, both the analogs significantly inhibit VEGF and VEGFR-2 gene expression in endothelial cells grown for 144 h in a fibrin matrix and the VEGF secretion in conditioned media. CONCLUSIONS: The inhibition of endothelial activities suggests potential therapeutic utility for administration of somatostatin sst(1 )receptor-selective agonists in the proliferative diseases involving angiogenesis.

Regulation of insulin and glucagon secretion from rat pancreatic islets in vitro by somatostatin analogues.

Somatostatin is an inhibitor of hormone secretion through specific receptors (sst1-5). The aim of this study was to investigate the putative regulatory role of somatostatin analogues on the secretion of insulin and glucagon by rat pancreatic islets. After 48 h exposure only the non-selective agonists (somatostatin, octreotide and SOM-230) inhibited insulin accumulation. The inhibition of insulin secretion was accompanied by increased islet insulin contents. None of the analogues showed a consistent effect on the glucagon accumulation in the medium after 48 h. Since we observed a difference in the regulatory effect between the non-selective and selective analogues, combinations of selective analogues were studied. Combination of sst2+sst5 agonists inhibited the medium insulin accumulation, while combination of sst1+sst2 analogues caused a decrease in glucagon accumulation. After removal of somatostatin a rebound effect with increased insulin secretion were observed. This effect was reversed after 6 h. For SOM-230 insulin secretion continued to be suppressed even after the analogue was removed and returned to control values after 3 h. As for glucagon secretion there was an initial decline after culture with octreotide, while the other substances failed to induce any changes. In summary, non-selective somatostatin analogues or combinations of receptor selective analogues may cause inhibition of hormone secretion from rat pancreatic islets. For insulin and glucagon, combinations of sst2+sst5 and sst1+sst2, respectively may exert this effects. Thus, our data suggest that more than one sst must be involved to down-regulate islet glucagon and insulin secretion.

Does metabolic syndrome mitigate weight loss in overweight Mexican American women treated for 1-year with orlistat and lifestyle modification?

AIMS: To investigate the effects of a pharmacotherapy (orlistat) plus lifestyle management (OLM) intervention on weight loss in Mexican American women with and without metabolic syndrome (MS). METHODS: One hundred and seven female participants aged 21-65 years and of Mexican origin were randomized to either OLM or a wait-list control group (WLC) for one year. The lifestyle interventions were tailored to exhibit features of the Mexican culture. Within each group, subjects with MS were compared to those without MS to assess whether its presence mitigates weight loss. Risk factors for MS also were assessed. RESULTS: Participants with MS in the OLM group experienced significant decreases in weight and body mass index (BMI) as compared to participants without MS. Participants with MS in the OLM group and who completed the study lost 9.3+/-7.5 kg (20.5+/-16.5 lb) as compared to participants with MS in the WLC group, who only lost 0.2+/-3.1 kg (0.4+/-6.8 lb). Further, participants with MS in the OLM group who completed the study experienced a 3.1+/-3.9 kg/m2 decrease in BMI whereas participants with MS in the WLC group only experienced a 0.1+/-1.2 kg/m2 decrease in BMI. No changes in other MS risk factors were significant. CONCLUSIONS: Patients with MS experienced significant weight loss and decreases in BMI as a result of a lifestyle and pharmacotherapy intervention.

Inference for magnitudes and delays of responses in the FIAC data using BRAINSTAT/FMRISTAT.

We used straightforward linear mixed effects models as described in Worsley et al. together with recent advances in smoothing to control the degrees of freedom, and random field theory based on discrete local maxima. This has been implemented in BRAINSTAT, a Python version of FMRISTAT. Our main novelty is voxel-wise inference for both magnitude and delay (latency) of the hemodynamic response. Our analysis appears to be more sensitive than that of Dehaene-Lambertz et al. Our main findings are greater magnitude (1.08% +/- 0.17%) and delay (0.153 +/- 0.035 s) for different sentences compared to same sentences, together with a smaller but still significantly greater magnitude for different speaker compared to same speaker (0.47% +/- 0.08%).

Detecting fMRI activation allowing for unknown latency of the hemodynamic response.

Several authors have suggested allowing for unknown latency of the hemodynamic response by incorporation of hemodynamic derivative terms into the linear model for the statistical analysis of fMRI data. In this paper, we show how to use random field theory to provide a P value for local maxima of two test statistics that have been recently proposed for detecting activation based on this analysis.

Brain-derived neurotrophic factor promotes bovine oocyte cytoplasmic competence for embryo development.

The ability of an oocyte to support early embryonic development requires both nuclear and cytoplasmic maturation. We have investigated the effects of brain-derived neurotrophic factor (BDNF) on maturation of the bovine oocyte and embryo development after parthenogenetic activation. By RT-PCR and immunohistochemistry, cumulus and oocytes were shown to express mRNA and protein for BDNF and the p75 common neurotrophin receptor. However, mRNA for the BDNF-specific full length and truncated isoforms of the TrkB receptor are only detected in cumulus, suggesting that oocytes and cumulus differ in their capacity to respond to neurotrophin signalling. In in vitro maturation experiments, the proportion of cumulus oocyte complexes maturing to metaphase II was not altered by BDNF in groups lacking fetal calf serum (FCS), but was significantly lower than the positive control containing 10% FCS (P < 0.01). However, after maturation, the proportion of parthenogenetically activated oocytes forming blastocysts was highest for 10 ng/ml BDNF (24%, n = 95) followed by 100 ng/ml BDNF (18%, n = 91) and 10% FCS (15%, n = 103), which in turn were greater than no serum (10%, n = 83; P < 0.01). Maturation in the presence of a BDNF blocking antibody resulted in a blastocyst yield that was comparable to the absence of serum, and lower than in the presence of BDNF (P < 0.01). Similar effects on progression to metaphase II and blastocyst formation were observed using oocytes matured without cumulus. Together, these results provide the first evidence for a role for neurotrophins in promoting oocyte cytoplasmic competence to support embryonic development, despite being insufficient in the absence of serum to enhance nuclear maturation.

Novel ghrelin analogs with improved affinity for the GH secretagogue receptor stimulate GH and prolactin release from human pituitary cells.

OBJECTIVE: Ghrelin, a recently identified 28-amino acid peptide is a potent GH secretagogue (GHS) produced predominantly by the stomach. Ghrelin stimulates GH secretion through binding to the GHS receptor in the hypothalamus and pituitary. In addition to the GH-releasing action, ghrelin has been found to be a powerful orexigenic factor. To assess the direct in vitro effects of ghrelin on human pituitary hormone secretion we have produced a panel of novel ghrelin analogs (molecular weight, 3323-3384; human native ghrelin, 3371) with enhanced affinity for the human GHS receptor (IC(50) 0.38-1.09 nM; human ghrelin, 1.2-2.2 nM). METHODS: The peptidic analogs were tested for their effect on GH secretion using dispersed human fetal pituitaries (21 to 23 weeks of gestation) and cultured GH- and prolactin (PRL)-secreting adenomas. The expression of the GHS receptor in normal (fetal and adult) human pituitary tissues, GH- and PRL-cell adenomas was established using RT-PCR. RESULTS: The effects of ghrelin, its analogs and GH-releasing hormone (GHRH) alone or in combination on GH and PRL secretion were compared at various concentrations. The ghrelin analogs stimulated GH release by 35-60% from human fetal pituitary cells (1-10 nM; P<0.05) and by 50-75% from cultured pituitary adenomas (10 nM; P<0.05). This releasing effect was dose-dependent, achieving maximal stimulation with analog concentrations at 100 nM. Human ghrelin was less potent as compared with its analogs in stimulating human GH, in keeping with the improved binding affinity of the analogs for the GHS-1a receptor. The ghrelin analogs and GHRH had comparable effects on GH secretion from both normal and adenomatous cells, and in combination produced an additive stimulatory effect on GH (150%; P<0.0001). In contrast, ghrelin and its analogs induced a comparable increase in PRL release ranging between 25 and 40% (P<0.05) from fetal cells and 30 and 70% (P<0.001) from cultured PRL-cell and mixed GH-PRL adenomas. CONCLUSIONS: Our results have demonstrated for the first time that ghrelin analogs with enhanced affinity for the GHS receptor are potent stimulators of GH secretion from human pituitary cells, and thus may possess potential clinical therapeutic benefits.

Expression and function of somatostatin receptor subtype 1 in human growth hormone secreting pituitary tumors deriving from patients partially responsive or resistant to long-term treatment with somatostatin analogs.

The role of somatostatin (SS) receptor subtype 1 (SSTR(1)) in mediating the inhibitory effect of SS on growth hormone (GH) secreting pituitary tumors has been recently demonstrated. In the present study, we evaluated the effect of the selective SSTR(1) agonist BIM-23745 on in vitro GH secretion in GH-secreting pituitary tumor cells, deriving from patients resistant or partially responsive to octreotide long-acting release (octreotide-LAR) or lanreotide therapy in vivo and expressing SSTR(1) mRNA. In addition, the inhibiting effect of BIM-23745 on the GH secretion was compared with that of octreotide. Our data demonstrate that (1) SSTR(1) receptor was present in 56.25% (9/16) of the GH-secreting adenomas examined; (2) in all GH-secreting pituitary tumors that expressed SSTR(1), BIM-23745 significantly inhibited GH secretion in vitro, and (3) when SSTR(1) subtype was present in tumors from patients resistant to octreotide-LAR or lanreotide therapy, BIM-23745 was able to inhibit the in vitro GH secretion. In conclusion, the results of the current study suggest that SS analogs selective for the SSTR(1) may represent a further useful approach for the treatment of acromegaly in patients resistant or partially responsive to octreotide-LAR or lanreotide treatment in vivo.

Weight loss in obese Mexican Americans treated for 1-year with orlistat and lifestyle modification.

OBJECTIVE: To evaluate the effectiveness of a culturally appropriate lifestyle intervention combined with orlistat in producing weight loss with obese Mexican-American women. SUBJECTS: Mexican-American women (N=108), aged 21-65 y, with a body mass index (BMI) > or =27 kg/m(2) were randomized to 1 y of treatment with orlistat and a culturally tailored lifestyle modification intervention (OLM; n=56) or a wait-list control group (WLC; n=52). DESIGN: A randomized, controlled, open-label 12-month study. Orlistat was dosed at 120 mg, three times per day. The OLM intervention included behavior modification, a low-fat (< or =30% of total daily calories) diet, and moderate physical activity (> or =150 min/week). MEASUREMENT: Primary outcomes included changes in body weight (kg), BMI, waist circumference, blood pressure, glucose, and lipids. RESULTS: A total of 72 (37 OLM, 35 WLC) and 66 participants (32 OLM, 34 WLC) completed the 6- and 12-month follow-ups, respectively. Repeated-measures ANOVA demonstrated a significant time x treatment interaction (Wilks' lambda=12.61; P<0.001), indicating that OLM-treated patients achieved significant weight loss relative to the WLC group during the study (mean percentage weight loss+/-s.e.m.; -8.1%+/-1.2 vs -1.6%+/-0.7 at 6 months and -8.8%+/-1.5 vs -0.2%+/-1.0 at 12 months, respectively). OLM-treated patients also experienced significant reductions in waist circumference, low-density-lipoprotein, and total cholesterol. CONCLUSIONS: This study demonstrates the effectiveness of an intervention combining orlistat and lifestyle modification with Mexican-American women, a population with substantial risk for obesity.

Psychometric characteristics of the General Well-Being Schedule (GWB) with African-American women.

The General Well-Being Schedule (GWB) is a brief, reliable, and valid instrument used in population studies to assess psychological well-being, although its validity with African-Americans has yet to be established. This study evaluated the reliability, validity, and factor structure of the GWB in a sample of 599 overweight African-American women who participated in multicenter weight loss trial. The results of the factor analysis indicate that the GWB is primarily unidimensional and that the existence of the six hypothesized subscales was not supported. The GWB demonstrated evidence of concurrent and construct validity when examined in association with measures of self-concept, depression, and several health behaviors. The results of this study suggest that the GWB is a reliable and valid measure of psychological well-being in African-American women.

Demonstration of enhanced potency of a chimeric somatostatin-dopamine molecule, BIM-23A387, in suppressing growth hormone and prolactin secretion from human pituitary somatotroph adenoma cells.

In acromegaly, the combination of somatostatin (SS) and dopamine (DA) agonists has been shown to enhance suppression of GH secretion. In the present study, a new chimeric molecule, BIM-23A387, which selectively binds to the SS subtype 2 receptor (sst(2); K(i) = 0.10 nM) and to the DA D2 receptor (D2DR; K(i) = 22.1 nM) was tested in cultures prepared from 11 human GH-secreting tumors for its ability to suppress GH and prolactin (PRL) secretion. The chimeric compound was compared with individual sst(2) and D2DR agonists of comparable activity at the individual receptors. All tumors expressed both sst(2) and D2DR mRNAs (0.8 +/- 0.2 and 4.7 +/- 0.7 copy/copy beta-glucuronidase mRNA, respectively). In cell cultures from seven octreotide-sensitive tumors, the maximal inhibition of GH release induced by the individual sst(2) and D2DR analogs and by BIM-23A387 was similar. However, the mean EC(50) for GH suppression by BIM-23A387 (0.2 pM) was 50 times lower than that of the individual sst(2) and D2DR analogs, either used individually or combined. Similar data were obtained in four tumors that were only partially responsive to octreotide. The inhibition of GH release by BIM-23A387 was only partially reversed by the D2R2 antagonist, sulpiride, or by the sst(2) antagonist, BIM-23454. Only when both antagonists were combined was the GH suppressive effect of BIM-23A387 totally reversed. Finally, BIM-23A387 produced a mean 73 +/- 6% inhibition of PRL in six mixed GH plus PRL tumors. These data demonstrate an enhanced potency of the chimeric molecule, BIM-23A387, in suppressing GH and PRL secretion from acromegalic tumors, which cannot be explained merely on the basis of binding affinity for SS and/or DA receptors.