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The serine hydrolase monoacylglycerol lipase (MAGL) is the rate-limiting enzyme responsible for the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) into arachidonic acid and glycerol. Inhibition of 2-AG degradation leads to elevation of 2-AG, the most abundant endogenous agonist of the cannabinoid receptors (CBs) CB1 and CB2. Activation of these receptors has demonstrated beneficial effects on mood, appetite, pain, and inflammation. Therefore, MAGL inhibitors have the potential to produce therapeutic effects in a vast array of complex human diseases. The present report describes the pharmacologic characterization of [1-(4-fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone (JNJ-42226314), a reversible and highly selective MAGL inhibitor. JNJ-42226314 inhibits MAGL in a competitive mode with respect to the 2-AG substrate. In rodent brain, the compound time- and dose-dependently bound to MAGL, indirectly led to CB1 occupancy by raising 2-AG levels, and raised norepinephrine levels in cortex. In vivo, the compound exhibited antinociceptive efficacy in both the rat complete Freund’s adjuvant–induced radiant heat hypersensitivity and chronic constriction injury–induced cold hypersensitivity models of inflammatory and neuropathic pain, respectively. Though 30 mg/kg induced hippocampal synaptic depression, altered sleep onset, and decreased electroencephalogram gamma power, 3 mg/kg still provided approximately 80% enzyme occupancy, significantly increased 2-AG and norepinephrine levels, and produced neuropathic antinociception without synaptic depression or decreased gamma power. Thus, it is anticipated that the profile exhibited by this compound will allow for precise modulation of 2-AG levels in vivo, supporting potential therapeutic application in several central nervous system disorders. SIGNIFICANCE STATEMENT Potentiation of endocannabinoid signaling activity via inhibition of the serine hydrolase monoacylglycerol lipase (MAGL) is an appealing strategy in the development of treatments for several disorders, including ones related to mood, pain, and inflammation. [1-(4-Fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone is presented in this report to be a novel, potent, selective, and reversible noncovalent MAGL inhibitor that demonstrates dose-dependent enhancement of the major endocannabinoid 2-arachidonoylglycerol as well as efficacy in models of neuropathic and inflammatory pain.

PurposeTo assess feasibility of producing intelligible and comprehensible speech with an electrolarynx; measure anxiety, communication ease, and satisfaction before/after electrolarynx training; and identify barriers/facilitators.MethodsWe included tracheostomized adults from 3 units following commands, reading English, and mouthing words. On enrolment, we measured anxiety, ease, and satisfaction with communication. We gave electrolarynx instruction for ≤5 days then 2 independent raters assessed intelligibility, sentence comprehensibility (9-point difficulty scale), and Electrolarynx Effectiveness Score (EES), and re-evaluated anxiety, communication ease, and satisfaction. Interviews explored barriers/facilitators.Measurements and main resultsWe recruited 24 participants (Jan2015-Dec2016). Mean (SD) intelligibility was 45%(18%) words correct: 57%(21%) when facing. Mean comprehension difficulty was 6.4(2.0) overall, indicating moderate difficulty (5.5(2.5) scored visualizing). Mean EES was 2.9(1.0) (3 = improved lip-reading through recognizable sounds). Anxiety decreased from median 3.8 to 2.0 (P = .007). Communication was rated easier (median 15 vs 12, P = .04) whereas satisfaction remained similar (P = .06). Facilitators included device friendliness, patient independence, and word intelligibility. Barriers were patient weakness, difficulty positioning the device, and limited sentence as opposed to word intelligibility.ConclusionThe electrolarynx may aid intelligible speech for some tracheostomized patients if the communication partner can visualize the users face, and reduce anxiety and make patient perceived communication easier.

Emerging data continues to point towards a relationship between neuroinflammation and neuropsychiatric disorders. ATP-induced activation of P2X7 results in IL-1β release causing neuroinflammation and microglial activation. This study describes the in-vitro and in-vivo neuropharmacology of a novel brain-penetrant P2X7 antagonist, JNJ-55308942, currently in clinical development. JNJ-55308942 is a high-affinity, selective, brain-penetrant (brain/plasma of 1) P2X7 functional antagonist. In human blood and in mouse blood and microglia, JNJ-55308942 attenuated IL-1β release in a potent and concentration-dependent manner. After oral dosing, the compound exhibited both dose and concentration-dependent occupancy of rat brain P2X7 with an ED(50) of 0.07 mg/kg. The P2X7 antagonist (3 mg/kg, oral) blocked Bz-ATP-induced brain IL-1β release in conscious rats, demonstrating functional effects of target engagement in the brain. JNJ-55308942 (30 mg/kg, oral) attenuated LPS-induced microglial activation in mice, assessed at day 2 after a single systemic LPS injection (0.8 mg/kg, i.p.), suggesting a role for P2X7 in microglial activation. In a model of BCG-induced depression, JNJ-55308942 dosed orally (30 mg/kg), reversed the BCG-induced deficits of sucrose preference and social interaction, indicating for the first time a role of P2X7 in the BCG model of depression, probably due to the neuroinflammatory component induced by BCG inoculation. Finally, in a rat model of chronic stress induced sucrose intake deficit, JNJ-55308942 reversed the deficit with concurrent high P2X7 brain occupancy as measured by autoradiography. This body of data demonstrates that JNJ-55308942 is a potent P2X7 antagonist, engages the target in brain, modulates IL-1β release and microglial activation leading to efficacy in two models of anhedonia in rodents.

Rationale: Several studies have explored the experiences of ventilator-assisted individuals living at home with family caregivers. However, few explore the experiences of these individuals as they ...

OBJECTIVES: To perform a multicenter study to assess growth failure in hospitalized infants with gastroschisis. STUDY DESIGN: This study included neonates with gastroschisis within sites in the University of California Fetal Consortium (UCFC). The study’s primary outcome was growth failure at hospital discharge, defined as a weight or length z-score decrease > 0.8 from birth. Regression analysis was performed to assess changes in z-scores over time. RESULTS: Among 125 infants with gastroschisis, the median gestational age was 37 weeks (IQR 35–37). Length of stay was 32 days (23–60); 55% developed weight or length growth failure at discharge (28% had weight growth failure, 42% had length growth failure, and 15% had both weight and length growth failure). Weight and length z-scores at 14 d, 30 d, and discharge were less than birth (p

Objectives Family caregivers of patients requiring prolonged mechanical ventilation may experience physical and psychological morbidity associated with a protracted intensive care unit experience. Our aim was to explore potentially modifiable support needs and care processes of importance to family caregivers of patients requiring prolonged mechanical ventilation and transition from the intensive care unit to a specialised weaning centre. Research methodology/design A longitudinal qualitative descriptive interview study. Data was analysed using directed content analysis. Setting A 6-bed specialised weaning centre in Toronto, Canada. Findings Eighteen family caregivers completed interviews at weaning centre admission (100%), and at two-weeks (40%) and three-months after discharge (22%) contributing 29 interviews. Caregivers were primarily women (61%) and spouses (50%). Caregivers perceived inadequate informational, emotional, training, and appraisal support by health care providers limiting understanding of prolonged ventilation, participation in care and decision-making, and readiness for weaning centre transition. Participants reported long-term physical and psychological health changes including alterations to sleep, energy, nutrition and body weight. Conclusions Deficits in informational, emotional, training, and appraisal support of family caregivers of prolonged mechanical ventilation patients may increase caregiver burden and contribute to poor health outcomes. Strategies for providing support and maintaining family caregiver health-related quality of life are needed.

Dual orexin receptor antagonists have been shown to promote sleep in various species, including humans. Emerging research indicates that selective orexin-2 receptor (OX2R) antagonists may offer specificity and a more adequate sleep profile by preserving normal sleep architecture. Here, we characterized JNJ-42847922 ([5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone), a high-affinity/potent OX2R antagonist. JNJ-42847922 had an approximate 2-log selectivity ratio versus the human orexin-1 receptor. Ex vivo receptor binding studies demonstrated that JNJ-42847922 quickly occupied OX2R binding sites in the rat brain after oral administration and rapidly cleared from the brain. In rats, single oral administration of JNJ-42847922 (3-30 mg/kg) during the light phase dose dependently reduced the latency to non-rapid eye movement (NREM) sleep and prolonged NREM sleep time in the first 2 hours, whereas REM sleep was minimally affected. The reduced sleep onset and increased sleep duration were maintained upon 7-day repeated dosing (30 mg/kg) with JNJ-42847922, then all sleep parameters returned to baseline levels following discontinuation. Although the compound promoted sleep in wild-type mice, it had no effect in OX2R knockout mice, consistent with a specific OX2R-mediated sleep response. JNJ-42847922 did not increase dopamine release in rat nucleus accumbens or produce place preference in mice after subchronic conditioning, indicating that the compound lacks intrinsic motivational properties in contrast to zolpidem. In a single ascending dose study conducted in healthy subjects, JNJ-42847922 increased somnolence and displayed a favorable pharmacokinetic and safety profile for a sedative/hypnotic, thus emerging as a promising candidate for further clinical development for the treatment of insomnia.

A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structure–activity relationships of the new compounds are described. Two of these compounds, (S)-(2-fluoro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 29) and (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 35), were found to have robust P2X7 receptor occupancy at low doses in rat with ED50 values of 0.06 and 0.07 mg/kg, respectively. Compound 35 had notable solubility compared to 29 and showed good tolerability in preclinical species. Compound 35 was chosen as a clinical candidate for advancement into phase I clinical trials to assess safety and tolerability in healthy human...

We sought to evaluate the effectiveness of a multi-component, case manager-led exacerbation prevention/management model for reducing emergency department visits. Secondary outcomes included hospitalisation, mortality, health-related quality of life, chronic obstructive pulmonary disease (COPD) severity, COPD self-efficacy, anxiety and depression.Two-centre randomised controlled trial recruiting patients with ≥2 prognostically important COPD-associated comorbidities. We compared our multi-component intervention including individualised care/action plans and telephone consults (12-weekly then 9-monthly) with usual care (both groups). We used zero-inflated Poisson models to examine emergency department visits and hospitalisation; Cox proportional hazard model for mortality.We randomised 470 participants (236 intervention, 234 control). There were no differences in number of emergency department visits or hospital admissions between groups. We detected difference in emergency department visit risk, for those that visited the emergency department, favouring the intervention (RR 0.74, 95% CI 0.63-0.86). Similarly, risk of hospital admission was lower in the intervention group for those requiring hospital admission (RR 0.69, 95% CI 0.54-0.88). Fewer intervention patients died (21

BACKGROUND: Growing numbers of critically ill patients require prolonged mechanical ventilation and experience difficulty with weaning. Specialized centres may facilitate weaning through focused interprofessional expertise with an emphasis on rehabilitation.OBJECTIVE: To characterize the population of a specialized prolonged-ventilation weaning centre (PWC) in Ontario, and to report weaning, mobility, discharge and survival outcomes.METHODS: Data from consecutively admitted patients were retrospectively extracted from electronic and paper medical records by research staff and verified by the primary investigator.RESULTS: From January 2004 to March 2011, 144 patients were admitted: 115 (80%) required ventilator weaning, and 29 (20%) required tracheostomy weaning or noninvasive ventilation. Intensive care unit length of stay before admission was a median 51 days (interquartile range [IQR] 35 to 86 days). Of the patients admitted for ventilator weaning, 76 of 115 (66% [95% CI 55% to 75%]) achieved a 24 h tracheostomy mask trial in a median of 15 days (IQR eight to 25 days). Weaning success, defined as no further ventilation for seven consecutive days, was achieved by 61 patients (53% [95% CI 44% to 62%]) in a median duration of 62 days (IQR 46 to 95 days) of ventilation, and 14 days (IQR nine to 29 days) after PWC admission. Seventeen patients died during admission. Of the 91 patients discharged from the PWC for one year, 43 (47.3% [95% CI 37.3% to 57.4%]) survived; of the 78 discharged for two years, 27 (34.6% [95% CI 25.0% to 45.7%]) were alive; of the 53 discharged for three years, 19 (35.9% [95% CI 24.3% to 49.3%]) were alive; and seven of 22 (31.8% [95% CI 16.4% to 52.7%]) survived to five years.CONCLUSIONS: Weaning success was moderate despite a prolonged intensive care unit stay before admission, but was comparable with studies reporting weaning outcomes from centres in other countries. Few patients survived to five years.

Orexin-1 receptor antagonists have been shown to block the reinforcing effects of drugs of abuse and food. However, whether blockade of orexin-2 receptor has similar effects has not been determined. We have recently described the in vitro and in vivo effects of JNJ-10397049, a selective and brain penetrant orexin-2 receptor antagonist.The goal of these studies was to evaluate whether systemic administration of JNJ-10397049 blocks the rewarding effects of ethanol and reverses ethanol withdrawal in rodents. As a comparison, SB-408124, a selective orexin-1 receptor antagonist, was also evaluated.Rats were trained to orally self-administer ethanol (8% v/v) or saccharin (0.1% v/v) under a fixed-ratio 3 schedule of reinforcement. A separate group of rats received a liquid diet of ethanol (8% v/v) and withdrawal signs were evaluated 4 h after ethanol discontinuation. In addition, ethanol-induced increases in extracellular dopamine levels in the nucleus accumbens were tested. In separate experiments, the acquisition, expression, and reinstatement of conditioned place preference (CPP) were evaluated in mice.Our results indicate that JNJ-10397049 (1, 3, and 10 mg/kg, sc) dose-dependently reduced ethanol self-administration without changing saccharin self-administration, dopamine levels, or withdrawal signs in rats. Treatment with JNJ-10397049 (10 mg/kg, sc) attenuated the acquisition, expression, and reinstatement of ethanol CPP and ethanol-induced hyperactivity in mice. Surprisingly, SB-408124 (3, 10 and 30 mg/kg, sc) did not have any effect in these procedures.Collectively, these results indicate, for the first time, that blockade of orexin-2 receptors is effective in reducing the reinforcing effects of ethanol.

A few recent studies suggest that brain histamine levels and signaling via H(3) receptors play an important role in modulation of alcohol stimulation and reward in rodents.The present study characterized the effects of a novel, selective, and brain penetrant H(3) receptor antagonist (JNJ-39220675) on the reinforcing effects of alcohol in rats.The effect of JNJ-39220675 on alcohol intake and alcohol relapse-like behavior was evaluated in selectively bred alcohol-preferring (P) rats using the standard two-bottle choice method. The compound was also tested on operant alcohol self administration in non-dependent rats and on alcohol-induced ataxia using the rotarod apparatus. In addition, alcohol-induced dopamine release in the nucleus accumbens was tested in freely moving rats.Subcutaneous administration of the selective H(3) receptor antagonist dose-dependently reduced both alcohol intake and preference in alcohol-preferring rats. JNJ-39220675 also reduced alcohol preference in the same strain of rats following a 3-day alcohol deprivation. The compound significantly and dose-dependently reduced alcohol self-administration without changing saccharin self-administration in alcohol non-dependent rats. Furthermore, the compound did not change the ataxic effects of alcohol, alcohol elimination rate, nor alcohol-induced dopamine release in nucleus accumbens.These results indicate that blockade of H(3) receptor should be considered as a new attractive mechanism for the treatment of alcoholism.

Orexins are peptides produced by lateral hypothalamic neurons that exert a prominent role in the maintenance of wakefulness by activating orexin-1 (OX1R) and orexin-2 (OX2R) receptor located in wake-active structures. Pharmacological blockade of both receptors by the dual OX1/2R antagonist (2R)-2-[(1S)-6,7-dimethoxy-1-{2-[4-(trifluoromethyl)phenyl]ethyl}-3,4-dihydroisoquinolin-2(1H)-yl]-N-methyl-2-phenylethanamide (almorexant) has been shown to promote sleep in animals and humans during their active period. However, the selective distribution of OX1R and OX2R in distinct neuronal circuits may result in a differential impact of these receptors in sleep-wake modulation. The respective role of OX1R and OX2R on sleep in correlation with monoamine release was evaluated in rats treated with selective antagonists alone or in combination. When administered in either phase of the light/dark cycle, the OX2R antagonist 1-(2,4-dibromophenyl)-3-[(4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl]urea (JNJ-10397049) decreased the latency for persistent sleep and increased nonrapid eye movement and rapid eye movement sleep time. Almorexant produced less hypnotic activity, whereas the OX1R antagonist 1-(6,8-difluoro-2-methylquinolin-4-yl)-3-[4-(dimethylamino)phenyl]urea (SB-408124) had no effect. Microdialysis studies showed that either OX2R or OX1/2R antagonism decreased extracellular histamine concentration in the lateral hypothalamus, whereas both OX1R and OX1/2R antagonists increased dopamine release in the prefrontal cortex. Finally, coadministration of the OX1R with the OX2R antagonist greatly attenuated the sleep-promoting effects of the OX2R antagonist. These results indicate that blockade of OX2R is sufficient to initiate and prolong sleep, consistent with the hypothesis of a deactivation of the histaminergic system. In addition, it is suggested that simultaneous inhibition of OX1R attenuates the sleep-promoting effects mediated by selective OX2R blockade, possibly correlated with dopaminergic neurotransmission.

Triple reuptake inhibitors, which block the serotonin transporter (SERT), norepinephrine transporter (NET) and dopamine transporter (DAT) in the central nervous system have been described as therapeutic alternatives for classical selective serotonin reuptake inhibitors, with advantages due to their multiple mechanisms of action. JNJ-7925476 (trans-6-(4-ethynylphenyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline) is a selective and potent inhibitor of the SERT, NET, and DAT (K(i)=0.9, 17 and 5.2 nM, respectively). Following subcutaneous dosing in rat, JNJ-7925476 was rapidly absorbed into the plasma, and drug concentrations in the brain tracked with those in the plasma but were 7-fold higher. The ED(50) values for JNJ-7925476 occupancy of the SERT, NET, and DAT in rat brain were 0.18, 0.09 and 2.4 mg/kg, respectively. JNJ-7925476 (0.1-10 mg/kg, s.c.) rapidly induced a robust, dose-dependent increase in extracellular serotonin, dopamine, and norepinephrine levels in rat cerebral cortex. The compound also showed potent antidepressant-like activity in the mouse tail suspension test (ED(50)=0.3 mg/kg, i.p.). These results demonstrate that JNJ-7925476 is a triple reuptake inhibitor with in-vivo efficacy in biochemical and behavioral models of depression.

Background We sought to describe prevalence and care practices for patients experiencing prolonged mechanical ventilation (PMV), defined as ventilation for 21 or more consecutive days and medical stability. Methods We provided the survey to eligible units via secure Web link to a nominated unit champion from April to November 2012. Weekly telephone and e-mail reminders were sent for 6 weeks. Results Response rate was 215 (90%) of 238 units identifying 308 patients requiring PMV on the survey day occupying 11% of all Canadian ventilator-capable beds. Most units (81%) used individualized plans for both weaning and mobilization. Weaning and mobilization protocols were available in 48% and 38% of units, respectively. Of those units with protocols, only 25% reported weaning guidance specific to PMV, and 11% reported mobilization content for PMV. Only 30% of units used specialized mobility equipment. Most units referred to speech language pathologists (88%); use of communication technology was infrequent (11%). Only 29% routinely referred to psychiatry/psychology, and 17% had formal discharge follow-up services. Conclusions Prolonged mechanical ventilation patients occupied 11% of Canadian acute care ventilator bed capacity. Most units preferred an individualized approach to weaning and mobilization with considerable variation in weaning methods, protocol availability, access to specialized rehabilitation equipment, communication technology, psychiatry, and discharge follow-up.

Summary Objective To compare memories and recall of intensive care unit and specialised weaning centre admission, characterise health-related quality of life and psychological morbidity, and examine the relationship between delusional memories and psychological outcomes. Methods We recruited participants following hospitalisation that included ICU admission and subsequent weaning in a specialised centre. We administered validated questionnaires to assess memory and recall of both care locations, anxiety, depression, post-traumatic stress symptomatology and health-related quality of life. Results Of 53 eligible patients discharged from the weaning centre over seven years, we recruited 27 participants. Participants had similar numbers of factual and feeling memories but reported more delusional memories for ICU than the weaning centre (1.6 vs. 0.7, P = 0.004). Nine (39%) participants scored ≥11 on the hospital anxiety and depression scale (anxiety) and were more likely to experience delusional memories (P = 0.008). Thirst (70%), no control (70%), noise (65%) were most frequently recalled ICU experiences. Procedures (83%), night awakening (70%), inability to sleep (70%) most frequently recalled from the weaning centre. Conclusion Delusional memories and anxiety disorder were prevalent and associated suggesting interventions to ameliorate delusional memories may reduce anxiety. Difficulty sleeping and thirst were common experiences.

An increasing body of evidence suggests that the purinergic receptor P2X, ligand-gated ion channel, 7 (P2X7) in the CNS may play a key role in neuropsychiatry, neurodegeneration and chronic pain. In this study, we characterized JNJ-47965567, a centrally permeable, high-affinity, selective P2X7 antagonist.We have used a combination of in vitro assays (calcium flux, radioligand binding, electrophysiology, IL-1β release) in both recombinant and native systems. Target engagement of JNJ-47965567 was demonstrated by ex vivo receptor binding autoradiography and in vivo blockade of Bz-ATP induced IL-1β release in the rat brain. Finally, the efficacy of JNJ-47965567 was tested in standard models of depression, mania and neuropathic pain.JNJ-47965567 is potent high affinity (pKi 7.9 ± 0.07), selective human P2X7 antagonist, with no significant observed speciation. In native systems, the potency of the compound to attenuate IL-1β release was 6.7 ± 0.07 (human blood), 7.5 ± 0.07 (human monocytes) and 7.1 ± 0.1 (rat microglia). JNJ-47965567 exhibited target engagement in rat brain, with a brain EC50 of 78 ± 19 ng·mL(-1) (P2X7 receptor autoradiography) and functional block of Bz-ATP induced IL-1β release. JNJ-47965567 (30 mg·kg(-1) ) attenuated amphetamine-induced hyperactivity and exhibited modest, yet significant efficacy in the rat model of neuropathic pain. No efficacy was observed in forced swim test.JNJ-47965567 is centrally permeable, high affinity P2X7 antagonist that can be used to probe the role of central P2X7 in rodent models of CNS pathophysiology.

Background: Success in undergraduate medical courses in the UK can be predicted by school exit examination (A level) grades. There are no documented predictors of success in UK graduate entry medicine (GEM) courses. This study looks at the examination performance of GEM students to identify factors which may predict success; of particular interest was A level score.\ud Methods: Data was collected for students graduating in 2004, 2005 and 2006, including demographic details (age and gender), details of previous academic achievement (A level total score and prior degree) and examination results at several points during the degree course.\ud Results: Study group comprised 285 students. Statistical analyses identified no significant variables when looking at clinical examinations. Analysis of pass/fail data for written examinations showed no relationship with A level score. However, both percentage data for the final written examination and the analysis of the award of honours showed A level scores of AAB or higher were associated with better performance (p

In rodents 5-hydroxytryptamine type 7 (5-HT(7)) receptor blockade has been shown to be effective in models of depression and to increase the latency to rapid eye movement (REM) sleep and decrease REM duration. In the clinic, the REM sleep reduction observed with many antidepressants may serve as a biomarker. We report here the preclinical and clinical evaluation of a 5-HT(7) receptor antagonist, (3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1-(phenylmethyl)pyrazolo[3,4-d]azepine 2-hydroxy-1,2,3-propanetricarboxylate) (JNJ-18038683). In rodents, JNJ-18038683 increased the latency to REM sleep and decreased REM duration, and this effect was maintained after repeated administration for 7 days. The compound was effective in the mouse tail suspension test. JNJ-18038683 enhanced serotonin transmission, antidepressant-like behavior, and REM sleep suppression induced by citalopram in rodents. In healthy human volunteers JNJ-18038683 prolonged REM latency and reduced REM sleep duration, demonstrating that the effect of 5-HT(7) blockade on REM sleep translated from rodents to humans. Like in rats, JNJ-18038683 enhanced REM sleep suppression induced by citalopram in humans, although a drug-drug interaction could not be ruled out. In a double-blind, active, and placebo-controlled clinical trial in 225 patients suffering from major depressive disorder, neither treatment with pharmacologically active doses of JNJ-18038683 or escitalopram separated from placebo, indicating a failed study lacking assay sensitivity. Post hoc analyses using an enrichment window strategy, where all the efficacy data from sites with an implausible high placebo response [placebo group Montgomery-Åsberg Depression Rating Scale (MADRS)= 12] and from sites with no placebo response (MADRS= 28) are removed, there was a clinically meaningful difference between JNJ-18038683 and placebo. Further clinical studies are required to characterize the potential antidepressant efficacy of JNJ-18038683.

Neuropeptide S (NPS) is known to produce anxiolytic-like effects and facilitate extinction of conditioned fear. Catecholaminergic neurotransmission in the medial prefrontal cortex (mPFC) has been suggested to be crucially involved in these brain functions. In the current study we investigated the effect of NPS on the release of dopamine and serotonin in the mPFC by in vivo microdialysis in rats. Central administration of NPS dose-dependently enhanced extracellular levels of dopamine and its major metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), with maximal effects lasting up to 120 min. In contrast, no effect on serotonergic neurotransmission was detected. Dopamine release in the mPFC has been previously linked to modulation of anxiety states and fear extinction. The present results may thus provide a physiological and anatomical basis for the reported effects of NPS on these behaviors.

Between 2000 and 2006 Leicester-Warwick Medical Schools (LWMS) provided parallel courses for graduate and school-leaver entrants into medicine. The parallel courses were based upon a single curriculum with ;identical teaching programmes and assessment methods over the two sites (Warwick and Leicester). Warwick runs the curriculum over an accelerated 4-year period for its graduate-entry students. LWMS hence provides a unique opportunity to compare outcomes for these two contrasting groups of students.We carried out an observational, quantitative cohort study over a 6-year period covering three cohorts of students who graduated in 2004, 2005 and 2006, respectively, using examination scores as outcome measures. We compared the examination performance of school-leaver and graduate-entry students in written and clinical examinations. These included intermediate clinical examinations, final clinical and final written examinations for both sets of students. Examination data were collected from original mark sheets and university databases at Warwick and Leicester. A-level data were collected from the national University College Admissions Service (UCAS) and compared against examination performance throughout medical school examinations.Graduate-entry students performed as well as school-leaver students prior to entering the full-time clinical element of the course despite having significantly lower A-level grades. School-leaver entrants performed better on midpoint examinations, but had lost this advantage by the time they sat final professional examinations.This is the first large-scale UK study to compare the performance of graduate-entry and school-leaver medical students following the same clinical curriculum and using the same assessments. Graduate-entry students performed as well as undergraduates in final examinations despite lower A-level grades and a shorter 4-year accelerated course.

The lack of potent, selective, brain penetrant Y(2) receptor antagonists has hampered in vivo functional studies of this receptor.Here, we report the in vitro and in vivo characterization of JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), a novel Y(2) receptor antagonist.The affinity of JNJ-31020028 was determined by inhibition of the PYY binding to human Y(2) receptors in KAN-Ts cells and rat Y(2) receptors in rat hippocampus. The functional activity was determined by inhibition of PYY-stimulated calcium responses in KAN-Ts cells expressing a chimeric G protein Gqi5 and in the rat vas deferens (a prototypical Y(2) bioassay). Ex vivo receptor occupancy was revealed by receptor autoradiography. JNJ-31020028 was tested in vivo with microdialysis, in anxiety models, and on corticosterone release.JNJ-31020028 bound with high affinity (pIC(50) = 8.07 +/- 0.05, human, and pIC(50) = 8.22 +/- 0.06, rat) and was100-fold selective versus human Y(1), Y(4), and Y(5) receptors. JNJ-31020028 was demonstrated to be an antagonist (pK(B) = 8.04 +/- 0.13) in functional assays. JNJ-31020028 occupied Y(2) receptor binding sites (approximately 90% at 10 mg/kg) after subcutaneous administration in rats. JNJ-31020028 increased norepinephrine release in the hypothalamus, consistent with the colocalization of norepinephrine and neuropeptide Y. In a variety of anxiety models, JNJ-31020028 was found to be ineffective, although it did block stress-induced elevations in plasma corticosterone, without altering basal levels, and normalized food intake in stressed animals without affecting basal food intake.These results suggest that Y(2) receptors may not be critical for acute behaviors in rodents but may serve modulatory roles that can only be elucidated under specific situational conditions.

Wake-promoting agents such as modafinil are used in the clinic as adjuncts to antidepressant therapy in order to alleviate lethargy. The wake-promoting action of histamine H(3) receptor antagonists has been evidenced in numerous animal studies. They may therefore be a viable strategy for use as an antidepressant therapy in conjunction with selective serotonin reuptake inhibitors. JNJ-28583867 (2-Methyl-4-(4-methylsulfanyl-phenyl)-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline) is a selective and potent histamine H(3) receptor antagonist (K(i)=10.6 nM) and inhibitor of the serotonin transporter (SERT) (K(i)=3.7 nM), with 30-fold selectivity for SERT over the dopamine and norepinephrine transporters. After subcutaneous administration, JNJ-28583867 occupied both the histamine H(3) receptor and the SERT in rat brain at low doses (

In 58 patients with transfusion dependent anemia, we compared cardiac function, as assessed by gated pooled cardiac scan at rest and during exercise stress, with liver iron concentrations (LIC) as determined by adequate biopsy samples. There was no relationship between LIC and cardiac function and deaths occurred in patients with LIC levels below those that are usually associated with cardiac death. LIC should not be used as a surrogate to determine risk of cardiac complications but purely for management of the hepatic iron load. Other methods, particularly magnetic resonance imaging, should be used to assess cardiac iron overload.

We evaluated the safety and efficacy of outpatient renal biopsy by prospectively comparing outpatient and inpatient renal biopsies in which patients were given the choice between having the procedure as an inpatient or an outpatient. Three hundred fifty renal biopsies were performed between January 1992 and August 1994; 118 patients had the procedure as an outpatient and 232 patients had the procedure with discharge planned for the following day. There was no difference between the two groups in terms of patient age, sex, or renal function. The complication rate for the two groups was not significantly different, with two inpatients having loin pain and one having macroscopic hematuria compared with one outpatient having loin pain and one having macroscopic hematuria. The biopsies provided samples of comparable size. We conclude that outpatient renal biopsy is a safe procedure and provides adequate tissue samples.

Significant numbers of infiltrating mononuclear cells are commonly observed in solid tumours, although their role in restricting tumour growth is not clear. Tumour-infiltrating lymphocytes (TIL) from 38 patients with colorectal cancer, in parallel with peripheral blood lymphocytes (PBL), were assayed to determine their ability to proliferate in response to concanavalin A (ConA), interleukin-2 (IL-2), ConA+IL-2, phorbol 12-myristate 13-acetate (PMA)+ionomycin ionomycin (IOM), and staphylococcal enterotoxin B(SEB). These reagents were selected to give a range of weak to strong proliferative responses either via or independent of the T cell receptor. Proliferation of TIL was significantly lower than that of PBL in all cultures: ConA (P0.001), IL-2 (P = 0.002), ConA+IL-2 (P0.001), PMA+IOM (P0.001), SEB (P = 0.002). In addition to the low proliferative capacity of TIL, production of cytokines by TIL may also play a role in control of tumour growth. We have assayed IFN gamma production in the supernatants from 16 paired TIL and PBL cultures, and tumour necrosis factor alpha (TNF alpha) in 6 paired cultures. TNF alpha concentrations were significantly lower in TIL cultures than in PBL cultures stimulated with ConA (P0.05), but no different in control or IL-2 stimulated cultures. IFN gamma levels did not significantly differ between PBL and TIL cultures, indicating that despite the restricted proliferative capacity of TIL, these cells remain capable of secreting significant amounts of IFN gamma.

The role of 5-HT₇ receptor has been demonstrated in various animal models of mood disorders; however its function in cognition remains largely speculative. This study evaluates the effects of SB-269970, a selective 5-HT₇ antagonist, in a translational model of working memory deficit and investigates whether it modulates cortical glutamate and/or dopamine neurotransmission in rats. The effect of SB-269970 was evaluated in the delayed non-matching to position task alone or in combination with MK-801, a non-competitive NMDA receptor antagonist, and, in separate experiments, with scopolamine, a non-selective muscarinic antagonist. SB-269970 (10 mg/kg) significantly reversed the deficits induced by MK-801 (0.1 mg/kg) but augmented the deficit induced by scopolamine (0.06 mg/kg). The ability of SB-269970 to modulate MK-801-induced glutamate and dopamine extracellular levels was separately evaluated using biosensor technology and microdialysis in the prefrontal cortex of freely moving rats. SB-269970 normalized MK-801 -induced glutamate but not dopamine extracellular levels in the prefrontal cortex. Rat plasma and brain concentrations of MK-801 were not affected by co-administration of SB-269970, arguing for a pharmacodynamic rather than a pharmacokinetic mechanism. These results indicate that 5-HT₇ receptor antagonists might reverse cognitive deficits associated with NMDA receptor hypofunction by selectively normalizing glutamatergic neurotransmission.

In a retrospective review of 21 bone marrow transplantation procedures (BMT), we identified ten episodes of acute pulmonary edema coinciding with significant weight gain in the second week after BMT. When we prospectively observed nine consecutive BMT recipients, six patients developed acute pulmonary edema associated with significant (p less than 0.05) weight gain and an increase in echocardiographically determined left ventricular end diastolic diameter. These findings led to a prospective prophylactic intervention study of 30 consecutive BMT patients. Prophylactic intervention consisting of reduced fluid volume of parenteral alimentation, and diuretic therapy was instituted at any clinical sign of fluid overload. No episode of pulmonary edema occurred. The dramatic difference--acute pulmonary edema occurred in 16/30 untreated vs 0/30 treated cases--suggests that this post-BMT complication is critically related to fluid balance and can be prevented by careful clinical examination, close monitoring of weight change, avoidance of fluid overload and the appropriate use of diuretic therapy.

Introduction Multiple investigations often result in a lengthy process from the onset of lung cancer–related symptoms until diagnosis. An unpublished chart audit indicated suboptimal delays in patients' courses from onset of symptoms until diagnosis of cancer. Methods The Time to Treat Program was designed for patients with clinical or radiographic suspicion of lung cancer. Pre- and postimplementation data on median wait times were compared. Results From April 2005 to January 2007, 430 patients were referred. After Time to Treat Program implementation, the median time from suspicion of lung cancer to referral for specialist consultation decreased from 20 days to 6 days, and the median time from such referral to the actual consultation date decreased from 17 days to 4 days. The median time from specialist consultation to computed tomography scan decreased from 52 days to 3 days, and the median time from computed tomography scan to diagnosis decreased from 39 days to 6 days. Overall, the median time from suspicion of lung cancer to diagnosis decreased from 128 days to 20 days. Of all patients in the Time to Treat Program, 33% were eventually diagnosed with lung cancer. Conclusions Time to Treat Program was effective in shortening the time from suspicion of lung cancer to diagnosis and reduced time intervals at each step in the process. Earlier diagnosis of lung cancer may allow increased treatment options for patients and may improve outcomes.

Following sclerotherapy of varicose veins, 158 limbs of 154 patients were randomized to be bandaged with either crepe or Coban for 6 weeks each, or with Coban for 3 days only. Objective assessment of vein eradication and subjective evaluation of symptoms 3 months after completion of treatment showed no clear differences between these regimens. Significantly more discomfort was experienced with Coban than crepe when used for 6 weeks. It is suggested that, following sclerotherapy, 3 days is an adequate period of bandaging when using Coban. Such a policy would considerably reduce the inconvenience to patients during treatment.

A group of patients was studied during the infusion of Intralipid as part of a parenteral nutrition regimen. Peripheral blood lymphocyte function was unaffected, but monocyte function (chemotaxis) was significantly depressed. A group of healthy volunteers received an intravenous bolus of 20% Intralipid. Blood was taken before and 15 min afterward for immunological studies, and the same changes were seen following Intralipid. Prior subcutaneous injection of 5000 U of heparin did not affect either immunological parameter, but completely prevented the changes in monocyte function caused by Intralipid. Electronmicrographs of monocytes from volunteers after injection of Intralipid, and autoradiographs of cells incubated with 14C-Intralipid in vitro, showed phagocytosis of fat particles by monocytes. These data suggest that Intralipid can have potentially serious side effects on the immune system, and that they may be alleviated by the use of subcutaneous heparin. ( Journal of Parenteral and Enteral Nutrition8:...

A case of retroperitoneal fibrosis involving the testicle is presented. The widespread extent of the retroperitoneal fibrosis syndrome is reviewed briefly. The literature contains little information concerning the aetiology of testicular involvement in the disease process, which generally affects the para-aortic tissues. The physical signs mimic testicular neoplasm. A common embryological derivation of the tissues affected is postulated.

Endoscopic sphincterotomy (ES) is widely used in the treatment of patients with common bile duct (CBD) stones following cholecystectomy. The technique has now been extended to patients with gallbladders still present and the results of ES in 100 such patients is reported. Fifty-nine were considered unsuitable for surgery (Group A), in 38 ES was performed as a preliminary to cholecystectomy (Group B) and in 3 ES was performed following emergency cholecystostomy (Group C). ES was achieved in 98 patients and stones completely extracted in 91 patients. In Group A 5 patients required surgery, in 3 because of technical failure and in 2 because of empyema of the gallbladder. One patient who presented in extremis died following failure to extract a large CBD stone. On follow-up (4-50 months), 16 patients have died but in only one from gallbladder sepsis, and one has had a cholecystectomy for pain. In Group B choledochotomy was avoided in 29 of the 37 patients who agreed to cholecystectomy. In Group C no further surgery was required and all patients in Groups B and C remain well. These results indicate that ES is an effective technique for treating patients with CBD stones with the gallbladder in situ, either alone in patients considered unsuitable for surgery or as an adjunct to surgery.

Confirmed ciguatera poisoning is reported in three Canadian adults who ingested grouper imported from Florida. Two required hospitalization for management of marked gastrointestinal, neurological, and cardiovascular disturbances. Outside of endemic areas, the recognition of this type of fish poisoning may be inadequate. The pathogenesis, diagnosis, and therapy of the disease are outlined.

Since in vivo studies indicate that older erythro cytes hemolyze preferentially in drug-induced hemolysis, differential centrifugation was used to separate young and old normal and G-6-PD deficient er

We examined the biopsy specimens of 62 patients with diabetic nephropathy to establish whether the myofibroblast (MF) has a role in progressive interstitial fibrosis and to ascertain whether a relationship existed between MF activity and severity of arteriolosclerosis. MF were identified by morphology and alpha smooth muscle actin (alpha SMA) immunostaining. Analysis of vascular injury was performed by counting the number of interstitial arterioles after staining endothelial cells with von Willebrand factor (VWF) antibody. Arteriosclerosis was quantified by using a computer-aided image analyzer to measure the arteriolar wall surface and total arteriolar surface area, and the ratio of wall to total surface area was expressed as the index of arteriosclerosis (IA). Fractional area of interstitium (IFA), alpha SMA, and collagen III (Coll III) were quantitated by point counting. Results were related to structural and functional parameters using rank correlation coefficients. There was a strong correlation between IFA and Coll III staining (r = 0.83; P0.001). The alpha SMA staining correlated with IFA (r = 0.56; P0.001) and Coll III (r = 0.47; P0.001), and there were significant correlations between alpha SMA and total urinary protein (r = 0.47; P0.001), renal function (plasma creatinine) at time of biopsy (r = 0.51; P0.001), and the percent change in plasma creatinine after 4 years (delta Cr) (r = 0.37; P = 0.01). The IA correlated significantly with Coll III (r = 0.29; P = 0.02), glomerular filtration rate (GFR) (r = 0.39; P = 0.008), and creatinine (r = 0.33; P = 0.01), but no correlation was observed between alpha SMA and IA (r = 0.16; P = 0.23) or IA and delta Cr (r = -0.04; P = 0.6). Strong correlations could be shown between arteriolar density, IFA (r = 0.75; P0.001), alpha SMA (r = -0.36; P = 0.034), and Coll III (r = -0.66; P0.0001). The MF appears to have a significant role in the progression of diabetic nephropathy. Ischemia secondary to arteriosclerosis may contribute to interstitial fibrosis through fibroblast modulation into MF.