Linking the supersymmetric standard model to the cosmological constant.

String theory has no parameter except the string scale M S , so the Planck scale M Pl, the supersymmetry-breaking scale , the electroweak scale m EW as well as the vacuum energy density (cosmological constant) Λ are to be determined dynamically at any local minimum solution in the string theory landscape. Here we consider a model that links the supersymmetric electroweak phenomenology (bottom up) to the string theory motivated flux compactification approach (top down). In this model, supersymmetry is broken by a combination of the racetrack Kähler uplift mechanism, which naturally allows an exponentially small positive Λ in a local minimum, and the anti-D3-brane in the KKLT scenario. In the absence of the Higgs doublets from the supersymmetric standard model, one has either a small Λ or a big enough , but not both. The introduction of the Higgs fields (with their soft terms) allows a small Λ and a big enough simultaneously. Since an exponentially small Λ is statistically preferred (as the properly normalized probability distribution P(Λ) diverges at Λ = 0+), identifying the observed Λobs to the median value Λ50% yields m EW ∼ 100 GeV. We also find that the warped anti-D3-brane tension has a SUSY-breaking scale ∼ 100 m EW while the SUSY-breaking scale that directly correlates with the Higgs fields in the visible sector is ≃ m EW.

Recognizing Axionic Dark Matter by Compton and de Broglie Scale Modulation of Pulsar Timing.

Light axionic dark matter, motivated by string theory, is increasingly favored for the "no weakly interacting massive particle era". Galaxy formation is suppressed below a Jeans scale of ≃10^{8} M_{⊙} by setting the axion mass to m_{B}∼10^{-22} eV, and the large dark cores of dwarf galaxies are explained as solitons on the de Broglie scale. This is persuasive, but detection of the inherent scalar field oscillation at the Compton frequency ω_{B}=(2.5 months)^{-1}(m_{B}/10^{-22} eV) would be definitive. By evolving the coupled Schrödinger-Poisson equation for a Bose-Einstein condensate, we predict the dark matter is fully modulated by de Broglie interference, with a dense soliton core of size ≃150 pc, at the Galactic center. The oscillating field pressure induces general relativistic time dilation in proportion to the local dark matter density and pulsars within this dense core have detectably large timing residuals of ≃400 nsec/(m_{B}/10^{-22} eV). This is encouraging as many new pulsars should be discovered near the Galactic center with planned radio surveys. More generally, over the whole Galaxy, differences in dark matter density between pairs of pulsars imprints a pairwise Galactocentric signature that can be distinguished from an isotropic gravitational wave background.

Hofmeister Anion Effects on Thermodynamics of Caffeine Partitioning between Aqueous and Cyclohexane Phases.

Specific anion effects on the thermodynamics of caffeine partitioning between aqueous and cyclohexane phases were studied in the presence of 11 sodium salts by utilizing UV-vis spectroscopy. It is observed that weakly hydrated anions such as ClO4-, SCN-, and I- salt caffeine into the aqueous phase and increase the standard Gibbs free energy for caffeine transfer. On the other hand, well-hydrated anions such as CO32- and SO42- salt caffeine molecules out of the aqueous solution and promote the transfer process. Results suggest that weakly hydrated anions associate with the hydrophobic patches of caffeine including three methyl groups and a flat heteroatomic ring to solvate caffeine molecules. Well-hydrated anions are excluded from the caffeine surface to salt caffeine molecules out of aqueous solution. Moreover, the enthalpy and entropy of caffeine transfer were obtained by measuring the standard Gibbs free energy for caffeine transfer at varied temperatures. The transfer of caffeine from the aqueous to cyclohexane phase was an endothermic process driven by the entropy of caffeine transfer. However, the trend in standard Gibbs free energy across the Hofmeister series was determined by the enthalpy of caffeine transfer. These results provide an enthalpic origin to explain the Hofmeister trends in aqueous solution.

Nucleus accumbens deep-brain stimulation efficacy in ACTH-pretreated rats: alterations in mitochondrial function relate to antidepressant-like effects.

Mitochondrial dysfunction has a critical role in the pathophysiology of mood disorders and treatment response. To investigate this, we established an animal model exhibiting a state of antidepressant treatment resistance in male Wistar rats using 21 days of adrenocorticotropic hormone (ACTH) administration (100 µg per day). First, the effect of ACTH treatment on the efficacy of imipramine (10 mg kg(-1)) was investigated alongside its effect on the prefrontal cortex (PFC) mitochondrial function. Second, we examined the mood-regulatory actions of chronic (7 day) high-frequency nucleus accumbens (NAc) deep-brain stimulation (DBS; 130 Hz, 100 µA, 90 µS) and concomitant PFC mitochondrial function. Antidepressant-like responses were assessed in the open field test (OFT) and forced swim test (FST) for both conditions. ACTH pretreatment prevented imipramine-mediated improvement in mobility during the FST (P<0.05). NAc DBS effectively improved FST mobility in ACTH-treated animals (P<0.05). No improvement in mobility was observed for sham control animals (P>0.05). Analyses of PFC mitochondrial function revealed that ACTH-treated animals had decreased capacity for adenosine triphosphate production compared with controls. In contrast, ACTH animals following NAc DBS demonstrated greater mitochondrial function relative to controls. Interestingly, a proportion (30%) of the ACTH-treated animals exhibited heightened locomotor activity in the OFT and exaggerated escape behaviors during the FST, together with general hyperactivity in their home-cage settings. More importantly, the induction of this mania-like phenotype was accompanied by overcompensative increased mitochondrial respiration. Manifestation of a DBS-induced mania-like phenotype in imipramine-resistant animals highlights the potential use of this model in elucidating mechanisms of mood dysregulation.

Unified selective sorting approach to analyse multi-electrode extracellular data.

Extracellular data analysis has become a quintessential method for understanding the neurophysiological responses to stimuli. This demands stringent techniques owing to the complicated nature of the recording environment. In this paper, we highlight the challenges in extracellular multi-electrode recording and data analysis as well as the limitations pertaining to some of the currently employed methodologies. To address some of the challenges, we present a unified algorithm in the form of selective sorting. Selective sorting is modelled around hypothesized generative model, which addresses the natural phenomena of spikes triggered by an intricate neuronal population. The algorithm incorporates Cepstrum of Bispectrum, ad hoc clustering algorithms, wavelet transforms, least square and correlation concepts which strategically tailors a sequence to characterize and form distinctive clusters. Additionally, we demonstrate the influence of noise modelled wavelets to sort overlapping spikes. The algorithm is evaluated using both raw and synthesized data sets with different levels of complexity and the performances are tabulated for comparison using widely accepted qualitative and quantitative indicators.

Feasibility of investigating differential proteomic expression in depression: implications for biomarker development in mood disorders.

The objective of this study was to determine whether proteomic profiling in serum samples can be utilized in identifying and differentiating mood disorders. A consecutive sample of patients with a confirmed diagnosis of unipolar (UP n=52) or bipolar depression (BP-I n=46, BP-II n=49) and controls (n=141) were recruited. A 7.5-ml blood sample was drawn for proteomic multiplex profiling of 320 proteins utilizing the Myriad RBM Discovery Multi-Analyte Profiling platform. After correcting for multiple testing and adjusting for covariates, growth differentiation factor 15 (GDF-15), hemopexin (HPX), hepsin (HPN), matrix metalloproteinase-7 (MMP-7), retinol-binding protein 4 (RBP-4) and transthyretin (TTR) all showed statistically significant differences among groups. In a series of three post hoc analyses correcting for multiple testing, MMP-7 was significantly different in mood disorder (BP-I+BP-II+UP) vs controls, MMP-7, GDF-15, HPN were significantly different in bipolar cases (BP-I+BP-II) vs controls, and GDF-15, HPX, HPN, RBP-4 and TTR proteins were all significantly different in BP-I vs controls. Good diagnostic accuracy (ROC-AUC⩾0.8) was obtained most notably for GDF-15, RBP-4 and TTR when comparing BP-I vs controls. While based on a small sample not adjusted for medication state, this discovery sample with a conservative method of correction suggests feasibility in using proteomic panels to assist in identifying and distinguishing mood disorders, in particular bipolar I disorder. Replication studies for confirmation, consideration of state vs trait serial assays to delineate proteomic expression of bipolar depression vs previous mania, and utility studies to assess proteomic expression profiling as an advanced decision making tool or companion diagnostic are encouraged.

Effects of Preventative Ankle Taping on Planned Change-of-Direction and Reactive Agility Performance and Ankle Muscle Activity in Basketballers.

This study investigated the effects of preventative ankle taping on planned change-of-direction and reactive agility performance and peak ankle muscle activity in basketballers. Twenty male basketballers (age = 22.30 ± 3.97 years; height = 1.84 ± 0.09 meters; body mass = 85.96 ± 11.88 kilograms) with no ankle pathologies attended two testing sessions. Within each session, subjects completed six planned and six reactive randomized trials (three to the left and three to the right for each condition) of the Y-shaped agility test, which was recorded by timing lights. In one session, subjects had both ankles un-taped. In the other, both ankles were taped using a modified subtalar sling. Peak tibialis anterior, peroneus longus (PL), peroneus brevis (PB), and soleus muscle activity was recorded for both the inside and outside legs across stance phase during the directional change, which was normalized against 10-meter sprint muscle activity (nEMG). Both the inside and outside cut legs during the change-of-direction step were investigated. Repeated measures ANOVA determined performance time and nEMG differences between un-taped and taped conditions. There were no differences in planned change-of-direction or reactive agility times between the conditions. Inside cut leg PL nEMG decreased when taped for the planned left, reactive left, and reactive right cuts (p = 0.01). Outside leg PB and soleus nEMG increased during the taped planned left cut (p = 0.02). There were no other nEMG changes during the cuts with taping. Taping did not affect change-of-direction or agility performance. Inside leg PL activity was decreased, possibly due to the tape following the line of muscle action. This may reduce the kinetic demand for the PL during cuts. In conclusion, ankle taping did not significantly affect planned change-of-direction or reactive agility performance, and did not demonstrate large changes in activity of the muscle complex in healthy basketballers. Key pointsAnkle taping using the modified subtalar sling will not affect planned change-of-direction or reactive agility performance as measured by the Y-shaped agility test in healthy male basketball players.Ankle taping using the modified subtalar sling will also generally not affect the activity of the muscles about the ankle. There was some indication for reductions in the activity of the PL in the inside leg of certain cuts.The tape used for the modified subtalar sling may have supported the line of action of the PL, which could reduce the kinetic demand placed on this muscle, and provide a potential fatigue-reducing component for cutting actions.The subtalar sling taping of the ankle in healthy basketball players did not have any adverse effects on the muscle activity of the ankle-foot complex during planned change-of-direction or reactive agility performance tasks.

Towards a classification of biomarkers of neuropsychiatric disease: from encompass to compass.

There is currently considerable imprecision in the nosology of biomarkers used in the study of neuropsychiatric disease. The neuropsychiatric field lags behind others such as oncology, wherein, rather than using 'biomarker' as a blanket term for a diverse range of clinical phenomena, biomarkers have been actively classified into separate categories, including prognostic and predictive tests. A similar taxonomy is proposed for neuropsychiatric diseases in which the core biology remains relatively unknown. This paper divides potential biomarkers into those of (1) risk, (2) diagnosis/trait, (3) state or acuity, (4) stage, (5) treatment response and (6) prognosis, and provides illustrative exemplars. Of course, biomarkers rely on available technology and, as we learn more about the neurobiological correlates of neuropsychiatric disorders, we will realize that the classification of biomarkers across these six categories can change, and some markers may fit into more than one category.

Planned and reactive agility performance in semiprofessional and amateur basketball players.

CONTEXT: Research indicates that planned and reactive agility are different athletic skills. These skills have not been adequately assessed in male basketball players. PURPOSE: To define whether 10-m-sprint performance and planned and reactive agility measured by the Y-shaped agility test can discriminate between semiprofessional and amateur basketball players. METHODS: Ten semiprofessional and 10 amateur basketball players completed 10-m sprints and planned- and reactive-agility tests. The Y-shaped agility test involved subjects sprinting 5 m through a trigger timing gate, followed by a 45° cut and 5-m sprint to the left or right through a target gate. In the planned condition, subjects knew the cut direction. For reactive trials, subjects visually scanned to find the illuminated gate. A 1-way analysis of variance (P < .05) determined between-groups differences. Data were pooled (N = 20) for a correlation analysis (P < .05). RESULTS: The reactive tests differentiated between the groups; semiprofessional players were 6% faster for the reactive left (P = .036) and right (P = .029) cuts. The strongest correlations were between the 10-m sprints and planned-agility tests (r = .590-.860). The reactive left cut did not correlate with the planned tests. The reactive right cut moderately correlated with the 10-m sprint and planned right cut (r = .487-.485). CONCLUSIONS: The results reemphasized that planned and reactive agility are separate physical qualities. Reactive agility discriminated between the semiprofessional and amateur basketball players; planned agility did not. To distinguish between male basketball players of different ability levels, agility tests should include a perceptual and decision-making component.

Training support staff to modify fluids to appropriate safe consistencies for adults with intellectual disabilities and dysphagia: an efficacy study.

BACKGROUND: Modifying the consistency of food and drink is a strategy commonly used in the management of dysphagia for people with intellectual disabilities (ID). People with ID often depend on others for the preparation of food and drink and therefore depend on those caregivers achieving the correct consistency to keep them safe and avoid discomfort during mealtimes. Clinical experience and prior research have demonstrated that although training can improve modification, carers often find modification difficult and potentially stressful and recommend additional support for carers. Fluid consistency is often modified through the addition of powdered thickener. This study investigates the efficacy of typical training and use of consistency guides, the Thickness Indicator Model (TIM) tubes, in helping carers to modify fluids accurately. METHOD: A 3 × 3 pre-post experimental design with a control group was employed to compare the observed accuracy of modification across three groups and at three time points (pre-intervention baseline, immediately post-training intervention and 3-10 months post-training). Sixty-two paid carers who supported people with ID were recruited to participate in the study and each was randomly allocated to one of the three groups: a control group given written guidance only, a group who received typical training and written guidance and a group who received training, written guidance and the TIM tubes. RESULTS & CONCLUSIONS: Typical training resulted in significantly greater carer accuracy in modifying fluid consistencies when compared with written guidance alone. Use of the TIM tubes also significantly improved accuracy in the modification of drinks compared with the group who modified with the aid of written guidance alone. At 3-10-month follow-up only the group who received typical training alongside the TIM tubes were significantly more accurate than the Written Guidance group. Further research is warranted to ascertain the effectiveness of the training and the utility of the TIM tubes in improving accuracy over a longer time scale and in individuals' usual living environments.

Ventral tegmental ionotropic glutamate receptor stimulation of nucleus accumbens tonic dopamine efflux blunts hindbrain-evoked phasic neurotransmission: implications for dopamine dysregulation disorders.

Activation of glutamate receptors within the ventral tegmental area (VTA) stimulates extrasynaptic (basal) dopamine release in terminal regions, including the nucleus accumbens (NAc). Hindbrain inputs from the laterodorsal tegmental nucleus (LDT) are critical for elicitation of phasic VTA dopamine cell activity and consequent transient dopamine release. This study investigated the role of VTA ionotropic glutamate receptor (iGluR) stimulation on both basal and LDT electrical stimulation-evoked dopamine efflux in the NAc using in vivo chronoamperometry and fixed potential amperometry in combination with stearate-graphite paste and carbon fiber electrodes, respectively. Intra-VTA infusion of the iGluR agonists (±)-α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA; 1 µg/µl) or N-methyl-d-aspartic acid (NMDA; 2 µg/µl) enhanced basal NAc dopamine efflux. This iGluR-mediated potentiation of basal dopamine efflux was paralleled by an attenuation of LDT-evoked transient NAc dopamine efflux, suggesting that excitation of basal activity effectively inhibited the capacity of hindbrain afferents to elicit transient dopamine efflux. In line with this, post-NMDA infusion of the dopamine D2 autoreceptor (D2R) agonist quinpirole (1 µg/µl; intra-VTA) partially recovered NMDA-mediated attenuation of LDT-evoked NAc dopamine, while concurrently attenuating NMDA-mediated potentiation of basal dopamine efflux. Post-NMDA infusion of quinpirole (1 µg/µl) alone attenuated basal and LDT-evoked dopamine efflux. Taken together, these data reveal that hyperstimulation of basal dopamine transmission can stunt hindbrain burst-like stimulation-evoked dopamine efflux. Inhibitory autoreceptor mechanisms within the VTA help to partially recover the magnitude of phasic dopamine efflux, highlighting the importance of both iGluRs and D2 autoreceptors in maintaining the functional balance of tonic and phasic dopamine neurotransmission. Dysregulation of this balance may have important implications for disorders of dopamine dysregulation such as attention deficit hyperactivity disorder.

The surgical aspects of Role 2 Afloat.

The current configuration of the surgical component of the Role 2 Afloat team is described, including an outline of the equipment available. The lessons learned from a recent exercise, where a Role 2 Afloat team was deployed on RFA CARDIGAN BAY are outlined and expanded, emphasising the difficulties of providing damage control surgery in the maritime environment.

MRK-409 (MK-0343), a GABAA receptor subtype-selective partial agonist, is a non-sedating anxiolytic in preclinical species but causes sedation in humans.

MRK-409 binds to α1-, α2-, α3- and α5-containing human recombinant GABA(A) receptors with comparable high affinity (0.21-0.40 nM). However, MRK-409 has greater agonist efficacy at the α3 compared with α1 subtypes (respective efficacies relative to the full agonist chlordiazepoxide of 0.45 and 0.18). This compound readily penetrates the brain in rats and occupies the benzodiazepine site of GABA(A) receptors, measured using an in vivo [(3)H]flumazenil binding assay, with an Occ(50) of 2.2 mg/kg p.o. and a corresponding plasma EC(50) of 115 ng/mL. Behaviourally, the α3-preferring agonist efficacy profile of MRK-409 produced anxiolytic-like activity in rodent and primate unconditioned and conditioned models of anxiety with minimum effective doses corresponding to occupancies, depending on the particular model, ranging from ∼35% to 65% yet there were minimal overt signs of sedation at occupancies greater than 90%. In humans, however, safety and tolerability studies showed that there was pronounced sedation at a dose of 2 mg, resulting in a maximal tolerated dose of 1 mg. This 2 mg dose corresponded to a C(max) plasma concentration of 28 ng/mL, which, based on the rodent plasma EC(50) for occupancy of 115 ng/mL, suggested that sedation in humans occurs at low levels of occupancy. This was confirmed in human positron emission tomography studies, in which [(11)C]flumazenil uptake following a single dose of 1 mg MRK-409 was comparable to that of placebo, indicating that occupancy of GABA(A) receptor benzodiazepine binding sites by MRK-409 was below the limits of detection (i.e. <10%). Taken together, these data show that MRK-409 causes sedation in humans at a dose (2 mg) corresponding to levels of occupancy considerably less than those predicted from rodent models to be required for anxiolytic efficacy (∼35-65%). Thus, the preclinical non-sedating anxiolytic profile of MRK-409 did not translate into humans and further development of this compound was halted.

Preclinical and clinical pharmacology of TPA023B, a GABAA receptor α2/α3 subtype-selective partial agonist.

In the accompanying paper we describe how MRK-409 unexpectedly produced sedation in man at relatively low levels of GABA(A) receptor occupancy (∼10%). Since it was not clear whether this sedation was mediated via the α2/α3 or α1 GABA(A) subtype(s), we characterized the properties of TPA023B, a high-affinity imidazotriazine which, like MRK-409, has partial agonist efficacy at the α2 and α3 subtype but is an antagonist at the α1 subtype, at which MRK-409 has weak partial agonism. TPA023B gave dose- and time-dependent occupancy of rat brain GABA(A) receptors as measured using an in vivo [(3)H]flumazenil binding assay, with 50% occupancy corresponding to a respective dose and plasma drug concentration of 0.09 mg/kg and 19 ng/mL, the latter of which was similar to that observed in mice (25 ng/mL) and comparable to values obtained in baboon and man using [(11)C]flumazenil PET (10 and 5.8 ng/mL, respectively). TPA023B was anxiolytic in rodent and primate (squirrel monkey) models of anxiety (elevated plus maze, fear-potentiated startle, conditioned suppression of drinking, conditioned emotional response) yet had no significant effects in rodent or primate assays of ataxia and/or myorelaxation (rotarod, chain-pulling, lever pressing), up to doses (10 mg/kg) corresponding to occupancy of greater than 99%. In man, TPA023B was well tolerated at a dose (1.5 mg) that produced occupancy of >50%, suggesting that the sedation previously seen with MRK-409 is due to the partial agonist efficacy of that compound at the α1 subtype, and highlighting the importance of antagonist efficacy at this particular GABA(A) receptor population for avoiding sedation in man.

Infection prevention and control in the design of healthcare facilities.

The lead paper, "Healthcare-Associated Infections as Patient Safety Indicators," written by Gardam, Lemieux, Reason, van Dijk and Goel, puts forward the design of healthcare facilities as one of many strategies to improve patient safety with respect to healthcare-associated infections. This commentary explores some of the issues in balancing infection prevention and control priorities with other needs and values brought to the design process. This balance is challenged not only by a lack of supporting evidence but also by the superficial nature in which infection prevention and control are often discussed within a design context. For the physical environment to support any patient safety initiative, the design of the processes must be developed in conjunction with that of the physical environment so that compliance can be natural and convenient. Finally, consideration is given to the value of documenting decision-making related to infection prevention and control in facility design and ongoing assessments of existing facilities.

Anti-mycobacterial therapy in Crohn's disease heals mucosa with longitudinal scars.

BACKGROUND: A possible causative link between Crohn's disease and Mycobacterium avium ss paratuberculosis has been suggested. AIM: To report unique scarring in Crohn's disease patients treated with anti-Mycobacterium avium ss paratuberculosis therapy. PATIENTS: A retrospective review of 52 patients with severe Crohn's disease was conducted. Thirty-nine patients who had at least one follow-up colonoscopy during treatment were included. METHODS: Patients received rifabutin (up to 600 mg/day), clofazimine (up to 100 mg/day) and clarithromycin (up to 1 g/day) - anti-Mycobacterium avium ss paratuberculosis therapy - for 6 months to 9 years. Ramp-up dosing was used. Colonoscopies and histological analyses monitored progress. RESULTS: Twenty-two patients (56.4%, 22/39) healed with unusual scarring, which appeared as branched, ribbon-like, elevated lines. In 2/6 patients (33.3%) who had > 3 years of treatment after scarring occurred, scars receded, becoming imperceptible as full healing occurred. Histologically, a marked reduction in inflammation occurred in 15/39 patients (38.5%). Of these, 6/15 patients (40%) displayed restoration of normal mucosa. Longitudinal scarring occurred in 12/15 patients (80%) with improved histology. CONCLUSIONS: The presence of scarring fading to normal mucosa on anti-MAP therapy implies a more profound healing not seen with standard anti-inflammatory and immunosuppressant drugs. Longitudinal scarring and consequent healing with normal histology should become a standard treatment goal for Crohn's disease.

Healing and the healthcare village: beyond the mega-hospital to a new model of health design.

If the delivery of healthcare and the creation of architecture share the common goal of improving the quality of life, then the role of healthcare architecture has never been more important.

Differences and similarities in sexual and contraceptive knowledge, attitudes, and behavior among Latino male adolescent students in California, United States and Lima, Peru.

To identify the differences and similarities in sexual and contraceptive knowledge, attitudes, and behavior among Latino male adolescent students living in California and Lima. Self-administered, anonymous surveys were completed by Latino male students aged 12-19 participating in California, and by male adolescent students in four high schools in Lima. Both surveys contained similar questions allowing for comparisons regarding sexual activity and contraceptive behavior. The mean age of male students were 16 and 15 years, respectively. More California males reported having engaged in sexual intercourse (69% vs 43%. The sexual debut was 13 years in both samples. More students in California were aware of their risk of pregnancy at first sexual intercourse than in Lima (82% vs 50%). One-third of the California males reported communicating with their partner about sex and contraception to be "easy" as compared to 53% of males in Lima. More students in California reported knowing a place to obtain contraceptives if they need them (85% vs 63%), having ever gotten someone pregnant (29% vs 7%), and having fathered a child (67% vs 16%).

Brane world solution to the cosmological constant problem.

We consider a model with two parallel (positive tension) 3-branes separated by a distance L in five-dimensional spacetime. If the interbrane space is anti--de Sitter, or is not precisely anti--de Sitter but contains no event horizons, the effective four-dimensional cosmological constant seen by observers on one of the branes (chosen to be the visible brane) becomes exponentially small as L grows large.

The novel NK1 receptor antagonist MK-0869 (L-754,030) and its water soluble phosphoryl prodrug, L-758,298, inhibit acute and delayed cisplatin-induced emesis in ferrets.

The anti-emetic profile of the novel brain penetrant tachykinin NK1 receptor antagonist MK-0869 (L-754,030) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluor o)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine and its water soluble prodrug, L-758,298, has been examined against emesis induced by cisplatin in ferrets. In a 4 h observation period, MK-0869 and L-758,298 (3 mg/kg i.v. or p.o.) inhibited the emetic response to cisplatin (10 mg/kg i.v.). The anti-emetic protection afforded by MK-0869 (0.1 mg/kg i.v.) was enhanced by combined treatment with either dexamethasone (20 mg/kg i.v.) or the 5-HT3 receptor antagonist ondansetron (0.1 mg/kg i.v.). In a model of acute and delayed emesis, ferrets were dosed with cisplatin (5 mg/kg i.p.) and the retching and vomiting response recorded for 72 h. Pretreatment with MK-0869 (4-16 mg/kg p.o.) dose-dependently inhibited the emetic response to cisplatin. Once daily treatment with MK-0869 (2 and 4 mg/kg p.o.) completely prevented retching and vomiting in all ferrets tested. Further when daily dosing began at 24 h after cisplatin injection, when the acute phase of emesis had already become established, MK-0869 (4 mg/kg p.o. at 24 and 48 h after cisplatin) prevented retching and vomiting in three out of four ferrets. These data show that MK-0869 and its prodrug, L-758,298, have good activity against cisplatin-induced emesis in ferrets and provided a basis for the clinical testing of these agents for the treatment of emesis associated with cancer chemotherapy.