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The effect of aging on the break-up dynamics of Laponite suspensions was studied in an extensional geometry. It was found that samples of increased age undergo stronger necking at the midpoint. The thinning of samples, driven purely by motion of the plates, was compared with standard shear rheology to understand how the dynamics are related to the sample properties. The Laponite suspensions exhibit a growing stress overshoot with monotonically decreasing yield strain as they age. However, it is shown that the thinning curves in extension are only a good indicator of the sample’s static yield stress, being insensitive to its yield strain. These measurements suggest that following an initial linear visco-elastic regime, samples accumulate significant plastic deformations prior to the complete yielding of the sample. The implications of this for the importance of assessing changes to the ductile—brittle nature of samples are also discussed. Graphical abstract

Background Microbial composition-based risk score (MRS) was recently developed and validated to predict future risk of developing Crohn’s disease (CD) among healthy first-degree relatives (FDR) of CD patients. We hypothesized that stool metabolomic profiles, some of which are linked to the gut microbiome, are associated with future risk of CD. Aims To assess the association of stool metabolomic profile with onset of CD and to determine the correlation between stool metabolites and the MRS Methods Healthy FDR of CD patients were recruited as part of the nested case-control cohort of the CCC-GEM Project. Healthy FDRs who later developed CD (n=56) were matched approximately 1:1 by age, sex, follow-up duration, and geographical location with control FDRs remaining healthy (n=66). Stool metabolomics were assessed using the Metabolon’s DiscoveryHD4™ platform, and the stool microbiome characterised by 16s rDNA amplicon sequencing. We fitted a multivariable conditional logistic regression model on the disease status as a function of individual stool metabolites. We additionally performed Spearman correlation between each stool metabolite and the MRS. Results Among 1,029 stool metabolites that were analyzed, 79 were associated with future risk of CD (p Conclusions Stool metabolite profiles may predict future risk of CD. A subset of these metabolites have significant correlation with the MRS with consistent direction of effect. This may suggest that stool metabolites mediate the putative effect of the gut microbiome on CD risk. Further validation in the full GEM cohort is warranted. Funding Agencies CCC, CIHRThe Leona M. and Harry B. Helmsley Charitable Trust; Kenneth Croitoru is the recipient of the Canada Research Chair in Inflammatory Bowel Diseases; Sun-Ho Lee is a recipient of the Imagine/ CIHR/CAG Fellowship Award; Sun-Ho Lee, Juan Antonio Raygoza Garay, and Williams Turpin are recipients of fellowship awards from the Department of Medicine, Mount Sinai Hospital, Toronto, Canada.

We experimentally investigate the nature of 2D phase transitions in a quasi-2D granular fluid. Using a surface decorated with periodically spaced dimples we observe interfacial tension between coexisting granular liquid and crystal phases. Measurements of the orientational and translational order parameters and associated susceptibilities indicate that the surface topography alters the order of the phase transition from a two-step continuous one to a first-order liquid-solid one. The interplay of boundary inelasticity and geometry, either order promoting or inhibiting, controls whether it is the granular crystal or the granular fluid which makes contact with the edge. This order induced wetting has important consequences, determining how coexisting phases separate spatially.

Background We recently developed and validated a microbial composition-based risk score (MRS) that predicts future risk of Crohn’s disease (CD) development among healthy first-degree relatives (FDR) of CD patients. We hypothesized that stool metabolomic profiles may mediate the effect of microbiome-based risk on future onset of CD. Methods Healthy FDRs of CD patients were recruited as part of the CCC-GEM Project. Stool metabolomics data were available in the nested case-control cohort (a subset of CCC-GEM cohort) whereby FDRs who later developed CD (n=56) were matched approximately 1:1 by age, sex, follow-up duration, and geographical location with control FDRs remaining healthy (n=66). Stool metabolomics were assessed using the Metabolon’s DiscoveryHD4™ platform, and the stool microbiome characterized by 16s rDNA amplicon sequencing. A multivariable conditional logistic regression model was evaluated on the disease development as a function of individual stool metabolites. Spearman correlation evaluated the rank values between stool metabolites and the MRS. Results 122 healthy FDRs (median age 15 years, 60% female) were followed for a median 5.2 years. Among 1,029 stool metabolites that were analyzed, 79 were associated with future risk of CD (p Conclusion Changes in stool metabolite profiles may predict future risk of CD. A subset of these metabolites has significant correlation with the MRS with consistent direction of effect. This may suggest that these particular stool metabolites mediate the putative effects of the gut microbiome on CD risk. Further validation in the entire GEM cohort is warranted.

Background The gut microbiome may play a role in gut barrier homeostasis including epithelial barrier integrity and function. However, data are scarce and limited to animal studies. We aimed to assess if alterations in the gut microbiome are associated with altered intestinal permeability. Methods We utilized the Genetic Environmental Microbial (CCC GEM) cohort of healthy first-degree relatives of patients with Crohn’s disease. Gut barrier function was assessed using the ratio of urinary fractional excretion of lactulose to mannitol (LMR). Stool bacterial DNA was extracted and sequenced for the V4 hypervariable region of the 16S rDNA gene using MiSeq and processed using QIIME2. PICRUSt2 was used to impute Microbial functions. In order to identify robust associations, the overall cohort was divided based on geographic region into a North American discovery cohort (n=2,472) and non-North American external validation cohort (n=655). LMR>0.025 was defined as abnormal. LMR-microbiome associations were assessed using generalized estimating equation multivariable regression model and Random Forest (RF) classifier algorithm. q Results The median age of the entire cohort was 17.0 years [IQR 12.0; 24.0], 52.6% were females and 25.4% had LMR>0.025. In the discovery cohort, subjects with LMR>0.025 had markedly reduced alpha diversity (Chao1 index, estimate= -0.0037, p=4.0e-04) and altered beta diversity (Bray-Curtis dissimilarity index, PERMANOVA: pseudo-F statistic = 2.99, p=1.0e-03). Eight bacterial genera and 52 microbial pathways were identified to be associated with LMR>0.025 (q Conclusion Gut microbiome community composition and microbial pathways are associated with gut barrier function. These findings may identify microbial targets that enhance barrier function.

Background Primary sclerosing cholangitis associated Inflammatory bowel disease (PSC-IBD) carries significant morbidity risk. Alterations in bile acid profiles has been shown to modulate chronic inflammation in IBD, but data in PSC-IBD comorbidity is scarce. We aimed to assess associations of serum and stool bile acids (BA) with PSC-IBD phenotype versus ulcerative colitis (UC) and the degree of liver fibrosis in PSC-IBD patients Methods In this cross-sectional study, bile acids were profiled in 52 PSC-IBD and 50 UC subjects. Quantitation of bile acids was performed by reversed phase ultrahigh performance liquid chromatography/multiple reaction monitoring mass spectrometry with negative ion detection (TMIC, Alberta, CA). After data filtering and normalization, 71 serum and 76 stool BA were available for analysis. Logistic regression was used to assess associations between BA levels and disease phenotype (PSC-IBD versus UC). Among the PSC-IBD group, linear regression was used to assess associations of fibrosis degree (severe (F4) versus no/mild (F0-3) fibrosis, measured by FibroScan®) with BA profile. Age, sex and ursodeoxycholic acid treatment were included as co-variates in all models and alkaline phosphatase (ALP) was added as co-variate for the liver fibrosis analysis. False discovery rate Results PSC-IBD and UC group had similar age and sex distribution. In the multivariable logistic regression, 26 serum BA were significantly associated with PSC-IBD (Figure 1). Decreased concentrations of taurine/glycine-primary BA [odds ratio(OR)=0.97, 95% confidence interval (CI) 0.95–0.99], taurine/glycine-secondary BA [OR=0.98, 95%CI 0.97–0.99] and sulfated-BA [OR=0.96, 95%CI 0.95–0.98], and increased concentrations of conjugated-BA [OR=1.02, 95%CI 1.01–1.03] and glucuronidated-BA [OR=1.06, 95%CI 1.02–1.1] were associated with PSC-IBD phenotype (q Conclusion Decreased concentration of sulfated-BA was associated with PSC-IBD phenotype with and without cholestasis compared to UC group. Lower sulfated-BA concentration was also associated with severe degree of liver fibrosis among PSC-IBD subjects. This inverse relationship between sulfated-BA levels and PSC-IBD and the degree of fibrosis should be further explored in future mechanistic studies

We thank the anonymous referee for the comments and suggestions that have helped to improve the paper. We are grateful to Peter Jonker who enabled the WHT observation of this target during his program W19AN003. We thank Peter Brown its contribution with data from the Neil Gehrels Swift Observatory. CPG and MS acknowledge support from EU/FP7-ERC grant No. [615929]. MO acknowledges support from UNRN PI2018 40B696 grant. GP acknowledges support by ANID – Millennium Science Initiative – ICN12_009. NER acknowledges support from MIUR, PRIN 2017 (grant 20179ZF5KS). MF is supported by a Royal Society - Science Foundation Ireland University Research Fellowship. MS is supported by generous grants from VILLUM FONDEN (13261, 28021) and by a project grant (8021-00170B) from the Independent Research Fund Denmark. LG was funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 839090. JB, DH, DAH, and CP were supported by NSF grant AST-1911225. TMB was funded by the CONICYT PFCHA / DOCTORADOBECAS CHILE/2017-72180113. This work has been partially supported by the Spanish grant PGC2018-095317-B-C21 within the European Funds for Regional Development (FEDER). Based on observations made with the Nordic Optical Telescope, owned in collaboration by theUniversity of Turku and Aarhus University, and operated jointly by Aarhus University, the University of Turku and the University of Oslo, representing Denmark, Finland and Norway, the University of Iceland and Stockholm University at the Observatorio del Roque de los Muchachos, La Palma, Spain, of the Instituto de Astrofisica de Canarias. Observations from the NOT were obtained through the NUTS and NUTS2 collaboration which are supported in part by the Instrument Centre for Danish Astrophysics (IDA). The data presented here were obtained in part with ALFOSC, which is provided by the Instituto de Astrofisica de Andalucia (IAA) under a joint agreement with the University of Copenhagen and NOTSA. Based on observations made with the GTC telescope, in the Spanish Observatorio del Roque de los Muchachos of the Instituto de Astrofísica de Canarias, under Director’s Discretionary Time. This work has made use of data from the Asteroid Terrestrialimpact Last Alert System (ATLAS) project. ATLAS is primarily funded to search for near earth asteroids through NASA grants NN12AR55G, 80NSSC18K0284, and 80NSSC18K1575; by products of the NEO search include images and catalogues from the survey area. The ATLAS science products have been made possible through the contributions of the University of Hawaii Institute for Astronomy, the Queen’s University Belfast, the Space Telescope Science Institute, and the South African Astronomical Observatory. The Liverpool Telescope is operated on the island of La Palma by Liverpool John Moores University in the Spanish Observatorio del Roque de los Muchachos of the Instituto de Astrofisica de Canarias with financial support from the UK Science and Technology Facilities Council. This work makes use of data from the Las Cumbres Observatory network., We present the photometric and spectroscopic evolution of supernova (SN) 2019cad during the first similar to 100 d from explosion. Based on the light-curve morphology, we find that SN 2019cad resembles the double-peaked Type Ib/c SN 2005bf and the Type Ic PTF11mnb. Unlike those two objects, SN 2019cad also shows the initial peak in the redder bands. Inspection of the g-band light curve indicates the initial peak is reached in similar to 8 d, while the r-band peak occurred similar to 15 d post-explosion. A second and more prominent peak is reached in all bands at similar to 45 d past explosion, followed by a fast decline from similar to 60 d. During the first 30 d, the spectra of SN 2019cad show the typical features of a Type Ic SN, however, after 40 d, a blue continuum with prominent lines of Si II lambda 6355 and C II lambda 6580 is observed again. Comparing the bolometric light curve to hydrodynamical models, we find that SN 2019cad is consistent with a pre-SN mass of 11 M-circle dot, and an explosion energy of 3.5 x 10(51) erg. The light-curve morphology can be reproduced either by a double-peaked Ni-56 distribution with an external component of 0.041 M-circle dot, and an internal component of 0.3 M-circle dot or a double-peaked Ni-56 distribution plus magnetar model (P similar to 11 ms and B similar to 26 x 10(14) G). If SN 2019cad were to suffer from significant host reddening (which cannot be ruled out), the Ni-56 model would require extreme values, while the magnetar model would still be feasible., European Commission 615929, UNRN PI2018 40B696, Ministry of Education, Universities and Research (MIUR), Research Projects of National Relevance (PRIN) 20179ZF5KS, Science Foundation Ireland, Magnus Ehrnrooth foundation, Vilho, Yrjo and Kalle Vaisala Foundation of the Finnish academy of Science and Letters, VILLUM FONDEN 13261 28021, Independent Research Fund Denmark - European Union'sHorizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant 839090, National Science Foundation (NSF) AST-1911225, CONICYT PFCHA/DOCTORADOBECAS CHILE/2017-72180113, Spanish grant within the European Funds for Regional Development (FEDER) PGC2018-095317-B-C21, Instrument Centre for Danish Astrophysics (IDA), National Aeronautics & Space Administration (NASA) NN12AR55G 80NSSC18K0284 80NSSC18K1575, UK Research & Innovation (UKRI), Science & Technology Facilities Council (STFC), ANID -Millennium Science Initiative ICN12 009, Jenny and AnttiWihuri foundation, ANID BECAS/DOCTORADO NACIONAL 21202412 W19AN003

Background Altered gut microbiota composition and function has been associated with inflammatory bowel diseases (IBD) including ulcerative colitis (UC), but causality and mechanisms remain unknown. Most studies have examined patients with active or treated disease and little is known about microbial compositional or functional changes that occur before disease onset. Aims We studied a longitudinal cohort of subjects at risk for IBD to define the fecal microbial composition and function in subjects prior to UC onset (pre-UC) and at diagnosis (post-UC), and in matched at-risk subjects that remained healthy. Methods Fecal samples were collected from healthy individuals at-risk for IBD (pre-UC; n=13) and subjects were followed longitudinally until UC diagnosis (post-UC, n=9), at which point another fecal sample was collected. Fecal samples from a cohort of matched at-risk individuals that did not develop UC were used as healthy controls (n=48). We applied 16S rRNA gene sequencing, next generation shotgun sequencing, in vitro proteolytic assays and gnotobiotic colonizations to define the microbial composition and proteolytic function in fecal samples. Results The microbiota of post-UC subjects clustered separately from pre-UC and HC subjects, based on bray-curtis and unweighted UniFrac, had reduced alpha-diversity, and had reduced abundance of Aldercreutzia compared to pre-UC and HC. In vitro functional analysis revealed increased fecal proteolytic and elastase activity in pre-UC and post-UC samples compared to HC. Metagenomics identified pathways and gene families related to protein metabolism and proteases/peptides that were significantly different between HC and pre-UC samples, suggesting a bacterial component to the pre-UC proteolytic signature. Elastase activity inversely correlated with the relative abundance of Adlercreutzia, and other potentially beneficial taxa, and directly correlated with Bacteroides vulgatus, a known proteolytic taxon. High elastase activity was confirmed in Bacteroides isolates from fecal samples. Bacterial contribution and functional significance of the proteolytic signature was investigated in germ-free adults and litters born from dams colonized with HC, pre-UC or post-UC microbiota. Mice colonized with pre-UC microbiota at adulthood or neonatally developed higher fecal proteolytic activity and an inflammatory immune tone compared with HC colonized mice. Conclusions We have identified increased fecal proteolytic activity that precedes clinical diagnosis of UC and associates with gut microbiota changes. This may constitute a non-invasive biomarker of inflammation to monitor at-risk populations that can be targeted therapeutically with anti-proteases. Funding Agencies CAG, CCC, CIHR

In general, questions of model credibility introduce more problems in a generic model than they do in models developed for one specific application since a generic formulation must allow for many applications of the model. This paper addresses the issues of model testing, verification, and validation for a generic electro-optic sensor system model. A structural approach to testing, verification, and validation is proposed that builds increasing confidence through bottom-up testing, structured verification procedures, and carefully selected validation metrics. These metrics are based on a geometrical view of model outputs that may be compared with measurements using qualitative methods or quantitative approaches involving image processing, artificial neural networks, or fuzzy pattern recognition. The advantage over traditional validation methods is most marked in the case of complex models with many key quantities where it not only provides insight about the validity but also about sensitivities. These validation tools have been applied, in conjunction with more traditional metrics, to the testing, verification, and validation of the generic model configured as a thermal imager system.

Cortical spreading depression (CSD) and peri-infarct depolarisation (PID) are related phenomena that have been associated with the human clinical syndromes of migraine (CSD), head injury and stroke (PID). Nevertheless the existence of CSD in man remains controversial, despite the detection of this phenomenon in the brains of most, if not all, other animal species investigated. This failure to unambiguously detect CSD clinically may be at least partly due to the anatomically complex, gyrencephalic structure of the human brain. This study was designed to establish conditions for the study of CSD in the brain of a gyrencephalic species using the noninvasive technique of magnetic resonance imaging (MRI). The 3-dimensional (3D) gyrencephalic anatomy of the cat brain was examined to determine the imaging conditions necessary to detect CSD events. Orthogonal transverse, sagittal and horizontal T1-weighted image slices showed that the marginal and suprasylvian gyri were the most appropriate cortical structures to study CSD. This was in view of (1) their simple geometry: (2) their lengthy extent of grey matter orientated rostrocaudally in the cortex: (3) their separation by a sulcus across which CSD spread could be studied and (4) the discontinuity in the grey matter in these regions between the right and left hemispheres dorsal to the corpus callosum. The structure suggested by the T1-weighted images was corroborated by systematic diffusion tensor imaging to map the fractional anisotropy and diffusion trace. Thus a single horizontal image plane could visualise the neighbouring suprasylvian and marginal gyri of both cerebral hemispheres, whereas its complex shape and position ruled out the ectosylvian gyrus for CSD studies. With the horizontal imaging plane, CSD events were reproducibly detected by animating successive diffusion-weighted MR images following local KCl stimulation of the cortical surface. In single image frames, CSD detection and characterisation required image subtraction or statistical mapping methods that, nevertheless, yielded concordant results. In repeat experiments, CSD events were qualitatively similar in appearance whether elicited by sustained or transient KCl applications. Our experimental approach thus successfully describes cat brain anatomy in vivo, and elucidates the necessary conditions for the application of MRI methods to detect CSD propagation.

Cortical spreading depression (CSD) in the gyrencephalic cat brain was detected with diffusion-weighted echoplanar (DWEP) magnetic resonance imaging (4-8/min for 1-2 hours) using a horizontal imaging plane through the suprasylvian (SG) and marginal gyri. A t-statistic mapping technique allowed a quantitative characterization of the passage of events through single-image pixels (0.15 mm(2)), thus providing a resolution unavailable to previous studies in which time-dependent changes instead were derived from averaging data over relatively large ROIs. Using the enhanced analysis, CSD events initiated by KCl could be quantified for the first time as primary or secondary according to their spatial and temporal features. Primary events covered 26.2 +/- 9.9 mm(2)of cortical surface (mean +/- SD, n = 7 experiments) and propagated rapidly (3.5 +/- 0.65 mm * min(-1)) with a hemispherical geometry. In contrast, the subsequent secondary events were multiple, spatially restricted (covering 7.6 +/- 4.6 mm(2), P < 0.005), slower in propagation (2.6 +/- 0.41 mm * min(-1), P < 0.012), and often confined to the originating gyrus (26 out of 59 events). However, both event types were associated with significantly reduced apparent diffusion coefficients (ADCs; from 800 to approximately 660 x 10(-6) mm(2)* s(-1), P < 0.05) that were similar for both primary (21 +/- 5.1%) and secondary waves (18 +/- 7. 7%) and that had similar durations (full width at half-maximal height: 86 +/- 17 vs. 79 +/- 20 seconds, respectively). These findings associate CSD for the first time with two categories of ADC disturbance that are similar in amplitude and duration but that differ in spatial extent, velocity, and extensiveness of spread.

Summary and ConclusionsThe chemotherapeutic action of streptomycin used alone or in combination with one of two sulfones or sulfadiazine was studied in experimental tuberculosis in guinea pigs.Evidence has been obtained to indicate that the therapeutic effect from combined treatment is greater than the sum of effects from the individual components.The chemotherapeutic effectiveness (ratio of extent of tuberculous involvement in a group of untreated controls and treated groups) in a group of guinea pigs treated with 40 mg (40,000 units) streptomycin per kg of body weight daily was 14.4. Previously treatment with 10 to 15 mg per kg per day under similar conditions gave a chemotherapeutic effectiveness of 5.2.The chemotherapeutic effectiveness of combined therapy with 20 mg streptomycin per kg per day plus 500 mg 4-amino-4′-propylaminodiphenylsulfone per kg per day was 28.6. The chemotherapeutic effectiveness of the sulfone alone was 3.7.Similar though less marked potentiation was obtained in combined therap...

This paper discusses the integration of a number of advanced image and data processing technologies in support of the development of next-generation Situational Awareness systems for counter-terrorism and crime fighting applications. In particular, the paper discusses the European Union Framework 7 'SAMURAI' project, which is investigating novel approaches to interactive Situational Awareness using cooperative networks of heterogeneous imaging sensors. Specific focus is given to novel Data Fusion aspects of the research which aim to improve system performance through intelligently fusing both image data and non image data sources, resolving human-machine conflicts, and refining the Situational Awareness picture. In addition, the paper highlights some recent advances in supporting image processing technologies. Finally, future trends in image-based Situational Awareness are identified, such as Post-Event Analysis (also known as 'Back-Tracking'), and the associated technical challenges are discussed.

The real-time fusion of imagery from two or more complementary sensors offers significant operational benefits for both operator-in-the-loop and automated processing systems. This paper reports on a new image fusion framework that can be used to maximise detection, recognition and identification performance within the context of low false-alarm rate operation. The Intelligent Image Fusion (I2F) architecture presented here allows exploitation of data at the information level as well as at the pixel-level, and can do so in an adaptable and intelligent manner. In this paper the architecture is examined in terms of design, applicability to a range of tasks, and performance factors such as adaptability, flexibility and utility. The relationship between algorithm design and hardware implementation, and the consequential impact on system performance, is also reviewed. Particular consideration is given to size, weight and power constraints that exist for some systems and their implications for processing optimisation and implementation on different processing platforms. Results are presented from the outcome of quantitative studies, development programmes and system trials.

Military helicopter operations are often constrained by environmental conditions, including low light levels and poor weather. Recent experience has also shown the difficulty presented by certain terrain when operating at low altitude by day and night. For example, poor pilot cues over featureless terrain with low scene contrast, together with obscuration of vision due to wind-blown and re-circulated dust at low level (brown out). These sorts of conditions can result in loss of spatial awareness and precise control of the aircraft. Atmospheric obscurants such as fog, cloud, rain and snow can similarly lead to hazardous situations and reduced situational awareness. Day Night All Weather (DNAW) systems applied research sponsored by UK Ministry of Defence (MoD) has developed a multi-resolution real time Image Fusion system that has been flown as part of a wider flight trials programme investigating increased situational awareness. Dual-band multi-resolution adaptive image fusion was performed in real-time using imagery from a Thermal Imager and a Low Light TV, both co-bore sighted on a rotary wing trials aircraft. A number of sorties were flown in a range of climatic and environmental conditions during both day and night. (Neutral density filters were used on the Low Light TV during daytime sorties.) This paper reports on the results of the flight trial evaluation and discusses the benefits offered by the use of Image Fusion in degraded visual environments.

Apoptosis triggered by endoplasmic reticulum (ER) stress is associated with various pathophysiological conditions including neurodegenerative diseases and ischemia. However, the mechanism by which ER stress induces neuronal apoptosis remains controversial. Here we identify the pathway of apoptosis carried out in sympathetic neurons triggered to die by ER stress-inducing agent tunicamycin. We find that ER stress induces a neuronal apoptotic pathway which upregulates BH3-only genes DP5 and Puma. Importantly, we show that ER stress commits neurons to die before cytochrome c release and this commitment requires Bax activation and c-jun N-terminal kinase signaling. Furthermore, ER stress engages the mitochondrial pathway of death as neurons release cytochrome c and Apaf-1 deficiency is sufficient to block apoptosis. Our findings identify a critical function of Bax in committing neurons to ER stress-induced apoptosis and clarify the importance of the apoptosome as the non-redundant caspase activation pathway to execute neuronal apoptosis in response to ER stress.

The conventional approach to modeling electro-optic sensor systems is to develop separate models for individual systems or classes of system, depending on the detector technology employed in the sensor and the application. However, this ignores commonality in design and in components of these systems. A generic approach is presented for modeling a variety of sensor systems, operating in the infrared waveband, that also allows systems to be modeled with different levels of detail and at different stages of the product life cycle. The provision of different model types (parametric and image-flow descriptions) within the generic framework can allow valuable insights to be gained.

5-HT(2) receptor antagonists promote slow wave sleep (SWS) in humans and rats, conversely 5-HT(2) agonists inhibit SWS in rats. These alterations are thought to be predominantly mediated via the 5-HT(2C) receptor subtype. It is evident that 5-HT(2) receptor function also plays an important role in depression. Here, we examine the acute effect of the selective 5-HT(2C) receptor antagonist 5-methyl-1-[[-2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-triflouromethylindoline hydrochloride (SB-243213-A) on rat sleep in comparison to the selective serotonin reuptake inhibitor (SSRI) paroxetine. Both SB-243213-A (10 mg/kg po) and paroxetine (3 mg/kg po) significantly increased deep SWS (SWS2) quantity (27% and 24%, respectively) and reduced paradoxical sleep (PS) quantity (35%) during the sleep period. Following SB-243213-A, SWS2 occurrence frequency was reduced (24.1%); however, elevated quantity of SWS2 can be attributed to an increase in occurrence duration (81%). Reduced PS quantity results from a decrease in occurrence frequency (46%). In comparison, paroxetine increased SWS2 occurrence frequency (50%), with decreased frequency (27%) and duration (21%) of PS. The data for SB-243213-A in the present study is consistent with that following ritanserin supporting 5-HT(2C) receptor subtype mediation of this response. The similar effect of SB-243213-A to paroxetine with regard to PS quantity provides further evidence that 5-HT(2C) receptor antagonists maybe beneficial in the treatment of depression/anxiety.

Cortical spreading depression (CSD) in the gyrencephalic cat brain was detected with diffusion-weighted echoplanar (DWEP) magnetic resonance imaging (4-8/min for 1-2 hours) using a horizontal imaging plane through the suprasylvian (SG) and marginal gyri. A t-statistic mapping technique allowed a quantitative characterization of the passage of events through single-image pixels (0.15 mm(2)), thus providing a resolution unavailable to previous studies in which time-dependent changes instead were derived from averaging data over relatively large ROIs. Using the enhanced analysis, CSD events initiated by KCl could be quantified for the first time as primary or secondary according to their spatial and temporal features. Primary events covered 26.2 +/- 9.9 mm(2)of cortical surface (mean +/- SD, n = 7 experiments) and propagated rapidly (3.5 +/- 0.65 mm * min(-1)) with a hemispherical geometry. In contrast, the subsequent secondary events were multiple, spatially restricted (covering 7.6 +/- 4.6 mm(2), P0.005), slower in propagation (2.6 +/- 0.41 mm * min(-1), P0.012), and often confined to the originating gyrus (26 out of 59 events). However, both event types were associated with significantly reduced apparent diffusion coefficients (ADCs; from 800 to approximately 660 x 10(-6) mm(2)* s(-1), P0.05) that were similar for both primary (21 +/- 5.1%) and secondary waves (18 +/- 7. 7%) and that had similar durations (full width at half-maximal height: 86 +/- 17 vs. 79 +/- 20 seconds, respectively). These findings associate CSD for the first time with two categories of ADC disturbance that are similar in amplitude and duration but that differ in spatial extent, velocity, and extensiveness of spread.

The novel 5-HT(7) receptor antagonist, SB-269970-A, potently displaced [(3)H]-5-CT from human 5-HT(7(a)) (pK(i) 8.9+/-0.1) and 5-HT(7) receptors in guinea-pig cortex (pK(i) 8.3+/-0.2). 5-CT stimulated adenylyl cyclase activity in 5-HT(7(a))/HEK293 membranes (pEC(50) 7.5+/-0.1) and SB-269970-A (0.03 - 1 microM) inhibited the 5-CT concentration-response with no significant alteration in the maximal response. The pA(2) (8.5+/-0.2) for SB-269970-A agreed well with the pK(i) determined from [(3)H]-5-CT binding studies. 5-CT-stimulated adenylyl cyclase activity in guinea-pig hippocampal membranes (pEC(50) of 8.4+/-0.2) was inhibited by SB-269970-A (0.3 microM) with a pK(B) (8.3+/-0.1) in good agreement with its antagonist potency at the human cloned 5-HT(7(a)) receptor and its binding affinity at guinea-pig cortical membranes. 5-HT(7) receptor mRNA was highly expressed in human hypothalamus, amygdala, thalamus, hippocampus and testis. SB-269970-A was CNS penetrant (steady-state brain : blood ratio of ca. 0.83 : 1 in rats) but was rapidly cleared from the blood (CLb=ca. 140 ml min(-1) kg(-1)). Following a single dose (3 mg kg(-1)) SB-269970 was detectable in rat brain at 30 (87 nM) and 60 min (58 nM). In guinea-pigs, brain levels averaged 31 and 51 nM respectively at 30 and 60 min after dosing, although the compound was undetectable in one of the three animals tested. 5-CT (0.3 mg kg(-1) i.p.) induced hypothermia in guinea-pigs was blocked by SB-269970-A (ED(50) 2.96 mg kg(-1) i.p.) and the non-selective 5-HT(7) receptor antagonist metergoline (0.3 - 3 mg kg(-1) s.c.), suggesting a role for 5-HT(7) receptor stimulation in 5-CT induced hypothermia in guinea-pigs. SB-269970-A (30 mg kg(-1)) administered at the start of the sleep period, significantly reduced time spent in Paradoxical Sleep (PS) during the first 3 h of EEG recording in conscious rats.

Orexin-A is a novel neuropeptide initially isolated from hypothalamic extracts but now known to be present in fibres distributed throughout the rat CNS including many regions associated with sleep-wake regulation. The recognition of a particularly dense innervation of orexinergic nerves in the locus coeruleus, together with the observed increase in firing rate of locus coeruleus neurons following application of orexin-A in vitro, further highlighted a potential involvement of the peptide in modulating the arousal state. The present study was undertaken to determine the effects of intracerebroventricularly (ICV) administered orexin-A on the sleep-wake cycle of conscious rats using electroencephalographic and electromyographic recordings. When administered at the onset of the normal sleep period, orexin-A (1, 10 or 30 microg/rat ICV) produced a dose-dependent increase in the time rats spent awake during the second and third hours after dosing. The enhancement of arousal was accompanied by a marked reduction in paradoxical sleep and deep slow wave sleep at the highest dose. The latency to the first occurrence of paradoxical sleep was also prolonged. This overall profile of increased arousal and decreased paradoxical sleep is consistent with a high rate of firing of locus coeruleus neurons as would be expected to occur following ICV administration of orexin-A. It is concluded that orexin-A may play an important physiological role in regulating the sleep-wake state, a hypothesis considerably strengthened by the recently reported narcoleptic phenotype of prepro-orexin (the precursor for orexin-A) knockout mice.

Journal bearings today are generally designed to operate under such conditions that laminar flow prevails in the lubricant film. However, with the continuing trend in machine design toward higher speeds, there is the possibility that the limits of laminar flow may be exceeded in many bearings of the future. In the investigation reported in this paper, the load-carrying and frictional characteristics of a journal bearing were studied at speeds ranging up to five times the critical speed. The “critical speed” is defined as that rotational velocity which just causes breakdown of laminar flow.

It has been shown previously that p, p'-diaminodiphenylsulfone-N-N'-dextrose sulfonate (promin) in concentrations of 20 mg % inhibits the growth of the tubercle bacillus in culture media.1 Also promin administered orally1 or in the diet2 retards the tuberculous process in guinea pigs. To determine the mechanism of the action of promin upon the virulence of the tubercle bacillus experiments were designed to ascertain the effect of prolonged cultivation of the bacillus on the medium containing the drug in low concentrations. Changes in virulence of the strain were determined by the degree of invasiveness of the attenuated strain, (a) when inoculated upon the chorio-allantoic membrane of the chick embryo and (b) when inoculated intraperitoneally into guinea pigs.Methods. The A 27 strain of human tubercle bacilli was selected since this strain was known to have a moderately high degree of virulence. The bacilli were grown in a culture medium consisting of beef bouillon plus 5% glycerine with 10 mg % of promin...

Summary and Conclusions The tubercle bacillus grown on a synthetic (Kirchner's) medium produces fluorescent substances in the course of its growth, part of which is alkali-resistant and its chemical nature undetermined, while the other, the greater part, is alkali-labile and behaves like riboflavin. During the lag period of 8 to 10 days of little or no growth only the alkali-resistant fraction was in evidence. With the beginning of growth there was a progressive increase in fluorescent material, the rate of increase being relatively greater in the alkali-labile fraction. The addition to Kirchner's medium of small amounts of iron as ferrous sulfate, or 2 per cent sucrose, or both, increased the amount of fluorescent material formed and also stimulated the growth of A27. Experiments with three riboflavin related compounds have shown that isoriboflavin had little or no effect on the growth of the tubercle bacillus or in antagonizing the formation of fluorescent material by the tubercle bacillus. Diaminophenazine (i.e. dinitrophenazine reduced with iron) inhibited growth of the tubercle bacillus and apparently may have also reduced riboflavin production. The third substance tested, 4-amino-ribitylxylidine, inhibited the growth of the tubercle bacillus when added to Kirchner's medium in the high concentration of 50 mg per cent. When added in concentrations of 1 to 20 mg per cent it appears to have been metabolized by the growing tubercle bacillus in part to riboflavin, and this endogenous source of riboflavin seemed to have little effect on growth.

A computer-accessible file of bibliographic data, on the liquidus of the class of inorganic salt systems that contains at least one alkali halide, is retrospective to 1875 and is being kept current relative to Chemical Abstracts Condensates tapes. The bibliographic data are in free text with some format restrictions for facilitating file management and translation to conform to other systems or computers.

SummaryA method is described for the isolation and identification of 4,4′-diamino-diphenylsulfone (DDS) in the urine of rabbits. The method is based on the solubility of the hydrochloride of DDS in water and the relative insolubility of the base in water but its ready solubility in ethyl acetate.Up to 70% of the total diazotizable material excreted in the urine following oral administration of DDS to rabbits has been isolated as unchanged DDS. Not more than about 5% of the diazotizable material may be in an altered form, and this probably as conjugated DDS. Partition chromatography indicated that it was not the acetylated derivative of DDS.

SummaryA method has been described for tracing reduced degradation products of trinitrotoluene in experimental animals. The role of these products in trinitrotoluene poisoning remains to be determined.

Comments and conclusionsThe favorable results reported by Shpanir for the benzyl furamide were based on experiments in mice. Though the mouse test is currently in use in several laboratories for screening of compounds for possible antitubercular activity we are not impressed with it as a satisfactory test object(8). It is possible that the present results are at variance with those of Shpanir on account of species differences.N-Benzyl-2-furamide has no appreciable activity in experimental tuberculosis in guinea pigs. So far the sulfones alone, next to streptomycin, have been demonstrated to have a definitely suppressive effect on this disease.

In 1973 the federal government moved to limit drug reimbursement to providers in federally sponsored or supported programs, to the lowest cost at which the drug is generally and consistently available unless a difference in therapeutic effect can be demonstrated between the brand name and generic drug. This paper examines the political evolution and rationale for this program and explores the issues surrounding the ongoing controversy regarding publicly financed programs offering drug benefits. The authors speculate that the government's first attempt to control prices of pharmaceuticals, prior to enactment of some form of national health insurance, if successful, will call forth pharmaceutical industry strategies which could negate program benefits.