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ObjectiveTo evaluate the feasibility of twice daily rehabilitation in older patients admitted to an acute care of the elderly (ACE) hospital ward.MethodThis was a prospective single-site, cohort study of twice daily interventions provided by ACE physiotherapists, occupational therapists and/or allied health assistants in an ACE hospital ward. The feasibility of twice daily therapy was evaluated using a range of outcomes including satisfaction, fidelity and limited efficacy.ResultsA total of 220 patients were included (median age 86 [IQR 81-91]years, 54% female, with a median length of hospital stay of 7 [IQR 5-10] days). Twice daily therapy was delivered on 71% (n=757) of patient admitted weekdays (fidelity). Moderate-to-large effect sizes were observed in patient functional and mobility measures during their hospital stay and most patients (74%) were able to be successfully discharged home (limited efficacy). Both staff and patients reported high levels of satisfaction with physiotherapy and occupational therapy while on the ACE ward.ConclusionTwice daily therapy with acutely hospitalised elderly patients is feasible, facilitated discharge home, and is associated with high patient and staff satisfaction.

Background: Antibodies targeting the N-methyl-D-aspartate receptor (NMDAR) have been detected in patients with psychosis. However, studies measuring the IgG subclass in serum have provided variable estimates of prevalence, and it is unclear whether these antibodies are more common in patients than controls. Because these inconsistencies could be due to methodological approaches and patient characteristics, we aimed to investigate the effect of these factors on heterogeneity., Methods: We searched Web of Science and Ovid (MEDLINE and PsycINFO) for cross-sectional and case-control studies published between Jan 1, 2000, and May 5, 2019, that reported NMDAR IgG antibody seropositivity in patients with psychosis. Pooled proportions and odds ratios (ORs) were derived using random-effects models. We estimated between-study variance (τ 2 ) and the proportion of observed variance due to heterogeneity (I 2 ). We then used univariable random-effects meta-regression analysis to investigate the effect of study factors on heterogeneity of proportions and ORs. Our protocol was registered on PROSPERO (CRD42018099874)., Findings: Of 1276 articles in the initial search, 28 studies were eligible for inclusion, including 14 cross-sectional studies and 14 case-control studies. In cross-sectional studies, NMDAR IgG antibodies were detected in 0·73% (95% CI 0·09-1·38; I 2 56%; p=0·026) of patients with psychosis, and in case-control studies, patients with psychosis were not significantly more likely to be seropositive than healthy individuals (OR 1·57, 95% CI 0·78-3·16; I 2 15%; p=0·20). Meta-regression analyses indicated that heterogeneity was significantly associated with assay type across both study designs, illness stage in cross-sectional studies, and study quality in case-control studies. Compared with studies using a fixed cell-based assay, cross-sectional and case-control studies using the live method yielded higher pooled prevalence estimates (0·36% [95% CI -0·23 to 0·95] vs 2·97% [0·70 to 5·25]) and higher ORs (0·65 [0·33 to 1·29] vs 4·43 [1·73 to 11·36]). In cross-sectional studies, the prevalence was higher in exclusively first-episode samples than in multi-episode or mixed samples (2·18% [0·25 to 4·12] vs 0·16% [-0·31 to 0·63]), and in case-control studies, higher ORs were reported in low-quality studies than in high-quality studies (3·80 [1·47 to 9·83] vs 0·72 [0·36 to 1·42])., Interpretation: Higher estimates of NMDAR IgG antibody prevalence have been obtained with the live cell-based assay, and studies using this method find that seropositivity is more common in patients with psychosis than in controls. The effects of illness stage and study quality on heterogeneity were not consistent across study designs, and we provide clear recommendations for clinicians and researchers regarding interpreting these findings., Funding: None., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Infantile myofibromatosis, the most common fibrous tumor of infancy, is classified in 2 forms; as a solitary nodule or as numerous, widely-distributed multicentric lesions with or without visceral involvement. Although benign, multicentric myofibromas are still associated with a high incidence of morbidity and mortality due to the infiltration of critical structures. Herein, we present a case of an infant with aggressive PDGFRB and NOTCH3 mutation-negative myofibromas distributed throughout the vascular, respiratory, and gastrointestinal systems. The extensive disease resulted in pulmonary hypertension, respiratory failure and gastrointestinal obstruction refractory to chemotherapy and unamenable to surgical resection. Despite the presence of numerous highly invasive myofibromas, multiple imaging modalities largely underestimated, or even missed, tumors found at autopsy. This case demonstrates the limitations of radiographic imaging to assess disease burden in multicentric infantile myofibromatosis. The postmortem findings of extensive disease far exceeding what was demonstrated by multiple imaging modalities suggests that pediatricians should have a high index of suspicion for undetected tumors if clinical deterioration is otherwise unexplained., (© 2020 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Delivering access to sufficient food, energy and water resources to ensure human wellbeing is a major concern for governments worldwide. However, it is crucial to account for the 'nexus' of interactions between these natural resources and the consequent implications for human wellbeing. The private sector has a critical role in driving positive change towards more sustainable nexus management and could reap considerable benefits from collaboration with researchers to devise solutions to some of the foremost sustainability challenges of today. Yet opportunities are missed because the private sector is rarely involved in the formulation of deliverable research priorities. We convened senior research scientists and influential business leaders to collaboratively identify the top forty questions that, if answered, would best help companies understand and manage their food-energy-water-environment nexus dependencies and impacts. Codification of the top order nexus themes highlighted research priorities around development of pragmatic yet credible tools that allow businesses to incorporate nexus interactions into their decision-making; demonstration of the business case for more sustainable nexus management; identification of the most effective levers for behaviour change; and understanding incentives or circumstances that allow individuals and businesses to take a leadership stance. Greater investment in the complex but productive relations between the private sector and research community will create deeper and more meaningful collaboration and cooperation., Competing Interests: Compliance with ethical standardsThis exercise was explicitly devised to take into account the interests of scientists, businesses and civil society. Those who took part in the prioritisation process (voting and workshop stages) are all listed as co-authors in this study except Monica Contestabile (Nature Publishing Group). Whilst the individuals who participated represented their own opinions, please note in the author details the companies and organisations whose employees have helped to shape and prioritise these research questions.

Background: Psychosis is a common presenting feature in antibody-mediated encephalitis, for which prompt recognition and treatment usually leads to remission. We aimed to investigate whether people with circumscribed schizophrenia-like illnesses have such antibodies-especially antibodies against the N-methyl-D-aspartate receptor (NMDAR)-more commonly than do healthy controls., Methods: We recruited patients aged 14-35 years presenting to any of 35 mental health services sites across England with first-episode psychosis, less than 6 weeks of treatment with antipsychotic medication, and a score of 4 or more on at least one selected Positive and Negative Syndrome Scale (PANSS) item. Patients and controls provided venous blood samples. We completed standardised symptom rating scales (PANSS, ACE-III, GAF) at baseline, and tested serum samples for antibodies against NMDAR, LGI1, CASPR2, the GABA A receptor, and the AMPA receptor using live cell-based assays. Treating clinicians assessed outcomes of ICD diagnosis and functioning (GAF) at 6 months. We included healthy controls from the general population, recruited as part of another study in Cambridge, UK., Findings: Between Feb 1, 2013, and Aug 31, 2014, we enrolled 228 patients with first-episode psychosis and 105 healthy controls. 20 (9%) of 228 patients had serum antibodies against one or more of the neuronal cell surface antibodies compared with four (4%) of 105 controls (unadjusted odds ratio 2·4, 95% CI 0·8-7·3). These associations remained non-significant when adjusted for current cigarette smoking, alcohol consumption, and illicit drug use. Seven (3%) patients had NMDAR antibodies compared with no controls (p=0·0204). The other antibodies did not differ between groups. Antibody-positive patients had lower PANSS positive, PANSS total, and catatonia scores than did antibody-negative patients. Patients had comparable scores on other PANSS items, ACE-III, and GAF at baseline, with no difference in outcomes at 6 months., Interpretation: Some patients with first-episode psychosis had antibodies against NMDAR that might be relevant to their illness, but did not differ from patients without NMDAR antibodies in clinical characteristics. Our study suggests that the only way to detect patients with these potentially pathogenic antibodies is to screen all patients with first-episode psychosis at first presentation., Funding: Medical Research Council., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Earthquakes may be induced by a wide range of anthropogenic activities such as mining, fluid injection and extraction, and hydraulic fracturing. In recent years, the increased occurrence of induced seismicity and the impact of some of these earthquakes on the built environment have heightened both public concern and regulatory scrutiny, motivating the need for a framework for the management of induced seismicity. Efforts to develop systems to enable control of seismicity have not yet resulted in solutions that can be applied with confidence in most cases. The more rational approach proposed herein is based on applying the same risk quantification and mitigation measures that are applied to the hazard from natural seismicity. This framework allows informed decision-making regarding the conduct of anthropogenic activities that may cause earthquakes. The consequent risk, if related to non-structural damage (when re-location is not an option), can be addressed by appropriate financial compensation. If the risk poses a threat to life and limb, then it may be reduced through the application of strengthening measures in the built environment-the cost of which can be balanced against the economic benefits of the activity in question-rather than attempting to ensure that some threshold on earthquake magnitude or ground-shaking amplitude is not exceeded. However, because of the specific characteristics of induced earthquakes-which may occur in regions with little or no natural seismicity-the procedures used in standard earthquake engineering need adaptation and modification for application to induced seismicity.

The identification of the neonatal FcR (FcRn) as an IgG homeostasis regulator has led to research aimed at delineating a role for FcRn in humorally mediated disease. FcRn is a class I-related molecule that prolongs the half-life of serum IgG by preferentially binding IgG at low pH and inhibiting its degradation. Its role in protective immunity to infectious organisms is unknown. We investigated the function of FcRn in the murine model of Lyme arthritis, caused by infection with Borrelia burgdorferi. We infected FcRn(-/-) and wild-type mice with B. burgdorferi and monitored the development of arthritis. Infected FcRn(-/-) mice demonstrated decreased serum levels of anti-B. burgdorferi antibodies and borreliacidal activity. Moreover, these mutant mice developed increased ankle swelling and joint histopathology following infection. Our data suggest that FcRn ameliorates murine Lyme arthritis by preventing the degradation of protective borreliacidal antibodies.

Antibody responses to outer surface protein A (OspA) of Borrelia burgdorferi may occur during periods of arthritis late in the clinical course of untreated Lyme disease. These antibody responses are paradoxical, given the conclusive evidence demonstrating that B. burgdorferi transmitted to the mammalian host expresses little or no OspA. The parallel occurrence of OspA antibodies and arthritic episodes suggests that OspA expression is upregulated during infection with B. burgdorferi. We hypothesized that this was due to the inflammatory environment caused by the immune response to the spirochete. To test our hypothesis, we adapted an in vivo model that mimics the host-pathogen interaction. Dialysis chambers containing B. burgdorferi were implanted into the peritoneal cavities of mice in the presence or absence of zymosan, a yeast cell wall extract that induces inflammation. Spirochetes were harvested 2 days later, and OspA expression was assessed at the protein and transcription level by Western blotting and real-time reverse transcription-PCR, respectively. Flow cytometry was also utilized to evaluate OspA protein expression on individual spirochetes. B. burgdorferi maintained in an inflammatory in vivo environment show an increased OspA expression relative to B. burgdorferi kept under normal in vivo conditions. Furthermore, host-adapted B. burgdorferi with a low OspA phenotype upregulates OspA expression when transferred to an inflammatory in vivo environment. The results obtained by these techniques uniformly identify inflammation as a mediator of in vivo OspA expression in host-adapted B. burgdorferi, providing insights into the behavior of live spirochetes in the mammalian host.

The purpose of this study was to identify the significance and clinical correlation of steatosis in donor and posttransplantation liver biopsies. One hundred twenty-six liver biopsies with fatty change from 86 liver transplant patients were reviewed. Micro- and macro-steatosis were graded semiquantitatively and correlated with clinical and other pathologic parameters. Fifty-one donor biopsy specimens, from 50 patients, had combinations of micro- (predominantly) and macro-steatosis. One of 2 patients with high-grade micro- and macro-steatosis required a retransplantation on the third day. Three early deaths were not related to graft dysfunction. In 36 patients, steatosis developed after transplantation. In 13 of 36, steatosis was seen in the early postoperative period with a background of severe ischemic injury, 6 of whom died within 45 days posttransplantation. Other causes of steatosis developing after liver transplantation included hepatitis C (n = 12), alcoholic steatohepatitis (n = 3), diabetes mellitus or obesity (n = 7) and poor nutrition (n = 2). The presence of steatosis in 1 patient's donor and all posttransplantation biopsy specimens remained unexplained. In conclusion, (1) microsteatosis in donor liver biopsy specimens has no effect on graft function; (2) ischemic injury with development of steatosis in the early posttransplantation period may be associated with poor clinical outcome; and (3) steatosis in the posttransplantation period is uncommon and usually related to recurrent or acquired hepatitis C.

Gustducin is a transducin-like G protein (guanine nucleotide-binding protein) that is expressed in taste bud cells. Gustducin is believed to be involved in bitter and possibly sweet taste transduction. In the present study, we demonstrate that a subset of type II cells displays immunoreactivity to antisera directed against gustducin in taste buds of rat circumvallate papilla. Immunogold particles are present both in the microvilli and cytoplasm of the immunoreactive cells. Quantitative analysis of the data suggests that the number of colloidal gold particles (P<0.001) and nanogold particles (P<0.01) in the immunoreactive type II cells are much greater than in type I cells. There are also approximately 2.5 times (P<0.05) as many colloidal gold particles associated with the microvilli versus the cytoplasm in the immunoreactive type II cells. The ultrastructural distribution of gustducin immunoreactivity is consistent with its proposed role in the initial events of sensory transduction by gustatory receptor cells., (Copyright 2000 Wiley-Liss, Inc.)

SNAP-25 is a 25 kDa protein believed to be involved in the processes of membrane fusion and exocytosis associated with neurotransmitter release. In the present study we present evidence that SNAP-25-like immunoreactivity can be used as a marker for taste cells with synapses in rat circumvallate papillae. SNAP-25 immunoreactivity is present in most intragemmal nerve processes and a small subset of taste cells. Intense immunoreactivity is associated with the nerve plexus located below the base of the taste bud. Of a total of 87 taste cells with synapses onto nerve processes, 80 of the presynaptic taste cells had SNAP-25 immunoreactivity. The association of SNAP-25 immunoreactivity with taste cells possessing synapses suggests that these cells may be gustatory receptor cells. Because this SNAP-25 antibody can label taste cells with synapses, it may also serve as a useful tool for future studies correlating structure with function in the taste bud., (Copyright 2000 Wiley-Liss, Inc.)

The relationship between relative intensity of transition segments and identification of diphthongs has been investigated. In the first experiment, synthesized stimuli were used. The stimuli differed in the amount of attenuation of the transition segment which ranged from 0 to 15 dB. It was expected that [diphthong in text] responses would be obtained for stimuli with attenuated transitions. The stimuli were tested in quiet, noise, and reverberation with ten normal-hearing and seven hearing-impaired subjects. For the stimulus with the most attenuated transition, the normal-hearing subjects gave no [diphthong in text] responses and the hearing-impaired subjects gave only 20% [diphthong in text] responses in quiet. However, in noise, both groups of subjects gave 70% [diphthong in text] responses and in reverberation, the normal-hearing subjects gave 95% and the hearing-impaired subjects gave 90% [diphthong in text] responses. Generally, less transition attenuation was needed for the hearing-impaired than for the normal-hearing subjects to give [diphthong in text] responses. These findings indicated that identification errors in noise and reverberation for naturally produced diphthongs might be related to the intensity of their transition segments. In the second experiment, naturally produced diphthongs [diphthongs in text] from the Nábĕlek et al. [J. Acoust. Soc. Am. 92, 1228-1246 (1992)] study were spectrally analyzed. There were 30 different tokens for each diphthong. The results of the analyses indicated significant correlations between the number of identification errors for these diphthongs made by either normal-hearing or hearing-impaired subjects and the relative intensities of the F2 transition segment. In both noise and reverberation there were fewer errors for the diphthong tokens characterized by high intensity F2 transitions.

The purpose of this study was to investigate the possibility of estimating client-assessed hearing aid performance before hearing aids are purchased. Aided performance was represented by the Profile of Hearing Aid Performance (PHAP, Cox & Gilmore, 1990). Multiple regression was applied to 16 unaided predictor variables and to 8 response variables. The response variables were the scores from the seven PHAP subscales plus the overall PHAP score, which were obtained from 46 participants. Audiologic, demographic, and psychological information was included among the 16 predictor variables. The average widths of 95% prediction intervals showed that, with the exception of the Aversiveness of Sounds and Ease of Communication subscales, PHAP subscale scores were predicted within 15% on average. Eighty percent or more of the individual participants' PHAP scores were predicted within 15% for all but the Aversiveness of Sounds subscale. The predictor variables appearing in regression equations for the greatest number of PHAP subscales include age, Communication Strategies and Personal Adjustment scores from the Communication Profile for the Hearing Impaired (Demorest & Erdman, 1986), Revised Speech Perception in Noise (Bilger, Neutzel, Rabinowitz, & Rzeczkowski, 1984; Kalikow, Stevens, & Elliott, 1977) test scores, comfortable loudness levels, and the difference between National Acoustic Laboratories' target gain (Byrne & Dillon, 1986) and actual insertion gain. Further testing of the models on additional participants would be needed to determine their clinical applicability. In addition to being potentially useful for predicting client-assessed aided performance, the equations obtained in this study identify relationships between the aided and unaided variables that can be applied in the counseling of new hearing aid users.

Recent reports suggest aortoembolism is an important cause of stroke. Although transesophageal echocardiography visualizes the aortic arch, diagnosis of aortoembolism stroke is not common. We investigated reasons for this discrepancy at our institution. We reviewed charts and transesophageal echocardiography videotapes of 16 patients with recent ischemic stroke or transient ischemic attack who had undergone transesophageal echocardiography. For each patient, we determined the most likely cause of cerebral ischemia, and we compared the official transesophageal echocardiography report to our interpretation of the videotape. In our videotape review, 13 patients had good visualization of the aortic arch. Of 6 patients with atherosclerosis in the arch, 1 had high-grade carotid stenosis, 1 had atrial fibrillation, 1 had "small-vessel disease," and 3 had cerebral ischemia of unknown cause. The official reports did not mention aortic arch disease in 4 of 6 patients. A possible cause of cerebral ischemia was identified in 6 of 7 patients with normal aortic arches. Of 3 patients who had poor visualization of the aortic arch, one had "small-vessel disease," and 2 had ischemic stroke of unknown cause despite extensive workups. We conclude that aortic arch disease is common in patients with ischemic stroke and transient ischemic attack and may be a cause of cerebral ischemia, especially in patients with stroke or transient ischemic attack due to small-vessel occlusion or of unknown cause. Aortic arch disease may not be identified as the cause of stroke or transient ischemic attack because (a) transesophageal echocardiography is not done, (b) transesophageal echocardiography is done but the aortic arch is not visualized, (c) transesophageal echocardiography is done, the aortic arch is visualized, but the examiner does not comment on aortic arch disease, or (d) despite transesophageal echocardiography identification of arotic arch disease, the treating physician does not consider the aorta to be a potential source of embolization., (Copyright © 1995 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Location of boundaries (the 50% response point) and slopes of identification functions were determined for synthesized /a-aI/ vowel continua. Within each continuum, the stimuli contained a steady-state segment followed by a transition in which the frequencies of formants changed in time. Here, F1 changed in a downward direction and F2 changed in an upward direction. Total duration of each stimulus was 200 ms. The duration of the transition was increased in steps from 0 to 140 ms. Two patterns of formant transition were used: (1) formants changing in the direction of, but not reaching, target frequencies (except in the end-point stimulus), and (2) formants reaching F1 and F2 targets. The data were collected with ten normal-hearing and ten hearing-impaired subjects. The boundaries and slopes were determined for four listening conditions: quiet, noise, short reverberation (0.8 s), and long reverberation (1.1 s). The location of boundaries depended upon: (1) pattern of formant transitions, (2) listening condition, and (3) status of subjects' hearing. Generally, longer transitions were needed for formants changing in the direction of, but not reaching, target frequencies, than for those reaching F1 and F2 targets. The required transition durations were similar in quiet and noise, but were longer in reverberation. The hearing-impaired subjects generally required longer transitions to reach the boundaries than normal-hearing subjects. The slopes of the identification functions were shallower in either noise or reverberation than in quiet and were shallower for hearing-impaired than for normal-hearing subjects. In reverberation, the slopes for formants reaching targets were shallower than the slopes for stimuli with formants changing in the direction of target frequencies. The relationships between these findings and identification errors for naturally produced tokens of the diphthong /aI/ are discussed.

Locations of boundaries and slopes of identification functions were tested for /I-epsilon/ vowel continua with steady-state and linearly changing formant trajectories. In experiment 1, the boundaries and slopes for arbitrarily selected trajectory directions were determined for ten normal-hearing and ten hearing-impaired subjects in three listening conditions: Quiet, noise, and reverberation. The boundaries did not depend upon the group of subjects or the listening condition. A boundary shift was found for stimuli with F1 changing in a downward direction relative to boundaries for stimuli with either only F1 or with both F1 and F2 changing in an upward direction. The slope of the identification function for stimuli with F1 changing in a downward direction was shallower than the slopes for stimuli with steady-state formants or stimuli with F1 changing in an upward direction. The slopes obtained from the hearing-impaired subjects were shallower than those of the normal-hearing subjects and were shallower in noise than in either quiet or reverberation. In experiment 2, boundaries and slopes for the trajectory directions found in the natural vowels /I/ and /epsilon/, F1 changing in an upward direction and F2 in a downward direction, were determined for nine normal-hearing subjects in two listening conditions, quiet and reverberation. The boundary for stimuli with both F1 and F2 changing in directions characteristic for natural vowels was shifted relative to the boundary for stimuli with steady-state formants. The directions of the boundary shifts in experiments 1 and 2 indicated a perceptual emphasis on the initial sections of changing F1 and F2. Sound quality of the end-point /I/ and /epsilon/ stimuli depended upon F1 and F2 trajectories. For both vowels, the best quality judgments were found for the stimuli with natural F1 and F2 trajectory directions. The quality judgments were weakly correlated with the slopes of identification functions, with better quality judgments being associated with steeper slopes.

The preparations of thienotriazolodiazepines bearing a substituted ethynyl group at the 2-position, and the corresponding cis-olefins and fully saturated analogues are described. The compounds were evaluated as potential antagonists of platelet-activating factor (PAF) in in vitro and in vitro test models. The new thienotriazolodiazepines are compared with known related compounds such as WEB 2086 (compound 6) and the phenylethyl derivatives 27 and 28.

A series of [1,2,4]triazolo[4,3-alpha][1,4]benzodiazepines bearing an ethynyl functionality at the 8-position and the isosteric thieno[3,2-f][1,2,4]triazolo[4,3-alpha][1,4]diazepines were prepared and evaluated as antagonists of platelet activating factor. The effects of substitution were explored in in vitro and in vivo test systems designed to measured PAF-antagonistic activity. Results are discussed and compared with previously published data. Many of the compounds had activity superior to WEB 2086, compound 1. In general, the thieno analogues exhibited better oral activity than the corresponding benzodiazepines. The duration of activity upon oral administration was modulated by the substitution on the acetylenic side chain. Compounds 71 and 81 were selected for further pharmacological evaluation as a result of their good oral potency and exceptionally long duration of action.

A series of N-[4-(3-pyridinyl)butyl] 3-substituted propenyl carboxamide derivatives bearing an unsaturated bicyclic moiety in the 3-position was prepared and evaluated for PAF (platelet activating factor) antagonist activity. These compounds represent conformationally constrained direct analogues of the corresponding potent 5-aryl-pentadienecarboxamides (5). Most of the new compounds were active in a PAF-binding assay employing whole, washed dog platelets as the receptor source and inhibited PAF-induced bronchoconstriction in guinea pigs after intravenous administration. However, oral activity in the PAF-induced bronchoconstriction model was highly sensitive to the nature and substitution of the bicyclic ring system. The most interesting compounds included [R-(E)]-(1-butyl-6-methoxy-2-naphthyl)-N-[1-methyl-4-(3- pyridinyl)butyl]-2-propenamide (4b), [R-(E)]-(3-butyl-6-methoxy-2- benzo[b]thiophene-yl)-N-[1-methyl-4-(3-pyridinyl)butyl]-2-propenamide (4k), and [R-(E)]-(3-butyl-6-methoxy-1-methyl-2-indoly)-N-[1-ethyl-4- (3-pyridinyl)butyl]-2-propenamide (4l) which inhibited PAF-induced broncho-constriction in guinea pigs with IC50s of 3.0-5.4 mg/kg, when the animals were challenged 2 h after drug treatment. They were also highly effective 6 h after a 50 mg/kg oral dose. This study supports the notion that the key remote aromatic ring present in the 5-arylpentadienecarboxamides (5) is preferentially coplanar with the diene system for good PAF antagonist activity.

A chemically synthesized form of leukotriene E4 (LTE4) has been studied for its ability to induce contractions in isolated guinea pig ilea, to induce vascular permeability changes in rat skin when injected intradermally, and to induce bronchoconstriction in guinea pigs after intravenous injection. The synthetic compound induced a contraction in the guinea pig ileum which was slower in developing than that induced by histamine but faster in developing than that induced by a crude preparation of SRS-A isolated from guinea pig lung. The compound was 70-fold more active than histamine on the guinea pig ileum (EC50 of 5 x 10(-9) and 3.5 x 10(-7) M, respectively). FPL 55712, a known SRS-A antagonist, exhibited the same potency in blocking the contractions elicited by the synthetic material as it did in blocking contractions produced by guinea pig SRS-A generated biologically (IC50 of 3.5 x 10(-8) M). The synthetic LTE4 induced a dose dependent increase in vascular permeability in the rat skin which was antagonized by the intravenous injection of FPL 55712 (ID50 of 1.2 mg/kg). The synthetic material was also a potent bronchoconstrictor in the guinea pig when injected intravenously. The bronchoconstriction, too, was antagonized by FPL 55712 when injected intravenously (ID50 of 0.2 mg/kg). In both the rat and guinea pig, FPL 55712 exhibited a short duration of action in vivo. The in vivo model systems discussed in this study, utilizing the synthetic form of LTE4 should be useful in the future evaluation of other SRS-A antagonists.

The effects of Ro 21-7634 and disodium cromoglycate (cromoglycate) on the in vitro release of mediators of anaphylaxis from rat peritoneal cells and guinea pig lung tissue were compared. Ro 21-7634 was 25 fold more potent than cromoglycate as an inhibitor of antigen-induced histamine release from passively sensitized (IgE) rat peritoneal cells. Ro 21-7634 was also the more potent inhibitor of both compound 48/80- and concanavalin A-induced histamine release from rat peritoneal cells. The two drugs shared the common properties of producing the same maximal level of inhibition in each of the above releasing systems and exhibiting a time and concentration dependent loss of inhibitory activity when added to the cells prior to the releasing agent. Neither drug inhibited ionophore A23187-or ionophore X537A-induced histamine release from these cells. Ro 21-7634 inhibited antigen-induced (IgG1) histamine and SRS-A release from actively sensitized guinea pig lung fragments, whereas cromoglycate did not. The results indicate that Ro 21-7634 and cromoglycate act through a common mechanism to inhibit allergic mediator release and that Ro 21-7634 is the more potent inhibitor.

A series of N-[4-(3-pyridinyl)butyl]-1,1'-biphenyl-4-carboxamides was prepared, and the compounds were evaluated for platelet-activating factor (PAF) antagonist activity in a binding assay employing washed, whole dog platelets and in vivo for their ability to inhibit PAF-induced bronchoconstriction in the guinea pig. The inclusion of a methyl group in the R configuration on the side-chain carbon adjacent to the carboxamide nitrogen atom of these derivatives resulted in a marked enhancement of potency in the binding assay for compounds unsubstituted in the biphenyl 2-position and, more importantly, in improved oral bioavailability. Previous work with related pyrido[2,1-b]-quinazoline-8-carboxamides suggests that the presence of such an alkyl group improves bioavailability by rendering the resulting compounds resistant to degradation by liver amidases. The most interesting compounds to emerge from this work are (R)-2-bromo-3',4'-dimethoxy-N-[1-methyl-4-(3-pyridinyl)butyl]-1,1'-bi phe nyl- 4-carboxamide (33) and (R)-2-butyl-3',4'-dimethoxy-N-[1-methyl-4-(3-pyridinyl)butyl]- 1,1'-biphenyl-4-carboxamide (40) each of which inhibits PAF-induced bronchoconstriction in the guinea pig by greater than 55%. 6 h after an oral dose of 50 mg/kg.

A series of compounds in which the 4-acetyl-3-hydroxy-2-propylphenoxy moiety of the standard SRS-A antagonist, FPL-55712, is linked by a polymethylene or a polyether chain to substituted (aryloxy)alkanoic acids was prepared. The compounds were evaluated for their ability to antagonize SRS-A-induced contractions of guinea pig ilea and LTE-induced bronchoconstriction in the guinea pig. The results showed that the compounds were all less potent than FPL-55712 in vitro, yet surprisingly, most were more potent by the inhalation route of administration. Some of the most potent analogues were selected for further pharmacological evaluation and, by inhalation, exhibited selective antagonism of leukotrienes as compared with PAF or histamine. In comparison to FPL-55712, compounds 28 and 37 were more potent against LTE (40- and 80-fold, respectively), LTD (4- and 3-fold, respectively), and LTC (27- and 20-fold, respectively) induced bronchoconstriction when tested by inhalation.

Members of a series of basic amide and ester derivatives of 2-substituted pyrido[2,1-b]quinazoline-8-carboxylic acids were prepared and evaluated for their ability to prevent slow-reacting substance of anaphylaxis (SRS-A) induced contractions of guinea pig ilea. The results indicate that the presence of a branched-chain alkyl group in the 2-position and a sterically demanding substituted aminoethyl carboxylate or carboxamide in the 8-position give optimal in vitro activity. The phenylpiperazine 25 was further found to block SRS-A-related symptomatology after intravenous administration in two animal models.

Leutriene (LTC4) is one of the components of Slow Reacting Substance of Anaphylaxis (SRS-A) and is a potent constrictor of guinea pig ilea. The contraction is likely to be a receptor-mediated process. Here we report the existence of specific binding sites for 3H-LTC4 in a crude membrane preparation from guinea pig ileal longitudinal muscle. At 4 degrees C in the presence of 20 mM Serine-borate, binding increases linearly with protein concentration, reaches equilibrium in 10 minutes, and is reversible upon addition of 3 x 10(-5) M unlabelled LTC4. The dissociation curve is consistent with the existence of more than one class of binding site. Ca++ and Mg++ greatly enhance the binding of 3H-LTC4 at equilibrium. In the presence of 5 mM CaCl2 and MgCl2 not only LTC4 (IC50 10(-7)M), but also LTD4 (albeit with much lower affinity, IC50 = 6 x 10(-5) M) and the SRS-A antagonist FPL 55712 (IC50 = 10(-5) M) can compete with 3H-LTC4 for its binding sites. FPL 55712 only displaces 60-70% of the total amount bound, while LTC4 displaces 90-95%. These studies indicate that multiple classes of binding sites exist for 3H-LTC4 in guinea pig ileal longitudinal muscle, and that at least part of these binding sites might be related to the ability of LTC4 to contract guinea pig ilea.

A series of binary (aryloxy)propanolamines has been prepared and examined in vitro and in vivo for beta-adrenoreceptor blocking activity. These symmetrical compounds consist of two (S)-(phenyloxy)propanolamine pharmacophores coupled through alkylenedioxy or poly(oxyethylenedioxy) linking units of varying lengths. Examples of such binary compounds linked through the 2,2', 3,3', and 4,4' positions in the aromatic rings of the pharmacophores have been prepared. In vitro and in vivo test data indicate that the 2,2' compounds tend to be selective beta 2-adrenergic blocking agents, the 4,4' binaries tend to be selective beta 1-blocking agents, and those compounds with 3,3' linkages exhibit intermediate selectivities. One of the 4,4'-linked binary compounds, 4s, exhibited potent, cardioselective beta-blockade in vivo, which was of short duration and was accompanied by a prolonged tachycardia.

A number of indoles containing the 2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl side chain have been prepared by standard methods. Alternate, novel syntheses of indole-2-carboxamides and indole-2-carbonitriles have been developed. The title compound, 7e, was found to be a potent inhibitor of bovine prostaglandin synthetase in vitro and to lower serum prostaglandin levels after oral or intraperitoneal administration to rats. Consistent with prostaglandin synthetase inhibition, 7e prevented arachidonic acid induced diarrhea in mice and also collagen, ADP, or epinephrine induced platelet aggregation in human platelet-rich plasma. In contrast to many prostaglandin synthetase and platelet-aggregation inhibitors, 7e had neither ulcerogenicity nor systemic antiinflammatory activity in rats.

Vacuum drying, under appropriate conditions, diminishes the warping and buckling of epoxy semithin sections and enhances visualization with light microscopy. Treatment of sections with chloroform or variations in the drying times or temperatures did not reduce wrinkling.